Intermittent Metronomic Drug Schedule Is Essential for Activating Antitumor Innate Immunity and Tumor Xenograft Regression12

PubMed Central

Chen, Chong-Sheng; Doloff, Joshua C; Waxman, David J

2014-01-01

Metronomic chemotherapy using cyclophosphamide (CPA) is widely associated with antiangiogenesis; however, recent studies implicate other immune-based mechanisms, including antitumor innate immunity, which can induce major tumor regression in implanted brain tumor models. This study demonstrates the critical importance of drug schedule: CPA induced a potent antitumor innate immune response and tumor regression when administered intermittently on a 6-day repeating metronomic schedule but not with the same total exposure to activated CPA administered on an every 3-day schedule or using a daily oral regimen that serves as the basis for many clinical trials of metronomic chemotherapy. Notably, the more frequent metronomic CPA schedules abrogated the antitumor innate immune and therapeutic responses. Further, the innate immune response and antitumor activity both displayed an unusually steep dose-response curve and were not accompanied by antiangiogenesis. The strong recruitment of innate immune cells by the 6-day repeating CPA schedule was not sustained, and tumor regression was abolished, by a moderate (25%) reduction in CPA dose. Moreover, an ∼20% increase in CPA dose eliminated the partial tumor regression and weak innate immune cell recruitment seen in a subset of the every 6-day treated tumors. Thus, metronomic drug treatment must be at a sufficiently high dose but also sufficiently well spaced in time to induce strong sustained antitumor immune cell recruitment. Many current clinical metronomic chemotherapeutic protocols employ oral daily low-dose schedules that do not meet these requirements, suggesting that they may benefit from optimization designed to maximize antitumor immune responses. PMID:24563621

A comparison of 2 influenza vaccine schedules in 6- to 23-month-old children.

PubMed

Englund, Janet A; Walter, Emmanuel B; Fairchok, Mary P; Monto, Arnold S; Neuzil, Kathleen M

2005-04-01

Trivalent inactivated influenza vaccine (TIV) is recommended for all children ages 6 to 23 months. Delivering 2 doses of TIV at least 4 weeks apart to young children receiving this vaccine for the first time is challenging. We compared the immunogenicity and reactogenicity of the standard 2-dose regimen of TIV administered in the fall with an early schedule of a single spring dose followed by a fall dose of the same vaccine in healthy toddlers 6 to 23 months of age. Children were recruited in the spring to be randomized into either the standard or early schedule. An additional group was also enrolled in the fall as part of a nonrandomized standard comparison group. The 2002-2003 licensed TIV was administered in the spring; the fall 2003-2004 vaccine contained the same 3 antigenic components. Reactogenicity was assessed by parental diaries and telephone surveillance. Blood was obtained after the second dose of TIV for all children. The primary outcome measure was antibody response to influenza A/H1N1, A/H3N2, and B after 2 doses of vaccine, as determined by hemagglutination-inhibition titers > or =1:32 and geometric mean titer (GMT). Two hundred nineteen children were randomized to receive either the standard or early TIV schedule; 40 additional children were enrolled in the fall in the nonrandomized standard group. Response rates in the combined standard versus early groups were similar overall: 78% (GMT: 48) vs 76% (GMT: 57) to H1N1, 89% (GMT: 115) vs 88% (GMT: 129) to H3N2, and 52% (GMT: 24) vs 60% (GMT: 28) to B. Reactogenicity after TIV in both groups of children was minimal and did not differ by dose, age, or time between doses. Reaction rates were higher in those receiving TIV and concomitant vaccines compared with those receiving TIV alone. Overall rates of fever >38 degrees C axillary and injection-site pain, redness, or swelling were 5.4%, 3.1%, 0.9%, and 1.1%, respectively. When the spring and fall influenza vaccines had the same 3 antigenic components, the early vaccine schedule resulted in similar immunogenicity and reactogenicity compared with the standard schedule. When the vaccine components do not change between years, initiating influenza vaccine in the spring at the time of routine office visits would facilitate full immunization of children against influenza earlier in the season.

Challenges in early clinical development of adjuvanted vaccines.

PubMed

Della Cioppa, Giovanni; Jonsdottir, Ingileif; Lewis, David

2015-06-08

A three-step approach to the early development of adjuvanted vaccine candidates is proposed, the goal of which is to allow ample space for exploratory and hypothesis-generating human experiments and to select dose(s) and dosing schedule(s) to bring into full development. Although the proposed approach is more extensive than the traditional early development program, the authors suggest that by addressing key questions upfront the overall time, size and cost of development will be reduced and the probability of public health advancement enhanced. The immunogenicity end-points chosen for early development should be critically selected: an established immunological parameter with a well characterized assay should be selected as primary end-point for dose and schedule finding; exploratory information-rich end-points should be limited in number and based on pre-defined hypothesis generating plans, including system biology and pathway analyses. Building a pharmacodynamic profile is an important aspect of early development: to this end, multiple early (within 24h) and late (up to one year) sampling is necessary, which can be accomplished by sampling subgroups of subjects at different time points. In most cases the final target population, even if vulnerable, should be considered for inclusion in early development. In order to obtain the multiple formulations necessary for the dose and schedule finding, "bed-side mixing" of various components of the vaccine is often necessary: this is a complex and underestimated area that deserves serious research and logistical support. Copyright © 2015 Elsevier Ltd. All rights reserved.

A descriptive feasibility study to evaluate scheduled oral analgesic dosing at home for the management of postoperative pain in preschool children following tonsillectomy.

PubMed

Sutters, Kimberly A; Holdridge-Zeuner, Danielle; Waite, Steven; Paul, Steven M; Savedra, Marilyn C; Lanier, Brent; Mahoney, Karla; Miaskowski, Christine

2012-03-01

The purpose of this study, in a sample of preschool children (ages 3-5 years; N = 47), was to evaluate the feasibility of scheduled analgesic dosing following outpatient tonsillectomy in order to optimize pain management. Parents were instructed to give their child acetaminophen with hydrocodone (167 mg/5 mL) every 4 hours around the clock for the first 3 days following surgery. Parents recorded ratings of their child's pain with/without swallowing using the Faces, Legs, Activity, Cry, and Consolability (FLACC) behavioral pain scale, pain relief ratings, and severity of analgesic side effects in a home diary. Audiotaped interviews were conducted with parents to document descriptions of their experiences in managing their child's pain at home. Mean FLACC scores with/without swallowing were less than two at each measurement time and pain relief scores increased over time. Total analgesic dose decreased, and the number of missed doses increased over the first 3 days after surgery. Moderate-to-severe daytime sedation, nausea, vomiting, and constipation were reported by parents. Study results suggest that acetaminophen with hydrocodone is effective in relieving preschool children's pain following tonsillectomy and that parental adherence to a scheduled analgesic regimen decreases over time. Time-contingent dosing was associated with moderate to severe side effects and should be addressed in discharge teaching with parents. Findings provide insight into parents' perspective of pain management at home following tonsillectomy and methods for relieving their child's pain. Wiley Periodicals, Inc.

Adherence to isoniazid prophylaxis among HIV-infected children: a randomized controlled trial comparing two dosing schedules

PubMed Central

le Roux, Stanzi M; Cotton, Mark F; Golub, Jonathan E; le Roux, David M; Workman, Lesley; Zar, Heather J

2009-01-01

Background Tuberculosis contributes significantly to morbidity and mortality among HIV-infected children in sub-Saharan Africa. Isoniazid prophylaxis can reduce tuberculosis incidence in this population. However, for the treatment to be effective, adherence to the medication must be optimized. We investigated adherence to isoniazid prophylaxis administered daily, compared to three times a week, and predictors of adherence amongst HIV-infected children. Methods We investigated adherence to study medication in a two centre, randomized trial comparing daily to three times a week dosing of isoniazid. The study was conducted at two tertiary paediatric care centres in Cape Town, South Africa. Over a 5 year period, we followed 324 HIV-infected children aged ≥ 8 weeks. Adherence information based on pill counts was available for 276 children. Percentage adherence was calculated by counting the number of pills returned. Adherence ≥ 90% was considered to be optimal. Analysis was done using summary and repeated measures, comparing adherence to the two dosing schedules. Mean percentage adherence (per child during follow-up time) was used to compare the mean of each group as well as the proportion of children achieving an adherence of ≥ 90% in each group. For repeated measures, percentage adherence (per child per visit) was dichotomized at 90%. A logistic regression model with generalized estimating equations, to account for within-individual correlation, was used to evaluate the impact of the dosing schedule. Adjustments were made for potential confounders and we assessed potential baseline and time-varying adherence determinants. Results The overall adherence to isoniazid was excellent, with a mean adherence of 94.7% (95% confidence interval [CI] 93.5-95.9); similar mean adherence was achieved by the group taking daily medication (93.8%; 95% CI 92.1-95.6) and by the three times a week group (95.5%; 95% CI 93.8-97.2). Two-hundred and seventeen (78.6%) children achieved a mean adherence of ≥ 90%. Adherence was similar for daily and three times a week dosing schedules in univariate (odds ratio [OR] 0.88; 95% CI 0.66-1.17; P = 0.38) and multivariate (adjusted OR 0.85; 95% CI 0.64-1.11; P = 0.23) models. Children from overcrowded homes were less adherent (adjusted OR 0.71; 95% CI 0.54-0.95; P = 0.02). Age at study visit was predictive of adherence, with better adherence achieved in children older than 4 years (adjusted OR 1.96; 95% CI 1.16-3.32; P = 0.01). Conclusion Adherence to isoniazid was excellent regardless of the dosing schedule used. Intermittent dosing of isoniazid prophylaxis can be considered as an alternative to daily dosing, without compromising adherence or efficacy. Trial registration Clinical Trials NCT00330304 PMID:19886982

Phase I Design for Completely or Partially Ordered Treatment Schedules

PubMed Central

Wages, Nolan A.; O’Quigley, John; Conaway, Mark R.

2013-01-01

The majority of methods for the design of Phase I trials in oncology are based upon a single course of therapy, yet in actual practice it may be the case that there is more than one treatment schedule for any given dose. Therefore, the probability of observing a dose-limiting toxicity (DLT) may depend upon both the total amount of the dose given, as well as the frequency with which it is administered. The objective of the study then becomes to find an acceptable combination of both dose and schedule. Past literature on designing these trials has entailed the assumption that toxicity increases monotonically with both dose and schedule. In this article, we relax this assumption for schedules and present a dose-schedule finding design that can be generalized to situations in which we know the ordering between all schedules and those in which we do not. We present simulation results that compare our method to other suggested dose-schedule finding methodology. PMID:24114957

Rotavirus specific maternal antibodies and immune response to RV3-BB neonatal rotavirus vaccine in New Zealand.

PubMed

Chen, Mee-Yew; Kirkwood, Carl D; Bines, Julie; Cowley, Daniel; Pavlic, Daniel; Lee, Katherine J; Orsini, Francesca; Watts, Emma; Barnes, Graeme; Danchin, Margaret

2017-05-04

Maternal antibodies, acquired passively via placenta and/or breast milk, may contribute to the reduced efficacy of oral rotavirus vaccines observed in children in developing countries. This study aimed to investigate the effect of rotavirus specific maternal antibodies on the serum IgA response or stool excretion of vaccine virus after any dose of an oral rotavirus vaccine, RV3-BB, in parallel to a Phase IIa clinical trial conducted at Dunedin Hospital, New Zealand. At the time of the study rotavirus vaccines had not been introduced in New Zealand and the burden of rotavirus disease was evident. Rotavirus specific IgG and serum neutralizing antibody (SNA) levels in cord blood and IgA levels in colostrum and breast milk samples collected ∼4 weeks, ∼20 weeks and ∼28 weeks after birth were measured. Infants were randomized to receive the first dose of vaccine at 0-5 d (neonatal schedule) or 8 weeks (infant schedule). Breast feeding was with-held for 30 minutes before and after vaccine administration. The relationship between rotavirus specific IgG and SNA levels in cord blood and IgA in colostrum and breast milk at the time of first active dose of RV3-BB vaccine and level of IgA response and stool excretion after 3 doses of vaccine was assessed using linear and logistic regression. Forty infants received 3 doses of RV3-BB rotavirus vaccine and were included in the analysis of the neonatal and infant groups. Rotavirus specific IgA in colostrum (neonatal schedule group) and breast milk at 4 weeks (infant schedule group) was identified in 14/21 (67%) and 14/17 (82%) of infants respectively. There was little evidence of an association between IgA in colostrum or breast milk IgA at 4 weeks, or between cord IgG or SNA level, and IgA response or stool excretion after 3 doses of RV3-BB, or after one dose (neonatal schedule) (all p>0.05). The level of IgA in colostrum or breast milk and level of placental IgG and SNA did not impact on the serum IgA response or stool excretion following 3 doses of RV3-BB Rotavirus Vaccine administered using either a neonatal or infant schedule in New Zealand infants.

A current and historical perspective on disparities in US childhood pneumococcal conjugate vaccine adherence and in rates of invasive pneumococcal disease: Considerations for the routinely-recommended, pediatric PCV dosing schedule in the United States

PubMed Central

McLaughlin, John M; Utt, Eric A; Hill, Nina M; Welch, Verna L; Power, Edward; Sylvester, Gregg C

2016-01-01

Previous research has suggested that reducing the US 4-dose PCV13 schedule to a 3-dose schedule may provide cost savings, despite more childhood pneumococcal disease. The study also stressed that dose reduction should be coupled with improved PCV adherence, however, US PCV uptake has leveled-off since 2008. An estimated 24–36% of US children aged 5–19 months are already receiving a reduced PCV schedule (i.e., missing ≥1 dose). This raises a practical concern that, under a reduced, 3-dose schedule, a similar proportion of children may receive ≤2 doses. It is also unknown if a reduced, 3-dose PCV schedule in the United States will afford the same disease protection as 3-dose schedules used elsewhere, given lower US PCV adherence. Finally, more assurance is needed that, under a reduced schedule, racial, socioeconomic, and geographic disparities in PCV adherence will not correspond with disproportionately higher rates of pneumococcal disease among poor or minority children. PMID:26376039

Dopaminergic Actions of D-Amphetamine on Schedule-Induced Polydipsia in Rats

ERIC Educational Resources Information Center

Pellon, Ricardo; Ruiz, Ana; Rodriguez, Cilia; Flores, Pilar

2007-01-01

Schedule-induced polydipsia in rats was developed by means of a fixed-time 60-s schedule of food presentation. The acute administration of d-amphetamine sulfate (0.1-3.0 mg/kg) produced a dose-dependent decrease in the rate of licking. D-Amphetamine shifted to the left the temporal distribution of adjunctive drinking within interfood intervals.…

Sustained-release theophylline and nocturnal asthma, once-daily and unequal dosing schedules.

PubMed

Smolensky, M H; D'Alonzo, G E; Kunkel, G; Barnes, P J

1987-01-01

Many asthmatic patients experience aggravation of symptoms overnight resulting in disruption of their sleep. Sustained-release theophylline represents at this time a major bronchodilator medication which possesses a sufficient duration of activity to avert the nocturnal breathing distress of asthma. Circadian rhythm-adapted theophylline schedules consisting of unequal dosing--more or all the drug taken in the evening--have proven efficacious in clinical investigations for certain patients. Although the kinetic behavior of some formulations is affected by food, the circadian rhythm-adapted schedules represent a significant step forward toward the goal of optimizating sustained-release theophyllines for patients who experience nighttime symptoms.

Evaluation of early immune response-survival relationship in cynomolgus macaques after Anthrax Vaccine Adsorbed vaccination and Bacillus anthracis spore challenge.

PubMed

Sivko, G S; Stark, G V; Tordoff, K P; Taylor, K L; Glaze, E; VanRaden, M; Schiffer, J M; Hewitt, J A; Quinn, C P; Nuzum, E O

2016-12-12

Anthrax Vaccine Adsorbed (AVA, BioThrax) is approved by the US Food and Drug Administration for post-exposure prophylaxis (PEP) of anthrax in adults. The PEP schedule is 3 subcutaneous (SC) doses (0, 14 and 28 days), in conjunction with a 60 day course of antimicrobials. The objectives of this study were to understand the onset of protection from AVA PEP vaccination and to assess the potential for shortening the duration of antimicrobial treatment (http://www.phe.gov/Preparedness/mcm/phemce/Documents/2014-phemce-sip.pdf). We determined the efficacy against inhalation anthrax in nonhuman primates (NHP) of the first two doses of the PEP schedule by infectious challenge at the time scheduled for receipt of the third PEP dose (Day 28). Forty-eight cynomolgus macaques were randomized to five groups and vaccinated with serial dilutions of AVA on Days 0 and 14. NHP were exposed to Bacillus anthracis Ames spores on Day 28 (target dose 200 LD 50 equivalents). Anti-protective antigen (PA) IgG and toxin neutralizing antibody (TNA) responses to vaccination and in post-challenge survivors were determined. Post-challenge blood and selected tissue samples were assessed for B. anthracis at necropsy or end of study (Day 56). Pre-challenge humoral immune responses correlated with survival, which ranged from 24 to 100% survival depending on vaccination group. Surviving, vaccinated animals had elevated anti-PA IgG and TNA levels for the duration of the study, were abacteremic, exhibited no apparent signs of infection, and had no gross or microscopic lesions. However, survivors had residual spores in lung tissues. We conclude that the first two doses of the PEP schedule provide high levels of protection by the scheduled timing of the third dose. These data may also support consideration of a shorter duration PEP antimicrobial regimen. Copyright © 2016 Elsevier Ltd. All rights reserved.

FDA-sunlamp recommended Maximum Timer Interval And Exposure Schedule: consensus ISO/CIE dose equivalence.

PubMed

Dowdy, John C; Czako, Eugene A; Stepp, Michael E; Schlitt, Steven C; Bender, Gregory R; Khan, Lateef U; Shinneman, Kenneth D; Karos, Manuel G; Shepherd, James G; Sayre, Robert M

2011-09-01

The authors compared calculations of sunlamp maximum exposure times following current USFDA Guidance Policy on the Maximum Timer Interval and Exposure Schedule, with USFDA/CDRH proposals revising these to equivalent erythemal exposures of ISO/CIE Standard Erythema Dose (SED). In 2003, [USFDA/CDRH proposed replacing their unique CDRH/Lytle] erythema action spectrum with the ISO/CIE erythema action spectrum and revising the sunlamp maximum exposure timer to 600 J m(-2) ISO/CIE effective dose, presented as being biologically equivalent. Preliminary analysis failed to confirm said equivalence, indicating instead ∼38% increased exposure when applying these proposed revisions. To confirm and refine this finding, a collaboration of tanning bed and UV lamp manufacturers compiled 89 UV spectra representing a broad sampling of U.S. indoor tanning equipment. USFDA maximum recommended exposure time (Te) per current sunlamp guidance and CIE erythemal effectiveness per ISO/CIE standard were calculated. The CIE effective dose delivered per Te averaged 456 J(CIE) m(-2) (SD = 0.17) or ∼4.5 SED. The authors found that CDRH's proposed 600 J(CIE) m(-2) recommended maximum sunlamp exposure exceeds current Te erythemal dose by ∼33%. The current USFDA 0.75 MED initial exposure was ∼0.9 SED, consistent with 1.0 SED initial dose in existing international sunlamp standards. As no sunlamps analyzed exceeded 5 SED, a revised maximum exposure of 500 J(CIE) m(-2) (∼80% of CDRH's proposal) should be compatible with existing tanning equipment. A tanning acclimatization schedule is proposed beginning at 1 SED thrice-weekly, increasing uniformly stepwise over 4 wk to a 5 SED maximum exposure in conjunction with a tan maintenance schedule of twice-weekly 5 SED sessions, as biologically equivalent to current USFDA sunlamp policy.

Duration of protection against hepatitis A for the current two-dose vaccine compared to a three-dose vaccine schedule in children

PubMed Central

Raczniak, Gregory A.; Thomas, Timothy K.; Bulkow, Lisa R.; Negus, Susan E.; Zanis, Carolyn L.; Bruce, Michael G.; Spradling, Philip R.; Teshale, Eyasu H.; McMahon, Brian J.

2015-01-01

Background Hepatitis A is mostly a self-limiting disease but causes substantial economic burden. Consequently, United States Advisory Committee for Immunization Practices recommends inactivated hepatitis A vaccination for all children beginning at age 1 year and for high risk adults. The hepatitis A vaccine is highly effective but the duration of protection is unknown. Methods We examined the proportion of children with protective hepatitis A antibody levels (anti-HAV ≥20 mIU/mL) as well as the geometric mean concentration (GMC) of anti-HAV in a cross sectional convenience sample of individuals aged 12–24 years, who had been vaccinated with a two-dose schedule in childhood, with the initial dose at least 5 years ago. We compared a subset of data from persons vaccinated with two-doses (720 EL.U.) at age 3–6 years with a demographically similar prospective cohort that received a three-dose (360 EL.U.) schedule and have been followed for 17 years. Results No significant differences were observed when comparing GMC between the two cohorts at 10 (P = 0.467), 12 (P = 0.496), and 14 (P = 0.175) years post-immunization. For the three-dose cohort, protective antibody levels remain for 17 years and have leveled-off over the past 7 years. Conclusion The two- and three-dose schedules provide similar protection >14 years after vaccination, indicating a booster dose is not needed at this time. Plateauing anti-HAV GMC levels suggest protective antibody levels may persist long-term. PMID:23470239

Effect of treatment in fractionated schedules with the combination of x-irradiation and six cytotoxic drugs on the RIF-1 tumor and normal mouse skin

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

Lelieveld, P.; Scoles, M.A.; Brown, J.M.

1985-01-01

RIF-1 tumors, implanted syngeneically in the gastrocnemius muscles of the right hind legs of C3H/Km mice, were treated either with X ray alone, drug alone, or drug and X ray combined. The drugs tested were bleomycin, BCNU, cis-diamminedichloro platinum, adriamycin, cyclophosphamide, and actinomycin-D. All drugs were administered either in the maximum tolerated dose or a dose that causes minimal tumor growth delay. Both drugs and X rays were administered either as a single dose or in five daily fractions. In addition to the single modality controls, seven different schedules of combined modalities were tested. Tumors were measured periodically after treatmentmore » in order that the day at which each tumor reached 4 times its initial cross-sectional area, i.e., its size at the time of treatment, could be determined. The effect of treatment on tumors was based upon excess growth delay (GD), i.e., T400% (treated)-T400% (untreated control). Treatment effects for the same combined modality schedules were also determined for normal skin, using the early skin reaction as an endpoint. Dose effect factors (DEF) were computed for all combined modality schedules and were based upon calculated radiation dose equivalents. We also calculated supra-additivity ratios, SR/sub I/ and SR/sub II/, therapeutic gain factors and adjusted therapeutic gain factors. The only drugs to produce significant supra-additivity with X rays were cis-Pt and cyclo.« less

A DESCRIPTIVE FEASIBILITY STUDY TO EVALUATE SCHEDULED ORAL ANALGESIC DOSING AT HOME FOR THE MANAGEMENT OF POSTOPERATIVE PAIN IN PRESCHOOL CHILDREN FOLLOWING TONSILLECTOMY

PubMed Central

Sutters, Kimberly A.; Holdridge-Zeuner, Danielle; Waite, Steven; Paul, Steven M.; Savedra, Marilyn C.; Lanier, Brent; Mahoney, Karla; Miaskowski, Christine

2012-01-01

Objectives The purpose of this study, in a sample of preschool children (ages 3 to 5 years; N=47), was to evaluate the feasibility of scheduled analgesic dosing following outpatient tonsillectomy in order to optimize pain management. Methods Parents were instructed to give their child acetaminophen with hydrocodone (167mg/5ml) every 4 hours around-the-clock for the first 3 days following surgery. Parents recorded ratings of their child’s pain with/without swallowing using the Faces, Legs, Activity, Cry, and Consolability (FLACC) behavioral pain scale, pain relief ratings, and severity of analgesic side effects in a home diary. Audiotaped interviews were conducted with parents to document descriptions of their experiences in managing their child’s pain at home. Results Mean FLACC scores with/without swallowing were less than 2 at each measurement time and pain relief scores increased over time. Total analgesic dose decreased and the number of missed doses increased over the first 3 days after surgery. Moderate-to-severe daytime sedation, nausea, vomiting, and constipation were reported by parents. Discussion Study results suggest that acetaminophen with hydrocodone is effective in relieving preschool children’s pain following tonsillectomy, and that parental adherence to a scheduled analgesic regimen decreases over time. Time-contingent dosing was associated with moderate to severe side effects, and should be addressed in discharge teaching with parents. Findings provide insight into parents’ perspective of pain management at home following tonsillectomy and methods for relieving their child’s pain. PMID:22313591

Effect of 2',3'-didehydro-3'-deoxythymidine in an in vitro hollow-fiber pharmacodynamic model system correlates with results of dose-ranging clinical studies.

PubMed Central

Bilello, J A; Bauer, G; Dudley, M N; Cole, G A; Drusano, G L

1994-01-01

We sought to validate an in vitro system which could predict the minimal effect dose of antiretroviral agents. Mixtures of uninfected CEM cells and CEM cells chronically infected with human immunodeficiency virus (HIV) type 1 MN were exposed to 2',3'-didehydro-3'-deoxythymidine (D4T) in vitro in a hollow-fiber model which simulates the plasma concentration-time profile of D4T in patients. Drug concentration was adjusted to simulate continuous intravenous infusion, or an intravenous bolus administered twice daily. The effect of the dosing regimen was measured with viral infectivity, p24 antigen, and reverse transcriptase or PCR for unintegrated HIV DNA. Dose deescalation studies on a twice-daily dosing schedule predicted a minimum effect dose of 0.5 mg/kg of body weight per day which correlated with the results of a clinical trial. Antiviral effect was demonstrated to be independent of schedule for every 12-h dosing versus continuous infusion. Finally, at or near the minimal effect dose, efficacy appeared to depend on the viral load. The ability of this in vitro pharmacodynamic model to assess the response of HIV-infected cells to different doses and schedules of antiviral agents may be useful in the design of optimal dosing regimens for clinical trials but requires validation with other types of antiretroviral agents. PMID:8092842

Rotavirus specific maternal antibodies and immune response to RV3-BB neonatal rotavirus vaccine in New Zealand

PubMed Central

Chen, Mee-Yew; Kirkwood, Carl D.; Bines, Julie; Cowley, Daniel; Pavlic, Daniel; Lee, Katherine J.; Orsini, Francesca; Watts, Emma; Barnes, Graeme; Danchin, Margaret

2017-01-01

ABSTRACT Background: Maternal antibodies, acquired passively via placenta and/or breast milk, may contribute to the reduced efficacy of oral rotavirus vaccines observed in children in developing countries. This study aimed to investigate the effect of rotavirus specific maternal antibodies on the serum IgA response or stool excretion of vaccine virus after any dose of an oral rotavirus vaccine, RV3-BB, in parallel to a Phase IIa clinical trial conducted at Dunedin Hospital, New Zealand. At the time of the study rotavirus vaccines had not been introduced in New Zealand and the burden of rotavirus disease was evident. Methods: Rotavirus specific IgG and serum neutralizing antibody (SNA) levels in cord blood and IgA levels in colostrum and breast milk samples collected ∼4 weeks, ∼20 weeks and ∼28 weeks after birth were measured. Infants were randomized to receive the first dose of vaccine at 0–5 d (neonatal schedule) or 8 weeks (infant schedule). Breast feeding was with-held for 30 minutes before and after vaccine administration. The relationship between rotavirus specific IgG and SNA levels in cord blood and IgA in colostrum and breast milk at the time of first active dose of RV3-BB vaccine and level of IgA response and stool excretion after 3 doses of vaccine was assessed using linear and logistic regression. Results: Forty infants received 3 doses of RV3-BB rotavirus vaccine and were included in the analysis of the neonatal and infant groups. Rotavirus specific IgA in colostrum (neonatal schedule group) and breast milk at 4 weeks (infant schedule group) was identified in 14/21 (67%) and 14/17 (82%) of infants respectively. There was little evidence of an association between IgA in colostrum or breast milk IgA at 4 weeks, or between cord IgG or SNA level, and IgA response or stool excretion after 3 doses of RV3-BB, or after one dose (neonatal schedule) (all p>0.05). Conclusions: The level of IgA in colostrum or breast milk and level of placental IgG and SNA did not impact on the serum IgA response or stool excretion following 3 doses of RV3-BB Rotavirus Vaccine administered using either a neonatal or infant schedule in New Zealand infants. PMID:28059609

Persistence of rubella and mumps antibodies, following changes in the recommended age for the second dose of MMR vaccine in Portugal.

PubMed

Gonçalves, G; Frade, J; Nascimento, M S J; Mesquita, J R; Nunes, C

2016-11-01

In Portugal, the recommended age for the second dose of MMR (MMR2) was changed from 10-13 years to 5-6 years for those born in 1994 and afterwards. This study aimed to assess if MMR schedule and time elapsed from the last dose are associated with the concentration of rubella and mumps IgG antibodies. Three Portuguese birth cohorts (convenience samples) were selected for this study (66, 59 and 41 participants born respectively in 1990-1993, 1994-1995 and 2001-2003). Geometric mean concentrations (GMC) for mumps IgG were respectively 36, 30 and 38 RU/ml (P = 0·236) and for rubella IgG were 18, 20 and 17 IU/ml (P = 0·641). For both specific antibodies, no differences were observed with time since MMR2. Receiving MMR2 at 5-6 or 10-13 years was not associated with concentration of both antibodies. The GMC of rubella IgG was lower in males (P = 0·029). Taking into account previous evidence and the logistics needed to change vaccination schedules, it seems reasonable that sustaining very high coverage with two doses of MMR is currently the most pragmatic way to control mumps and rubella rather than any changes to the schedule.

Factors associated with the immune response to hepatitis A vaccination in HIV-infected patients in the era of highly active antiretroviral therapy.

PubMed

Mena, Guillermo; García-Basteiro, Alberto L; Llupià, Anna; Díez, Consolación; Costa, Josep; Gatell, Josep-María; García, Felipe; Bayas, José-María

2013-08-12

HIV seropositivity is considered a risk factor for complications in hepatitis A virus (HAV) infection. HAV vaccination schedules are widely implemented in HIV-infected patients, but the immune response remains impaired. We analysed the response to vaccination (antiHAV titres ≥20IU/l) in 282 HIV-infected patients included in a standard (1440 Elisa Units (EU) at 0, 6 months) or rapidly accelerated schedule (720 EU at 0, 7, 21 days and 6 months) between 1997 and 2009. Factors associated with the response to vaccination were analysed using logistic regression. The overall response rate was 73.4%. Male sex (OR: 0.16, 95% CI 0.05-0.51) and hepatitis C virus co-infection (OR: 0.30, 95% CI 0.14-0.74) were associated with a lower probability of response. Protective antibody response was associated with a higher CD4/CD8 ratio (OR: 3.69, 95% CI 1.3-10.5) and having received two doses of standard schedule (compared with patients receiving only one dose of the same schedule) (OR: 2.51, 95% CI 1.22-5.15). Three doses of the rapidly accelerated schedule were not more effective than a single dose of 1440 EU (OR: 1.32, 95% CI 0.48-3.63). The low responses observed in patients receiving a single dose suggest the need to emphasize adhesion to vaccination protocols to avoid failure. The CD4/CD8 ratio may be considered as an immune status marker which could help to better choose the moment of vaccination. Our findings underscore the importance of identifying strategies that optimize the timing and effectiveness of hepatitis A vaccination in HIV-infected patients and of the need for further studies on individual factors such as sex and hepatitis C co-infection that may affect the response to vaccination. Likewise, the sub-optimal effectiveness of three doses of 720 EU in the rapidly accelerated schedule, if confirmed in future studies, might lead to a revision of the current schedule recommended for HIV-infected travellers. Copyright © 2013 Elsevier Ltd. All rights reserved.

Immunogenicity and safety of a live attenuated shingles (herpes zoster) vaccine (Zostavax®) in individuals aged ≥ 70 years: a randomized study of a single dose vs. two different two-dose schedules.

PubMed

Vesikari, Timo; Hardt, Roland; Rümke, Hans C; Icardi, Giancarlo; Montero, Jordi; Thomas, Stéphane; Sadorge, Christine; Fiquet, Anne

2013-04-01

Disease protection provided by herpes zoster (HZ) vaccination tends to reduce as age increases. This study was designed to ascertain whether a second dose of the HZ vaccine, Zostavax(®), would increase varicella zoster virus (VZV)-specific immune response among individuals aged ≥ 70 y. Individuals aged ≥ 70 y were randomized to receive HZ vaccine in one of three schedules: a single dose (0.65 mL), two doses at 0 and 1 mo, or two doses at 0 and 3 mo. VZV antibody titers were measured at baseline, 4 weeks after each vaccine dose, and 12 mo after the last dose. In total, 759 participants (mean age 76.1 y) were randomized to receive vaccination. Antibody responses were similar after a single dose or two doses of HZ vaccine [post-dose 2/post-dose 1 geometric mean titer (GMT) ratios for the 1-mo or 3-mo schedules were 1.11, 95% confidence interval (CI) 1.02-1.22 and 0.78, 95% CI 0.73-0.85], respectively). The 12-mo post-dose 2/12-mo post-dose 1 GMT ratio was similar for the 1-mo schedule and for the 3-mo schedule (1.06, 95% CI 0.96-1.17 and 1.08, 95% CI 0.98-1.19, respectively). Similar immune responses were observed in participants aged 70-79 y and those aged ≥ 80 y. HZ vaccine was generally well tolerated, with no evidence of increased adverse event incidence after the second dose with either schedule. Compared with a single-dose regimen, two-dose vaccination did not increase VZV antibody responses among individuals aged ≥ 70 y. Antibody persistence after 12 mo was similar with all three schedules.

Bias of phencyclidine discrimination by the schedule of reinforcement.

PubMed Central

McMillan, D E; Wenger, G R

1984-01-01

Pigeons, trained to discriminate phencyclidine from saline under a procedure requiring the bird to track the location of a color, received cumulative doses of phencyclidine, pentobarbital, or d-amphetamine with a variety of schedules of reinforcement in effect (across phases). When the same second-order schedules were used to reinforce responding after either saline or phencyclidine administration, stimulus control by phencyclidine did not depend on the schedule parameter. When different second-order schedules were used that biased responding toward the phencyclidine-correlated key color, pigeons responded on the phencyclidine-correlated key at lower doses of phencyclidine and pentobarbital than when the second-order schedule biased responding toward the saline key color. A similar but less marked effect was obtained with d-amphetamine. Attempts to produce bias by changing reinforcement magnitude (duration of food availability) were less successful. A signal-detection analysis of dose-effect curves for phencyclidine under two of the second-order schedules employed suggested that at low doses of phencyclidine, response bias is a major determinant of responding. As doses were increased, position preferences occurred and response bias decreased; at higher doses both response bias and position preference decreased and discriminability increased. With low doses of pentobarbital, responding again was biased but increasing doses produced position preference with only small increases in discriminability. At low doses of d-amphetamine responding also was biased, but bias did not decrease consistently with dose nor did discriminability increase. These experiments suggest that the schedule of reinforcement can be used to bias responding toward or away from making the drug-correlated response in drug discrimination experiments, and that signal-detection analysis and analysis of responding at a position can be used to separate the discriminability of the drug state from other effects of the drug on responding. PMID:6481300

Evolution of resistance to anti-cancer therapy during general dosing schedules

PubMed Central

Foo, Jasmine; Michor, Franziska

2009-01-01

Anti-cancer drugs targeted to specific oncogenic pathways have shown promising therapeutic results in the past few years; however, drug resistance remains an important obstacle for these therapies. Resistance to these drugs can emerge due to a variety of reasons including genetic or epigenetic changes which alter the binding site of the drug target, cellular metabolism or export mechanisms. Obtaining a better understanding of the evolution of resistant populations during therapy may enable the design of more effective therapeutic regimens which prevent or delay progression of disease due to resistance. In this paper, we use stochastic mathematical models to study the evolutionary dynamics of resistance under time-varying dosing schedules and pharmacokinetic effects. The populations of sensitive and resistant cells are modeled as multi-type non-homogeneous birth-death processes in which the drug concentration affects the birth and death rates of both the sensitive and resistant cell populations in continuous time. This flexible model allows us to consider the effects of generalized treatment strategies as well as detailed pharmacokinetic phenomena such as drug elimination and accumulation over multiple doses. We develop estimates for the probability of developing resistance and moments of the size of the resistant cell population. With these estimates, we optimize treatment schedules over a subspace of tolerated schedules to minimize the risk of disease progression due to resistance as well as locate ideal schedules for controlling the population size of resistant clones in situations where resistance is inevitable. Our methodology can be used to describe dynamics of resistance arising due to a single (epi)genetic alteration in any tumor type. PMID:20004211

The impact of closed-loop electronic medication management on time to first dose: a comparative study between paper and digital hospital environments.

PubMed

Austin, Jodie A; Smith, Ian R; Tariq, Amina

2018-01-22

Closed-loop electronic medication management systems (EMMS) are recognised as an effective intervention to improve medication safety, yet evidence of their effectiveness in hospitals is limited. Few studies have compared medication turnaround time for a closed-loop electronic versus paper-based medication management environment. To compare medication turnaround times in a paper-based hospital environment with a digital hospital equipped with a closed-loop EMMS, consisting of computerised physician order entry, profiled automated dispensing cabinets packaged with unit dose medications and barcode medication administration. Data were collected during 2 weeks at three private hospital sites (one with closed-loop EMMS) within the same organisation network in Queensland, Australia. Time between scheduled and actual administration times was analysed for first dose of time-critical and non-critical medications located on the ward or sourced via pharmacy. Medication turnaround times at the EMMS site were less compared to the paper-based sites (median, IQR: 35 min, 8-57 min versus 120 min, 30-180 min, P < 0.001). For time-critical medications, 77% were administered within 60 min of scheduled time at the EMMS site versus 38% for the paper-based sites. Similar difference was observed for non-critical medications, 80% were administered within 60 min of their scheduled time at the EMMS site versus 41% at the paper-based facilities. The study indicates medication turnaround times utilising a closed-loop EMMS are less compared to paper-based systems. This improvement may be attributable to increased accessibility of medications using automated dispensing cabinets and electronic medication administration records flagging tasks to nurses in real time. © 2018 Royal Pharmaceutical Society.

Minimizing metastatic risk in radiotherapy fractionation schedules

NASA Astrophysics Data System (ADS)

Badri, Hamidreza; Ramakrishnan, Jagdish; Leder, Kevin

2015-11-01

Metastasis is the process by which cells from a primary tumor disperse and form new tumors at distant anatomical locations. The treatment and prevention of metastatic cancer remains an extremely challenging problem. This work introduces a novel biologically motivated objective function to the radiation optimization community that takes into account metastatic risk instead of the status of the primary tumor. In this work, we consider the problem of developing fractionated irradiation schedules that minimize production of metastatic cancer cells while keeping normal tissue damage below an acceptable level. A dynamic programming framework is utilized to determine the optimal fractionation scheme. We evaluated our approach on a breast cancer case using the heart and the lung as organs-at-risk (OAR). For small tumor α /β values, hypo-fractionated schedules were optimal, which is consistent with standard models. However, for relatively larger α /β values, we found the type of schedule depended on various parameters such as the time when metastatic risk was evaluated, the α /β values of the OARs, and the normal tissue sparing factors. Interestingly, in contrast to standard models, hypo-fractionated and semi-hypo-fractionated schedules (large initial doses with doses tapering off with time) were suggested even with large tumor α/β values. Numerical results indicate the potential for significant reduction in metastatic risk.

Critical dose and toxicity index of organs at risk in radiotherapy: Analyzing the calculated effects of modified dose fractionation in non–small cell lung cancer

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

Pedicini, Piernicola, E-mail: ppiern@libero.it; Strigari, Lidia; Benassi, Marcello

2014-04-01

To increase the efficacy of radiotherapy for non–small cell lung cancer (NSCLC), many schemes of dose fractionation were assessed by a new “toxicity index” (I), which allows one to choose the fractionation schedules that produce less toxic treatments. Thirty-two patients affected by non resectable NSCLC were treated by standard 3-dimensional conformal radiotherapy (3DCRT) with a strategy of limited treated volume. Computed tomography datasets were employed to re plan by simultaneous integrated boost intensity-modulated radiotherapy (IMRT). The dose distributions from plans were used to test various schemes of dose fractionation, in 3DCRT as well as in IMRT, by transforming the dose-volumemore » histogram (DVH) into a biological equivalent DVH (BDVH) and by varying the overall treatment time. The BDVHs were obtained through the toxicity index, which was defined for each of the organs at risk (OAR) by a linear quadratic model keeping an equivalent radiobiological effect on the target volume. The less toxic fractionation consisted in a severe/moderate hyper fractionation for the volume including the primary tumor and lymph nodes, followed by a hypofractionation for the reduced volume of the primary tumor. The 3DCRT and IMRT resulted, respectively, in 4.7% and 4.3% of dose sparing for the spinal cord, without significant changes for the combined-lungs toxicity (p < 0.001). Schedules with reduced overall treatment time (accelerated fractionations) led to a 12.5% dose sparing for the spinal cord (7.5% in IMRT), 8.3% dose sparing for V{sub 20} in the combined lungs (5.5% in IMRT), and also significant dose sparing for all the other OARs (p < 0.001). The toxicity index allows to choose fractionation schedules with reduced toxicity for all the OARs and equivalent radiobiological effect for the tumor in 3DCRT, as well as in IMRT, treatments of NSCLC.« less

Antipsychotic treatment dosing profile in patients with schizophrenia evaluated with electronic monitoring (MEMS®).

PubMed

Acosta, Francisco J; Ramallo-Fariña, Yolanda; Bosch, Esperanza; Mayans, Teresa; Rodríguez, Carlos J; Caravaca, Ana

2013-05-01

Although the Medication Event Monitoring System (MEMS®) device offers accurate information on treatment dosing profile, such profile has never been studied in patients with schizophrenia. Enhancing our knowledge on this issue would help in developing intervention strategies to improve adherence to antipsychotic treatment in these patients. 74 outpatients with schizophrenia were monitored with the MEMS device for a 3-month period, for evaluation of antipsychotic treatment dosing profile, possible influence of medication schedule-related variables, adherence to treatment--considering dose intake within prescribed timeframes--and possible Hawthorne's effect of using the MEMS device. Dose-omission gaps occurred in 18.7% of monitoring days, most frequently during weekends, almost significantly. Almost one-third of prescribed doses were taken out of prescribed time. Neither the prescribed number of daily doses nor the indicated time of the day for dose intake (breakfast, dinner), were associated with correct antipsychotic dosing. Excess-dose was rare in general, and more frequent out of prescribed dose timeframe. No Hawthorne's effect was found for the MEMS device. Adherence reached only 35% according to a definition that included dose intake within prescribed timeframes. Antipsychotic treatment dosing was considerably irregular among patients with schizophrenia. Strategies to reduce dose-omission gaps and increase dosing within prescribed timeframes seem to be necessary. Gaining knowledge on precise oral antipsychotic dosing profiles or the influence of schedule-related variables may be useful to design strategies towards enhancing adherence. There appears to be no Hawthorne's effect associated with the use of MEMS devices in outpatients with schizophrenia. Copyright © 2013 Elsevier B.V. All rights reserved.

Schedule Dependence in Cancer Therapy: Intravenous Vitamin C and the Systemic Saturation Hypothesis

PubMed Central

Miranda Massari, Jorge R.; Duconge, Jorge; Riordan, Neil H.; Ichim, Thomas

2013-01-01

Despite the significant number of in vitro and in vivo studies to assess vitamin C effects on cancer following the application of large doses and its extensive use by alternative medicine practitioners in the USA; the precise schedule for successful cancer therapy is still unknown. Based on interpretation of the available data, we postulate that the relationship between Vitamin C doses and plasma concentration x time, the capability of tissue stores upon distribution, and the saturable mechanism of urinary excretion are all important determinants to understand the physiology of high intravenous vitamin C dose administration and its effect on cancer. Practitioners should pay more attention to the cumulative vitamin C effect instead of the vitamin C concentrations to account for observed discrepancy in antitumor response. We suggest that multiple, intermittent, short-term intravenous infusions of vitamin C over a longer time period will correlate with greater antitumor effects than do single continuous IV doses of the same total exposure. This approach would be expected to minimize saturation of renal reabsorption, providing a continuous “dynamic flow” of vitamin C in the body for optimal systemic exposure and clinical outcomes. This prevents the “systemic saturation” phenomena, which may recycle vitamin C and render it less effective as an anticancer agent. Nonetheless, more pharmacokinetic and pharmacodynamic studies are needed to fully understand this schedule-dependence phenomenon. PMID:24860238

Sustained Immunogenicity of 2-dose Human Papillomavirus 16/18 AS04-adjuvanted Vaccine Schedules in Girls Aged 9–14 Years: A Randomized Trial

PubMed Central

Puthanakit, Thanyawee; Cheng-Hsun, Chiu; Ren-Bin, Tang; Schwarz, Tino; Pellegrino, Angelo; Esposito, Susanna; Frenette, Louise; McNeil, Shelly; Durando, Paolo; Rheault, Paul; Giaquinto, Carlo; Horn, Michael; Petry, Karl Ulrich; Peters, Klaus; Azhar, Toma; Hillemanns, Peter; De Simoni, Stephanie; Friel, Damien; Pemmaraju, Suryakiran; Hezareh, Marjan; Thomas, Florence; Descamps, Dominique; Folschweiller, Nicolas; Struyf, Frank

2017-01-01

Abstract Background. We previously reported the noninferiority 1 month after the last dose of 2-dose human papillomavirus 16/18 AS04-adjuvanted (AS04-HPV-16/18) vaccine schedules at months 0 and 6 (2D_M0,6) and months 0 and 12 (2D_M0,12) in girls aged 9–14 years compared with a 3-dose schedule at months 0, 1, and 6 (3D_M0,1,6) in women aged 15–25 years. Here, we report the results at study end (month 36 [M36]). Methods. Girls were randomized 1:1 and received 2 vaccine doses either 6 months (2D_M0,6) or 12 months apart (2D_M0,12); women received 3 doses at months 0, 1, and 6 (3D_M0,1,6). Endpoints included noninferiority of HPV-16/18 antibodies for 2D_M0,6 versus 3D_M0,1,6; 2D_M0,12 versus 3D_M0,1,6; and 2D_M0,12 versus 2D_M0,6; and assessment of neutralizing antibodies, T cells, B cells, and safety. Results. At M36, the 2D_M0,6 and 2D_M0,12 schedules remained noninferior to the 3D_M0,1,6 schedule in terms of seroconversion rates and 3D/2D geometric mean titers for anti-HPV-16 and anti-HPV-18. All schedules elicited sustained immune responses up to M36. Conclusions. Both 2-dose schedules in young girls remained noninferior to the 3-dose schedule in women up to study conclusion at M36. The AS04-HPV-16/18 vaccine administered as a 2-dose schedule was immunogenic and well tolerated in young girls. PMID:28591778

Chemotherapeutic strategies in metastatic colorectal cancer: an overview of current clinical trials.

PubMed

Köhne-Wömpner, C H; Schmoll, H J; Harstrick, A; Rustum, Y M

1992-04-01

5-Fluorouracil (5-FU) is still the mainstay of chemotherapy in patients with metastatic colorectal cancer. A prolonged infusion of 5-FU is more active than any other schedule of 5-FU used to date. Cisplatin does not improve treatment results compared with 5-FU alone and is not recommended outside clinical trials. Biomodulation of 5-FU is a major step forward in the treatment of colorectal cancer patients and as the standard chemotherapy for advanced colorectal cancer. Two schedules of folinic acid daily for 5-day (low and high doses) and weekly high dose in combination with daily or weekly 5-FU are the most widely used schedules. Although the response rates to either schedule are comparable, the profile of toxicity is different, being stomatitis for the daily schedule and diarrhea for the weekly schedule as the dose-limiting toxicity. Modulation of 5-FU by methotrexate is time dependent. An interval of 24 hours between methotrexate and 5-FU is necessary for effective modulation. Other modulators, like interferon and N-phosphonoactyl-L-aspartate (PALA), are promising treatment options currently under investigation in randomized trials. The data from phase II and III trials using modulation of 5-FU by folinic acid, PALA, or methotrexate, or using continuous infusion 5-FU indicate that all of these strategies are active. Randomized trials are currently underway to further investigate these therapeutic approaches and whether a specific modulation offers more therapeutic advantages.

Evaluation of the immunogenicity of the quadrivalent HPV vaccine using 2 versus 3 doses at month 21: An epidemiological surveillance mechanism for alternate vaccination schemes

PubMed Central

Hernández-Ávila, Mauricio; Torres-Ibarra, Leticia; Stanley, Margaret; Salmerón, Jorge; Cruz-Valdez, Aurelio; Muñoz, Nubia; Herrero, Rolando; Villaseñor-Ruíz, Ignacio F; Lazcano-Ponce, Eduardo

2016-01-01

The cost of HPV vaccines and the need for 3 doses remains a barrier for their inclusion in routine vaccination schedules for girls in low and middle income countries. In a non-inferiority study, we aimed to compare the immunogenicity of a standard 3 doses and a 2 doses schedule. We enrolled 450 participants in an open-label non-randomized clinical trial to evaluate the immunogenicity induced at different ages by the licensed HPV6/11/16/18 quadrivalent vaccine in a 2 doses schedule (0–6 months, n = 150 girls aged 9–10 y) and 3 doses schedule (0, 2, and 6 months; n = 150 girls aged 9–10 y and n=150 women aged 18 to 24 years). To assess the antibody response, blood samples were obtained at Month 7 and 21 after the first vaccination from participants in all study groups. cLIA testing was performed at Merck Research Laboratories. Antibody levels were expressed as milli-Merck units (mMU) per ml. Primary outcome was non-inferiority (95% CI, lower bound >0.5) of the geometric mean titers (GMT) ratios for HPV6, HPV11, HPV16 and HPV18 antibodies 7 and 21 months after the first dose among girls receiving 2 doses compared with young women and girls receiving 3 doses. All vaccinees were seropositive for both HPV16 and HPV18 antibodies at month 7. At month 21, 98.5 and 56.6% of women 18–24 y old were seropositive for HPV16 and 18, respectively. For girls in the three doses group, seropositivity rates were 99.3 and 86.3% for HPV16 and 18, respectively. For girls in the two doses group rates were 99.3 and 70.2% for HPV16 and 18, respectively. The two doses schedule was non-inferior compared to the 3 doses schedule in same-age girls and to the group of adult women after 21 months of the first vaccine dose. Our results are in agreement with similar trials evaluating the immune response of a 2 doses schedule of both HPV vaccines, supporting the recent WHO recommendation as well as the Mexican policy to incorporate the 2 doses schedule for girls aged 9–11 y. PMID:26211489

Baseline Preferences for Daily, Event-Driven, or Periodic HIV Pre-Exposure Prophylaxis among Gay and Bisexual Men in the PRELUDE Demonstration Project.

PubMed

Vaccher, Stefanie J; Gianacas, Christopher; Templeton, David J; Poynten, Isobel M; Haire, Bridget G; Ooi, Catriona; Foster, Rosalind; McNulty, Anna; Grulich, Andrew E; Zablotska, Iryna B

2017-01-01

The effectiveness of daily pre-exposure prophylaxis (PrEP) is well established. However, there has been increasing interest in non-daily dosing schedules among gay and bisexual men (GBM). This paper explores preferences for PrEP dosing schedules among GBM at baseline in the PRELUDE demonstration project. Individuals at high-risk of HIV were enrolled in a free PrEP demonstration project in New South Wales, Australia, between November 2014 and April 2016. At baseline, they completed an online survey containing detailed behavioural, demographic, and attitudinal questions, including their ideal way to take PrEP: daily (one pill taken every day), event-driven (pills taken only around specific risk events), or periodic (daily dosing during periods of increased risk). Overall, 315 GBM (98% of study sample) provided a preferred PrEP dosing schedule at baseline. One-third of GBM expressed a preference for non-daily PrEP dosing: 20% for event-driven PrEP, and 14% for periodic PrEP. Individuals with a trade/vocational qualification were more likely to prefer periodic to daily PrEP [adjusted odds ratio (aOR) = 4.58, 95% confidence intervals (95% CI): (1.68, 12.49)], compared to individuals whose highest level of education was high school. Having an HIV-positive main regular partner was associated with strong preference for daily, compared to event-driven PrEP [aOR = 0.20, 95% CI: (0.04, 0.87)]. Participants who rated themselves better at taking medications were more likely to prefer daily over periodic PrEP [aOR = 0.39, 95% CI: (0.20, 0.76)]. Individuals' preferences for PrEP schedules are associated with demographic and behavioural factors that may impact on their ability to access health services and information about PrEP and patterns of HIV risk. At the time of data collection, there were limited data available about the efficacy of non-daily PrEP schedules, and clinicians only recommended daily PrEP to study participants. Further research investigating how behaviours and PrEP preferences change correspondingly over time is needed. ClinicalTrials.gov NCT02206555. Registered 28 July 2014.

A randomised, double-blind, placebo-controlled, crossover study to assess the efficacy and safety of three dosing schedules of agalsidase alfa enzyme replacement therapy for Fabry disease.

PubMed

Hughes, D A; Deegan, P B; Milligan, A; Wright, N; Butler, L H; Jacobs, A; Mehta, A B

2013-07-01

Anecdotal reports suggest that the currently approved dosing interval of agalsidase alfa (0.2 mg/kg/2 weeks) for Fabry disease treatment is too long. This randomised, double-blind, placebo-controlled, crossover study investigated three altered dosing intervals. 18 Fabry patients received three agalsidase alfa dosing schedules, each for four weeks (A: 0.2 mg/kg∗2 weeks, B: 0.1 mg/kg/week, C: 0.2 mg/kg/week). Health state, pain levels, sweat volume and latency and plasma and urinary globotriaosylceramide levels were recorded throughout the study. No significant differences were found among the schedules for the primary efficacy outcome of self-assessed health state, or for pain scores. A trend toward increased sweat volume on QSART testing, and reduced urine globotriaosylceramide concentration were seen with treatment schedule C. Agalsidase alfa was safe and well tolerated with all schedules. In conclusion, the primary analyses did not find weekly infusions of agalsidase alfa to be statistically better than the approved dosing schedule however the data indicates that further studies with more patients over a longer period are required to more accurately determine the optimum dose and schedule. Copyright © 2013 Elsevier Inc. All rights reserved.

Immunogenicity and reactogenicity of alternative schedules of HPV vaccine in Vietnam: a cluster randomized noninferiority trial.

PubMed

Neuzil, Kathleen M; Canh, Do Gia; Thiem, Vu Dinh; Janmohamed, Amynah; Huong, Vu Minh; Tang, Yuxiao; Diep, Nguyen Thi Ngoc; Tsu, Vivien; LaMontagne, D Scott

2011-04-13

Human papillomavirus (HPV) vaccine programs may decrease the morbidity and mortality due to cervical cancer seen among women in low-resource countries. However, the 3-dose schedule over a 6-month period is a potential barrier to vaccine introduction in such settings. To determine the immunogenicity and reactogenicity of different dosing schedules of quadrivalent HPV vaccine in adolescent girls in Vietnam. Open-label, cluster randomized, noninferiority study (conducted between October 2007 and January 2010) assessing 4 schedules of an HPV vaccine delivered in 21 schools to 903 adolescent girls (aged 11-13 years at enrollment) living in northwestern Vietnam. Intramuscular injection of 3 doses of quadrivalent HPV vaccine delivered on a standard dosing schedule (at 0, 2, and 6 months) and 3 alternative dosing schedules (at 0, 3, and 9 months; at 0, 6, and 12 months; or at 0, 12, and 24 months). Serum anti-HPV geometric mean titers (GMT) measured 1 month after the third dose of the HPV vaccine was administered; GMT was determined by type-specific competitive immunoassay. Noninferiority of each alternative vaccination dosing schedule was achieved if the lower bound of the multiplicity-adjusted confidence interval (CI) of the type-specific GMT ratio for HPV-16 and HPV-18 was greater than 0.5 (primary outcome). Safety outcomes were immediate reactions, local reactions, fever within 7 days after each dose, and serious adverse events up to 30 days following the last dose. In the intention-to-treat analysis, 809 girls who received at least 1 HPV vaccine dose had valid serum measurements 1 month after the third dose. After the third dose, the GMTs for those in the standard schedule group who received doses at 0, 2, and 6 months were 5808.0 (95% CI, 4961.4-6799.0) for HPV-16 and 1729.9 (95% CI, 1504.0-1989.7) for HPV-18; 5368.5 (95% CI, 4632.4-6221.5) and 1502.3 (95% CI, 1302.1-1733.2), respectively, for those whose received doses at 0, 3, and 9 months; 5716.4 (95% CI, 4876.7-6700.6) and 1581.5 (95% CI, 1363.4-1834.6), respectively, for those who received doses at 0, 6, and 12 months; and 3692.5 (95% CI, 3145.3-4334.9) and 1335.7 (95% CI, 1191.6-1497.3), respectively, for those who received doses at 0, 12, and 24 months. Noninferiority criteria were met for the alternative schedule groups that received doses at 0, 3, and 9 months (HPV-16 GMT ratio: 0.92 [95% CI, 0.71-1.20]; HPV-18 GMT ratio: 0.87 [95% CI, 0.68-1.11]) and at 0, 6, and 12 months (HPV-16 GMT ratio: 0.98 [95% CI, 0.75-1.29]; HPV-18 GMT ratio: 0.91 [95% CI, 0.71-1.17]). Prespecified noninferiority criteria were not met for the alternative schedule group that received doses at 0, 12, and 24 months (HPV-16 GMT ratio: 0.64 [95% CI, 0.48-0.84]; HPV-18 GMT ratio: 0.77 [95% CI, 0.62-0.96]). Pain at the injection site was the most common adverse event. Among adolescent girls in Vietnam, administration of the HPV vaccine on standard and alternative schedules was immunogenic and well tolerated. The use of 2 alternative dosing schedules (at 0, 3, and 9 months and at 0, 6, and 12 months) compared with a standard schedule (at 0, 2, and 6 months) did not result in inferior antibody concentrations. clinicaltrials.gov Identifier: NCT00524745.

Humoral and Cell-Mediated Immune Responses to Alternate Booster Schedules of Anthrax Vaccine Adsorbed in Humans

PubMed Central

Sabourin, Carol L.; Schiffer, Jarad M.; Niemuth, Nancy A.; Semenova, Vera A.; Li, Han; Rudge, Thomas L.; Brys, April M.; Mittler, Robert S.; Ibegbu, Chris C.; Wrammert, Jens; Ahmed, Rafi; Parker, Scott D.; Babcock, Janiine; Keitel, Wendy; Poland, Gregory A.; Keyserling, Harry L.; El Sahly, Hana; Jacobson, Robert M.; Marano, Nina; Plikaytis, Brian D.; Wright, Jennifer G.

2016-01-01

Protective antigen (PA)-specific antibody and cell-mediated immune (CMI) responses to annual and alternate booster schedules of anthrax vaccine adsorbed (AVA; BioThrax) were characterized in humans over 43 months. Study participants received 1 of 6 vaccination schedules: a 3-dose intramuscular (IM) priming series (0, 1, and 6 months) with a single booster at 42 months (4-IM); 3-dose IM priming with boosters at 18 and 42 months (5-IM); 3-dose IM priming with boosters at 12, 18, 30, and 42 months (7-IM); the 1970 licensed priming series of 6 doses (0, 0.5, 1, 6, 12, and 18 months) and two annual boosters (30 and 42 months) administered either subcutaneously (SQ) (8-SQ) or IM (8-IM); or saline placebo control at all eight time points. Antibody response profiles included serum anti-PA IgG levels, subclass distributions, avidity, and lethal toxin neutralization activity (TNA). CMI profiles included frequencies of gamma interferon (IFN-γ)- and interleukin 4 (IL-4)-secreting cells and memory B cells (MBCs), lymphocyte stimulation indices (SI), and induction of IFN-γ, IL-2, IL-4, IL-6, IL-1β, and tumor necrosis factor alpha (TNF-α) mRNA. All active schedules elicited high-avidity PA-specific IgG, TNA, MBCs, and T cell responses with a mixed Th1-Th2 profile and Th2 dominance. Anti-PA IgG and TNA were highly correlated (e.g., month 7, r2 = 0.86, P < 0.0001, log10 transformed) and declined in the absence of boosters. Boosters administered IM generated the highest antibody responses. Increasing time intervals between boosters generated antibody responses that were faster than and superior to those obtained with the final month 42 vaccination. CMI responses to the 3-dose IM priming remained elevated up to 43 months. (This study has been registered at ClinicalTrials.gov under registration no. NCT00119067.) PMID:26865594

Impact of concomitant dexamethasone dosing schedule on bortezomib-induced peripheral neuropathy in multiple myeloma.

PubMed

Kumar, Shaji K; Laubach, Jacob P; Giove, Thomas J; Quick, Maureen; Neuwirth, Rachel; Yung, Godwin; Rajkumar, S Vincent; Richardson, Paul G

2017-09-01

Peripheral neuropathy (PN) is the most troublesome adverse event associated with the proteasome inhibitor bortezomib. Studies suggest an inflammatory aetiology for bortezomib-induced PN (BiPN) and it has been hypothesized that reducing inflammation with concomitant dexamethasone may reduce BiPN incidence and/or severity. We retrospectively analysed PN rates from 32 studies (2697 patients with previously untreated multiple myeloma) incorporating bortezomib and differing dexamethasone schedules: partnered dosing (days of and after bortezomib), weekly dosing, and other dosing schedules (e.g. days 1-4, 8-11). Pooled overall PN rates were 45·5%, 63·9%, and 47·5%, respectively, with 5·3%, 11·0%, and 9·6% grade ≥3. Adjusting for potential confounders (age, gender, presence of thalidomide, bortezomib treatment duration), PN rates in patients on partnered dosing schedules appeared lower than in patients on weekly or other dosing schedules. Analyses conducted using patient-level data suggest that cumulative dexamethasone dose, a potential confounding factor, is unlikely to have influenced the analyses. Findings were similar in a separate pooled analysis excluding data from regimens incorporating thalidomide, when pooled overall PN rates were 50·1%, 63·9%, and 48·3%, respectively, with 4·2%, 11·0%, and 8·6% grade ≥3. These findings suggest that partnered dexamethasone dosing may result in less severe BiPN compared with alternative dexamethasone dosing schedules. © 2017 John Wiley & Sons Ltd.

Human papillomavirus vaccination coverage using two-dose or three-dose schedule criteria.

PubMed

Lin, Xia; Rodgers, Loren; Zhu, Liping; Stokley, Shannon; Meites, Elissa; Markowitz, Lauri E

2017-10-13

In October 2016, the Advisory Committee on Immunization Practices (ACIP) updated the human papillomavirus (HPV) vaccination recommendation to include a 2-dose schedule for U.S. adolescents initiating the vaccine series before their 15th birthday. We analyzed records for >4million persons aged 9-17years receiving any HPV vaccine by the end of each quarter during January 1, 2014-September 30, 2016 from six Immunization Information Systems Sentinel Sites, and reclassified HPV vaccination up-to-date coverage according to the updated recommendations. Compared with HPV vaccination up-to-date coverage by the 3-dose schedule only, including criteria for either a 2-dose or 3-dose schedule increased up-to-date coverage in 11-12, 13-14, and 15-17 year-olds by 4.5-8.5 percentage points. The difference between 3-dose up-to-date coverage and 2- or 3-dose up-to-date coverage was greatest in late 2016. These data provide baseline HPV vaccination coverage using current ACIP recommendations. Published by Elsevier Ltd.

Impact of conventional fractionated RT to pelvic lymph nodes and dose-escalated hypofractionated RT to prostate gland using IMRT treatment delivery in high-risk prostate cancer

NASA Astrophysics Data System (ADS)

Pervez, Nadeem

Prostate cancer is the most common cancer among Canadian men. The standard treatment in high-risk category is radical radiation, with androgen suppression treatment (AST). Significant disease progression is reported despite this approach. Radiation dose escalation has been shown to improve disease-free survival; however, it results in higher toxicities. Hypofractionated radiation schedules (larger dose each fraction in shorter overall treatment time) are expected to deliver higher biological doses. A hypofractionated scheme was used in this study to escalate radiation doses with AST. Treatment was well tolerated acutely. Early results of self-administered quality of life reported by patients shows a decrease in QOL which is comparable to other treatment schedules. Significant positional variation of the prostate was observed during treatment. Therefore, we suggest daily target verification to avoid a target miss. Initial late effects are reasonable and early treatment outcomes are promising. Longer follow-up is required for full outcomes assessments.

A phase I trial of two sequence-specific schedules of decitabine and vorinostat in patients with acute myeloid leukemia

PubMed Central

How, Jonathan; Minden, Mark D.; Brian, Leber; Chen, Eric X.; Brandwein, Joseph; Schuh, Andre C.; Schimmer, Aaron D.; Gupta, Vikas; Webster, Sheila; Degelder, Tammy; Haines, Patricia; Stayner, Lee-Anne; McGill, Shauna; Wang, Lisa; Piekarz, Richard; Wong, Tracy; Siu, Lillian L.; Espinoza-Delgado, Igor; Holleran, Julianne L.; Egorin, Merrill J.; Yee, Karen W. L.

2015-01-01

This phase I trial evaluated two schedules of escalating vorinostat in combination with decitabine every 28 days: (i) sequential or (ii) concurrent. There were three dose-limiting toxicities: grade 3 fatigue and generalized muscle weakness on the sequential schedule (n = 1) and grade 3 fatigue on the concurrent schedule (n = 2). The maximum tolerated dose was not reached on both planned schedules. The overall response rate (ORR) was 23% (three complete response [CR], two CR with incomplete incomplete blood count recovery [CRi], one partial response [PR] and two morphological leukemic free state [MLFS]). The ORR for all and previously untreated patients in the sequential arm was 13% (one CRi; one MLFS) and 0% compared to 30% (three CR; one CRi; one PR; one MLFS) and 36% in the concurrent arm (p = 0.26 for both), respectively. Decitabine plus vorinostat was safe and has clinical activity in patients with previously untreated acute myeloid leukemia. Responses appear higher with the concurrent dose schedule. Cumulative toxicities may limit long-term usage on the current dose/schedules. PMID:25682963

Curative chemotherapy for acute myeloid leukemia: the development of high-dose ara-C from the laboratory to bedside.

PubMed

Capizzi, R L

1996-01-01

In the bench to bedside development of drugs to treat patients with cancer, the common guide to dose and schedule selection is toxicity to normal organs patterned after the preclinical profile of the drug. An understanding of the cellular pharmacology of the drug and specifically the cellular targets linked to the drug's effect is of substantial value in assisting the clinical investigator in selecting the proper dose and schedule of drug administration. The clinical development of ara-C for the treatment of acute myeloid leukemia (AML) provides a useful paradigm for the study of this process. An understanding of the cellular pharmacology, cytokinetics and pharmacokinetics of ara-C in leukemic mice showed substantial schedule-dependency. Exposure to high doses for a short duration (C x t) resulted in a palliative therapeutic outcome. In marked contrast, exposure to lower doses for a protracted period (c x T) was curative. Clinical use of ara-C in patients with AML patterned after the murine experience, c x T approach, has been of limited benefit in terms of long-term disease-free survival. Studies with human leukemia blasts from patients have shown that for the majority of patients, the initial rate-limiting step is membrane transport, the characteristics of which are substantially affected by extracellular drug concentration (dose). This pharmacologic impediment is eliminated with the blood levels attained during the infusion of gram doses (1-3 gm/m2) of the drug (high-dose ara-C, HiDaC) for shorter periods of time, a C x t approach. Clinical confirmation of these pharmacologic observations is evident in the therapeutic efficacy of HiDaC in patients with relapsed or SDaC-refractory acute leukemia. This is further emphasized by the significantly improved leukemia-free survival of patients with AML treated with HiDaC intensification during remission compared to those patients treated with milligram doses typical of SDaC protocols. Thus, the identification and monitoring of important parameters of drug action in tumors during the course of a clinical trial can be of substantial assistance in optimizing drug dose and schedule so as to attain the best therapeutic index.

Linked Orders Improve Safety in Scheduling and Administration of Chemotherapeutic Agents

PubMed Central

Whipple, Nancy; Boulware, Joy; Danca, Kala; Boyarin, Kirill; Ginsberg, Eliot; Poon, Eric; Sweet, Micheal; Schade, Sue; Rogala, Jennifer

2010-01-01

The pharmacologic treatment for cancer must adhere to complex, finely orchestrated treatment plans, including not only chemotherapy medications, but pre/post-hydration, anti-emetics, anti-anxiety, and other medications that are given before, during and after chemotherapy doses. The treatment plans specify the medications and dictate precise dosing, frequency, and timing. This is a challenge to most Computerized Physician Order Entry (CPOE), Pharmacy and Electronic Medication Administration record (eMAR) Systems. Medications are scheduled on specific dates, referred to as chemo days, from the onset of the treatment, and precisely timed on the designated chemo day. For patients enrolled in research protocols, the adherence to the defined schedule takes on additional import, since variation is a violation of the protocol. If the oncologist determines that medications must be administered outside the defined constraints, the patient must be un-enrolled from the protocol and the course of therapy is re-written. Pharmacy and eMAR systems utilized in processing chemotherapy medications must be able to support the intricate relationships between each drug defined in the treatment plans. PMID:21347104

Effect of extended-release dexmethylphenidate and mixed amphetamine salts on sleep: a double-blind, randomized, crossover study in youth with attention-deficit hyperactivity disorder.

PubMed

Santisteban, J A; Stein, M A; Bergmame, L; Gruber, R

2014-09-01

We sought to determine the dose-response effects of extended-release (ER) dexmethylphenidate (d-MPH) and ER mixed amphetamine salts (MAS) on objective measures of sleep. This was an 8-week, double-blind, placebo-controlled, randomized, two period, crossover study of youth with attention-deficit hyperactivity disorder (ADHD) as confirmed by the Kiddie Schedule for Affective Disorders for School-Age Children-Present and Lifetime version (K-SADS-PL). Children aged 10-17 years were recruited from clinical practice, colleague referrals, and flyers. Participants were randomized to initially receive either d-MPH or MAS. During each 4-week drug period, children received three dose levels (10, 20, and 25/30 mg) in ascending order, with placebo substituted for active medication in a randomized fashion during 1 week of the study. After 4 weeks, participants were switched to the alternative medication for another 4 weeks of treatment. The main outcome measure was sleep duration as measured by actigraphy. Children, parents, and researchers were blinded to drug, dose, and placebo status. Sixty-five participants met the inclusion criteria and were enrolled in the study. Of these, 37 participants with sufficient sleep data for analysis were included. Sleep schedule measures showed a significant effect for dose on sleep start time (F(1,36) = 6.284; p < 0.05), with a significantly later sleep start time when children were receiving 20- or 30-mg doses, compared with placebo (p < 0.05). A significant dose effect was found on actual sleep duration (F(1,36) = 8.112; p < 0.05), with significantly shorter actual sleep duration for subjects receiving 30 mg compared with those receiving placebo (p < 0.05). There were no significant differences on sleep duration or sleep schedule between the two stimulant medications. The trial is complete and closed to follow-up. Higher stimulant doses were associated with reduced sleep duration and later sleep start times, regardless of medication class. ClinicalTrials.gov: NCT00393042.

Long-term outcome of 56 dogs with nasal tumours treated with four doses of radiation at intervals of seven days.

PubMed

Mellanby, R J; Stevenson, R K; Herrtage, M E; White, R A S; Dobson, J M

2002-08-31

A retrospective study was undertaken on 56 dogs treated for nasal tumours by megavoltage radiotherapy with a hypofractionated schedule consisting of four doses of 9 Gy given at intervals of seven days. The dogs were followed until they died or were euthanased. The clinical signs had improved in 53 of the 56 dogs by the end of the treatment schedule. Mild acute radiation side effects were observed in the majority of the dogs but late radiation side effects were rare. Kaplan-Meier survival analysis revealed a median survival time after the final dose of radiation of 212 days. The one- and two-year survival rates were 45 per cent and 15 per cent. Fifty of the dogs were euthanased because the initial clinical signs recurred.

Safety and immunogenicity of RV3-BB human neonatal rotavirus vaccine administered at birth or in infancy: a randomised, double-blind, placebo-controlled trial.

PubMed

Bines, Julie E; Danchin, Margaret; Jackson, Pamela; Handley, Amanda; Watts, Emma; Lee, Katherine J; West, Amanda; Cowley, Daniel; Chen, Mee-Yew; Barnes, Graeme L; Justice, Frances; Buttery, Jim P; Carlin, John B; Bishop, Ruth F; Taylor, Barry; Kirkwood, Carl D

2015-12-01

Despite the success of rotavirus vaccines, suboptimal vaccine efficacy in regions with a high burden of disease continues to present a challenge to worldwide implementation. A birth dose strategy with a vaccine developed from an asymptomatic neonatal rotavirus strain has the potential to address this challenge and provide protection from severe rotavirus disease from birth. This phase 2a randomised, double-blind, three-arm, placebo-controlled safety and immunogenicity trial was undertaken at a single centre in New Zealand between Jan 13, 2012, and April 17, 2014. Healthy, full-term (≥36 weeks gestation) babies, who weighed at least 2500 g, and were 0-5 days old at the time of randomisation were randomly assigned (1:1:1; computer-generated; telephone central allocation) according to a concealed block randomisation schedule to oral RV3-BB vaccine with the first dose given at 0-5 days after birth (neonatal schedule), to vaccine with the first dose given at about 8 weeks after birth (infant schedule), or to placebo. The primary endpoint was cumulative vaccine take (serum immune response or stool shedding of vaccine virus after any dose) after three doses. The immunogenicity analysis included all randomised participants with available outcome data. This trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12611001212943. 95 eligible participants were randomised, of whom 89 were included in the primary analysis. A cumulative vaccine take was detected in 27 (90%) of 30 participants in the neonatal schedule group after three doses of RV3-BB vaccine compared with four (13%) of 32 participants in the placebo group (difference in proportions 0·78, 95% CI 0·55-0·88; p<0·0001). 25 (93%) of 27 participants in the infant schedule group had a cumulative vaccine take after three doses compared with eight (25%) of 32 participants in the placebo group (difference in proportions 0·68, 0·44-0·81; p<0·0001). A serum IgA response was detected in 19 (63%) of 30 participants and 20 (74%) of 27 participants, and stool shedding of RV3-BB was detected in 21 (70%) of 30 participants and 21 (78%) of 27 participants in the neonatal and infant schedule groups, respectively. The frequency of solicited and unsolicited adverse events was similar across the treatment groups. RV3-BB vaccine was not associated with an increased frequency of fever or gastrointestinal symptoms compared with placebo. RV3-BB vaccine was immunogenic and well tolerated when given as a three-dose neonatal or infant schedule. A birth dose strategy of RV3-BB vaccine has the potential to improve the effectiveness and implementation of rotavirus vaccines. Australian National Health and Medical Research Council, the New Zealand Health Research Council, and the Murdoch Childrens Research Institute. Copyright © 2015 Elsevier Ltd. All rights reserved.

Relative dose intensity--improving treatment and outcomes in early-stage breast cancer: a retrospective study.

PubMed

Griffin, Deborah A; Penprase, Barbara; Klamerus, Justin F

2012-11-01

To determine the amount of chemotherapy delivered compared to amount of chemotherapy scheduled by calculating relative dose intensity (RDI) and to identify factors associated with nonadherence of scheduled treatment regimens for patients with early-stage breast cancer (ESBC). Retrospective, descriptive, correlational study. Two community hospital cancer centers in northern Michigan. 77 patients with ESBC receiving adjuvant chemotherapy. The RDI Calculator™ was used for data collection. A worksheet was developed for each patient and included characteristics, treatment information, and RDI calculations. SAS®, version 19.2, was used for multivariate analyses based on logistical regression analyzing relationships among dependent and independent variables. Dependent variables were RDI prescribed and RDI received. Independent variables included chemotherapy regimen, clinical characteristics, planned dose, and schedule. The average RDI was 86.6%. The average RDI was 86.7% for patients younger than age 65, and 85.5% for those 65 and older. The most common reasons for dose reduction or dose delay were treatment toxicity, chronic disease risk factors, age, unplanned versus planned treatment dose, institution (different standards of care), patient preference, and weight. Meeting treatment goals of RDI for patients with ESBC has been shown to increase the disease-free survival rate and positively affects overall survival. Nurses have the unique opportunity to case manage patients with ESBC throughout the spectrum of care. One of the key areas of focus is education of the patient and her family members from the time of diagnosis throughout treatment and rehabilitation.

Dose Schedule Optimization and the Pharmacokinetic Driver of Neutropenia

PubMed Central

Patel, Mayankbhai; Palani, Santhosh; Chakravarty, Arijit; Yang, Johnny; Shyu, Wen Chyi; Mettetal, Jerome T.

2014-01-01

Toxicity often limits the utility of oncology drugs, and optimization of dose schedule represents one option for mitigation of this toxicity. Here we explore the schedule-dependency of neutropenia, a common dose-limiting toxicity. To this end, we analyze previously published mathematical models of neutropenia to identify a pharmacokinetic (PK) predictor of the neutrophil nadir, and confirm this PK predictor in an in vivo experimental system. Specifically, we find total AUC and Cmax are poor predictors of the neutrophil nadir, while a PK measure based on the moving average of the drug concentration correlates highly with neutropenia. Further, we confirm this PK parameter for its ability to predict neutropenia in vivo following treatment with different doses and schedules. This work represents an attempt at mechanistically deriving a fundamental understanding of the underlying pharmacokinetic drivers of neutropenia, and provides insights that can be leveraged in a translational setting during schedule selection. PMID:25360756

Optimizing Chemotherapy Dose and Schedule by Norton-Simon Mathematical Modeling

PubMed Central

Traina, Tiffany A.; Dugan, Ute; Higgins, Brian; Kolinsky, Kenneth; Theodoulou, Maria; Hudis, Clifford A.; Norton, Larry

2011-01-01

Background To hasten and improve anticancer drug development, we created a novel approach to generating and analyzing preclinical dose-scheduling data so as to optimize benefit-to-toxicity ratios. Methods We applied mathematical methods based upon Norton-Simon growth kinetic modeling to tumor-volume data from breast cancer xenografts treated with capecitabine (Xeloda®, Roche) at the conventional schedule of 14 days of treatment followed by a 7-day rest (14 - 7). Results The model predicted that 7 days of treatment followed by a 7-day rest (7 - 7) would be superior. Subsequent preclinical studies demonstrated that this biweekly capecitabine schedule allowed for safe delivery of higher daily doses, improved tumor response, and prolonged animal survival. Conclusions We demonstrated that the application of Norton-Simon modeling to the design and analysis of preclinical data predicts an improved capecitabine dosing schedule in xenograft models. This method warrants further investigation and application in clinical drug development. PMID:20519801

The new World Health Organization recommendation on the 2-dose measles vaccine schedule and the way forward in African Region

PubMed Central

Biellik, Robin Julian; Davis, Robert

2017-01-01

The new W.H.O. recommendation, which drops the coverage criterion for adoption of the 2-dose measles vaccine schedule, makes some African countries eligible for the 2-dose schedule which were previously ineligible. We look at the implications of the new recommendation for Ethiopia and Nigeria, the two largest African countries which are eligible under the new recommendation. PMID:29296149

A phase I and pharmacologic trial of two schedules of the proteasome inhibitor, PS-341 (bortezomib, velcade), in patients with advanced cancer.

PubMed

Dy, Grace K; Thomas, James P; Wilding, George; Bruzek, Laura; Mandrekar, Sumithra; Erlichman, Charles; Alberti, Dona; Binger, Kim; Pitot, Henry C; Alberts, Steven R; Hanson, Lorelei J; Marnocha, Rebecca; Tutsch, Kendra; Kaufmann, Scott H; Adjei, Alex A

2005-05-01

To define the toxicities, pharmacodynamics, and clinical activity of the proteasome inhibitor, PS-341 (bortezomib), in patients with advanced malignancies. Twenty-eight patients (14 male and 14 female) received PS-341 twice weekly for 4 of 6 weeks (schedule I). Because toxicity necessitated dose omissions on this schedule, 16 additional patients (12 male and 4 female) received PS-341 twice weekly for 2 of every 3 weeks (schedule II). A total of 73 courses of treatment was given (median, 2; range, 1-4). Inhibition of 20S proteasome activity in peripheral blood mononuclear cells (PBMC) and accumulation of proteasome-targeted polypeptides in tumor tissue were evaluated as pharmacodynamic markers of PS-341 activity. The most common toxicity was thrombocytopenia, which was dose limiting at 1.7 mg/m2 (schedule I) and 1.6 mg/m2 (schedule II), respectively. Sensory neuropathy was dose-limiting in a patient in schedule I. Grade > or =3 toxicities for schedule I were constipation, fatigue, myalgia, and sensory neuropathy. Grade > or =3 toxicities for schedule II were dehydration resulting from diarrhea, nausea and vomiting, fatigue, hypoglycemia, and hypotension. The maximum tolerated dose was 1.5 mg/m2 for both schedules. Reversible dose-dependent decreases in 20S proteasome activity in PBMCs were observed, with 36% inhibition at 0.5 mg/m2, 52% at 0.9 mg/m2, and 75% at 1.25 mg/m2. Accumulation of proteasome-targeted polypeptides was detected in tumor samples after treatment with PS-341. A patient with multiple myeloma had a partial response. PS-341 given 1.5 mg/m2 twice weekly for 2 of every 3 weeks is well tolerated and should be further studied.

Conditioned pharmacotherapeutic effects: a preliminary study.

PubMed

Ader, Robert; Mercurio, Mary Gail; Walton, James; James, Deborra; Davis, Michael; Ojha, Valerie; Kimball, Alexa Boer; Fiorentino, David

2010-02-01

To test the hypothesize that psoriasis patients treated under a partial schedule of pharmacologic (corticosteroid) reinforcement would show less severe symptoms and relapse than those given the same amount of drug under standard conditions. Behavioral conditioning as an inherent component of many pharmacotherapeutic protocols has never been examined. A double-blind, simple randomization intervention was conducted with 46 patients from California and New York. Initially, lesions were treated with 0.1% acetonide triamcinolone under standard treatment conditions. Thereafter, a Standard Therapy group continued on continuous reinforcement (active drug every treatment) with 100% of the initial dose; Partial Reinforcement patients received a full dose 25% to 50% of the time and placebo medication other times; Dose Control patients received continuous reinforcement with 25% to 50% of the initial dose. Severity of disease scores in California neither supported nor refuted the hypothesis. In New York, where there was no difference between Partial Reinforcement and Dose Control groups at baseline, partial reinforcement effected a greater reduction in lesion severity than Dose Control conditions and did not differ from Standard Therapy patients receiving two to four times more drug. For the entire population, the frequency of relapse under partial reinforcement (26.7%) was lower than in Dose Control patients (61.5%) and did not differ from full-dose treatment (22.2%). A partial schedule of pharmacotherapeutic reinforcement could maintain psoriasis patients with a cumulative amount of corticosteroid that was relatively ineffective when administered under standard treatment conditions. Conceivably, corticosteroid administration only one quarter or half as frequently as currently prescribed is sufficient to treat psoriasis. We posit, however, that these preliminary observations implicate conditioning processes in-and for the design of-regimens of pharmacotherapy.

Comparison of dose volume parameters evaluated using three forward planning – optimization techniques in cervical cancer brachytherapy involving two applicators

PubMed Central

Basu-Roy, Somapriya; Kar, Sanjay Kumar; Das, Sounik; Lahiri, Annesha

2017-01-01

Purpose This study is intended to compare dose-volume parameters evaluated using different forward planning- optimization techniques, involving two applicator systems in intracavitary brachytherapy for cervical cancer. It looks for the best applicator-optimization combination to fulfill recommended dose-volume objectives in different high-dose-rate (HDR) fractionation schedules. Material and methods We used tandem-ring and Fletcher-style tandem-ovoid applicator in same patients in two fractions of brachytherapy. Six plans were generated for each patient utilizing 3 forward optimization techniques for each applicator used: equal dwell weight/times (‘no optimization’), ‘manual dwell weight/times’, and ‘graphical’. Plans were normalized to left point A and dose of 8 Gy was prescribed. Dose volume and dose point parameters were compared. Results Without graphical optimization, maximum width and thickness of volume enclosed by 100% isodose line, dose to 90%, and 100% of clinical target volume (CTV); minimum, maximum, median, and average dose to both rectum and bladder are significantly higher with Fletcher applicator. Even if it is done, dose to both points B, minimum dose to CTV, and treatment time; dose to 2 cc (D2cc) rectum and rectal point etc.; D2cc, minimum, maximum, median, and average dose to sigmoid colon; D2cc of bladder remain significantly higher with this applicator. Dose to bladder point is similar (p > 0.05) between two applicators, after all optimization techniques. Conclusions Fletcher applicator generates higher dose to both CTV and organs at risk (2 cc volumes) after all optimization techniques. Dose restriction to rectum is possible using graphical optimization only during selected HDR fractionation schedules. Bladder always receives dose higher than recommended, and 2 cc sigmoid colon always gets permissible dose. Contrarily, graphical optimization with ring applicators fulfills all dose volume objectives in all HDR fractionations practiced. PMID:29204164

Phase I dose-escalation studies of roniciclib, a pan-cyclin-dependent kinase inhibitor, in advanced malignancies.

PubMed

Bahleda, Rastislav; Grilley-Olson, Juneko E; Govindan, Ramaswamy; Barlesi, Fabrice; Greillier, Laurent; Perol, Maurice; Ray-Coquard, Isabelle; Strumberg, Dirk; Schultheis, Beate; Dy, Grace K; Zalcman, Gérard; Weiss, Glen J; Walter, Annette O; Kornacker, Martin; Rajagopalan, Prabhu; Henderson, David; Nogai, Hendrik; Ocker, Matthias; Soria, Jean-Charles

2017-06-06

To evaluate safety, pharmacokinetics, and maximum tolerated dose of roniciclib in patients with advanced malignancies, with dose expansion to evaluate clinical benefit at the recommended phase II dose (RP2D). Two phase I dose-escalation studies evaluated two roniciclib dosing schedules: 3 days on/4 days off or 4 weeks on/2 weeks off. The expansion phase included patients with small-cell lung cancer (SCLC), ovarian cancer, or tumour mutations involving the CDK signalling pathway. Ten patients were evaluable in the 4 weeks on/2 weeks off schedule (terminated following limited tolerability) and 47 in the 3 days on/4 days off schedule dose-escalation cohorts. On the 3 days on/4 days off schedule, RP2D was 5 mg twice daily in solid tumours (n=40); undetermined in lymphoid malignancies (n=7). Common roniciclib-related adverse events included nausea (76.6%), fatigue (65.8%), diarrhoea (63.1%), and vomiting (57.7%). Roniciclib demonstrated rapid absorption and dose-proportional increase in exposure. One partial response (1.0%) was observed. In RP2D expansion cohorts, the disease control rate (DCR) was 40.9% for patients with ovarian cancer (n=25), 17.4% for patients with SCLC (n=33), and 33.3% for patients with CDK-related tumour mutations (n=6). Roniciclib demonstrated an acceptable safety profile and moderate DCR in 3 days on/4 days off schedule.

Applying mathematical modeling to create job rotation schedules for minimizing occupational noise exposure.

PubMed

Tharmmaphornphilas, Wipawee; Green, Benjamin; Carnahan, Brian J; Norman, Bryan A

2003-01-01

This research developed worker schedules by using administrative controls and a computer programming model to reduce the likelihood of worker hearing loss. By rotating the workers through different jobs during the day it was possible to reduce their exposure to hazardous noise levels. Computer simulations were made based on data collected in a real setting. Worker schedules currently used at the site are compared with proposed worker schedules from the computer simulations. For the worker assignment plans found by the computer model, the authors calculate a significant decrease in time-weighted average (TWA) sound level exposure. The maximum daily dose that any worker is exposed to is reduced by 58.8%, and the maximum TWA value for the workers is reduced by 3.8 dB from the current schedule.

Public health impact and cost-effectiveness of the RTS,S/AS01 malaria vaccine: a systematic comparison of predictions from four mathematical models.

PubMed

Penny, Melissa A; Verity, Robert; Bever, Caitlin A; Sauboin, Christophe; Galactionova, Katya; Flasche, Stefan; White, Michael T; Wenger, Edward A; Van de Velde, Nicolas; Pemberton-Ross, Peter; Griffin, Jamie T; Smith, Thomas A; Eckhoff, Philip A; Muhib, Farzana; Jit, Mark; Ghani, Azra C

2016-01-23

The phase 3 trial of the RTS,S/AS01 malaria vaccine candidate showed modest efficacy of the vaccine against Plasmodium falciparum malaria, but was not powered to assess mortality endpoints. Impact projections and cost-effectiveness estimates for longer timeframes than the trial follow-up and across a range of settings are needed to inform policy recommendations. We aimed to assess the public health impact and cost-effectiveness of routine use of the RTS,S/AS01 vaccine in African settings. We compared four malaria transmission models and their predictions to assess vaccine cost-effectiveness and impact. We used trial data for follow-up of 32 months or longer to parameterise vaccine protection in the group aged 5-17 months. Estimates of cases, deaths, and disability-adjusted life-years (DALYs) averted were calculated over a 15 year time horizon for a range of levels of Plasmodium falciparum parasite prevalence in 2-10 year olds (PfPR2-10; range 3-65%). We considered two vaccine schedules: three doses at ages 6, 7·5, and 9 months (three-dose schedule, 90% coverage) and including a fourth dose at age 27 months (four-dose schedule, 72% coverage). We estimated cost-effectiveness in the presence of existing malaria interventions for vaccine prices of US$2-10 per dose. In regions with a PfPR2-10 of 10-65%, RTS,S/AS01 is predicted to avert a median of 93,940 (range 20,490-126,540) clinical cases and 394 (127-708) deaths for the three-dose schedule, or 116,480 (31,450-160,410) clinical cases and 484 (189-859) deaths for the four-dose schedule, per 100,000 fully vaccinated children. A positive impact is also predicted at a PfPR2-10 of 5-10%, but there is little impact at a prevalence of lower than 3%. At $5 per dose and a PfPR2-10 of 10-65%, we estimated a median incremental cost-effectiveness ratio compared with current interventions of $30 (range 18-211) per clinical case averted and $80 (44-279) per DALY averted for the three-dose schedule, and of $25 (16-222) and $87 (48-244), respectively, for the four-dose schedule. Higher ICERs were estimated at low PfPR2-10 levels. We predict a significant public health impact and high cost-effectiveness of the RTS,S/AS01 vaccine across a wide range of settings. Decisions about implementation will need to consider levels of malaria burden, the cost-effectiveness and coverage of other malaria interventions, health priorities, financing, and the capacity of the health system to deliver the vaccine. PATH Malaria Vaccine Initiative; Bill & Melinda Gates Foundation; Global Good Fund; Medical Research Council; UK Department for International Development; GAVI, the Vaccine Alliance; WHO. Copyright © 2016 Penny et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.

Public health impact and cost-effectiveness of the RTS,S/AS01 malaria vaccine: a systematic comparison of predictions from four mathematical models

PubMed Central

Penny, Melissa A; Verity, Robert; Bever, Caitlin A; Sauboin, Christophe; Galactionova, Katya; Flasche, Stefan; White, Michael T; Wenger, Edward A; Van de Velde, Nicolas; Pemberton-Ross, Peter; Griffin, Jamie T; Smith, Thomas A; Eckhoff, Philip A; Muhib, Farzana; Jit, Mark; Ghani, Azra C

2016-01-01

Summary Background The phase 3 trial of the RTS,S/AS01 malaria vaccine candidate showed modest efficacy of the vaccine against Plasmodium falciparum malaria, but was not powered to assess mortality endpoints. Impact projections and cost-effectiveness estimates for longer timeframes than the trial follow-up and across a range of settings are needed to inform policy recommendations. We aimed to assess the public health impact and cost-effectiveness of routine use of the RTS,S/AS01 vaccine in African settings. Methods We compared four malaria transmission models and their predictions to assess vaccine cost-effectiveness and impact. We used trial data for follow-up of 32 months or longer to parameterise vaccine protection in the group aged 5–17 months. Estimates of cases, deaths, and disability-adjusted life-years (DALYs) averted were calculated over a 15 year time horizon for a range of levels of Plasmodium falciparum parasite prevalence in 2–10 year olds (PfPR2–10; range 3–65%). We considered two vaccine schedules: three doses at ages 6, 7·5, and 9 months (three-dose schedule, 90% coverage) and including a fourth dose at age 27 months (four-dose schedule, 72% coverage). We estimated cost-effectiveness in the presence of existing malaria interventions for vaccine prices of US$2–10 per dose. Findings In regions with a PfPR2–10 of 10–65%, RTS,S/AS01 is predicted to avert a median of 93 940 (range 20 490–126 540) clinical cases and 394 (127–708) deaths for the three-dose schedule, or 116 480 (31 450–160 410) clinical cases and 484 (189–859) deaths for the four-dose schedule, per 100 000 fully vaccinated children. A positive impact is also predicted at a PfPR2–10 of 5–10%, but there is little impact at a prevalence of lower than 3%. At $5 per dose and a PfPR2–10 of 10–65%, we estimated a median incremental cost-effectiveness ratio compared with current interventions of $30 (range 18–211) per clinical case averted and $80 (44–279) per DALY averted for the three-dose schedule, and of $25 (16–222) and $87 (48–244), respectively, for the four-dose schedule. Higher ICERs were estimated at low PfPR2–10 levels. Interpretation We predict a significant public health impact and high cost-effectiveness of the RTS,S/AS01 vaccine across a wide range of settings. Decisions about implementation will need to consider levels of malaria burden, the cost-effectiveness and coverage of other malaria interventions, health priorities, financing, and the capacity of the health system to deliver the vaccine. Funding PATH Malaria Vaccine Initiative; Bill & Melinda Gates Foundation; Global Good Fund; Medical Research Council; UK Department for International Development; GAVI, the Vaccine Alliance; WHO. PMID:26549466

Once-daily dosing vs. conventional dosing schedule of mesalamine and relapse of quiescent ulcerative colitis: systematic review and meta-analysis.

PubMed

Ford, Alexander C; Khan, Khurram J; Sandborn, William J; Kane, Sunanda V; Moayyedi, Paul

2011-12-01

Maintenance therapy with 5-aminosalicylates (5-ASAs) is recommended in patients with quiescent ulcerative colitis (UC), but compliance rates are low. Once-daily dosing may improve adherence, but impact on the relapse of disease activity is unclear as no previous meta-analysis has studied this issue. MEDLINE, EMBASE, and the Cochrane central register of controlled trials were searched (through April 2011). Eligible randomized controlled trials (RCTs) recruited adults with quiescent UC, and compared once-daily dosing of 5-ASAs with a more frequent dosing schedule of an identical total daily dose of the same 5-ASA drug. Minimum treatment duration was 6 months. Trials reported a dichotomous assessment of relapse of disease activity at last point of follow-up. Data concerning non-compliance and adverse events were extracted, where reported. Effect of once-daily vs. more frequent dosing schedule was reported as relative risk (RR) of relapse with a 95% confidence interval (CI). The search identified 3,061 citations, and seven RCTs containing 2,745 patients were eligible. All RCTs used mesalamine. Relapse rates were not significantly different between once-daily and conventional dosing schedules for mesalamine (RR of relapse=0.94; 95% CI: 0.82-1.08). Non-compliance (RR=0.87; 95% CI: 0.46-1.66) and adverse events were no more likely with once-daily dosing (RR=1.08; 95% CI: 0.97-1.20). Once-daily dosing with mesalamine is as effective as conventional dosing schedules for the prevention of relapse of quiescent UC, although there is no definitive evidence that compliance with once-daily dosing is better. Adverse events occur at a similar frequency.

A randomized phase II trial evaluating different schedules of zoledronic acid on bone mineral density in patients with prostate cancer beginning androgen deprivation therapy.

PubMed

Lang, Joshua M; Wallace, Marianne; Becker, Jordan T; Eickhoff, Jens C; Buehring, Bjoern; Binkley, Neil; Staab, Mary Jane; Wilding, George; Liu, Glenn; Malkovsky, Miroslav; McNeel, Douglas G

2013-12-01

To assess the effects of timing and schedule of zoledronic acid (ZA) administration on bone mineral density (BMD) in patients beginning androgen deprivation therapy (ADT) for the treatment of recurrent prostate cancer. In this randomized, 3-arm trial, we evaluated changes in BMD after 3 different ZA administration schedules in men with recurrent prostate cancer who were beginning ADT. Forty-four patients were enrolled and randomized to receive a single dose of ZA given 1 week before beginning ADT (arm 1), a single dose of ZA given 6 months after beginning ADT (arm 2), or monthly administration of ZA starting 6 months after beginning ADT, for a total of 6 doses (arm 3). Patients who received ZA before ADT had a significant improvement in BMD at the total proximal femur and trochanter after 6 months compared with the other groups. In addition, only patients in the arm that received multiple doses improved lumbar spine BMD while on ADT, with these findings persisting to 24 months. However, this group also experienced more grade 1 adverse events. Analysis of these data suggests that ZA administration before initiation of ADT was superior to treatment 6 months after starting ADT in maintaining BMD. In addition, monthly ZA administration can increase BMD above baseline but is associated with more adverse events. Further study is needed to examine whether the timing and frequency of ZA therapy in patients on ADT can reduce fracture risk. Copyright © 2013 Elsevier Inc. All rights reserved.

[The effect of aluminum adjuvant and immunization schedule on immunogenicity of Sabin inactivated poliovirus vaccine].

PubMed

Wang, Fang; Zhang, Ming; Xie, Bing-Feng; Cao, Han; Tong, Shao-Yong; Wang, Jun-Rong; Yu, Xiao-Ping; Tang, Yang; Yang, Jing-Ran; Sun, Ming-Bo

2013-04-01

To study the effect of aluminume adjuvant and immunization schedule on immunogenicity of Sabin inactivated poliovirus vaccine. Four batches of Sabin IPV were produced by different concentrations of type 1, 2, and 3 poliovirus and administrated on three-dose schedule at 0, 1, 2 months and 0, 2, 4 months on rats. Serum samples were collected one month after each dose and neutralizing antibody titers against three types poliovirus were determined by micro-neutralization assay. The GMTs of neutralizing antibodies against three types poliovirus increased significantly and the seropositivity rates were 100% in all groups after 3 doses. There was no significant difference between two immunization schedules, and the 0, 2, 4 month schedule could induce higher level neutralizing antibody compared to the 0, 1, 2 month schedule. The groups with aluminum adjuvant could induce higher level neutralizing antibody compared to the groups without adjuvant. Aluminum djuvant and immunization schedule could improve the immunogenicity of Sabin IPV.

Use of the nonavalent HPV vaccine in individuals previously fully or partially vaccinated with bivalent or quadrivalent HPV vaccines.

PubMed

Van Damme, Pierre; Bonanni, Paolo; Bosch, F Xavier; Joura, Elmar; Kjaer, Susanne Krüger; Meijer, Chris J L M; Petry, Karl-Ulrich; Soubeyrand, Benoit; Verstraeten, Thomas; Stanley, Margaret

2016-02-03

With the availability of the nonavalent human papillomavirus (HPV) vaccine, vaccinees, parents and healthcare providers need guidance on how to complete an immunization course started with the bi- or quadrivalent vaccine and whether to revaccinate individuals who have completed a full immunization course with the bi- or quadrivalent vaccine. To answer these questions three parameters should be considered: age at the start of vaccination (9 to 14 years of age versus 15 years and older, the cut-off for 2 or 3 doses schedule), the number of doses already received and the time interval between doses. Based on a number of scenarios, we propose that the 9-valent vaccine can be used to complete an incomplete vaccination regimen or might be added to a previous completed schedule to extend protection. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Oral ifosfamide-mesna: a clinical investigation in advanced non-small-cell lung cancer.

PubMed

Manegold, C; Bischoff, H; Fischer, J R; Löchner, S; Peukert, M; Schmähl, A; Drings, P

1992-11-01

The purpose of this study was to evaluate the toxicity and response efficacy of fixed-dose oral ifosfamide (OI)-mesna (M) in advanced, non-small-cell lung cancer (NSCLC). OI was given in four different fractionated-dose treatment schedules with a total dose per cycle of either 3.0 g/m2, 6.0 g/m2, 7.5 g/m2 or 10 g/m2 (equivalent to a daily dose of either 750 mg, 1000 mg or 1250 mg.) M was given p.o. by drinking ampules. In the 64 patients (pts) included, a total of 305 treatment cycles were administered with no evidence of severe neurotoxicity. Twenty-two pts (37%) developed mild to moderate CNS toxicity. Neither myelosuppression, alopecia, gastrointestinal toxicity nor urotoxicity were clinical problems. On schedule 2 (6 g/m2), 3 of 14 evaluable pts (21%) had partial remissions (PR), and on schedule 3 (7.5 g/m2) 4 pts (25%) showed PRs. The median duration of response was 9 months (mts) for pts on schedule 2, and 8 mts for pts on schedule 3. We conclude that OIM can easily be tolerated in the same dose usually given intravenously (7.5 g/m2/mts), when patients at high risk for developing CNS toxicity have been previously excluded from therapy. In order to reduce CNS toxicity, it is suggested that the total dose per cycle should not exceed 7.5 g/m2 (1000 mg daily) within a fractionated-dose, 14-day treatment schedule. We further conclude that the tumor response efficacy of OIM in NSCLC is comparable to the one achieved by intravenously-administered IM, whereby the total monthly OI dose should not be less than 6.0 g/m2 (750 mg daily).

Effect of vaccination schedule on immune response of Macaca mulatta to cell culture-grown Rocky Mountain spotted fever vaccine.

PubMed Central

Sammons, L S; Kenyon, R H; Pedersen, C E

1976-01-01

The effect of vaccination schedule on the immune response of Macaca mulatta to formalin-inactivated chicken embryo cell culture (CEC)-grown Rickettsia rickettsii vaccine was studied. Schedules consisted of inoculation on day 1 only, on days 1 and 15, on days 1 and 30, on days 1, 8, and 15, or on days 1, 15, and 45. Humoral antibody measured by microagglutination and indirect immunofluorescence and resistance to challenge with 10(4) plaque-forming units of yolk sac-grown R. rickettsii were assessed. Seroconversion was noted in all monkeys after the first dose of vaccine. A second dose administered 8 or 15 days after the primary infection, or a third given 7 or 30 days after the second, produced no long-term effect on antibody titer. Only monkeys given two doses of vaccine at a 30-day interval showed an increase in antibody titer during the period before challenge. Vaccination with one, two, or three doses of CEC vaccine prevented development of rash and rickettsemia after challenge. The two-dose schedules appeared to induce the highest degree of resistance to challenge, as indicated by unaltered hematological parameters and body temperature in monkeys. The one- and three-dose schedules were somewhat less effective, in that some challenged monkeys within each group displayed febrile and leukocyte responses associated with Rocky Mountain spotted fever infection. Our data suggest that administration of two doses of CEC vaccine at 15- or 30-day intervals is the immunization schedule of choice. PMID:823173

Effect of reduced dose schedules and intramuscular injection of anthrax vaccine adsorbed on immunological response and safety profile: a randomized trial.

PubMed

Wright, Jennifer G; Plikaytis, Brian D; Rose, Charles E; Parker, Scott D; Babcock, Janiine; Keitel, Wendy; El Sahly, Hana; Poland, Gregory A; Jacobson, Robert M; Keyserling, Harry L; Semenova, Vera A; Li, Han; Schiffer, Jarad; Dababneh, Hanan; Martin, Sandra K; Martin, Stacey W; Marano, Nina; Messonnier, Nancy E; Quinn, Conrad P

2014-02-12

We evaluated an alternative administration route, reduced schedule priming series, and increased intervals between booster doses for anthrax vaccine adsorbed (AVA). AVA's originally licensed schedule was 6 subcutaneous (SQ) priming injections administered at months (m) 0, 0.5, 1, 6, 12 and 18 with annual boosters; a simpler schedule is desired. Through a multicenter randomized, double blind, non-inferiority Phase IV human clinical trial, the originally licensed schedule was compared to four alternative and two placebo schedules. 8-SQ group participants received 6 SQ injections with m30 and m42 "annual" boosters; participants in the 8-IM group received intramuscular (IM) injections according to the same schedule. Reduced schedule groups (7-IM, 5-IM, 4-IM) received IM injections at m0, m1, m6; at least one of the m0.5, m12, m18, m30 vaccine doses were replaced with saline. All reduced schedule groups received a m42 booster. Post-injection blood draws were taken two to four weeks following injection. Non-inferiority of the alternative schedules was compared to the 8-SQ group at m2, m7, and m43. Reactogenicity outcomes were proportions of injection site and systemic adverse events (AEs). The 8-IM group's m2 response was non-inferior to the 8-SQ group for the three primary endpoints of anti-protective antigen IgG geometric mean concentration (GMC), geometric mean titer, and proportion of responders with a 4-fold rise in titer. At m7 anti-PA IgG GMCs for the three reduced dosage groups were non-inferior to the 8-SQ group GMCs. At m43, 8-IM, 5-IM, and 4-IM group GMCs were superior to the 8-SQ group. Solicited injection site AEs occurred at lower proportions in the IM group compared to SQ. Route of administration did not influence the occurrence of systemic AEs. A 3 dose IM priming schedule with doses administered at m0, m1, and m6 elicited long term immunological responses and robust immunological memory that was efficiently stimulated by a single booster vaccination at 42 months. A priming series of 3 intramuscular doses administered at m0, m1, and m6 with a triennial booster was non-inferior to more complex schedules for achieving antibody response. Published by Elsevier Ltd.

Radiobiological modeling of two stereotactic body radiotherapy schedules in patients with stage I peripheral non-small cell lung cancer.

PubMed

Huang, Bao-Tian; Lin, Zhu; Lin, Pei-Xian; Lu, Jia-Yang; Chen, Chuang-Zhen

2016-06-28

This study aims to compare the radiobiological response of two stereotactic body radiotherapy (SBRT) schedules for patients with stage I peripheral non-small cell lung cancer (NSCLC) using radiobiological modeling methods. Volumetric modulated arc therapy (VMAT)-based SBRT plans were designed using two dose schedules of 1 × 34 Gy (34 Gy in 1 fraction) and 4 × 12 Gy (48 Gy in 4 fractions) for 19 patients diagnosed with primary stage I NSCLC. Dose to the gross target volume (GTV), planning target volume (PTV), lung and chest wall (CW) were converted to biologically equivalent dose in 2 Gy fraction (EQD2) for comparison. Five different radiobiological models were employed to predict the tumor control probability (TCP) value. Three additional models were utilized to estimate the normal tissue complication probability (NTCP) value for the lung and the modified equivalent uniform dose (mEUD) value to the CW. Our result indicates that the 1 × 34 Gy dose schedule provided a higher EQD2 dose to the tumor, lung and CW. Radiobiological modeling revealed that the TCP value for the tumor, NTCP value for the lung and mEUD value for the CW were 7.4% (in absolute value), 7.2% (in absolute value) and 71.8% (in relative value) higher on average, respectively, using the 1 × 34 Gy dose schedule.

Pevonedistat (MLN4924), a First-in-Class NEDD8-activating enzyme inhibitor, in patients with acute myeloid leukaemia and myelodysplastic syndromes: a phase 1 study.

PubMed

Swords, Ronan T; Erba, Harry P; DeAngelo, Daniel J; Bixby, Dale L; Altman, Jessica K; Maris, Michael; Hua, Zhaowei; Blakemore, Stephen J; Faessel, Hélène; Sedarati, Farhad; Dezube, Bruce J; Giles, Francis J; Medeiros, Bruno C

2015-05-01

This trial was conducted to determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the first in class NEDD8-activating enzyme (NAE) inhibitor, pevonedistat, and to investigate pevonedistat pharmacokinetics and pharmacodynamics in patients with acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). Pevonedistat was administered via a 60-min intravenous infusion on days 1, 3 and 5 (schedule A, n = 27), or days 1, 4, 8 and 11 (schedule B, n = 26) every 21-days. Dose escalation proceeded using a standard '3 + 3' design. Responses were assessed according to published guidelines. The MTD for schedules A and B were 59 and 83 mg/m(2) , respectively. On schedule A, hepatotoxicity was dose limiting. Multi-organ failure (MOF) was dose limiting on schedule B. The overall complete (CR) and partial (PR) response rate in patients treated at or below the MTD was 17% (4/23, 2 CRs, 2 PRs) for schedule A and 10% (2/19, 2 PRs) for schedule B. Pevonedistat plasma concentrations peaked after infusion followed by elimination in a biphasic pattern. Pharmacodynamic studies of biological correlates of NAE inhibition demonstrated target-specific activity of pevonedistat. In conclusion, administration of the first-in-class agent, pevonedistat, was feasible in patients with MDS and AML and modest clinical activity was observed. © 2015 John Wiley & Sons Ltd.

Understanding the antiangiogenic effect of metronomic chemotherapy through a simple mathematical model

NASA Astrophysics Data System (ADS)

Rodrigues, Diego S.; Mancera, Paulo F. A.; Pinho, Suani T. R.

2016-12-01

Despite the current and increasingly successful fight against cancer, there are some important questions concerning the efficiency of its treatment - in particular, the design of oncology chemotherapy protocols. Seeking efficiency, schedules based on more frequent, low-doses of drugs, known as metronomic chemotherapy, have been proposed as an alternative to the classical standard protocol of chemotherapy administration. The in silico approach may be very useful for providing a comparative analysis of these two kinds of protocols. In so doing, we found that metronomic schedules are more effective in eliminating tumour cells mainly due to their chemotherapeutic action on endothelial cells and that more frequent, low drug doses also entail outcomes in which the survival time of patient is increased.

Accuracy and optimal timing of activity measurements in estimating the absorbed dose of radioiodine in the treatment of Graves' disease

NASA Astrophysics Data System (ADS)

Merrill, S.; Horowitz, J.; Traino, A. C.; Chipkin, S. R.; Hollot, C. V.; Chait, Y.

2011-02-01

Calculation of the therapeutic activity of radioiodine 131I for individualized dosimetry in the treatment of Graves' disease requires an accurate estimate of the thyroid absorbed radiation dose based on a tracer activity administration of 131I. Common approaches (Marinelli-Quimby formula, MIRD algorithm) use, respectively, the effective half-life of radioiodine in the thyroid and the time-integrated activity. Many physicians perform one, two, or at most three tracer dose activity measurements at various times and calculate the required therapeutic activity by ad hoc methods. In this paper, we study the accuracy of estimates of four 'target variables': time-integrated activity coefficient, time of maximum activity, maximum activity, and effective half-life in the gland. Clinical data from 41 patients who underwent 131I therapy for Graves' disease at the University Hospital in Pisa, Italy, are used for analysis. The radioiodine kinetics are described using a nonlinear mixed-effects model. The distributions of the target variables in the patient population are characterized. Using minimum root mean squared error as the criterion, optimal 1-, 2-, and 3-point sampling schedules are determined for estimation of the target variables, and probabilistic bounds are given for the errors under the optimal times. An algorithm is developed for computing the optimal 1-, 2-, and 3-point sampling schedules for the target variables. This algorithm is implemented in a freely available software tool. Taking into consideration 131I effective half-life in the thyroid and measurement noise, the optimal 1-point time for time-integrated activity coefficient is a measurement 1 week following the tracer dose. Additional measurements give only a slight improvement in accuracy.

Retention of sequential drug discriminations under fixed-interval schedules for long time periods without training.

PubMed

Li, Mi; McMillan, Donald E

2003-08-22

The experiments showed that sequential drug discriminations can be learned and retained under a fixed-interval (FI) schedule for more than 18 months without additional training under a complex three-choice procedure. Pigeons were trained to discriminate among 5 mg/kg pentobarbital, 2 mg/kg D-amphetamine, and saline. After responding stabilized, dose-response curves were determined for other drugs. Subsequently, pentobarbital was replaced with 5 mg/kg morphine as a training drug, and D-amphetamine was replaced with 30 mg/kg caffeine. After the pigeons learned these new discriminations, dose-response curves were redetermined. Initially, chlordiazepoxide substituted for pentobarbital, cocaine substituted for D-amphetamine, and nicotine partially substituted for D-amphetamine. Morphine, Delta9-tetrahydrocannabinol, and caffeine did not substitute for either drug. After retraining with morphine and caffeine, responding occurred on the pentobarbital/morphine key after pentobarbital, chlordiazepoxide and morphine and on the D-amphetamine/caffeine key after D-amphetamine, cocaine and caffeine. After nicotine and Delta9-tetrahyrdocannabinol, responding occurred on the saline key. These data show that drug discriminations learned under fixed-interval schedules are retained for long time periods, even when discrimination training with other drugs occurs during the retention period.

Antibody persistence and booster responses 24-36 months after different 4CMenB vaccination schedules in infants and children: A randomised trial.

PubMed

Martinón-Torres, Federico; Carmona Martinez, Alfonso; Simkó, Róbert; Infante Marquez, Pilar; Arimany, Josep-Lluis; Gimenez-Sanchez, Francisco; Couceiro Gianzo, José Antonio; Kovács, Éva; Rojo, Pablo; Wang, Huajun; Bhusal, Chiranjiwi; Toneatto, Daniela

2018-03-01

This phase IIIb, open-label, multicentre, extension study (NCT01894919) evaluated long-term antibody persistence and booster responses in participants who received a reduced 2 + 1 or licensed 3 + 1 meningococcal serogroup B vaccine (4CMenB)-schedule (infants), or 2-dose catch-up schedule (2-10-year-olds) in parent study NCT01339923. Children aged 35 months to 12 years (N = 851) were enrolled. Follow-on participants (N = 646) were randomised 2:1 to vaccination and non-vaccination subsets; vaccination subsets received an additional 4CMenB dose. Newly enrolled vaccine-naïve participants (N = 205) received 2 catch-up doses, 1 month apart (accelerated schedule). Antibody levels were determined using human serum bactericidal assay (hSBA) against MenB indicator strains for fHbp, NadA, PorA and NHBA. Safety was also evaluated. Antibody levels declined across follow-on groups at 24-36 months versus 1 month post-vaccination. Antibody persistence and booster responses were similar between infants receiving the reduced or licensed 4CMenB-schedule. An additional dose in follow-on participants induced higher hSBA titres than a first dose in vaccine-naïve children. Two catch-up doses in vaccine-naïve participants induced robust antibody responses. No safety concerns were identified. Antibody persistence, booster responses, and safety profiles were similar with either 2 + 1 or 3 + 1 vaccination schedules. The accelerated schedule in vaccine-naïve children induced robust antibody responses. Copyright © 2017 GlaxoSmithKline SA. Published by Elsevier Ltd.. All rights reserved.

A Phase I and Pharmacokinetic Study of the Oral Histone Deacetylase Inhibitor, MS-275, in Patients with Refractory Solid Tumors and Lymphomas

PubMed Central

Gore, Lia; Rothenberg, Mace L.; O'Bryant, Cindy L.; Schultz, Mary Kay; Sandler, Alan B.; Coffin, Denise; McCoy, Candice; Schott, Astrid; Scholz, Catherine; Eckhardt, S. Gail

2010-01-01

Purpose To evaluate the toxicity profile, pharmacologic, and biological properties of 3-pyridylmethyl N-{4-[(2-aminophenyl)carbamoyl]benzyl}carbamate (MS-275), a histone deacetylase inhibitor, when administered orally on three different dosing schedules. Experimental Design Patients with advanced solid malignancies and lymphomas were treated on three dose schedules: once every other week, twice weekly for 3 weeks every 28 days, and once weekly for 3 weeks every 28 days. First-cycle plasma pharmacokinetics and peripheral blood mononuclear cell histone acetylation were determined. Results Twenty-seven patients received ≥149 courses of treatment. Hypophosphatemia and asthenia were dose limiting on the weekly and twice-weekly dosing schedules; there was no dose-limiting toxicity on the every other week schedule. Pharmacokinetic variables revealed dose-dependent and dose-proportional increases. Two of 27 patients showed partial remissions, including one patient with metastatic melanoma who had a partial response and has remained on study for >5 years. Six patients showed prolonged disease stabilization. Levels of histone H3 and H4 acetylation in peripheral blood mononuclear cells increased qualitatively but with a high degree of interpatient variation. Conclusions MS-275 is well tolerated at doses up to 6 mg/m2 every other week or 4 mg/m2 weekly for 3 weeks followed by 1 week of rest and results in biologically relevant plasma concentrations and antitumor activity. Twice-weekly dosing was not tolerable due to asthenia, and further evaluation of this schedule was halted. The recommended dose for further disease-focused studies is 4 mg/m2 given weekly for 3 weeks every 28 days or 2 to 6 mg/m2 given once every other week. PMID:18579665

Dose-finding study of intensive weekly alternating schedule of docetaxel, 5-fluorouracil, and oxaliplatin, FD/FOx regimen, in metastatic gastric cancer.

PubMed

Bruera, Gemma; Massacese, Silvia; Galvano, Antonio; Mas, Antonella Dal; Guadagni, Stefano; Calvisi, Giuseppe; Ciacco, Eugenio; Russo, Antonio; Ricevuto, Enrico

2018-04-17

Proper administration timing, dose-intensity, efficacy/toxicity ratio of triplet docetaxel (DTX), 5-fluorouracil (5-FU), and oxaliplatin (OXP) should be improved to safely perform three-drugs intensive first line in advanced gastric cancer (GC). This dose-finding study investigated recommended 5-FU and OXP doses, safety of triplet regimen and preliminary activity. Schedule: 12h-timed-flat-infusion 5-FU 700-1000 mg/m 2 /d 1-2, 8-9, 15-16, 22-23, with 100 mg/m 2 /d increase for dose level; DTX 50 mg/m 2 d 1, 15 fixed dose, OXP at three increasing dose-levels 60-70-80 mg/m 2 d 8, 22, every 4 weeks. Intra- and inter-patients dose-escalation was planned. Ten fit <75 years patients were enrolled: median age 59; young-elderly 4 (40%). From first to fifth dose level, 5 patients (1 per cohort) were enrolled according to intra-patient dose escalation, no dose-limiting toxicity (DLT) were reported. At sixth level, 1 DLT, G2 diarrhea, was reported, thus other 2 patients were enrolled, DLT 1/3 patients (33%). Maximum tolerated dose (MTD) was not reached. 5-FU and OXP recommended doses (RD) were 1000 mg/m 2 /d and 80 mg/m 2 , respectively. To confirm RD, other 3 patients were enrolled, without DLT. Cumulative G3-4 toxicities were: neutropenia 50%, leucopenia 20%, hypoalbuminemia 10%, mucositis 10%, asthenia 20%. Limiting toxicity syndromes were 30%, 25% in young-elderly, all multiple site. Objective response rate intent-to-treat 60%, disease control rate 90%. After 15 months follow-up, progression-free and overall survival, 6 and 17 months, respectively. First line intensive FD/FOx regimen adding DXT/5-FU/OXP can be safely administered at recommended doses in advanced GC, with promising high activity and efficacy.

Phase I Study of LY2606368, a Checkpoint Kinase 1 Inhibitor, in Patients With Advanced Cancer

PubMed Central

Infante, Jeffrey; Janku, Filip; Jones, Suzanne; Nguyen, Ly M.; Burris, Howard; Naing, Aung; Bauer, Todd M.; Piha-Paul, Sarina; Johnson, Faye M.; Kurzrock, Razelle; Golden, Lisa; Hynes, Scott; Lin, Ji; Lin, Aimee Bence; Bendell, Johanna

2016-01-01

Purpose The primary objective was to determine safety, toxicity, and a recommended phase II dose regimen of LY2606368, an inhibitor of checkpoint kinase 1, as monotherapy. Patients and Methods This phase I, nonrandomized, open-label, dose-escalation trial used a 3 + 3 dose-escalation scheme and included patients with advanced solid tumors. Intravenous LY2606368 was dose escalated from 10 to 50 mg/m2 on schedule 1 (days 1 to 3 every 14 days) or from 40 to 130 mg/m2 on schedule 2 (day 1 every 14 days). Safety measures and pharmacokinetics were assessed, and pharmacodynamics were measured in blood, hair follicles, and circulating tumor cells. Results Forty-five patients were treated; seven experienced dose-limiting toxicities (all hematologic). The maximum-tolerated doses (MTDs) were 40 mg/m2 (schedule 1) and 105 mg/m2 (schedule 2). The most common related grade 3 or 4 treatment-emergent adverse events were neutropenia, leukopenia, anemia, thrombocytopenia, and fatigue. Grade 4 neutropenia occurred in 73.3% of patients and was transient (typically < 5 days). Febrile neutropenia incidence was low (7%). The LY2606368 exposure over the first 72 hours (area under the curve from 0 to 72 hours) at the MTD for each schedule coincided with the exposure in mouse xenografts that resulted in maximal tumor responses. Minor intra- and intercycle accumulation of LY2606368 was observed at the MTDs for both schedules. Two patients (4.4%) had a partial response; one had squamous cell carcinoma (SCC) of the anus and one had SCC of the head and neck. Fifteen patients (33.3%) had a best overall response of stable disease (range, 1.2 to 6.7 months), six of whom had SCC. Conclusion An LY2606368 dose of 105 mg/m2 once every 14 days is being evaluated as the recommended phase II dose in dose-expansion cohorts for patients with SCC. PMID:27044938

Modelling the effects of booster dose vaccination schedules and recommendations for public health immunization programs: the case of Haemophilus influenzae serotype b.

PubMed

Charania, Nadia A; Moghadas, Seyed M

2017-09-13

Haemophilus influenzae serotype b (Hib) has yet to be eliminated despite the implementation of routine infant immunization programs. There is no consensus regarding the number of primary vaccine doses and an optimal schedule for the booster dose. We sought to evaluate the effect of a booster dose after receiving the primary series on the long-term disease incidence. A stochastic model of Hib transmission dynamics was constructed to compare the long-term impact of a booster vaccination and different booster schedules after receiving the primary series on the incidence of carriage and symptomatic disease. We parameterized the model with available estimates for the efficacy of Hib conjugate vaccine and durations of both vaccine-induced and naturally acquired immunity. We found that administering a booster dose substantially reduced the population burden of Hib disease compared to the scenario of only receiving the primary series. Comparing the schedules, the incidence of carriage for a 2-year delay (on average) in booster vaccination was comparable or lower than that observed for the scenario of booster dose within 1 year after primary series. The temporal reduction of symptomatic disease was similar in the two booster schedules, suggesting no superiority of one schedule over the other in terms of reducing the incidence of symptomatic disease. The findings underscore the importance of a booster vaccination for continued decline of Hib incidence. When the primary series provides a high level of protection temporarily, delaying the booster dose (still within the average duration of protection conferred by the primary series) may be beneficial to maintain longer-term protection levels and decelerate the decline of herd immunity in the population.

Strategically timing inhibition of phosphatidylinositol 3-kinase to maximize therapeutic index in estrogen receptor alpha-positive, PIK3CA-mutant breast cancer

PubMed Central

Yang, Wei; Hosford, Sarah R.; Dillon, Lloye M.; Shee, Kevin; Liu, Stephanie C.; Bean, Jennifer R.; Salphati, Laurent; Pang, Jodie; Zhang, Xiaolin; Nannini, Michelle A.; Demidenko, Eugene; Bates, Darcy; Lewis, Lionel D.; Marotti, Jonathan D.; Eastman, Alan R.; Miller, Todd W.

2016-01-01

Purpose Phosphatidylinositol 3-kinase (PI3K) inhibitors are being developed for the treatment of estrogen receptor α (ER)-positive breast cancer in combination with anti-estrogens. Understanding the temporal response and pharmacodynamic effects of PI3K inhibition in ER+ breast cancer will provide rationale for treatment scheduling to maximize therapeutic index. Experimental Design Anti-estrogen-sensitive and -resistant ER+ human breast cancer cell lines, and mice bearing PIK3CA-mutant xenografts were treated with the anti-estrogen fulvestrant, the PI3K inhibitor GDC-0941 (pictilisib; varied doses/schedules that provided similar amounts of drug each week), or combinations. Cell viability, signaling pathway inhibition, proliferation, apoptosis, tumor volume, and GDC-0941 concentrations in plasma and tumors were temporally measured. Results Treatment with the combination of fulvestrant and GDC-0941, regardless of dose/schedule, was significantly more effective than single-agent treatments in fulvestrant-resistant tumors. Short-term, complete PI3K inhibition blocked cell growth in vitro more effectively than chronic, incomplete inhibition. Longer-term PI3K inhibition hypersensitized cells to growth factor signaling upon drug withdrawal. Different schedules of GDC-0941 elicited similar tumor responses. While weekly high-dose GDC-0941 with fulvestrant continuously suppressed PI3K signaling for 72 hours, inducing a bolus of apoptosis and inhibiting proliferation, PI3K reactivation upon GDC-0941 washout induced a proliferative burst. Fulvestrant with daily low-dose GDC-0941 metronomically suppressed PI3K for 6–9 hours/day, repeatedly inducing small amounts of apoptosis and temporarily inhibiting proliferation, followed by proliferative rebound compared to fulvestrant alone. Conclusions Continuous and metronomic PI3K inhibition elicit robust anti-cancer effects in ER+, PIK3CA-mutant breast cancer. Clinical exploration of alternate treatment schedules of PI3K inhibitors with anti-estrogens is warranted. PMID:26733612

Strategically Timing Inhibition of Phosphatidylinositol 3-Kinase to Maximize Therapeutic Index in Estrogen Receptor Alpha-Positive, PIK3CA-Mutant Breast Cancer.

PubMed

Yang, Wei; Hosford, Sarah R; Dillon, Lloye M; Shee, Kevin; Liu, Stephanie C; Bean, Jennifer R; Salphati, Laurent; Pang, Jodie; Zhang, Xiaolin; Nannini, Michelle A; Demidenko, Eugene; Bates, Darcy; Lewis, Lionel D; Marotti, Jonathan D; Eastman, Alan R; Miller, Todd W

2016-05-01

Phosphatidylinositol 3-kinase (PI3K) inhibitors are being developed for the treatment of estrogen receptor α (ER)-positive breast cancer in combination with antiestrogens. Understanding the temporal response and pharmacodynamic effects of PI3K inhibition in ER(+) breast cancer will provide a rationale for treatment scheduling to maximize therapeutic index. Antiestrogen-sensitive and antiestrogen-resistant ER(+) human breast cancer cell lines and mice bearing PIK3CA-mutant xenografts were treated with the antiestrogen fulvestrant, the PI3K inhibitor GDC-0941 (pictilisib; varied doses/schedules that provided similar amounts of drug each week), or combinations. Cell viability, signaling pathway inhibition, proliferation, apoptosis, tumor volume, and GDC-0941 concentrations in plasma and tumors were temporally measured. Treatment with the combination of fulvestrant and GDC-0941, regardless of dose/schedule, was significantly more effective than that with single-agent treatments in fulvestrant-resistant tumors. Short-term, complete PI3K inhibition blocked cell growth in vitro more effectively than chronic, incomplete inhibition. Longer-term PI3K inhibition hypersensitized cells to growth factor signaling upon drug withdrawal. Different schedules of GDC-0941 elicited similar tumor responses. While weekly high-dose GDC-0941 with fulvestrant continuously suppressed PI3K signaling for 72 hours, inducing a bolus of apoptosis and inhibiting proliferation, PI3K reactivation upon GDC-0941 washout induced a proliferative burst. Fulvestrant with daily low-dose GDC-0941 metronomically suppressed PI3K for 6 to 9 hours/day, repeatedly inducing small amounts of apoptosis and temporarily inhibiting proliferation, followed by proliferative rebound compared with fulvestrant alone. Continuous and metronomic PI3K inhibition elicits robust anticancer effects in ER(+), PIK3CA-mutant breast cancer. Clinical exploration of alternate treatment schedules of PI3K inhibitors with antiestrogens is warranted. Clin Cancer Res; 22(9); 2250-60. ©2016 AACRSee related commentary by Toska and Baselga, p. 2099. ©2016 American Association for Cancer Research.

Immune Response And Anamnestic Immune Response In Children After A 3-Dose Primary Hepatitis B Vaccination.

PubMed

Afzal, Muhammad Faheem; Sultan, Muhammad Ashraf; Saleemi, Ahmad Imran

2016-01-01

Diseases caused by Hepatitis B virus (HBV) have a worldwide distribution. Pakistan adopted the recommendations of World Health Organization (WHO) for routine universal infant vaccination against hepatitis B in 2002, currently being administered at 6, 10, and 14 weeks of age in a combination vaccine. This study was conducted to determine the immune response & anamnestic immune response in children, 9 months-10 years of age, after a 3dose primary Hepatitis B vaccination. This cross sectional study was conducted in the Department of Paediatrics, King Edward Medical University/Mayo Hospital, Lahore, Pakistan, from January to June, 2014. A total of 200 children of either sex between the ages of 9 months to 10 years, documented to have received 3 doses of hepatitis B vaccines according to Expanded Program of Immunization (6,10,14 weeks) schedule in infancy, were recruited by consecutive sampling. The level of serum antiHBsAb by ELIZA was measured. Children with antiHBs titers ≥10 mIU/mL were considered to be immune. Those with anti HBsAb levels <10 mIU/mL were offered a booster dose of infant recombinant hepatitis B vaccine. The second serum sample was obtained 21-28 days following the administration of the booster dose and the anamnestic immune response was measured. Data was analysed using SPSS 17 to determine the relation between time interval since last vaccination and antibody titer. Chi square test was applied. Of the 200 children, protective antibody response was found in 58%. Median serological response was 18.60 (range 2.82 - 65.15). Antibody levels were found to have a statistically significant ( pvalue 0.019) negative correlation with the time since last administration of vaccine. A booster dose of Hepatitis B vacci ne was administered to all nonresponders, with each registering a statistically significant (pvalue 0.00) anamnestic response. The vaccination schedule with short dosage interval was unable to provide protection to 42% of the study population. Introduction of birth dose of Hepatitis B vaccine to the existing schedule is recommended.

Optimal radiotherapy dose schedules under parametric uncertainty

NASA Astrophysics Data System (ADS)

Badri, Hamidreza; Watanabe, Yoichi; Leder, Kevin

2016-01-01

We consider the effects of parameter uncertainty on the optimal radiation schedule in the context of the linear-quadratic model. Our interest arises from the observation that if inter-patient variability in normal and tumor tissue radiosensitivity or sparing factor of the organs-at-risk (OAR) are not accounted for during radiation scheduling, the performance of the therapy may be strongly degraded or the OAR may receive a substantially larger dose than the allowable threshold. This paper proposes a stochastic radiation scheduling concept to incorporate inter-patient variability into the scheduling optimization problem. Our method is based on a probabilistic approach, where the model parameters are given by a set of random variables. Our probabilistic formulation ensures that our constraints are satisfied with a given probability, and that our objective function achieves a desired level with a stated probability. We used a variable transformation to reduce the resulting optimization problem to two dimensions. We showed that the optimal solution lies on the boundary of the feasible region and we implemented a branch and bound algorithm to find the global optimal solution. We demonstrated how the configuration of optimal schedules in the presence of uncertainty compares to optimal schedules in the absence of uncertainty (conventional schedule). We observed that in order to protect against the possibility of the model parameters falling into a region where the conventional schedule is no longer feasible, it is required to avoid extremal solutions, i.e. a single large dose or very large total dose delivered over a long period. Finally, we performed numerical experiments in the setting of head and neck tumors including several normal tissues to reveal the effect of parameter uncertainty on optimal schedules and to evaluate the sensitivity of the solutions to the choice of key model parameters.

Safety and Immunogenicity of Sequential Rotavirus Vaccine Schedules

PubMed Central

Libster, Romina; McNeal, Monica; Walter, Emmanuel B.; Shane, Andi L.; Winokur, Patricia; Cress, Gretchen; Berry, Andrea A.; Kotloff, Karen L.; Sarpong, Kwabena; Turley, Christine B.; Harrison, Christopher J.; Pahud, Barbara A.; Marbin, Jyothi; Dunn, John; El-Khorazaty, Jill; Barrett, Jill

2016-01-01

BACKGROUND AND OBJECTIVES: Although both licensed rotavirus vaccines are safe and effective, it is often not possible to complete the schedule by using the same vaccine formulation. The goal of this study was to investigate the noninferiority of the immune responses to the 2 licensed rotavirus vaccines when administered as a mixed schedule compared with administering a single vaccine formulation alone. METHODS: Randomized, multicenter, open-label study. Healthy infants (6–14 weeks of age) were randomized to receive rotavirus vaccines in 1 of 5 different schedules (2 using a single vaccine for all doses, and 3 using mixed schedules). The group receiving only the monovalent rotavirus vaccine received 2 doses of vaccine and the other 4 groups received 3 doses of vaccine. Serum for immunogenicity testing was obtained 1 month after the last vaccine dose and the proportion of seropositive children (rotavirus immunoglobulin A ≥20 U/mL) were compared in all the vaccine groups. RESULTS: Between March 2011 and September 2013, 1393 children were enrolled and randomized. Immune responses to all the sequential mixed vaccine schedules were shown to be noninferior when compared with the 2 single vaccine reference groups. The proportion of children seropositive to at least 1 vaccine antigen at 1 month after vaccination ranged from 77% to 96%, and was not significantly different among all the study groups. All schedules were well tolerated. CONCLUSIONS: Mixed schedules are safe and induced comparable immune responses when compared with the licensed rotavirus vaccines given alone. PMID:26823540

Controversies in rabies vaccination.

PubMed

Ghosh, Tapan Kr

2003-06-01

Rabies is a cent per cent fatal disease and there should not be any controversy in giving rabies vaccine to the victims. WHO has fixed schedules for doses for both pre and post-exposure in different category of cases, which also help us to avoid all controversies. But controversies arise in five main areas, which are related to the strategies of rabies prevention. These are: (i) Replacing use of NTV by MTCV. (ii) Intradermal schedule of MTCV, in place of Essen protocol of 5 i.m. doses to reduce the cost. (iii) Acceptability and inclusion of pre-exposure doses of MTCV in the immunization schedule of children as additional vaccine (iv) Schedule for re-exposure in already post-exposure vaccinated cases and schedule for exposure in pre-exposure vaccinated cases. (v) Uses of RIG in WHO category III cases. If these controversial issues are considered scientifically, rabies prophylaxis will see the light of success.

Comparison of two melphalan protocols and evaluation of outcome and prognostic factors in multiple myeloma in dogs

PubMed Central

Fernández, Ricardo

2018-01-01

Background Multiple myeloma (MM) in dogs typically is treated with melphalan. A daily melphalan dosing schedule reportedly is well tolerated and associated with favorable outcome. Although anecdotally a pulse dose regimen has resulted in successful responses, little long‐term outcome and safety data is available regarding this dosing regimen for dogs with MM. Hypothesis/objectives (1) To compare outcome and adverse event profiles between pulse dose and daily dose melphalan schedules and (2) to report prognostic factors in dogs with MM treated with melphalan. We hypothesized that both protocols would have similar outcomes and tolerability. Animals Thirty‐eight client‐owned dogs diagnosed with MM receiving pulse dose (n = 17) or daily dose (n = 21) melphalan. Methods Retrospective cohort study assessing outcome and adverse events in dogs receiving either protocol. Risk factors were evaluated for their prognostic relevance. Results Both regimens were well tolerated and similarly effective, with an overall median survival time of 930 days. Renal disease and neutrophil‐to‐lymphocyte ratio (NLR) were negative prognostic factors, whereas hypercalcemia and osteolytic lesions were not prognostic factors in this study population. Conclusions and Clinical Importance Positive results support the use of either dosing regimen for the treatment of dogs with MM, and renal disease and NLR were negative prognostic factors. Prospective, controlled, and randomized studies are warranted to confirm these findings. PMID:29566439

Amphetamine increases schedule-induced drinking reduced by negative punishment procedures.

PubMed

Pérez-Padilla, Angeles; Pellón, Ricardo

2003-05-01

d-Amphetamine has been reported to increase schedule-induced drinking punished by lick-dependent signalled delays in food delivery. This might reflect a drug-behaviour interaction dependent on the type of punisher, because no such effect has been found when drinking was reduced by lick-contingent electric shocks. However, the anti-punishment effect of amphetamine could be mediated by other behavioural processes, such as a loss of discriminative control or an increase in the value of delayed reinforcers. To test the effects of d-amphetamine on the acquisition and maintenance of schedule-induced drinking reduced by unsignalled delays in food delivery. Rats received 10-s unsignalled delays initiated by each lick after polydipsia was induced by a fixed-time 30-s food reinforcement schedule or from the outset of the experiment. Yoked-control rats received these same delays but independently of their own behaviour. d-Amphetamine (0.1-3.0 mg/kg) was then tested IP. d-Amphetamine dose-dependently increased and then decreased punished schedule-induced drinking. The drug led to dose-dependent reductions when the delays were not contingent or when they were applied from the outset of training. These results support the contention that d-amphetamine has an increasing effect on schedule-induced drinking that has been previously reduced by a negative punishment procedure. This effect cannot be attributed to other potentially involved processes, and therefore support the idea that drug effects on punished behaviour depend on punishment being delays in food or shock deliveries.

Effect of a simple dose-escalation schedule on tramadol tolerability : assessment in the clinical setting.

PubMed

Tagarro, I; Herrera, J; Barutell, C; Díez, M C; Marín, M; Samper, D; Busquet, C; Rodríguez, M J

2005-01-01

To assess the effect of a very simple dose-escalation schedule on tramadol tolerability in clinical practice. This schedule consists of starting treatment with sustained-release tramadol 50mg twice daily, and escalating the dose around 7 days later to 100mg twice daily. Data from 1925 outpatients with non-malignant chronic pain were collected in this multicentre, prospective, comparative, non-randomised, open, observational study. A total of 1071 patients (55.6%) were included in the dose-escalation group (50mg group) and 854 patients (44.4%) in the control group (sustained-release tramadol 100mg twice daily; 100mg group). The proportion of patients who interrupted tramadol treatment due to the occurrence of adverse reactions was significantly lower in the 50mg group (5.6%) than in the 100mg group (12.6%) [p = 0.001]. In line with this, the proportion of patients who experienced at least one adverse reaction was significantly lower in the 50mg group (18.4%) than in the 100mg group (30.4%) [p = 0.001] and, interestingly, the two most frequently reported adverse reactions, nausea and dizziness, were found with a significantly lower frequency in the 50mg group (p < 0.001). Multivariate analysis showed that the risk of safety-related treatment cessations was 2.3 times higher in the 100mg group than in the 50mg group, and 2.2 times higher in females than in males. The two treatments were equally effective in reducing pain intensity (p = 0.121), measured as a reduction in pain score obtained by means of a visual analogue scale. The instauration of tramadol treatment, starting with sustained-release 50mg capsules twice daily and escalating the dose some days later to 100mg twice daily, was shown to be an effective and easy way to improve tramadol tolerability in clinical practice, whilst maintaining its analgesic efficacy.

Induction chemotherapy in metastatic neuroblastoma--does dose influence response? A critical review of published data standards, options and recommendations (SOR) project of the National Federation of French Cancer Centres (FNCLCC).

PubMed

Pinkerton, C R; Blanc Vincent, M P; Bergeron, C; Fervers, B; Philip, T

2000-09-01

The purpose of this study was to determine, from a review of published data, whether in stage 4 neuroblastoma in children over 1 year of age, the dose or scheduling of induction chemotherapy influenced the response rate in distant metastases. Publications relating to induction chemotherapy since the introduction of cisplatin/epipodophyllotoxin combinations were identified using Medline, Current Contents and personal reference lists. Thirteen publications were identified which described 17 regimens involving 948 children. The doses and the scheduling of the various regimens were compared with a standard regimen OPEC (vincristine, cisplatin, teniposide, cyclophosphamide). These were correlated with the reported response rates in the bone marrow. Due to a lack of standardisation in the nature of restaging investigations, timing of restaging and definitions of response it was difficult to compare all studies. The complete response rate at distant metastases ranged from less than 40% to over 90%. For individual drugs; the comparative doses given in each course ranged up to 4.2 g/m(2) for cyclophosphamide, 280 mg/m(2) for cisplatin, 600 mg/m(2) for etoposide and 4.5 mg/m(2) for vincristine. There was no evidence of any positive correlation between response rate in the marrow and either the dose of any individual drug or the schedule used. In contrast to a previous study which included a number of older studies where disease assessment was even more variable, this analysis has failed to show any justification for the routine use of very intensive induction regimens in this disease. Such an approach should only be taken in the context of randomised trials in which timing and methods of reassessment can be standardised. Until such studies demonstrate superiority either in terms of response rate or progression-free survival lower morbidity regimens should remain the standard therapy.

Tolerance to cocaine's effects on schedule-controlled behavior: role of delay between pause-ending responses and reinforcement.

PubMed

Macaskill, Anne C; Branch, Marc N

2012-01-01

The schedule of reinforcement under which behavior is maintained is an important contributor to whether tolerance to the behavioral effects of cocaine develops. Schedule parameter value (for example, fixed-ratio size) has been shown to affect the development of tolerance under some schedule types but not others, but the specific procedural variables causing this effect remain to be identified. To date, schedule-parameter-related tolerance has developed when a longer pause after reinforcement does not lead to a shorter delay between the response that ends the pause and reinforcement. The current study investigated the importance of this variable in pigeons using a multiple chained Fixed-Ratio 1, Fixed-Time x schedule, in which the first key peck in a trial produced a stimulus change and initiated a delay at the end of which food was presented regardless of whether or not additional pecks were made during the delay. Dose-response curves were assessed before, during and after chronic (daily) administration of cocaine. Tolerance to the pause-increasing effects of cocaine occurred to a similar degree regardless of the scheduled time between the end of the pause and reinforcement. Therefore, the relationship between pause length and delay to reinforcement does not provide an explanation for schedule-parameter-related tolerance. Copyright © 2011 Elsevier Inc. All rights reserved.

Non-standard radiotherapy fractionations delay the time to malignant transformation of low-grade gliomas.

PubMed

Henares-Molina, Araceli; Benzekry, Sebastien; Lara, Pedro C; García-Rojo, Marcial; Pérez-García, Víctor M; Martínez-González, Alicia

2017-01-01

Grade II gliomas are slowly growing primary brain tumors that affect mostly young patients. Cytotoxic therapies (radiotherapy and/or chemotherapy) are used initially only for patients having a bad prognosis. These therapies are planned following the "maximum dose in minimum time" principle, i. e. the same schedule used for high-grade brain tumors in spite of their very different behavior. These tumors transform after a variable time into high-grade gliomas, which significantly decreases the patient's life expectancy. In this paper we study mathematical models describing the growth of grade II gliomas in response to radiotherapy. We find that protracted metronomic fractionations, i.e. therapeutical schedules enlarging the time interval between low-dose radiotherapy fractions, may lead to a better tumor control without an increase in toxicity. Other non-standard fractionations such as protracted or hypoprotracted schemes may also be beneficial. The potential survival improvement depends on the tumor's proliferation rate and can be even of the order of years. A conservative metronomic scheme, still being a suboptimal treatment, delays the time to malignant progression by at least one year when compared to the standard scheme.

Compartmental model of 18F-choline

NASA Astrophysics Data System (ADS)

Janzen, T.; Tavola, F.; Giussani, A.; Cantone, M. C.; Uusijärvi, H.; Mattsson, S.; Zankl, M.; Petoussi-Henß, N.; Hoeschen, C.

2010-03-01

The MADEIRA Project (Minimizing Activity and Dose with Enhanced Image quality by Radiopharmaceutical Administrations), aims to improve the efficacy and safety of 3D functional imaging by optimizing, among others, the knowledge of the temporal variation of the radiopharmaceuticals' uptake in and clearance from tumor and healthy tissues. With the help of compartmental modeling it is intended to optimize the time schedule for data collection and improve the evaluation of the organ doses to the patients. Administration of 18F-choline to screen for recurrence or the occurrence of metastases in prostate cancer patients is one of the diagnostic applications under consideration in the frame of the project. PET and CT images have been acquired up to four hours after injection of 18F-choline. Additionally blood and urine samples have been collected and measured in a gamma counter. The radioactivity concentration in different organs and data of plasma clearance and elimination into urine were used to set-up a compartmental model of the biokinetics of the radiopharmaceutical. It features a central compartment (blood) exchanging with organs. The structure describes explicitly liver, kidneys, spleen, plasma and bladder as separate units with a forcing function approach. The model is presented together with an evaluation of the individual and population kinetic parameters, and a revised time schedule for data collection is proposed. This optimized time schedule will be validated in a further set of patient studies.

Systematic Review of the Indirect Effect of Pneumococcal Conjugate Vaccine Dosing Schedules on Pneumococcal Disease and Colonization

PubMed Central

2014-01-01

Background: To aid decision making for pneumococcal conjugate vaccine (PCV) use in infant national immunization programs, we summarized the indirect effects of PCV on clinical outcomes among nontargeted age groups. Methods: We systematically reviewed the English literature on infant PCV dosing schedules published from 1994 to 2010 (with ad hoc addition of 2011 articles) for outcomes on children >5 years of age and adults including vaccine-type nasopharyngeal carriage (VT-NP), vaccine-type invasive pneumococcal disease (VT-IPD) and syndromic pneumonia. Results: Of 12,980 citations reviewed, we identified 21 VT-IPD, 6 VT-NP and 9 pneumonia studies. Of these 36, 21 (58%) included 3 primary doses plus PCV or pneumococcal polysaccharide vaccine (PPV23) booster schedule (3+1 or 3+PPV23), 5 (14%) 3+0, 9 (25%) 2+1 and 1 (3%) 2+0. Most (95%) were PCV7 studies. Among observational VT-IPD studies, all schedules (2+1, 3+0 and 3+1) demonstrated reductions in incidence among young adult groups. Among syndromic pneumonia observational studies (2+1, 3+0 and 3+1), only 3+1 schedules showed significant indirect impact. Of 2 VT-NP controlled trials (3+0 and 3+1) and 3 VT-NP observational studies (2+1, 3+1 and 3+PPV23), 3+1 and 3+PPV23 schedules showed significant indirect effect. The 1 study to directly compare between schedules was a VT-NP study (2+0 vs. 2+1), which found no indirect effect on older siblings and parents of vaccinated children with either schedule. Conclusions: Indirect benefit of a 3+1 infant PCV dosing schedule has been demonstrated for VT-IPD, VT-NP and syndromic pneumonia; 2+1 and 3+0 schedules have demonstrated indirect effect only for VT-IPD. The choice of optimal infant PCV schedule is limited by data paucity on indirect effects, especially a lack of head-to-head studies and studies of PCV10 and PCV13. PMID:24336058

Immunogenicity of a three dose and five dose oral human rotavirus vaccine (RIX4414) schedule in south Indian infants.

PubMed

Kompithra, Rajeev Zachariah; Paul, Anu; Manoharan, Divya; Babji, Sudhir; Sarkar, Rajiv; Mathew, Leni G; Kang, Gagandeep

2014-08-11

This study was undertaken to compare the immunogenicity of a three dose and five dose schedule of an oral live-attenuated human rotavirus vaccine, Rotarix in south Indian infants. Healthy infants (N=90), six to seven weeks of age were enrolled to receive three doses (n=45) or five doses of Rotarix vaccine (n=45) along with other scheduled vaccines, each dose separated by a four week interval. Blood samples were taken before vaccination and one month post-dose three in the Rotarix three dose group and one month post-dose five in the Rotarix five dose group; all were tested for anti-rotavirus IgA by an antibody sandwich enzyme immunoassay. At baseline, >50% of infants had >20 units of anti-rotavirus IgA. The seroconversion rates after three and five doses were low and not significantly different in the two groups. However, among vaccine responders, children seropositive at baseline showed a much greater absolute increase in IgA antibody levels than children seronegative at baseline. Rotarix vaccine showed low immunogenicity in south Indian children and increasing the number of doses did not increase the proportion of infants seroconverting after vaccination. Copyright © 2014. Published by Elsevier Ltd.

Evaluation of Biologic Effective Dose and Schedule of Fractionation for Preoperative Radiotherapy for Rectal Cancer: Meta-Analyses and Meta-Regression;Rectal cancer; Preoperative radiotherapy; Biologic effective dose; Meta-analysis

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

Arruda Viani, Gustavo, E-mail: gusviani@gmail.com; Stefano, Eduardo Jose; Vendito Soares, Francisco

2011-07-15

Purpose: To evaluate whether the risk of local recurrence depends on the biologic effective dose (BED) or fractionation dose in patients with resectable rectal cancer undergoing preoperative radiotherapy (RT) compared with surgery alone. Methods and Materials: A meta-analysis of randomized controlled trials (RCTs) was performed. The MEDLINE, Embase, CancerLit, and Cochrane Library databases were systematically searched for evidence. To evaluate the dose-response relationship, we conducted a meta-regression analysis. Four subgroups were created: Group 1, RCTs with a BED >30 Gy{sub 10} and a short RT schedule; Group 2, RCTs with BED >30 Gy{sub 10} and a long RT schedule; Groupmore » 3, RCTs with BED {<=}30 Gy{sub 10} and a short RT schedule; and Group 4, RCTs with BED {<=}30 Gy{sub 10} and a long RT schedule. Results: Our review identified 21 RCTs, yielding 9,097 patients. The pooled results from these 21 randomized trials of preoperative RT showed a significant reduction in mortality for groups 1 (p = .004) and 2 (p = .03). For local recurrence, the results were also significant in groups 1 (p = .00001) and 2 (p = .00001).The only subgroup that showed a greater sphincter preservation (SP) rate than surgery was group 2 (p = .03). The dose-response curve was linear (p = .006), and RT decreased the risk of local recurrence by about 1.7% for each Gy{sub 10} of BED. Conclusion: Our data have shown that RT with a BED of >30 Gy{sub 10} is more efficient in reducing local recurrence and mortality rates than a BED of {<=}30 Gy{sub 10}, independent of the schedule of fractionation used. A long RT schedule with a BED of >30 Gy{sub 10} should be recommended for sphincter preservation.« less

SU-F-19A-08: Optimal Time Release Schedule of In-Situ Drug Release During Permanent Prostate Brachytherapy

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

Cormack, R; Ngwa, W; Makrigiorgos, G

Purpose: Permanent prostate brachytherapy spacers can be used to deliver sustained doses of radiosentitizing drug directly to the target, in order to enhance the radiation effect. Implantable nanoplatforms for chemo-radiation therapy (INCeRTs) have a maximum drug capacity and can be engineered to control the drug release schedule. The optimal schedule for sensitization during continuous low dose rate irradiation is unknown. This work studies the optimal release schedule of drug for both traditional sensitizers, and those that work by suppressing DNA repair processes. Methods: Six brachytherapy treatment plans were used to model the anatomy, implant geometry and calculate the spatial distributionmore » of radiation dose and drug concentrations for a range of drug diffusion parameters. Three state partial differential equations (cells healthy, damaged or dead) modeled the effect of continuous radiation (radiosensitivities α,β) and cellular repair (time tr) on a cell population. Radiosensitization was modeled as concentration dependent change in α,β or tr which with variable duration under the constraint of fixed total drug release. Average cell kill was used to measure effectiveness. Sensitization by means of both enhanced damage and reduced repair were studied. Results: Optimal release duration is dependent on the concentration of radiosensitizer compared to the saturation concentration (csat) above which additional sensitization does not occur. Long duration drug release when enhancing α or β maximizes cell death when drug concentrations are generally over csat. Short term release is optimal for concentrations below saturation. Sensitization by suppressing repair has a similar though less distinct trend that is more affected by the radiation dose distribution. Conclusion: Models of sustained local radiosensitization show potential to increase the effectiveness of radiation in permanent prostate brachytherapy. INCeRTs with high drug capacity produce the greatest benefit with drug release over weeks. If in-vivo drug concentrations are not able to approach saturation concentration, durations of days is optimal. DOD 1R21CA16977501; A. David Mazzone Awards Program 2012PD164.« less

Cocaine self-administration under variable-dose schedules in squirrel monkeys.

PubMed

Panlilio, Leigh V; Thorndike, Eric B; Schindler, Charles W

2006-06-01

Squirrel monkeys self-administered cocaine under a variable-dose schedule, with the dose varied from injection to injection. As in earlier studies with rats, post-injection pauses varied as a monotonic function of dose, allowing a cocaine dose-effect curve to be obtained during each session. These curves were shifted by pretreatment with dopamine antagonists, demonstrating that this procedure may provide an efficient means of evaluating treatments that affect drug self-administration. However, drug intake eventually became "dysregulated" after extensive training (100-300 sessions), with relatively short pauses following all doses. Dose-sensitivity was restored by adding a 60-s timeout period after each injection, suggesting that dysregulation occurred because the monkeys developed a tendency to self-administer another injection before the previous injection had been adequately distributed. Finally, when the response requirement under the variable-dose schedule was increased from 1 to 10, both the post-injection pause and the rate of responding following the pause ("run rates") were found to vary with dose. The dose-dependency of run rates suggests that post-injection pauses reflect not only motivational factors, such as satiety, but also the direct effects of cocaine on leverpressing.

Optimizing the dosing schedule of l-asparaginase improves its anti-tumor activity in breast tumor-bearing mice.

PubMed

Shiromizu, Shoya; Kusunose, Naoki; Matsunaga, Naoya; Koyanagi, Satoru; Ohdo, Shigehiro

2018-04-01

Proliferation of acute lymphoblastic leukemic cells is nutritionally dependent on the external supply of asparagine. l-asparaginase, an enzyme hydrolyzing l-asparagine in blood, is used for treatment of acute lymphoblastic leukemic and other related blood cancers. Although previous studies demonstrated that l-asparaginase suppresses the proliferation of cultured solid tumor cells, it remains unclear whether this enzyme prevents the growth of solid tumors in vivo. In this study, we demonstrated the importance of optimizing dosing schedules for the anti-tumor activity of l-asparaginase in 4T1 breast tumor-bearing mice. Cultures of several types of murine solid tumor cells were dependent on the external supply of asparagine. Among them, we selected murine 4T1 breast cancer cells and implanted them into BALB/c female mice kept under standardized light/dark cycle conditions. The growth of 4T1 tumor cells implanted in mice was significantly suppressed by intravenous administration of l-asparaginase during the light phase, whereas its administration during the dark phase failed to show significant anti-tumor activity. Decreases in plasma asparagine levels due to the administration of l-asparaginase were closely related to the dosing time-dependency of its anti-tumor effects. These results suggest that the anti-tumor efficacy of l-asparaginase in breast tumor-bearing mice is improved by optimizing the dosing schedule. Copyright © 2018 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

Implementation of a hepatitis A/B vaccination program using an accelerated schedule among high-risk inmates, Los Angeles County Jail, 2007-2010.

PubMed

Costumbrado, John; Stirland, Ali; Cox, Garrett; El-Amin, Alvin Nelson; Miranda, Armidia; Carter, Ann; Malek, Mark

2012-11-06

The Centers for Disease Control and Prevention recommend vaccination for men who have sex with men (MSM) and injection drug users against hepatitis A and B. This study is the first report of a hepatitis vaccination program in a United States jail with a combined vaccine using an accelerated schedule. Los Angeles County has the largest jail system in the nation and Men's Central Jail (MCJ) is the largest facility within that system. MCJ includes a unit for self-identified MSM, where approximately 2700 inmates are housed per year. Starting in August 2007, a combined hepatitis A and B vaccine was offered to all inmates housed in this special unit. Using an accelerated schedule (0-, 7-, 21-30 days, 12-month booster), a total of 3931 doses were administered to 1633 inmates as of June 2010. Of those, 77% received 2 doses, 58% received 3 doses, and 11% received the booster dose. Inmates who screened positive for a sexually transmitted infection in this unit were 1.3 times more likely to be vaccinated (95% CI 1.2-1.4) compared to others in the same housing unit who screened negative. Hepatitis vaccination initiatives can be successfully implemented in an urban jail among an extremely high-risk population using the accelerated, combined hepatitis A/B vaccine. Ours may be a useful model for other programs to vaccinate incarcerated populations. Copyright © 2012 Elsevier Ltd. All rights reserved.

A feasibility study: Selection of a personalized radiotherapy fractionation schedule using spatiotemporal optimization

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

Kim, Minsun, E-mail: mk688@uw.edu; Stewart, Robert D.; Phillips, Mark H.

2015-11-15

Purpose: To investigate the impact of using spatiotemporal optimization, i.e., intensity-modulated spatial optimization followed by fractionation schedule optimization, to select the patient-specific fractionation schedule that maximizes the tumor biologically equivalent dose (BED) under dose constraints for multiple organs-at-risk (OARs). Methods: Spatiotemporal optimization was applied to a variety of lung tumors in a phantom geometry using a range of tumor sizes and locations. The optimal fractionation schedule for a patient using the linear-quadratic cell survival model depends on the tumor and OAR sensitivity to fraction size (α/β), the effective tumor doubling time (T{sub d}), and the size and location of tumormore » target relative to one or more OARs (dose distribution). The authors used a spatiotemporal optimization method to identify the optimal number of fractions N that maximizes the 3D tumor BED distribution for 16 lung phantom cases. The selection of the optimal fractionation schedule used equivalent (30-fraction) OAR constraints for the heart (D{sub mean} ≤ 45 Gy), lungs (D{sub mean} ≤ 20 Gy), cord (D{sub max} ≤ 45 Gy), esophagus (D{sub max} ≤ 63 Gy), and unspecified tissues (D{sub 05} ≤ 60 Gy). To assess plan quality, the authors compared the minimum, mean, maximum, and D{sub 95} of tumor BED, as well as the equivalent uniform dose (EUD) for optimized plans to conventional intensity-modulated radiation therapy plans prescribing 60 Gy in 30 fractions. A sensitivity analysis was performed to assess the effects of T{sub d} (3–100 days), tumor lag-time (T{sub k} = 0–10 days), and the size of tumors on optimal fractionation schedule. Results: Using an α/β ratio of 10 Gy, the average values of tumor max, min, mean BED, and D{sub 95} were up to 19%, 21%, 20%, and 19% larger than those from conventional prescription, depending on T{sub d} and T{sub k} used. Tumor EUD was up to 17% larger than the conventional prescription. For fast proliferating tumors with T{sub d} less than 10 days, there was no significant increase in tumor BED but the treatment course could be shortened without a loss in tumor BED. The improvement in the tumor mean BED was more pronounced with smaller tumors (p-value = 0.08). Conclusions: Spatiotemporal optimization of patient plans has the potential to significantly improve local tumor control (larger BED/EUD) of patients with a favorable geometry, such as smaller tumors with larger distances between the tumor target and nearby OAR. In patients with a less favorable geometry and for fast growing tumors, plans optimized using spatiotemporal optimization and conventional (spatial-only) optimization are equivalent (negligible differences in tumor BED/EUD). However, spatiotemporal optimization yields shorter treatment courses than conventional spatial-only optimization. Personalized, spatiotemporal optimization of treatment schedules can increase patient convenience and help with the efficient allocation of clinical resources. Spatiotemporal optimization can also help identify a subset of patients that might benefit from nonconventional (large dose per fraction) treatments that are ineligible for the current practice of stereotactic body radiation therapy.« less

Basic PK/PD principles of drug effects in circular/proliferative systems for disease modelling.

PubMed

Jacqmin, Philippe; McFadyen, Lynn; Wade, Janet R

2010-04-01

Disease progression modelling can provide information about the time course and outcome of pharmacological intervention on the disease. The basic PK/PD principles of proliferative and circular systems within the context of modelling disease progression and the effect of treatment thereupon are illustrated with the goal to better understand/predict eventual clinical outcome. Circular/proliferative systems can be very complex. To facilitate the understanding of how a dosing regimen can be defined in such systems we have shown the derivation of a system parameter named the Reproduction Minimum Inhibitory Concentration (RMIC) which represents the critical concentration at which the system switches from growth to extinction. The RMIC depends on two parameters (RMIC = (R(0) - 1) x IC(50)): the basic reproductive ratio (R(0)) a fundamental parameter of the circular/proliferative system that represents the number of offspring produced by one replicating species during its lifespan, and the IC(50), the potency of the drug to inhibit the proliferation of the system. The RMIC is constant for a given system and a given drug and represents the lowest concentration that needs to be achieved for eradication of the system. When exposure is higher than the RMIC, success can be expected in the long term. Time varying inhibition of replicating species proliferation is a natural consequence of the time varying inhibitor drug concentrations and when combined with the dynamics of the circular/proliferative system makes it difficult to predict the eventual outcome. Time varying inhibition of proliferative/circular systems can be handled by calculating the equivalent effective constant concentration (ECC), the constant plasma concentration that would give rise to the average inhibition at steady state. When ECC is higher than the RMIC, eradication of the system can be expected. In addition, it is shown that scenarios that have the same steady state ECC whatever the dose, dosage schedule or PK parameters have also the same average R (0) in the presence of the inhibitor (i.e. R (0-INH)) and therefore lead to the same outcome. This allows predicting equivalent active doses and dosing schedules in circular and proliferative systems when the IC(50) and pharmacokinetic characteristics of the drugs are known. The results from the simulations performed demonstrate that, for a given system (defined by its RMIC), treatment success depends mainly on the pharmacokinetic characteristics of the drug and the dosing schedule.

Evaluation of a software module for adaptive treatment planning and re-irradiation.

PubMed

Richter, Anne; Weick, Stefan; Krieger, Thomas; Exner, Florian; Kellner, Sonja; Polat, Bülent; Flentje, Michael

2017-12-28

The aim of this work is to validate the Dynamic Planning Module in terms of usability and acceptance in the treatment planning workflow. The Dynamic Planning Module was used for decision making whether a plan adaptation was necessary within one course of radiation therapy. The Module was also used for patients scheduled for re-irradiation to estimate the dose in the pretreated region and calculate the accumulated dose to critical organs at risk. During one year, 370 patients were scheduled for plan adaptation or re-irradiation. All patient cases were classified according to their treated body region. For a sub-group of 20 patients treated with RT for lung cancer, the dosimetric effect of plan adaptation during the main treatment course was evaluated in detail. Changes in tumor volume, frequency of re-planning and the time interval between treatment start and plan adaptation were assessed. The Dynamic Planning Tool was used in 20% of treated patients per year for both approaches nearly equally (42% plan adaptation and 58% re-irradiation). Most cases were assessed for the thoracic body region (51%) followed by pelvis (21%) and head and neck cases (10%). The sub-group evaluation showed that unintended plan adaptation was performed in 38% of the scheduled cases. A median time span between first day of treatment and necessity of adaptation of 17 days (range 4-35 days) was observed. PTV changed by 12 ± 12% on average (maximum change 42%). PTV decreased in 18 of 20 cases due to tumor shrinkage and increased in 2 of 20 cases. Re-planning resulted in a reduction of the mean lung dose of the ipsilateral side in 15 of 20 cases. The experience of one year showed high acceptance of the Dynamic Planning Module in our department for both physicians and medical physicists. The re-planning can potentially reduce the accumulated dose to the organs at risk and ensure a better target volume coverage. In the re-irradiation situation, the Dynamic Planning Tool was used to consider the pretreatment dose, to adapt the actual treatment schema more specifically and to review the accumulated dose.

A Phase I study of intermittently dosed vorinostat in combination with bortezomib in patients with advanced solid tumors.

PubMed

Deming, Dustin A; Ninan, Jacob; Bailey, Howard H; Kolesar, Jill M; Eickhoff, Jens; Reid, Joel M; Ames, Matthew M; McGovern, Renee M; Alberti, Dona; Marnocha, Rebecca; Espinoza-Delgado, Igor; Wright, John; Wilding, George; Schelman, William R

2014-04-01

Accumulating evidence shows evidence of efficacy with the combination of vorinostat and bortezomib in solid tumors. We previously examined a once-daily continuous dosing schedule of vorinostat in combination with bortezomib which was well tolerated in cycles 1 and 2; however, there was concern regarding the tolerability through multiple cycles. This study was conducted to evaluate an intermittent dosing schedule of vorinostat with bortezomib. Vorinostat was initially administered orally twice daily on days 1-14 with bortezomib IV on days 1, 4, 8, and 11 of a 21 day cycle. Two DLTs (elevated ALT and fatigue) were observed at dose level 1, thus the protocol was amended to administer vorinostat intermittently twice daily on days 1-4 and 8-11. 29 patients were enrolled; 13 men and 16 women. Common cancer types included sarcoma, pancreatic, colorectal, GIST, and breast. The most common Grade 3-4 toxicities at any dose level included thrombocytopenia, fatigue, increased ALT, elevated INR, and diarrhea. DLTs in the intermittent dosing scheduled included thrombocytopenia and fatigue. The Cmax and AUC for the intermittent dosing regimen were similar to those observed in the daily dosing. In this heavily pretreated population, stable disease was observed in patients with sarcoma, colorectal adenocarcinoma and GIST. The MTD was established at vorinostat 300 mg BID on days 1-4 and 8-11 and bortezomib 1.3 mg/m(2) IV on days 1, 4, 8, and 11 of a 21 day cycle. Tolerability was not improved with the intermittent dosing schedule of vorinostat when compared to continuous dosing.

Pavor nocturnus: a complication of single daily tricyclic or neuroleptic dosage.

PubMed

Flemenbaum, A

1976-05-01

The author tested the hypothesis that a single bedtime dosage schedule of tricyclic or neuroleptic medication produces increased frequency of night terrors by administering a questionnaire to 30 medical patients who were not receiving such medications and 100 psychiatric patients on either multiple- or single-dosage schedules. Psychiatric patients on multiple-dosage schedules reported no more frightening dreams than the medical patients, whereas almost three-fourths of those receiving single bedtime doses had frightening dreams, a significant difference from the medical sample. This preliminary report is presented to call attention to the possible undesirable effects of a single dose schedule.

Methyl bromide as a quarantine treatment for Chlorophorus annularis (Coleoptera: Cerambycidae) in raw bamboo poles.

PubMed

Barak, Alan V; Weidong, Yang; Daojian, Yu; Yi, Jiao; Lin, Kang; Zhilin, Chen; Xingyuan, Ling; Guoping, Zhan

2009-06-01

At least 26 different species of insects of quarantine significance were intercepted from 1985 to 2005 on bamboo (Bambusa spp.) garden stakes from China. Three fifths of the live insects were cerambycids in nine genera, including Chlorophorus annularis F., the bamboo borer. The current APHIS-PPQ treatment is fumigation schedule T404-d, which requires high doses of methyl bromide (MeBr) for 24 h. No specific fumigation data exist for C. annularis. Chinese and American quarantine scientists cooperated in testing to determine whether this schedule, or lower doses, would be effective as a quarantine treatment for C. annularis infesting dried bamboo poles. A lower dose based on APHIS tests for solid wood packing (SWP) failed (3/511 survivors) at 56 g/m3 for 24 h at 10.0 degrees C. We therefore tested five progressive doses at five temperatures intermediate between the lower SWP schedule and the much higher applied doses (e.g., 120 g/m3 for 24 h at 10.0 degrees C) of schedule T404-d. Fumigations of infested bamboo poles conducted in 403.2-liter chambers with 52% vol:vol loading at doses of 48, 64, 80, 96, and 112 g/m3 at 26.7, 21.1, 15.6, 10.0, and 4.4 degrees C, respectively (20 total replicates, with 4 replicates per dose), had no survivors among 2,847 larvae, 140 pupae, and 122 adults. Control replicates (three) had a total of 455 live stages (397 larvae, 31 pupae, and 27 adults). Tests conducted with a sea/land cargo container loaded to 80% capacity with bamboo poles verified the ability of the schedule to maintain effective concentrations over 24 h in commercial-sized fumigations. We propose a new bamboo quarantine treatment schedule at reduced rates of applied MeBr.

Monitoring of timely and delayed vaccinations: a nation-wide registry-based study of Norwegian children aged < 2 years.

PubMed

Riise, Øystein Rolandsen; Laake, Ida; Bergsaker, Marianne Adeleide Riise; Nøkleby, Hanne; Haugen, Inger Lise; Storsæter, Jann

2015-11-13

Delayed vaccinations increase the risk for vaccine preventable diseases (VPDs). Monitoring of delayed vaccinations by using a national immunisation registry has not been studied in countries recommending a two-dose (3 and 5 months of age) primary series of e.g., pertussis vaccine. Surveillance/monitoring of all vaccinations may improve vaccination programmes functioning. We obtained information from the Norwegian immunisation registry (SYSVAK) on all programme vaccinations received at age up to 730 days in children born in 2010 (n = 63,382). Timely vaccinations were received up to 7 days after the recommended age. Vaccinations were considered delayed if they were received more than one month after the recommended age in the schedule. In vaccinated children, timely administration of the subsequent three doses of pertussis and one dose of measles occurred in 73.8, 47.6, 53.6 and 43.5 % respectively. Delay for one or more programme vaccinations (diphtheria, tetanus, pertussis, polio, Haemophilus influenza type B, invasive pneumococcal disease, measles, mumps or rubella) was present in 28,336 (44.7 %) children. Among those who were delayed the mean duration was 139 days. The proportion of children that had vaccinations delayed differed among counties (range 37.4 %-57.8 %). Immigrant children were more frequently delayed 52.3 % vs. 43.1 %, RR 1.21 (95 % CI 1.19, 1.24). Children scheduled for vaccines in the summer holiday month (July) were more frequently delayed than others (1(st) dose pertussis vaccine 6.5 % vs. 3.9 % RR 1.65 (95 % CI 1.48, 1.85). Priming against pertussis (2(nd) dose), pneumococcal (2(nd) dose) and measles (1(st) dose) was delayed in 16.8, 18.6 and 29.3 % respectively. Vaccinations were frequently delayed. Delayed vaccinations differed among counties and occurred more frequently during the summer vacation (July) and in the immigrant population. Monitoring improves programme surveillance and may be used on an annual basis.

Switching from oral extended-release methylphenidate to the methylphenidate transdermal system: continued ADHD symptom control and tolerability after abrupt conversion

PubMed Central

Arnold, L. E.; Hodgkins, P.; McKay, M.; Beckett-Thurman, L.; Greenbaum, M.; Bukstein, O.; Patel, A.; Bozzolo, D. R.

2013-01-01

Objective To evaluate symptom control and tolerability after abrupt conversion from oral extended-release methylphenidate (ER-MPH) to methylphenidate transdermal system (MTS) via a dose-transition schedule in children with attention-deficit/hyperactivity disorder (ADHD). Methods In a 4-week, prospective, multisite, open-label study, 171 children (164 intent-to-treat) with diagnosed ADHD aged 6–12 years abruptly switched from a stable dose of oral ER-MPH to MTS in nominal dosages of 10, 15, 20, and 30 mg using a predefined dose-transition schedule. After the first week on the scheduled dose, the dose was titrated to optimal effect. The primary effectiveness outcome was the change from baseline (while taking ER-MPH) to week 4 in ADHD-Rating Scale-IV (ADHD-RS-IV) total scores. Adverse events (AEs) were assessed throughout the study. Results Most subjects (58%) remained on the initial MTS dose defined by the dose-transition schedule; 38% increased and 4% decreased their MTS dose for optimization. MTS dose optimization resulted in significantly better ADHD-RS-IV total (mean ± SD) scores at week 4 than at baseline (9.9±7.47 vs 14.1±7.48; p<0.0001). The most commonly reported AEs included headache, decreased appetite, insomnia, and upper abdominal pain. Four subjects (2.3%) discontinued because of application site reactions and 3 discontinued because of other AEs. Conclusions Abrupt conversion from a stable dose of oral ER-MPH to MTS was accomplished using a predefined dose-transition schedule without loss of symptom control; however, careful titration to optimal dose is recommended. Most AEs were mild to moderate and, with the exception of application site reactions, were similar to AEs typically observed with oral MPH. Limitations of this study included its open-label sequential design without placebo, which could result in spurious attribution of improvement to the study treatment and precluded superiority determinations of MTS over baseline ER-MPH treatment. The apparent superiority of MTS was likely due to more careful titration and clinical monitoring rather than the product itself. NCT NCT00151983 PMID:19916704

Provider risk factors for medication administration error alerts: analyses of a large-scale closed-loop medication administration system using RFID and barcode.

PubMed

Hwang, Yeonsoo; Yoon, Dukyong; Ahn, Eun Kyoung; Hwang, Hee; Park, Rae Woong

2016-12-01

To determine the risk factors and rate of medication administration error (MAE) alerts by analyzing large-scale medication administration data and related error logs automatically recorded in a closed-loop medication administration system using radio-frequency identification and barcodes. The subject hospital adopted a closed-loop medication administration system. All medication administrations in the general wards were automatically recorded in real-time using radio-frequency identification, barcodes, and hand-held point-of-care devices. MAE alert logs recorded during a full 1 year of 2012. We evaluated risk factors for MAE alerts including administration time, order type, medication route, the number of medication doses administered, and factors associated with nurse practices by logistic regression analysis. A total of 2 874 539 medication dose records from 30 232 patients (882.6 patient-years) were included in 2012. We identified 35 082 MAE alerts (1.22% of total medication doses). The MAE alerts were significantly related to administration at non-standard time [odds ratio (OR) 1.559, 95% confidence interval (CI) 1.515-1.604], emergency order (OR 1.527, 95%CI 1.464-1.594), and the number of medication doses administered (OR 0.993, 95%CI 0.992-0.993). Medication route, nurse's employment duration, and working schedule were also significantly related. The MAE alert rate was 1.22% over the 1-year observation period in the hospital examined in this study. The MAE alerts were significantly related to administration time, order type, medication route, the number of medication doses administered, nurse's employment duration, and working schedule. The real-time closed-loop medication administration system contributed to improving patient safety by preventing potential MAEs. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Intravaginal high-dose-rate brachytherapy for stage I endometrial cancer: A randomized study of two dose-per-fraction levels

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

Sorbe, Bengt; Straumits, Andris; Karlsson, Leif

2005-08-01

Purpose To compare two different fractionation schedules for postoperative vaginal high-dose-rate (HDR) irradiation in endometrial carcinomas. Methods and Materials In a complete geographic series of 290 low-risk endometrial carcinomas, the efficacy and side effects of two different fractionation schedules for postoperative vaginal irradiation were evaluated. The patients were treated during the years 1989-2003. The tumors were in International Federation of Gynecology and Obstetrics Stages IA-IB and Grades 1-2. The HDR MicroSelectron afterloading equipment (iridium-192) was used. Perspex vaginal applicators with diameters of 20-30 mm were used, and the dose was specified at 5 mm from the surface of the applicator.more » Six fractions were given, and the overall treatment time was 8 days. The size of the dose per fraction was randomly set to 2.5 Gy (total dose of 15.0 Gy) or 5.0 Gy (total dose of 30.0 Gy). One hundred forty-four patients were treated with the 2.5-Gy fraction and 146 patients with the 5.0-Gy fraction. Results The overall locoregional recurrence rate of the complete series was 1.4% and the rate of vaginal recurrences 0.7%. There was no difference between the two randomized groups. The vaginal shortening measured by colpometry was not significant (p = 0.159) in the 2.5-Gy group (mean, 0.3 cm) but was highly significant (p < 0.000001) in the 5.0-Gy group (mean 2.1 cm) after 5 years. Mucosal atrophy and bleedings were significantly more frequent in the 5.0-Gy group. Symptoms noted in the 2.5-Gy group were not different from what could be expected in a normal group of postmenopausal women. Conclusion The fractionation schedule recommended for postoperative vaginal irradiation in low-risk endometrial carcinoma is six fractions of 2.5 Gy when the HDR technique is used.« less

Metronomic cyclophosphamide schedule-dependence of innate immune cell recruitment and tumor regression in an implanted glioma model

PubMed Central

Wu, Junjie; Waxman, David J.

2014-01-01

Metronomic cyclophosphamide (CPA) treatment activates robust innate anti-tumor immunity and induces major regression of large, implanted brain tumor xenografts when administered on an intermittent, every 6-day schedule, but not on a daily low-dose or a maximum-tolerated dose CPA schedule. Here, we used an implanted GL261 glioma model to compare five intermittent metronomic CPA schedules to elucidate the kinetics and schedule dependence of innate immune cell recruitment and tumor regression. Tumor-recruited natural killer cells induced by two every 6-day treatment cycles were significantly ablated one day after a third CPA treatment, but largely recovered several days later. Natural killer and other tumor-infiltrating innate immune cells peaked 12 days after the last CPA treatment on the every 6-day schedule, suggesting that drug-free intervals longer than 6 days may show increased efficacy. Metronomic CPA treatments spaced 9 or 12 days apart, or on an alternating 6 and 9 day schedule, induced extensive tumor regression, similar to the 6-day schedule, however, the tumor-infiltrating natural killer cell responses were not sustained, leading to rapid resumption of tumor regrowth after day 24, despite ongoing metronomic CPA treatment. Increasing the CPA dose prolonged the period of tumor regression on the every 9-day schedule, but natural killer cell activation was markedly decreased. Thus, while several intermittent metronomic CPA treatment schedules can activate innate immune cell recruitment leading to major tumor regression, sustained immune and anti-tumor responses are only achieved on the 6-day schedule. However, even with this schedule, some tumors eventually relapse, indicating a need for further improvements in immunogenic metronomic therapies. PMID:25069038

The Effect of Biologically Effective Dose and Radiation Treatment Schedule on Overall Survival in Stage I Non-Small Cell Lung Cancer Patients Treated With Stereotactic Body Radiation Therapy

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

Stahl, John M.; Ross, Rudi; Harder, Eileen M.

Purpose: To determine the effect of biologically effective dose (BED{sub 10}) and radiation treatment schedule on overall survival (OS) in patients with early-stage non-small cell lung cancer (NSCLC) undergoing stereotactic body radiation therapy (SBRT). Methods and Materials: Using data from 65 treatment centers in the United States, we retrospectively reviewed the records of T1-2 N0 NSCLC patients undergoing SBRT alone from 2006 to 2014. Biologically relevant covariates, including dose per fraction, number of fractions, and time between fractions, were used to quantify BED{sub 10} and radiation treatment schedule. The linear-quadratic equation was used to calculate BED{sub 10} and to generatemore » a dichotomous dose variable of <105 Gy versus ≥105 Gy BED{sub 10}. The primary outcome was OS. We used the Kaplan-Meier method, the log–rank test, and Cox proportional hazards regression with propensity score matching to determine whether prescription BED{sub 10} was associated with OS. Results: We identified 747 patients who met inclusion criteria. The median BED{sub 10} was 132 Gy, and 59 (7.7%) had consecutive-day fractions. Median follow-up was 41 months, and 452 patients (60.5%) had died by the conclusion of the study. The 581 patients receiving ≥105 Gy BED{sub 10} had a median survival of 28 months, whereas the 166 patients receiving <105 Gy BED{sub 10} had a median survival of 22 months (log–rank, P=.01). Radiation treatment schedule was not a significant predictor of OS on univariable analysis. After adjusting for T stage, sex, tumor histology, and Eastern Cooperative Oncology Group performance status, BED{sub 10} ≥105 Gy versus <105 Gy remained significantly associated with improved OS (hazard ratio 0.78, 95% confidence interval 0.62-0.98, P=.03). Propensity score matching on imbalanced variables within high- and low-dose cohorts confirmed a survival benefit with higher prescription dose. Conclusions: We found that dose escalation to 105 Gy BED{sub 10} and beyond may improve survival in NSCLC patients treated with SBRT.« less

Frightening dreams and dosage schedule of tricyclic and neuroleptic drugs.

PubMed

Strayhorn, J M; Nash, J L

1978-12-01

One previous study reported that psychiatric inpatients on bedtime-only doses of tricyclic or neuroleptic drugs reported more frequent frightening dreams than did those on divided daily doses. As a further test of this hypothesis, and in order to see whether differences in frequency of frightening dreams were a function of differences in total dream recall, we administered a questionnaire to outpatients in a Veterans Administration Hospital Mental Hygiene Clinic, asking about frequency of dream recall, frequency of frightening dream recall, and doses and times of any medications taken. Questionnaire reports of medications were checked with the medical record of the patient; for 48 patients on tricyclic or neuroleptic drugs the reports agreed, and the data of these patients were analyzed. Our findings corroborated the previous report of more frequent frightening dreams in patients on bedtime-only dosage schedules (p less than .01). In addition, we found no significant difference between the two groups with respect to frequency of dream recall; thus a difference in the affect of dreams, rather than a difference in quantity of dream recall, constituted the difference between the two groups. When a patient on bedtime doses of tricyclic or neuroleptic drugs has undesirable frightening dreams, the clinician should consider a change to divided daily doses.

Magnetic Resonance Imaging-Guided Adaptive Radiation Therapy: A "Game Changer" for Prostate Treatment?

PubMed

Pathmanathan, Angela U; van As, Nicholas J; Kerkmeijer, Linda G W; Christodouleas, John; Lawton, Colleen A F; Vesprini, Danny; van der Heide, Uulke A; Frank, Steven J; Nill, Simeon; Oelfke, Uwe; van Herk, Marcel; Li, X Allen; Mittauer, Kathryn; Ritter, Mark; Choudhury, Ananya; Tree, Alison C

2018-02-01

Radiation therapy to the prostate involves increasingly sophisticated delivery techniques and changing fractionation schedules. With a low estimated α/β ratio, a larger dose per fraction would be beneficial, with moderate fractionation schedules rapidly becoming a standard of care. The integration of a magnetic resonance imaging (MRI) scanner and linear accelerator allows for accurate soft tissue tracking with the capacity to replan for the anatomy of the day. Extreme hypofractionation schedules become a possibility using the potentially automated steps of autosegmentation, MRI-only workflow, and real-time adaptive planning. The present report reviews the steps involved in hypofractionated adaptive MRI-guided prostate radiation therapy and addresses the challenges for implementation. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Pharmacokinetic-Pharmacodynamic Model for the Effect of l-Arginine on Endothelial Function in Patients with Moderately Severe Falciparum Malaria

PubMed Central

Brussee, Janneke M.; Yeo, Tsin W.; Lampah, Daniel A.; Anstey, Nicholas M.

2015-01-01

Impaired organ perfusion in severe falciparum malaria arises from microvascular sequestration of parasitized cells and endothelial dysfunction. Endothelial dysfunction in malaria is secondary to impaired nitric oxide (NO) bioavailability, in part due to decreased plasma concentrations of l-arginine, the substrate for endothelial cell NO synthase. We quantified the time course of the effects of adjunctive l-arginine treatment on endothelial function in 73 patients with moderately severe falciparum malaria derived from previous studies. Three groups of 10 different patients received 3 g, 6 g, or 12 g of l-arginine as a half-hour infusion. The remaining 43 received saline placebo. A pharmacokinetic-pharmacodynamic (PKPD) model was developed to describe the time course of changes in exhaled NO concentrations and reactive hyperemia-peripheral arterial tonometry (RH-PAT) index values describing endothelial function and then used to explore optimal dosing regimens for l-arginine. A PK model describing arginine concentrations in patients with moderately severe malaria was extended with two pharmacodynamic biomeasures, the intermediary biochemical step (NO production) and endothelial function (RH-PAT index). A linear model described the relationship between arginine concentrations and exhaled NO. NO concentrations were linearly related to RH-PAT index. Simulations of dosing schedules using this PKPD model predicted that the time within therapeutic range would increase with increasing arginine dose. However, simulations demonstrated that regimens of continuous infusion over longer periods would prolong the time within the therapeutic range even more. The optimal dosing regimen for l-arginine is likely to be administration schedule dependent. Further studies are necessary to characterize the effects of such continuous infusions of l-arginine on NO and microvascular reactivity in severe malaria. PMID:26482311

Effect of Sampling Schedule on Pharmacokinetic Parameter Estimates of Promethazine in Astronauts

NASA Technical Reports Server (NTRS)

Boyd, Jason L.; Wang, Zuwei; Putcha, Lakshmi

2005-01-01

Six astronauts on the Shuttle Transport System (STS) participated in an investigation on the pharmacokinetics of promethazine (PMZ), a medication used for the treatment of space motion sickness (SMS) during flight. Each crewmember completed the protocol once during flight and repeated thirty days after returned to Earth. Saliva samples were collected at scheduled times for 72 h after PMZ administration; more frequent samples were collected on the ground than during flight owing to schedule constraints in flight. PMZ concentrations in saliva were determined by a liquid chromatographic/mass spectrometric (LC-MS) assay and pharmacokinetic parameters (PKPs) were calculated using actual flight and ground-based data sets and using time-matched sampling schedule on ground to that during flight. Volume of distribution (V(sub c)) and clearance (Cl(sub s),) decreased during flight compared to that from time-matched ground data set; however, Cl(sub s) and V(sub c) estimates were higher for all subjects when partial ground data sets were used for analysis. Area under the curve (AUC) normalized with administered dose was similar in flight and partial ground data; however AUC was significantly lower using time-matched sampling compared with the full data set on ground. Half life (t(sub 1/2)) was longest during flight, shorter with matched-sampling schedule on ground and shortest when complete data set from ground was used. Maximum concentration (C(sub max)), time for C(sub max), (t(sub max)), parameters of drug absorption, depicted a similar trend with lowest and longest respectively, during flight, lower with time-matched ground data and highest and shortest with full ground data.

Effect of sampling schedule on pharmacokinetic parameter estimates of promethazine in astronauts

NASA Astrophysics Data System (ADS)

Boyd, Jason L.; Wang, Zuwei; Putcha, Lakshmi

2005-08-01

Six astronauts on the Shuttle Transport System (STS) participated in an investigation on the pharmacokinetics of promethazine (PMZ), a medication used for the treatment of space motion sickness (SMS) during flight. Each crewmember completed the protocol once during flight and repeated thirty days after returned to Earth. Saliva samples were collected at scheduled times for 72 h after PMZ administration; more frequent samples were collected on the ground than during flight owing to schedule constraints in flight. PMZ concentrations in saliva were determined by a liquid chromatographic/mass spectrometric (LC-MS) assay and pharmacokinetic parameters (PKPs) were calculated using actual flight and ground-based data sets and using time-matched sampling schedule on ground to that during flight. Volume of distribution (Vc) and clearance (Cls) decreased during flight compared to that from time-matched ground data set; however, ClS and Vc estimates were higher for all subjects when partial ground data sets were used for analysis. Area under the curve (AUC) normalized with administered dose was similar in flight and partial ground data; however AUC was significantly lower using time-matched sampling compared with the full data set on ground. Half life (t1/2) was longest during flight, shorter with matched-sampling schedule on ground and shortest when complete data set from ground was used. Maximum concentration (Cmax), time for Cmax (tmax), parameters of drug absorption, depicted a similar trend with lowest and longest respectively, during flight, lower with time- matched ground data and highest and shortest with full ground data.

Comparison of two dosing schedules for subcutaneous injections of low-dose anti-CD20 veltuzumab in relapsed immune thrombocytopenia

PubMed Central

Liebman, Howard A.; Saleh, Mansoor N.; Bussel, James B.; Negrea, O. George; Horne, Heather; Wegener, William A.; Goldenberg, David M.

2016-01-01

We compared two dosing schedules for subcutaneous injections of a low-dose humanized anti-CD20 antibody, veltuzumab, in immune thrombocytopenia. Fifty adults with primary immune thrombocytopenia, in whom one or more lines of standard therapy had failed and who had a platelet count <30×109/L but no major bleeding, initially received escalating 80, 160, or 320 mg doses of subcutaneous veltuzumab administered twice, 2 weeks apart; the last group received once-weekly doses of 320 mg for 4 weeks. In all dose groups, injection reactions were transient and mild to moderate; there were no other safety issues. Forty-seven response-evaluable patients had 23 (49%) objective responses (platelet counts ≥30×109/L and ≥2 × baseline) including 15 (32%) complete responses (platelets ≥100×109/L). Responses (including complete responses) and bleeding reduction occurred in all dose groups and were not dose-dependent. In contrast, response duration increased progressively with total dose, reaching a median of 2.7 years with the four once-weekly 320-mg doses. Among nine responders retreated at relapse, three at higher dose levels responded again, including one patient who was retreated four times. In all dose groups, B-cell depletion occurred after the first dose until recovery starting 12 to 16 weeks after treatment. Veltuzumab serum levels increased with dose group according to total dose administered, but terminal half-life and clearance were comparable. Human anti-veltuzumab antibody titers developed without apparent dose dependence in nine patients, of whom six responded including five who had complete responses. Subcutaneous veltuzumab was convenient, well-tolerated, and active, without causing significant safety concerns. Platelet responses and bleeding reduction occurred in all dose groups, and response durability appeared to improve with higher doses. Clinicaltrials.gov identifier: NCT00547066 PMID:27515248

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

Hall, Matthew D.; Schultheiss, Timothy E., E-mail: schultheiss@coh.org; Smith, David D.

Purpose/Objective(s): To perform a meta-regression on published data and to model the 5-year probability of cataract development after hematopoietic stem cell transplantation (HSCT) with and without total body irradiation (TBI). Methods and Materials: Eligible studies reporting cataract incidence after HSCT with TBI were identified by a PubMed search. Seventeen publications provided complete information on radiation dose schedule, fractionation, dose rate, and actuarial cataract incidence. Chemotherapy-only regimens were included as zero radiation dose regimens. Multivariate meta-regression with a weighted generalized linear model was used to model the 5-year cataract incidence and contributory factors. Results: Data from 1386 patients in 21 seriesmore » were included for analysis. TBI was administered to a total dose of 0 to 15.75 Gy with single or fractionated schedules with a dose rate of 0.04 to 0.16 Gy/min. Factors significantly associated with 5-year cataract incidence were dose, dose times dose per fraction (D•dpf), pediatric versus adult status, and the absence of an ophthalmologist as an author. Dose rate, graft versus host disease, steroid use, hyperfractionation, and number of fractions were not significant. Five-fold internal cross-validation showed a model validity of 83% ± 8%. Regression diagnostics showed no evidence of lack-of-fit and no patterns in the studentized residuals. The α/β ratio from the linear quadratic model, estimated as the ratio of the coefficients for dose and D•dpf, was 0.76 Gy (95% confidence interval [CI], 0.05-1.55). The odds ratio for pediatric patients was 2.8 (95% CI, 1.7-4.6) relative to adults. Conclusions: Dose, D•dpf, pediatric status, and regimented follow-up care by an ophthalmologist were predictive of 5-year cataract incidence after HSCT. The low α/β ratio indicates the importance of fractionation in reducing cataracts. Dose rate effects have been observed in single institution studies but not in the combined data analyzed here. Although data were limited to articles with 5-year actuarial estimates, the development of radiation-induced cataracts extends beyond this time.« less

SU-E-T-619: Planning 131I Thyroid Treatments for Patients Requiring Hemodialysis

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

Stroud, D

Purpose: Treatment of 131I thyroid cancer patients who also require regular hemodialysis (HD) treatments requires consideration of the administered activity and the HD schedule. In this work the red bone marrow is considered the dose limiting organ and the treatment plan optimized the HD schedule with the amount of radioactivity administered. Methods: The ‘Safe’ dose was considered to be 2 Gy (200 rad) to the red bone marrow.1 131Iodine doses of 50 mCi to 100 mCi were modeled and found to require a range of HD schedules. In order to achieve the safe dose to the red marrow, more aggressivemore » HD schedules are required. 100 mCi required an aggressive HD treatment of every 24 hours for at least one week to achieve the ‘safe’ dose and an exposure appropriate for release from the hospital. A more normal schedule of HD beginning at 18 hours then every 48 hours allowed for up to 60 mCi administered dose allowed for a safe dose and expected release after less than one week.2In addition room was equipped with video cameras cameras for monitoring the patient and their vital signs from an adjacent room during HD. In this way the dialysis nurses were able to monitor the patient closely from an adjoining room. Results: Two HD patients were administered adjusted doses of about 50 mCi. The medical and nursing staff were exposed to no more than 4 mR for the entire treatment. The residual Iodine in the patient appeared to be normal after 4 to 6 days when the patient was released. Conclusion: With careful treatment planning 131Iodine treatments can be performed safely for patients needing HD and treatments appear to be as effective as those for patients with normal renal function.« less

Safety of veralipride for the treatment of vasomotor symptoms of menopause.

PubMed

Valencia, Marcelino Hernández; Arias, María de Jesús Vega; González, Cuauhtémoc Celis; Marín, Imelda Hernández; González, Juan Humberto Martín; Campos, Enrique Rafael Morcate; Rodríguez, María Antonia Basavilvazo; Álvarez, Ignacio Morales; Vargas, María Antonia Valdés; Flores, José Braulio Everardo Otero; Haro, Samuel Santoyo; Bonilla, Manuel Cortes; Escudero, Roberto Bernardo; Campero, Rosalba Alonso

2014-05-01

Veralipride is a nonhormonal option for the treatment of vasomotor symptoms of menopause. Incidence of adverse events in a Mexican population and drug compliance according to correct use were evaluated. We carried out a longitudinal, prospective, and analytical study in Mexican women who received veralipride to treat symptoms of menopause from 2011 to 2012. There were 386 treatment cycles; 272 were assigned to dosing schedule 1, which included 20 days of treatment with 10 days of suspension, and 114 were assigned to dosing schedule 2, which included 5 days of treatment and 2 days of suspension. A total of 57 adverse events were registered during the 386-month treatment. For the 20 × 10 dosing schedule, the highest incidence was observed for anxiety (2.2%), drowsiness, and weakness (1.5%); for the 5 × 2 dosing schedule, the highest incidence was observed for drowsiness (5.3%) and headache (2.6%). The Hamilton Depression Rating Scale was used to assess the presence and severity of depression; improvement was noted. The Unified Parkinson's Disease Rating Scale was used to assess neurological movement disorders; no adverse neurological events were detected. Based on the assessments of both women and physicians, the highest frequency was observed for "very satisfied" (45.5% and 52.3%, respectively), followed by "satisfied" (23.9% and 27.3%, respectively). Both dosing schedules show acceptable safety profiles for up to 6 months of use when used according to the contraindications in the current prescribing information for standard use (2012) and recent medical literature.

Comparison of dehydroepiandrosterone (DHEA) and pregnanolone with existing pharmacotherapies for alcohol abuse on ethanol- and food-maintained responding in male rats.

PubMed

Hulin, Mary W; Lawrence, Michelle N; Amato, Russell J; Weed, Peter F; Winsauer, Peter J

2015-03-01

The present study compared two putative pharmacotherapies for alcohol abuse and dependence, dehydroepiandrosterone (DHEA) and pregnanolone, with two Food and Drug Administration (FDA)-approved pharmacotherapies, naltrexone and acamprosate. Experiment 1 assessed the effects of different doses of DHEA, pregnanolone, naltrexone, and acamprosate on both ethanol- and food-maintained responding under a multiple fixed-ratio (FR)-10 FR-20 schedule, respectively. Experiment 2 assessed the effects of different mean intervals of food presentation on responding for ethanol under a FR-10 variable-interval (VI) schedule, whereas Experiment 3 assessed the effects of a single dose of each drug under a FR-10 VI-80 schedule. In Experiment 1, all four drugs dose-dependently decreased response rate for both food and ethanol, although differences in the rate-decreasing effects were apparent among the drugs. DHEA and pregnanolone decreased ethanol-maintained responding more potently than food-maintained responding, whereas the reverse was true for naltrexone. Acamprosate decreased responding for both reinforcers with equal potency. In Experiment 2, different mean intervals of food presentation significantly affected the number of food reinforcers obtained per session; however, changes in the number of food reinforcements did not significantly affect responding for ethanol. Under the FR-10 VI-80 schedule in Experiment 3, only naltrexone significantly decreased both the dose of alcohol presented and blood ethanol concentration (BEC). Acamprosate and pregnanolone had no significant effects on any of the dependent measures, whereas DHEA significantly decreased BEC, but did not significantly decrease response rate or the dose presented. In summary, DHEA and pregnanolone decreased ethanol-maintained responding more potently than food-maintained responding under a multiple FR-10 FR-20 schedule, and were more selective for decreasing ethanol self-administration than either naltrexone or acamprosate under that schedule. Experiment 2 showed that ethanol intake was relatively independent of the interval of reinforcement in the food-maintained component, and Experiment 3 showed that naltrexone was the most effective drug at the doses tested when the interval for food reinforcement was low and maintained under a variable-interval schedule. Copyright © 2015 Elsevier Inc. All rights reserved.

Comparison of dehydroepiandrosterone (DHEA) and pregnanolone with existing pharmacotherapies for alcohol abuse on ethanol- and food-maintained responding in male rats

PubMed Central

Hulin, Mary W.; Lawrence, Michelle N.; Amato, Russell J.; Weed, Peter F.; Winsauer, Peter J.

2015-01-01

The present study compared two putative pharmacotherapies for alcohol abuse and dependence, dehydroepiandrosterone (DHEA) and pregnanolone, with two Food and Drug Administration (FDA)-approved pharmacotherapies, naltrexone and acamprosate. Experiment 1 assessed the effects of different doses of DHEA, pregnanolone, naltrexone, and acamprosate on both ethanol- and food-maintained responding under a multiple fixed-ratio (FR)-10 FR-20 schedule, respectively. Experiment 2 assessed the effects of different mean intervals of food presentation on responding for ethanol under an FR-10 variable-interval (VI) schedule, whereas Experiment 3 assessed the effects of a single dose of each drug under a FR-10 VI-80 schedule. In Experiment 1, all four drugs dose-dependently decreased response rate for both food and ethanol, although differences in the rate-decreasing effects were apparent among the drugs. DHEA and pregnanolone decreased ethanol-maintained responding more potently than food-maintained responding, whereas the reverse was true for naltrexone. Acamprosate decreased responding for both reinforcers with equal potency. In Experiment 2, different mean intervals of food presentation significantly affected the number of food reinforcers obtained per session; however, changes in the number of food reinforcements did not significantly affect responding for ethanol. Under the FR-10 VI-80 schedule in Experiment 3, only naltrexone significantly decreased both the dose of alcohol presented and blood ethanol concentration (BEC). Acamprosate and pregnanolone had no significant effects on any of the dependent measures, whereas DHEA significantly decreased BEC, but did not significantly decrease response rate or the dose presented. In summary, DHEA and pregnanolone decreased ethanol-maintained responding more potently than food-maintained responding under a multiple FR-10 FR-20 schedule, and were more selective for decreasing ethanol self-administration than either naltrexone or acamprosate under that schedule. Experiment 2 showed that ethanol intake was relatively independent of the density of reinforcement in the food-maintained component, and Experiment 3 showed that naltrexone was the most effective drug at the doses tested when the density for food reinforcement was low and maintained under a variable-interval schedule. PMID:25620274

Phase I Study of RO4929097, a Gamma Secretase Inhibitor of Notch Signaling, in Patients With Refractory Metastatic or Locally Advanced Solid Tumors

PubMed Central

Tolcher, Anthony W.; Messersmith, Wells A.; Mikulski, Stanislaw M.; Papadopoulos, Kyriakos P.; Kwak, Eunice L.; Gibbon, Darlene G.; Patnaik, Amita; Falchook, Gerald S.; Dasari, Arvind; Shapiro, Geoffrey I.; Boylan, John F.; Xu, Zhi-Xin; Wang, Ka; Koehler, Astrid; Song, James; Middleton, Steven A.; Deutsch, Jonathan; DeMario, Mark; Kurzrock, Razelle; Wheler, Jennifer J.

2012-01-01

Purpose To determine the maximum-tolerated dose (MTD) and assess safety, pharmacokinetics, pharmacodynamics, and evidence of antitumor activity of RO4929097, a gamma secretase inhibitor of Notch signaling in patients with advanced solid malignancies. Patients and Methods Patients received escalating doses of RO4929097 orally on two schedules: (A) 3 consecutive days per week for 2 weeks every 3 weeks; (B) 7 consecutive days every 3 weeks. To assess reversible CYP3A4 autoinduction, the expanded part of the study tested three dosing schedules: (B) as above; modified A, 3 consecutive d/wk for 3 weeks; and (C) continuous daily dosing. Positron emission tomography scans with [18F]fluorodeoxyglucose (FDG-PET) were used to assess tumor metabolic effects. Results Patients on schedule A (n = 58), B (n = 47), and C (n = 5; expanded cohort) received 302 cycles of RO4929097. Common grade 1 to 2 toxicities were fatigue, thrombocytopenia, fever, rash, chills, and anorexia. Transient grade 3 hypophosphatemia (dose-limiting toxicity, one patient) and grade 3 pruritus (two patients) were observed at 27 mg and 60 mg, respectively; transient grade 3 asthenia was observed on schedule A at 80 mg (one patient). Tumor responses included one partial response in a patient with colorectal adenocarcinoma with neuroendocrine features, one mixed response (stable disease) in a patient with sarcoma, and one nearly complete FDG-PET response in a patient with melanoma. Effect on CYP3A4 induction was observed. Conclusion RO4929097 was well tolerated at 270 mg on schedule A and at 135 mg on schedule B; the safety of schedule C has not been fully evaluated. Further studies are warranted on the basis of a favorable safety profile and preliminary evidence of clinical antitumor activity. PMID:22529266

Immunogenicity and safety of a new hexavalent vaccine (DTaP5-IPV-HB-Hib) administered in a mixed primary series schedule with a pentavalent vaccine (DTaP5-IPV-Hib).

PubMed

Martinón-Torres, Federico; Boisnard, Florence; Thomas, Stéphane; Sadorge, Christine; Borrow, Ray

2017-06-27

DTaP5-IPV-HB-Hib vaccine is a fully-liquid, combination hexavalent vaccine. This phase III, open-label, multicentre study conducted in Spain, evaluated the immune response to all DTaP5-IPV-HB-Hib antigens when the vaccine was used in a mixed hexa/penta/hexa primary series. Infants (who had received one dose of hepatitis B vaccine at birth) received a mixed schedule including DTaP5-IPV-HB-Hib (PRP-OMP conjugate) at 2 and 6months of age, DTaP5-IPV-Hib at 4months, meningococcal serogroup C conjugate (MCC) vaccine at 2 and 4months, and routine rotavirus and pneumococcal vaccination. One month post-dose 3 of the mixed schedule, response rates were considered acceptable if the lower bound of the two-sided 95% confidence interval around the post-vaccination response rate was >90% for hepatitis B and >80% for Haemophilus influenzae type b (Hib). Secondary immunogenicity objectives included description of the antibody response to all hexavalent antigens one month after completion of the mixed schedule, and to MCC antigen one month after the second MCC dose. The safety profile after each dose of study vaccine was described. Of 385 healthy infants enrolled, 384 completed the study. The primary objective was achieved for both hepatitis B and Hib; the lower bound of the 2-sided 95% CI of the response rates (97.2% and 99.0%, respectively) were greater than the pre-specified acceptability thresholds. One month post-dose 3 of the mixed schedule, all participants were seroprotected against diphtheria, tetanus and polio. The mixed schedule induced a robust immune response to all hexavalent antigens. The co-administration of the hexavalent vaccine in a mixed schedule with MCC vaccine did not reduce the immune response to vaccine antigens. Vaccines were well tolerated. In conclusion, the acceptability of response rates against Hib and hepatitis B were demonstrated one month post-dose 3 of the mixed schedule; robust immune responses against all other hexavalent antigens were observed. clinicaltrial.gov: NCT01839188; EudraCT: 2012-004221-25. Copyright © 2017 Elsevier Ltd. All rights reserved.

Treatment of aplastic anaemia with lower-dose anti-thymocyte globulin produces similar response rates and survival as per standard dose anti-thymocyte globulin schedules.

PubMed

Scott, A; Morris, K; Butler, J; Mills, A K; Kennedy, G A

2016-10-01

Aplastic anaemia (AA) is a rare acquired bone marrow failure syndrome resulting from the immune-mediated destruction of haemopoietic stem cells. For adults in whom first-line haemopoietic progenitor cell transplantation is not feasible, combination anti-thymocyte globulin (ATGAM) plus cyclosporine A is standard therapy; however, there are minimal data available regarding the optimal ATGAM dosage in terms of efficacy and survival. Our institutions have historically used different dosing protocols of ATGAM in the treatment of AA. We aimed to review the outcome of AA patients treated with these protocols and compare them to the published literature. We conducted a retrospective study of 31 adults who received first-line ATGAM for AA and compared response rates and survival between cohorts who received standard (40 mg/kg/day D1-4) versus lower-dose (15 mg/kg/day D1-5) ATGAM schedules. There were similar rates of response (64 vs 71%, P = 1.0), relapse (33 vs 33%, P = 1.0), transformation (14 vs 24%, P = 0.66) or infection (43 vs 47%, P = 1.0), respectively, between standard and lower-dose cohorts. At a median follow up of 24 months, there was no statistical difference between standard and lower-dose cohorts in either event-free (42.2 vs 64.7%, P = 0.91) or overall survival (73.1 vs 88.2%, P = 0.75). Our experience suggests that lower-dose ATGAM at 15 mg/kg/day D1-5 as treatment of AA produces similar responses and outcomes as per standard-dose ATGAM schedules. Prospective trials comparing ATGAM dose schedules in AA are warranted. © 2016 Royal Australasian College of Physicians.

Psychomotor stimulant effects of beta-phenylethylamine in monkeys treated with MAO-B inhibitors.

PubMed

Bergman, J; Yasar, S; Winger, G

2001-12-01

Sufficiently high doses of beta-phenylethylamine (beta-PEA), a trace amine that is rapidly metabolized by monoamine oxidase-type B (MAO-B), can produce effects comparable to those of cocaine or methamphetamine (MA). The present experiments were conducted to study how the discriminative-stimulus (S(D)) and reinforcing-stimulus (S(R)) effects of beta-PEA in monkeys are modified by treatment with inhibitors of MAO-B [R-(-)-deprenyl and MDL 72974]. In studies of its S(D) effects, doses of beta-PEA up to 30 mg/kg engendered only sporadic responding on the drug-associated lever in squirrel monkeys that discriminated intramuscular injections of 0.3 mg/kg MA from vehicle whereas lower doses of 0.3-1.0 mg/kg beta-PEA produced full substitution when administered after either R-(-)-deprenyl or MDL 72974 (0.3 mg/kg). The MA-like S(D) effects of beta-PEA were attenuated by either dopamine D(1) or D(2) receptor blockers. In studies of its S(R) effects, high doses of beta-PEA maintained responding in two of three monkeys under a second-order fixed-interval schedule (3.0 or 10 mg/kg per injection) and two of three monkeys under a simple fixed ratio (FR) schedule (0.3-1.0 mg/kg per injection) of intravenous (i.v.) self-administration. MAO-B inhibition by R-(-)-deprenyl or MDL 72974 enhanced the S(R) effects of beta-PEA in all monkeys and, under the FR schedule, induced a 30-fold or greater leftward shift in the dose-response function for its i.v. self-administration. Based on time-course determinations, the enhanced S(R) effects of beta-PEA under the FR schedule were long-lasting and dissipated gradually over 3-7 days. These results show that inhibition of MAO-B enhances S(D) and S(R) effects of beta-PEA in monkeys, presumably by delaying its inactivation. MAO-B inhibition leading to increased levels of beta-PEA may be useful, alone or in combination with other therapeutic agents, in the pharmacological management of selected aspects of drug dependence.

An assessment of prime‐boost vaccination schedules with AS03A‐adjuvanted prepandemic H5N1 vaccines: a randomized study in European adults

PubMed Central

Gillard, Paul; Caplanusi, Adrian; Knuf, Markus; Roman, François; Walravens, Karl; Moris, Philippe; Dramé, Mamadou; Schwarz, Tino F.

2012-01-01

Please cite this paper as: Gillard et al. (2012) An assessment of prime‐boost vaccination schedules with AS03A‐adjuvanted prepandemic H5N1 vaccines: a randomized study in European adults. Influenza and Other Respiratory Viruses DOI: 10.1111/j.1750‐2659.2012.00349.x. Background  Long‐term persistence of immune response and safety of an H5N1 prepandemic influenza vaccine adjuvanted with AS03 (an α‐tocopherol oil‐in‐water emulsion‐based adjuvant system) was evaluated using various prime‐boost schedules that mimicked potential pandemic scenarios (NCT00430521). Methods  Five hundred and twelve healthy adults aged 18–60 years received primary vaccination with one or two doses (0, 21 days schedule) of the A/Vietnam/1194/2004 H5N1 vaccine followed by a booster dose (A/Vietnam/1194/2004 or A/Indonesia/05/2005 strain) six or twelve months later across eight randomized groups. Immunogenicity results by hemagglutination inhibition [HI] assay, microneutralization assay, and the cell‐mediated immune response (CMI) are reported here for the four groups boosted at Month 12. Results  A one‐dose‐adjuvanted primary administration followed 12 months later by a single‐adjuvanted booster dose containing a heterologous vaccine strain met or exceeded all US and European criteria for both strains. Increasing the interval between the first and second dose (from 21 days to 12 months) resulted in stronger cross‐reactive immune responses against the A/Indonesia/05/2005 strain. The HI antibody response against the two strains persisted for 6 months after the booster dose irrespective of the booster vaccine’s strain. The neutralizing antibody responses and the CMI observed in the study population paralleled the HI immune response. Overall, the vaccine had a clinically acceptable safety profile. Conclusion  The H5N1 vaccine in this study allowed for flexibility in the time interval between primary and booster vaccination and the use of a heterologous strain without impacting the strength of the humoral and cellular immune response to both vaccine strains. PMID:22405557

Postantibiotic and Sub-MIC Effects of Azithromycin and Isepamicin against Staphylococcus aureus and Escherichia coli

PubMed Central

Fuentes, F.; Izquierdo, J.; Martín, M. M.; Gomez-Lus, M. L.; Prieto, J.

1998-01-01

Investigations of pharmacodynamic parameters (postantibiotic effect [PAE], sub-MIC effects [SMEs], etc.) have been progressively employed for the design of dosing schedules of antimicrobial agents. However, there are fewer in vivo than in vitro data, probably because of the simplicity of the in vitro procedures. In this study, we have investigated the in vitro PAE, SME, and previously treated (postantibiotic [PA]) SME (1/2 MIC, 1/4 MIC and 1/8 MIC) of azithromycin and isepamicin against standard strains of Staphylococcus aureus and Escherichia coli by using centrifugation to remove the antibiotics. In addition, the in vivo PAE and SME have been studied with the thigh infection model in neutropenic mice. Finally, in vivo killing curves with two dosing schedules were determined to examine whether the PAE can cover the time that antimicrobial agents are below the MIC. The two antimicrobial agents induced moderate-to-high in vitro PAEs, SMEs, and PA SMEs against S. aureus (>8 h) and E. coli (3.38 to >7.64 h). The in vivo PAEs were also high (from 3.0 to 3.6 h), despite the fact that isepamicin had lower times above the MIC in serum. Only azithromycin showed a high in vivo SME against the two strains (1.22 and 1.75 h), which indicated that the in vivo PAEs were possibly overestimated. In the killing kinetics, no great differences (<0.5 log10) were observed between the schedule that took the PAE into account and the continuous administration of doses. These results are comparable with those of other authors and suggest that these antimicrobial agents could be administered at longer intervals without losing effectiveness. PMID:9527796

Rotavirus shedding following administration of RV3-BB human neonatal rotavirus vaccine.

PubMed

Cowley, Daniel; Boniface, Karen; Bogdanovic-Sakran, Nada; Kirkwood, Carl D; Bines, Julie E

2017-08-03

The RV3-BB human neonatal rotavirus vaccine aims to provide protection from severe rotavirus disease from birth. A phase IIa safety and immunogenicity trial was undertaken in Dunedin, New Zealand between January 2012 and April 2014. Healthy, full-term (≥ 36 weeks gestation) babies, who were 0-5 d old were randomly assigned (1:1:1) to receive 3 doses of oral RV3-BB vaccine with the first dose given at 0-5 d after birth (neonatal schedule), or the first dose given at about 8 weeks after birth (infant schedule), or to receive placebo (placebo schedule). Vaccine take (serum immune response or stool shedding of vaccine virus after any dose) was detected after 3 doses of RV3-BB vaccine in >90% of participants when the first dose was administered in the neonatal and infant schedules. The aim of the current study was to characterize RV3-BB shedding and virus replication following administration of RV3-BB in a neonatal and infant vaccination schedule. Shedding was defined as detection of rotavirus by VP6 reverse transcription polymerase chain reaction (RT-PCR) in stool on days 3-7 after administration of RV3-BB. Shedding of rotavirus was highest following vaccination at 8 weeks of age in both neonatal and infant schedules (19/30 and 17/27, respectively). Rotavirus was detected in stool on days 3-7, after at least one dose of RV3-BB, in 70% (21/30) of neonate, 78% (21/27) of infant and 3% (1/32) placebo participants. In participants who shed RV3-BB, rotavirus was detectable in stool on day 1 following RV3-BB administration and remained positive until day 4-5 after administration. The distinct pattern of RV3-BB stool viral load demonstrated using a NSP3 quantitative qRT-PCR in participants who shed RV3-BB, suggests that detection of RV3-BB at day 3-7 was the result of replication rather than passage through the gastrointestinal tract.

Irregular tick-borne encephalitis vaccination schedules: the effect of a single catch-up vaccination with FSME-IMMUN. A prospective non-interventional study.

PubMed

Schosser, Rudolf; Reichert, Anja; Mansmann, Ulrich; Unger, Bernd; Heininger, Ulrich; Kaiser, Reinhard

2014-04-25

Intervals longer than recommended are frequently encountered between doses of tick borne encephalitis virus (TBE) vaccines in both residents of and travelers to endemic regions. In clinical practice the management of individuals with lapsed TBE vaccination schedules varies widely and has in common that the underlying immunological evidence is scarce. The aim of this study was to generate data reliable enough to derive practical recommendations on how to continue vaccination with FSME-IMMUN in subjects with an irregular TBE vaccination history. Antibody response to a single catch-up dose of FSME-IMMUN was assessed in 1115 adults (age ≥16 years) and 125 children (age 6-15 years) with irregular TBE vaccination histories. Subjects of all age groups developed a substantial increase in geometric mean antibody concentration after a single catch-up TBE vaccination which was consistently lower in subjects with only one previous TBE vaccination compared to subjects with two or more vaccinations. Overall, >94% of young adults and children, and >93% of elderly subjects with an irregular TBE vaccination history achieved antibody levels ≥25U/ml irrespective of the number of previous TBE vaccinations. We conclude that TBE vaccination of subjects with irregular vaccination histories should be continued as if the previous vaccinations had been administered in a regular manner, with the stage of the vaccination schedule being determined by the number of previous vaccinations. Although lapsed vaccination schedules may leave subjects temporarily with inadequate protection against TBE infection, adequate protection can quickly be re-established in >93% of the subjects by a single catch-up dose of FSME-IMMUN, irrespective of age, number of previous vaccinations, and time interval since the last vaccination. Copyright © 2014 Anja Reichert. Published by Elsevier Ltd.. All rights reserved.

Aerobic exercise decreases the positive-reinforcing effects of cocaine.

PubMed

Smith, Mark A; Schmidt, Karl T; Iordanou, Jordan C; Mustroph, Martina L

2008-11-01

Aerobic exercise can serve as an alternative, non-drug reinforcer in laboratory animals and has been recommended as a potential intervention for substance abusing populations. Unfortunately, relatively little empirical data have been collected that specifically address the possible protective effects of voluntary, long-term exercise on measures of drug self-administration. The purpose of the present study was to examine the effects of chronic exercise on sensitivity to the positive-reinforcing effects of cocaine in the drug self-administration procedure. Female rats were obtained at weaning and immediately divided into two groups. Sedentary rats were housed individually in standard laboratory cages that permitted no exercise beyond normal cage ambulation; exercising rats were housed individually in modified cages equipped with a running wheel. After 6 weeks under these conditions, rats were surgically implanted with venous catheters and trained to self-administer cocaine on a fixed-ratio schedule of reinforcement. Once self-administration was acquired, cocaine was made available on a progressive ratio schedule and breakpoints were obtained for various doses of cocaine. Sedentary and exercising rats did not differ in the time to acquire cocaine self-administration or responding on the fixed-ratio schedule of reinforcement. However, on the progressive ratio schedule, breakpoints were significantly lower in exercising rats than sedentary rats when responding was maintained by both low (0.3mg/kg/infusion) and high (1.0mg/kg/infusion) doses of cocaine. In exercising rats, greater exercise output prior to catheter implantation was associated with lower breakpoints at the high dose of cocaine. These data indicate that chronic exercise decreases the positive-reinforcing effects of cocaine and support the possibility that exercise may be an effective intervention in drug abuse prevention and treatment programs.

Dose and timing in neurorehabilitation: Prescribing motor therapy after stroke

PubMed Central

Lang, Catherine E.; Lohse, Keith R.; Birkenmeier, Rebecca L.

2015-01-01

Purpose of the review Prescribing the most appropriate dose of motor therapy for individual patients is a challenge because minimal data are available and a large number of factors are unknown. This review explores the concept of dose and reviews the most recent findings in the field of neurorehabilitation, with a focus on relearning motor skills post stroke. Recent findings Appropriate dosing involves the prescription of a specific amount of an active ingredient, at a specific frequency and duration. Dosing parameters, particularly amount, are not well-defined or quantified in most studies. Compiling data across studies indicates a positive, moderate dose-response relationship, indicating that more movement practice results in better outcomes. This relationship is confounded by time post stroke however, where longer durations of scheduled therapy may not be beneficial in the first few hours, days, and/or weeks. Summary These findings suggest that substantially more movement practice may be necessary to achieve better outcomes for people living with the disabling consequences of stroke. Preclinical investigations are needed to elucidate many of the unknowns and allow for a more biologically-driven rehabilitation prescription process. Likewise, clinical investigations are needed to determine the dose-response relationships and examine the potential dose-timing interaction in humans. PMID:26402404

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.

[Post-exposure antirabies vaccination. Early serological response to vaccine cultivated on VERO cells using a reduced 2-1-1 schedule].

PubMed

Colnot, F; Sureau, P; Alexandre, J L; Arnaudo, J P; Hesse, J Y; Jeanmaire, H

1994-11-12

An abbreviated 2-1-1 schedule for post-exposure rabies vaccination would theoretically lead to more rapid production of specific antibodies than the classical schedule. We measured early serological response to the 2-1-1 schedule. Patients consulting the antirabies centre of the Epinal hospital from June 1992 to June 1993 who had never been vaccinated and whose exposure history justified antirabies vaccination were included in this study. Fifty subjects were vaccinated with PVRV (purified vero rabies vaccine, Pasteur Institute) cultured on VERO (vervet monkey origin) cells using the abbreviated 2-1-1 schedule of 2 doses (0.5 ml = 2.5 IU/dose) on day 0 and 1 dose on days 7 and 21. Antirabies antibodies were assayed using the Platelia Rage immunoenzyme method (Diagnostic Pasteur) on day 21. Titres above 0.5 IU were considered to give protection and non-protected subjects were seen again on day 28 for a supplementary dose. Only 34 subjects (68%) had protective antibody titres on day 21, but by day 28, 48 (96%) had acquired immunity. In this study population, the age range was from 1 to 83 years and age over 30 years appeared to delay antibody formation. These findings emphasize the importance of initial antirabies immunoglobulins if short incubation in suspected and the need for serological follow-up if delayed antibody formation is suspected (subjects over 30).

Effectiveness of different vaccine schedules for heptavalent and 13-valent conjugate vaccines against pneumococcal disease in the Community of Madrid.

PubMed

Latasa, P; Ordobás, M; Garrido-Estepa, M; Gil de Miguel, A; Sanz, J C; Barranco, M D; Insúa, E; García-Comas, L

2017-09-25

The heptavalent pneumococcal conjugate vaccine (PCV-7) was added to the childhood routine vaccination program in the Community of Madrid in November of 2006 with 3+1 recommended doses and a catch-up for those under 2years old. In June 2010, PCV-7 was replaced by 13-valent vaccine (PCV-13) with 2+1 recommended doses. In July of 2012, the PCV-13 was removed from the funded program and reintroduced again (2+1 recommended doses) in December 2014. In between, children were vaccinated privately with 3+1 recommended doses of PCV-13. The aim of this study was to evaluate the effectiveness of each vaccination schedule used in the Community of Madrid. We included all cases of invasive pneumococcal disease (IPD) reported between 2007 and 2015 to the Notifiable Diseases Surveillance System. Vaccination information was obtained from the Immunization Registry. Vaccine effectiveness (VE) was estimated using the indirect cohort design for cases with serotype information. A total 779 cases were included in the study. Among them 47.6% of the cases were primo-vaccinated with booster, 20% primo-vaccinated, 15.9% incompletely primo-vaccinated and 16.5% not vaccinated. The VE for ≥1 doses of any PCV was 82% (CI 95%: 67.8-89.9%): 91.9% (CI 95%: 76.5-97.2%) for PCV-7 and 77.2% (48.6-89.9%) for PCV-13. VE in those receiving the full 2+1 or 3+1 schedules was 100% for both vaccines. A high number of vaccine failures were reported in children before they had the opportunity to receive the booster dose, especially due to PCV-13-non-PCV-7 serotypes. VE was higher for PCV-7 compared to PCV-13, except for those that received the complete schedule with booster that achieved 100% of VE, which shows the relevance of the vaccines and complying with all doses scheduled. Copyright © 2017 Elsevier Ltd. All rights reserved.

Management of pegylated interferon alpha toxicity in adjuvant therapy of melanoma.

PubMed

Daud, Adil; Soon, Christopher; Dummer, Reinhard; Eggermont, Alexander M M; Hwu, Wen-Jen; Grob, Jean Jacques; Garbe, Claus; Hauschild, Axel

2012-08-01

Both native IFNα2b and pegylated IFNα2b (PegIFNα2b) are approved for the adjuvant treatment of high-risk melanoma. This review compares the toxicity profiles of high-dose IFNα2b (HDI) and PegIFNα2b, and provides recommendations on the management of common PegIFNα2b-related toxicities, based on available clinical data and published literature. The toxicity profile of PegIFNα2b at the approved dose (6 μg/kg/week for 8 weeks then 3 μg/kg/week for up to 5 years) is qualitatively similar to HDI in melanoma. The most common adverse events (AEs) are fatigue, anorexia, hepatotoxicity, flu-like symptoms, injection site reactions and depression. However, fatigue and flu-like symptoms appear less severe with PegIFNα2b, and toxicity seems to occur earlier, whereas with HDI toxicity may increase with time. Most AEs can be managed effectively by dose modification and aggressive symptom control. Dosing to tolerance using a three-step dose reduction schedule to maintain an ECOG performance status of 0 - 1 may enable patients experiencing toxicity to remain on treatment; this can be applied readily in clinical practice. PegIFNα2b is therefore a valuable alternative option for adjuvant treatment in melanoma, with a toxicity profile similar to that of HDI overall but a more convenient administration schedule.

Immunogenicity, reactogenicity and safety of the human rotavirus vaccine RIX4414 (Rotarix™) oral suspension (liquid formulation) when co-administered with expanded program on immunization (EPI) vaccines in Vietnam and the Philippines in 2006-2007.

PubMed

Anh, D D; Carlos, C C; Thiem, D V; Hutagalung, Y; Gatchalian, S; Bock, H L; Smolenov, I; Suryakiran, P V; Han, H H

2011-03-03

Evaluation of immunogenicity and safety of a 2-dose liquid formulation of human rotavirus vaccine, RIX4414 following WHO's Expanded Program on Immunization (EPI) schedule (0, 1, and 2 months; Month 0 indicates day of enrollment) in Vietnam and the Philippines. Infants aged 6-10 (mean=8.7 ± 1.07 weeks Vietnam) and 5-10 weeks (mean=6.6 ± 1.03 weeks Philippines) received two doses of RIX4414 vaccine (V) and one dose of placebo (PL) or three placebo doses concomitantly with commercially available diphtheria-tetanus-whole-cell pertussis, hepatitis B and oral poliovirus vaccines. The vaccination schedules were: V-V-PL, V-PL-V and PL-PL-PL (Vietnam); PL-V-V, V-PL-V and PL-PL-PL (Philippines). Anti-rotavirus seroconversion rate was assessed pre-vaccination and post-vaccination (ELISA cut-off=20 U/ml). 375 infants were enrolled in each country. Seroconversion rates at one month post-Dose 2 of RIX4414 were Vietnam 63.3% (95% CI: 54.3-71.6) in V-V-PL group and 81.5% (95% CI: 73.4-88) in V-PL-V group; Philippines 70% (95% CI: 61-78) in PL-V-V group and 59.2% (95% CI: 49.8-68) in V-PL-V group. Frequencies of solicited (8-day post-each dose) and unsolicited symptoms (31-day post-each dose) were similar. Two-doses of rotavirus vaccine administered within the WHO EPI offer flexibility in existing schedule, though both schedules provides good immune responses. Copyright © 2011 Elsevier Ltd. All rights reserved.

Immunogenicity of HPV prophylactic vaccines: Serology assays and their use in HPV vaccine evaluation and development.

PubMed

Pinto, Ligia A; Dillner, Joakim; Beddows, Simon; Unger, Elizabeth R

2018-01-17

When administered as standard three-dose schedules, the licensed HPV prophylactic vaccines have demonstrated extraordinary immunogenicity and efficacy. We summarize the immunogenicity of these licensed vaccines and the most commonly used serology assays, with a focus on key considerations for one-dose vaccine schedules. Although immune correlates of protection against infection are not entirely clear, both preclinical and clinical evidence point to neutralizing antibodies as the principal mechanism of protection. Thus, immunogenicity assessments in vaccine trials have focused on measurements of antibody responses to the vaccine. Non-inferiority of antibody responses after two doses of HPV vaccines separated by 6 months has been demonstrated and this evidence supported the recent WHO recommendations for two-dose vaccination schedules in both boys and girls 9-14 years of age. There is also some evidence suggesting that one dose of HPV vaccines may provide protection similar to the currently recommended two-dose regimens but robust data on efficacy and immunogenicity of one-dose vaccine schedules are lacking. In addition, immunogenicity has been assessed and reported using different methods, precluding direct comparison of results between different studies and vaccines. New head-to-head vaccine trials evaluating one-dose immunogenicity and efficacy have been initiated and an increase in the number of trials relying on immunobridging is anticipated. Therefore, standardized measurement and reporting of immunogenicity for the up to nine HPV types targeted by the current vaccines is now critical. Building on previous HPV serology assay standardization and harmonization efforts initiated by the WHO HPV LabNet in 2006, new secondary standards, critical reference reagents and testing guidelines will be generated as part of a new partnership to facilitate harmonization of the immunogenicity testing in new HPV vaccine trials. Copyright © 2018 Elsevier Ltd. All rights reserved.

Preliminary evaluation of safety and activity of recombinant human interleukin 11 in patients with active Crohn's disease.

PubMed

Sands, B E; Bank, S; Sninsky, C A; Robinson, M; Katz, S; Singleton, J W; Miner, P B; Safdi, M A; Galandiuk, S; Hanauer, S B; Varilek, G W; Buchman, A L; Rodgers, V D; Salzberg, B; Cai, B; Loewy, J; DeBruin, M F; Rogge, H; Shapiro, M; Schwertschlag, U S

1999-07-01

Recombinant human interleukin 11 (rhIL-11) is a cytokine with thrombocytopoietic activity and anti-inflammatory and mucosal protective effects. The objectives of this study were to investigate the safety and tolerability of rhIL-11 in patients with Crohn's disease and to explore the effects of dose and schedule on platelet count and Crohn's disease activity. A multicenter, double-masked, placebo-controlled, dose-escalation study of 76 patients with active Crohn's disease was performed. Patients were randomized to receive subcutaneous placebo or rhIL-11 at doses of 5, 16, or 40 microgram. kg-1. wk-1 given 2 or 5 times weekly for 3 weeks. Clinical and laboratory safety data were recorded, and disease activity was measured at each visit. Subcutaneous injection of rhIL-11 generally was well tolerated. Significantly greater increases in platelet counts were found among patients receiving rhIL-11 40 microgram. kg-1. wk-1 as 2 or 5 weekly doses and 16 microgram. kg-1. week-1 as 5 weekly doses compared with patients receiving placebo (P < 0.05). Patients receiving 16 microgram. kg-1. wk-1 had the highest clinical response rates, with a response seen in 42% of patients (5/12) receiving 5 weekly doses and 33% of patients (4/12) receiving 2 weekly doses, compared with 7% of patients (1/15) receiving placebo. Short-term treatment with rhIL-11 is well tolerated in patients with active Crohn's disease. The thrombocytopoietic effect of rhIL-11 seems to be both dose and schedule dependent and may be minimized with retained clinical benefit in Crohn's disease at 16 microgram. kg-1. wk-1 given in 2 equal doses.

Dose Schedule and Enhanced Conversational Recast Treatment for Children with Specific Language Impairment

ERIC Educational Resources Information Center

Meyers-Denman, Christina N.; Plante, Elena

2016-01-01

Purpose: Dosage has been identified as an important element of treatment that may affect treatment efficacy. The purpose of this study was to examine the role of dose schedule for treatment of grammatical morphology deficits in children with specific language impairment (SLI). Method: Sixteen 4-to-5-year-old children with SLI participated in a…

Efficacy of osmoprotectants on prevention and treatment of murine dry eye.

PubMed

Chen, Wei; Zhang, Xin; Li, Jinyang; Wang, Yu; Chen, Qi; Hou, Chao; Garrett, Qian

2013-09-19

To evaluate the efficacy of osmoprotectants on prevention and treatment of dry eye in a murine model. Dry eye was induced in mice by using an intelligently controlled environmental system (ICES). Osmoprotectants betaine, L-carnitine, erythritol, or vehicle (PBS) were topically administered to eyes four times daily following two schedules: schedule 1 (modeling prevention): dosing started at the beginning of housing in ICES and lasted for 21 or 35 days; schedule 2 (modeling treatment): dosing started after ICES-housed mice developed dry eye (day 21), continuing until day 35. Treatment efficacy was evaluated for corneal fluorescein staining; corneal epithelial apoptosis by TUNEL and caspase-3 assays; goblet cell numbers by PAS staining; and expression of inflammatory mediators, TNF-α, IL-17, IL-6, or IL-1β by using RT-PCR on days 0, 14, 21, and/or 35. Compared with vehicle, prophylactic administration of betaine, L-carnitine, or erythritol significantly decreased corneal staining and expression of TNF-α and IL-17 on day 21 (schedule 1). Treatment of mouse dry eye with osmoprotectants significantly reduced corneal staining on day 35 compared with day 21 (schedule 2). Relative to vehicle, L-carnitine treatment of mouse dry eye for 14 days (days 21 to 35) resulted in a significant reduction in corneal staining, number of TUNEL-positive cells, and expression of TNF-α, IL-17, IL-6, or IL-1β, as well as significantly increased the number of goblet cells. Topical application of betaine, L-carnitine, or erythritol systematically limited progression of environmentally induced dry eye. L-carnitine can also reduce the severity of such dry-eye conditions.

An oracle: antituberculosis pharmacokinetics-pharmacodynamics, clinical correlation, and clinical trial simulations to predict the future.

PubMed

Pasipanodya, Jotam; Gumbo, Tawanda

2011-01-01

Antimicrobial pharmacokinetic-pharmacodynamic (PK/PD) science and clinical trial simulations have not been adequately applied to the design of doses and dose schedules of antituberculosis regimens because many researchers are skeptical about their clinical applicability. We compared findings of preclinical PK/PD studies of current first-line antituberculosis drugs to findings from several clinical publications that included microbiologic outcome and pharmacokinetic data or had a dose-scheduling design. Without exception, the antimicrobial PK/PD parameters linked to optimal effect were similar in preclinical models and in tuberculosis patients. Thus, exposure-effect relationships derived in the preclinical models can be used in the design of optimal antituberculosis doses, by incorporating population pharmacokinetics of the drugs and MIC distributions in Monte Carlo simulations. When this has been performed, doses and dose schedules of rifampin, isoniazid, pyrazinamide, and moxifloxacin with the potential to shorten antituberculosis therapy have been identified. In addition, different susceptibility breakpoints than those in current use have been identified. These steps outline a more rational approach than that of current methods for designing regimens and predicting outcome so that both new and older antituberculosis agents can shorten therapy duration.

Immunogenicity, reactogenicity and safety of 2 doses of an adjuvanted herpes zoster subunit vaccine administered 2, 6 or 12 months apart in older adults: Results of a phase III, randomized, open-label, multicenter study.

PubMed

Lal, Himal; Poder, Airi; Campora, Laura; Geeraerts, Brecht; Oostvogels, Lidia; Vanden Abeele, Carline; Heineman, Thomas C

2018-01-02

In phase III trials, 2 doses of a herpes zoster (HZ) subunit vaccine (HZ/su; 50 µg varicella-zoster virus glycoprotein E [gE] and AS01 B Adjuvant System) administered 2-months apart in older adults (≥50 and ≥70 years) demonstrated >90% efficacy in preventing HZ and had a clinically acceptable safety profile. Here we report immunogenicity, reactogenicity and safety following administration of 2 HZ/su doses at intervals longer than 2 months. In this Phase III, open-label trial conducted in the US and Estonia, 354 adults ≥50 years were randomized 1:1:1 to receive 2 HZ/su doses 2, 6, or 12 months apart. gE-specific humoral immune responses were evaluated at pre-vaccination, 1 and 12 months post-dose 2. Co-primary objectives were to compare immune responses to HZ/su 1 month post-dose 2 when given 6-months or 12-months apart to those administered 2-months apart. For each participant, safety information was collected from dose 1 to 12 months post-dose 2. 346 participants completed the study and 343 were included in the according-to-protocol cohort for immunogenicity. One month post-dose 2, vaccine response rates were 96.5% (97.5% confidence interval [CI]: 90.4; 99.2) and 94.5% (97.5% CI: 87.6; 98.3) for the 0, 6- and 0, 12-month schedules, respectively, both schedules meeting the pre-defined criterion. Non-inferiority of anti-gE geometric mean concentrations was demonstrated for HZ/su administered on 0, 6-month compared to a 0, 2-month schedule; however, HZ/su administered on a 0, 12-month schedule did not meet the non-inferiority criterion. Injection site pain was the most commonly reported solicited adverse event (AE). 26 participants each reported at least 1 serious AE; none were assessed as related to vaccination. Immune responses to HZ/su administered at 0, 6-month were non-inferior to those elicited by a 0, 2-month schedule. HZ/su exhibited a clinically acceptable safety profile for all dosing intervals. Clinicaltrials.gov (NCT01751165). Copyright © 2017. Published by Elsevier Ltd.

Low-dose factor VIII infusion in Chinese adult haemophilia A patients: pharmacokinetics evidence that daily infusion results in higher trough level than with every-other-day infusion with similar factor VIII consumption.

PubMed

Hua, B; Lee, A; Fan, L; Li, K; Zhang, Y; Poon, M-C; Zhao, Y

2017-05-01

Pharmacokinetics (PK) modelling suggests improvement of trough levels are achieved by using more frequent infusion strategy. However, no clinical study data exists to confirm or quantify improvement in trough level, particularly for low-dose prophylaxis in patients with haemophilia A. To provide evidence that low dose daily (ED) prophylaxis can increase trough levels without increasing FVIII consumption compared to every-other-day (EOD) infusion. A cross-over study on 5 IU kg -1 FVIII daily vs. 10 IU kg -1 EOD infusions, each for 14 days was conducted at the PUMCH-HTC. On the ED schedule, trough (immediate prior to infusion), and peak FVIII:C levels (30 min after infusion) were measured on days 1-5; and trough levels alone on days 7, 9, 11 and 13. For the EOD schedule, troughs, peaks and 4-h postinfusion were measured on day 1; troughs and peaks on days 3, 5, and 7; troughs alone on days 9, 11 and 13 and 24-h postinfusion on days 2, 4 and 6. FVIII inhibitors were assessed on days 0 and 14 during both infusion schedules. Six patients were enrolled. PK evidence showed that daily prophylaxis achieved higher (~2 times) steady-state FVIII trough levels compared to EOD with the same total factor consumption. The daily prophylaxis had good acceptability among patients and reduced chronic pain in the joints in some patients. Our PK study shows low-dose factor VIII daily infusion results in higher trough level than with EOD infusion with similar factor VIII consumption in Chinese adult haemophilia A patients. © 2017 John Wiley & Sons Ltd.

Gemcitabine and cisplatin in a concomitant alternating chemoradiotherapy program for locally advanced head-and-neck cancer: A pharmacology-guided schedule

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

Numico, Gianmauro; Russi, Elvio G.; Vitiello, Raffele

Purpose: Administration of gemcitabine together with cisplatin at cytotoxic doses in a chemoradiotherapy regimen is hampered by a high degree of local toxicity. Using the pharmacologic properties of the drug we designed a modified schedule aimed at reducing toxicity while preserving activity. Methods and Materials: Patients with squamous cell carcinomas of the oral cavity, pharynx and larynx, bulky T4, and/or N2 to N3 were eligible. Gemcitabine was administered at a dose of 800 mg/m{sup 2} on Days 1 and 12 and cisplatin at a dose of 20 mg/m{sup 2} on Days 2 to 5, every 21 days for 3 courses.more » Radiotherapy, delivered with standard fractionation, was given on Days 8 to 12 and 15 to 19 and was repeated 3 times up to a total dose of {>=}60 Gy. Results: A total of 28 patients were selected. Grade 3 to 4 stomatitis was recorded in 25 patients (89%). Thirteen patients (46%) experienced Grade 3 to 4 neutropenia. Febrile neutropenia occurred in 8 patients (29%) and in 2 was complicated by infection and death. The overall complete response rate was 79%. At a median follow up of 71 months, 11 patients had a locoregional relapse (3-year locoregional control, 64%); 6 patients had distant metastases, among whom only 2 were without locoregional recurrence. The 3-year progression-free survival is 39% and 3-year overall survival has been 43%. Conclusion: The schedule modification did not attenuate local toxicity. Moreover, infections and especially pneumonia, were a major problem. The high activity of gemcitabine when combined with radiotherapy would most likely be better exploited in the context of modified radiation schemes.« less

Sex, PrEP, and Stigma: Experiences with HIV Pre-exposure Prophylaxis Among New York City MSM Participating in the HPTN 067/ADAPT Study.

PubMed

Franks, Julie; Hirsch-Moverman, Yael; Loquere, Avelino S; Amico, K Rivet; Grant, Robert M; Dye, Bonnie J; Rivera, Yan; Gamboa, Robert; Mannheimer, Sharon B

2018-04-01

The HPTN 067/Alternative Dosing to Augment Pre-Exposure Prophylaxis Pill Taking (ADAPT) study evaluated daily and non-daily dosing schedules for oral pre-exposure prophylaxis (PrEP) to prevent HIV. A qualitative sub-study including focus groups and in-depth interviews was conducted among men who have sex with men participating in New York City to understand their experience with PrEP and study dosing schedules. The 37 sub-study participants were 68% black, 11% white, and 8% Asian; 27% were of Hispanic/Latino ethnicity. Mean age was 34 years. Themes resulting from qualitative analysis include: PrEP is a significant advance for HIV prevention; non-daily dosing of PrEP is congruent with HIV risk; and pervasive stigma connected to HIV and risk behavior is a barrier to PrEP adherence, especially for non-daily dosing schedules. The findings underscore how PrEP intersects with other HIV prevention practices and highlight the need to understand and address multidimensional stigma related to PrEP use.

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.

Treatment of hyperthyroidism with radioiodine targeted activity: A comparison between two dosimetric methods.

PubMed

Amato, Ernesto; Campennì, Alfredo; Leotta, Salvatore; Ruggeri, Rosaria M; Baldari, Sergio

2016-06-01

Radioiodine therapy is an effective and safe treatment of hyperthyroidism due to Graves' disease, toxic adenoma, toxic multinodular goiter. We compared the outcomes of a traditional calculation method based on an analytical fit of the uptake curve and subsequent dose calculation with the MIRD approach, and an alternative computation approach based on a formulation implemented in a public-access website, searching for the best timing of radioiodine uptake measurements in pre-therapeutic dosimetry. We report about sixty-nine hyperthyroid patients that were treated after performing a pre-therapeutic dosimetry calculated by fitting a six-point uptake curve (3-168h). In order to evaluate the results of the radioiodine treatment, patients were followed up to sixty-four months after treatment (mean 47.4±16.9). Patient dosimetry was then retrospectively recalculated with the two above-mentioned methods. Several time schedules for uptake measurements were considered, with different timings and total number of points. Early time schedules, sampling uptake up to 48h, do not allow to set-up an accurate treatment plan, while schedules including the measurement at one week give significantly better results. The analytical fit procedure applied to the three-point time schedule 3(6)-24-168h gave results significantly more accurate than the website approach exploiting either the same schedule, or the single measurement at 168h. Consequently, the best strategy among the ones considered is to sample the uptake at 3(6)-24-168h, and carry out an analytical fit of the curve, while extra measurements at 48 and 72h lead only marginal improvements in the accuracy of therapeutic activity determination. Copyright © 2016 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

Human Neonatal Rotavirus Vaccine (RV3-BB) to Target Rotavirus from Birth.

PubMed

Bines, Julie E; At Thobari, Jarir; Satria, Cahya Dewi; Handley, Amanda; Watts, Emma; Cowley, Daniel; Nirwati, Hera; Ackland, James; Standish, Jane; Justice, Frances; Byars, Gabrielle; Lee, Katherine J; Barnes, Graeme L; Bachtiar, Novilia S; Viska Icanervilia, Ajeng; Boniface, Karen; Bogdanovic-Sakran, Nada; Pavlic, Daniel; Bishop, Ruth F; Kirkwood, Carl D; Buttery, Jim P; Soenarto, Yati

2018-02-22

A strategy of administering a neonatal rotavirus vaccine at birth to target early prevention of rotavirus gastroenteritis may address some of the barriers to global implementation of a rotavirus vaccine. We conducted a randomized, double-blind, placebo-controlled trial in Indonesia to evaluate the efficacy of an oral human neonatal rotavirus vaccine (RV3-BB) in preventing rotavirus gastroenteritis. Healthy newborns received three doses of RV3-BB, administered according to a neonatal schedule (0 to 5 days, 8 weeks, and 14 weeks of age) or an infant schedule (8 weeks, 14 weeks, and 18 weeks of age), or placebo. The primary analysis was conducted in the per-protocol population, which included only participants who received all four doses of vaccine or placebo within the visit windows, with secondary analyses performed in the intention-to-treat population, which included all participants who underwent randomization. Among the 1513 participants in the per-protocol population, severe rotavirus gastroenteritis occurred up to the age of 18 months in 5.6% of the participants in the placebo group (28 of 504 babies), in 1.4% in the neonatal-schedule vaccine group (7 of 498), and in 2.7% in the infant-schedule vaccine group (14 of 511). This resulted in a vaccine efficacy of 75% (95% confidence interval [CI], 44 to 91) in the neonatal-schedule group (P<0.001), 51% (95% CI, 7 to 76) in the infant-schedule group (P=0.03), and 63% (95% CI, 34 to 80) in the neonatal-schedule and infant-schedule groups combined (combined vaccine group) (P<0.001). Similar results were observed in the intention-to-treat analysis (1649 participants); the vaccine efficacy was 68% (95% CI, 35 to 86) in the neonatal-schedule group (P=0.001), 52% (95% CI, 11 to 76) in the infant-schedule group (P=0.02), and 60% (95% CI, 31 to 76) in the combined vaccine group (P<0.001). Vaccine response, as evidenced by serum immune response or shedding of RV3-BB in the stool, occurred in 78 of 83 participants (94%) in the neonatal-schedule group and in 83 of 84 participants (99%) in the infant-schedule group. The incidence of adverse events was similar across the groups. No episodes of intussusception occurred within the 21-day risk period after administration of any dose of vaccine or placebo, and one episode of intussusception occurred 114 days after the third dose of vaccine in the infant-schedule group. RV3-BB was efficacious in preventing severe rotavirus gastroenteritis when administered according to a neonatal or an infant schedule in Indonesia. (Funded by the Bill and Melinda Gates Foundation and others; Australian New Zealand Clinical Trials Registry number, ACTRN12612001282875 .).

Effectiveness of Haemophilus influenzae type b vaccines administered according to various schedules: systematic review and meta-analysis of observational data.

PubMed

Jackson, Charlotte; Mann, Andrea; Mangtani, Punam; Fine, Paul

2013-11-01

Conjugate vaccines against Haemophilus influenzae type b (Hib) are widely used. The full implications of Hib vaccination schedule for vaccine effectiveness (VE) are unclear. We searched the literature for observational studies reporting the effectiveness of conjugate Hib vaccines administered according to different schedules. We summarized dose-specific VE estimates, where appropriate, using random effects meta-analysis. Thirty-one eligible articles (reporting 30 studies conducted in 17 countries) were identified. Meta-analysis of case-control studies using community controls produced VE estimates against Hib meningitis of 55% (95% confidence interval: 2-80%, based on 3 studies), 96% (86-99%, 3 studies) and 96% (86-99%, 4 studies) after 1, 2 and 3 doses of vaccines other than the polyribosyl ribitol phosphate outer membrane protein vaccine. Estimates were similar using hospital controls. VE against invasive Hib disease in case-control studies was estimated as 59% (30-76%, 3 studies) and 97% (87-99%, 3 studies) for 1 and 3 doses (insufficient data were identified to estimate 2-dose VE). Point estimates from 2 studies suggested VE>90% after 1 dose of the polyribosyl ribitol phosphate outer membrane protein vaccine, but meta-analysis was not possible. Using data from 4 cohort studies, 3-dose VE was estimated as 94% (88-97%). There was some evidence that Hib vaccine was less effective when administered with acellular (rather than whole cell) pertussis vaccine. Weak evidence from 2 studies suggested that a booster confers some additional protection following full primary vaccination and may compensate for an incomplete primary series. Observational data suggest that ≥2 doses of Hib vaccine are required for high effectiveness, but do not strongly favor any particular schedule.

Booster dose vaccination for preventing hepatitis B.

PubMed

Poorolajal, Jalal; Hooshmand, Elham

2016-06-07

Antibodies against hepatitis B surface antigen (HBsAg) wane over time following hepatitis B immunisation; hence, it is unclear whether people vaccinated in three-dose or four-dose schedules of the hepatitis B vaccine are still immune when the hepatitis B surface antibody (anti-HBs) level in their body is undetectable, or lower than the level usually considered protective. This question may potentially be answered indirectly by measuring the anamnestic immune response to a booster dose of vaccine. The term 'booster' (or revaccination) refers to an additional dose of hepatitis B vaccine (HBV) given some time post-primary vaccination to induce immune memory and improve protection against hepatitis B virus (HBV) infection. To assess the benefits and harms of booster dose hepatitis B vaccination, more than five years after the primary vaccination, for preventing HBV infection in healthy individuals previously vaccinated with the hepatitis B vaccine, and with hepatitis B surface antibody (anti-HBs) levels below 10 mIU/mL. We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Science Citation Index Expanded, conference databases, and reference lists of articles to January 2016. We also contacted authors of articles. In addition, we searched ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform for ongoing trials (May 2016). Randomised clinical trials addressing anamnestic immune response to a booster dose of hepatitis B vaccine, more than five years after the primary vaccination, in apparently healthy participants, vaccinated in a three-dose or four-dose schedule of the hepatitis B vaccine during the primary vaccination, without receiving an additional dose or immunoglobulin. Both review authors decided if the identified studies met the inclusion criteria or not. Primary outcomes included the proportion of participants with anamnestic immune response in non-protected participants and signs of HBV infection. Secondary outcomes were the proportion of participants that developed local and systemic adverse events following a booster dose injection. We planned to report the weighted proportion with 95% confidence intervals (CIs). There were no eligible randomised clinical trials fulfilling the inclusion criteria of this review. We were unable to include any randomised clinical trials on the topic; only randomised clinical trials will be able to provide an answer as to whether a booster dose vaccination is able to protect against hepatitis B infection.

Effect of Age at Vaccination on Rotavirus Vaccine Effectiveness in Bolivian Infants.

PubMed

Burke, Rachel M; Tate, Jacqueline E; Pringle, Kimberly D; Patel, Manish; De Oliveira, Lucia H; Parashar, Umesh D

2018-01-16

Rotavirus vaccines are less effective in developing countries versus developed countries. One hypothesis for this difference in performance is that higher levels of maternal antibodies in developing countries may interfere with vaccine response, suggesting that delayed dosing could be beneficial. The present analysis aims to assess whether rotavirus vaccine effectiveness (VE) varies by age at vaccination during routine use in Bolivia. Data were merged from two post-licensure evaluations of monovalent rotavirus vaccine (RV1) in Bolivia, where two doses of RV1 are recommended at two and four months of age. For each dose, children were classified as receiving each dose "early," "on-time," or "late." Stratified unconditional logistic regression models were used to estimate VE, using unvaccinated children as the referent. VE was calculated as (1 - odds ratio) x 100%. Models were adjusted for hospital, age, and time since RV1 introduction (via including terms for month and year of birth). VE for two doses of RV1 tended to be higher in infants receiving the first dose early (VE 92%; 95% confidence interval [CI] [70%, 98%]), when compared to infants receiving their first dose on time (72% [62%, 81%]) or late (68% [51%, 79%]). Estimates of VE were not substantially different when comparing children by age at second dose (early: VE 76% [50%, 89%]; on time: VE 70% [50%, 89%]; late: VE 75% [60%, 84%]), including all children. Our results indicate that early administration may improve VE and support the current WHO recommendations for the RV1 schedule.

Inclusion of a variable RBE into proton and photon plan comparison for various fractionation schedules in prostate radiation therapy.

PubMed

Ödén, Jakob; Eriksson, Kjell; Toma-Dasu, Iuliana

2017-03-01

A constant relative biological effectiveness (RBE) of 1.1 is currently used in proton radiation therapy to account for the increased biological effectiveness compared to photon therapy. However, there is increasing evidence that proton RBE vary with the linear energy transfer (LET), the dose per fraction, and the type of the tissue. Therefore, this study aims to evaluate the impact of disregarding variations in RBE when comparing proton and photon dose plans for prostate treatments for various fractionation schedules using published RBE models and several α/β assumptions. Photon and proton dose plans were created for three generic prostate cancer cases. Three BED 3Gy equivalent schedules were studied, 78, 57.2, and 42.8 Gy in 39, 15, and 7 fractions, respectively. The proton plans were optimized assuming a constant RBE of 1.1. By using the Monte Carlo calculated dose-averaged LET (LET d ) distribution and assuming α/β values on voxel level, three variable RBE models were applied to the proton dose plans. The impact of the variable RBE was studied in the plan comparison, which was based on the dose distribution, DVHs, and normal tissue complication probabilities (NTCP) for the rectum. Subsequently, the physical proton dose was reoptimized for each proton plan based on the LET d distribution, to achieve a homogeneous RBE-weighted target dose when applying a specific RBE model and still fulfill the clinical goals for the rectum and bladder. All the photon and proton plans assuming RBE = 1.1 met the clinical goals with similar target coverage. The proton plans fulfilled the robustness criteria in terms of range and setup uncertainty. Applying the variable RBE models generally resulted in higher target doses and rectum NTCP compared to the photon plans. The increase was most pronounced for the fractionation dose of 2 Gy(RBE), whereas it was of less magnitude and more dependent on model and α/β assumption for the hypofractionated schedules. The reoptimized proton plans proved to be robust and showed similar target coverage and doses to the organs at risk as the proton plans optimized with a constant RBE. Model predicted RBE values may differ substantially from 1.1. This is most pronounced for fractionation doses of around 2 Gy(RBE) with higher doses to the target and the OARs, whereas the effect seems to be of less importance for the hypofractionated schedules. This could result in misleading conclusions when comparing proton plans to photon plans. By accounting for a variable RBE in the optimization process, robust and clinically acceptable dose plans, with the potential of lowering rectal NTCP, may be generated by reoptimizing the physical dose. However, the direction and magnitude of the changes in the physical proton dose to the prostate are dependent on RBE model and α/β assumptions and should therefore be used conservatively. © 2017 American Association of Physicists in Medicine.

Impact of fractionation on out-of-field survival and DNA damage responses following exposure to intensity modulated radiation fields

NASA Astrophysics Data System (ADS)

Ghita, Mihaela; Coffey, Caroline B.; Butterworth, Karl T.; McMahon, Stephen J.; Schettino, Giuseppe; Prise, Kevin M.

2016-01-01

To limit toxicity to normal tissues adjacent to the target tumour volume, radiotherapy is delivered using fractionated regimes whereby the total prescribed dose is given as a series of sequential smaller doses separated by specific time intervals. The impact of fractionation on out-of-field survival and DNA damage responses was determined in AGO-1522 primary human fibroblasts and MCF-7 breast tumour cells using uniform and modulated exposures delivered using a 225 kVp x-ray source. Responses to fractionated schedules (two equal fractions delivered with time intervals from 4 h to 48 h) were compared to those following acute exposures. Cell survival and DNA damage repair measurements indicate that cellular responses to fractionated non-uniform exposures differ from those seen in uniform exposures for the investigated cell lines. Specifically, there is a consistent lack of repair observed in the out-of-field populations during intervals between fractions, confirming the importance of cell signalling to out-of-field responses in a fractionated radiation schedule, and this needs to be confirmed for a wider range of cell lines and conditions.

Pharmacokinetics of metronomic chemotherapy: a neglected but crucial aspect.

PubMed

Bocci, Guido; Kerbel, Robert S

2016-11-01

Metronomic chemotherapy describes the close, regular administration of chemotherapy drugs at less-toxic doses over prolonged periods of time. In 2015, the results of randomized phase III clinical trials demonstrated encouraging, albeit limited, efficacy benefits of metronomic chemotherapy regimens administered as adjuvant maintenance therapy for the treatment of breast cancer, or as maintenance therapy in combination with an antiangiogenic agent for metastatic colorectal cancer. Owing to the investigational nature of this approach, metronomic chemotherapy regimens are highly empirical in terms of the optimal dose and schedule for the drugs administered; therefore, greater knowledge of the pharmacokinetics of metronomic chemotherapy is critical to the future success of this treatment strategy. Unfortunately, such preclinical and clinical pharmacokinetic studies are rare. Herein, we present situations in which active drug concentrations have been achieved with metronomic schedules, and discuss their associated pharmacokinetic parameters. We summarize examples from the limited number of clinical studies in order to illustrate the importance of assessing such pharmacokinetic parameters, and discuss the influence this information can have on improving efficacy and reducing toxicity.

Association between adherence measurements of metoprolol and health care utilization in older patients with heart failure

PubMed Central

Tu, Wanzhu; Morris, Andrew B.; Li, Jingjin; Wu, Jingwei; Young, James; Brater, D. Craig; Murray, Michael D.

2008-01-01

Objective Data from electronic dosing monitors and published pharmacokinetic parameters were used to derive medication adherence measures for immediate-release metoprolol and examine their association with health care utilization of outpatients aged 50 years or older with heart failure. Methods We used a 1-compartment model and published population pharmacokinetic parameters to estimate mean plasma metoprolol concentrations for patients treated for 6 to 12 months. In the absence of directly measured plasma concentrations, we calculated the intended mean plasma concentration (Cp′ave) under the assumption of perfect adherence to the prescribed dose and frequency of administration. Projected mean plasma concentrations (Cpave) were estimated by use of data from recorded dosing times. In addition to taking adherence (percentage of dose taken) and scheduling adherence (percentage of doses taken on schedule), we calculated the deviation from the intended exposure (ΔCpave = Cp′ave − Cpave) and the proportion of intended exposure achieved by the patient (Cpave/Cp′ave). We assessed the association between the adherence measures and the numbers of emergency department visits and hospital admissions experienced by the patients. Results Patients (N = 80) were aged 62 ± 8 years. Mean ΔCpave and Cpave/Cp′ave were 7.9 ng/mL (SD, 10.7) and 0.6 (SD, 0.3), respectively. Log-linear models adjusted for patient functional status indicated that greater deviation from the intended metoprolol exposure (ΔCpave) was associated with increased numbers of emergency department visits (P < .0001) and hospital admissions (P < .0001). A higher proportion of intended exposure (Cpave/Cp′ave) corresponded to a reduced number of emergency department visits (P = .0204) and hospital admissions (P = .0093). Taking adherence was univariately associated with both emergency department visits and hospital visits (P < .0001 and P = .0010, respectively). Scheduling adherence was associated with the number of emergency department visits (P = .0181) but not with the number of hospital admissions (P = .1602). Model selection procedures consistently chose the proposed measures over taking adherence and scheduling adherence. Conclusion Deviation from the intended exposure and proportion of intended exposure achieved by the patient are valid adherence measures for immediate-release metoprolol and are associated with health care utilization. The potential utility of these measures for other β-adrenergic antagonists and perhaps other cardiovascular drugs should be investigated. PMID:15735613

Has the Pattern of Practice in the Prescription of Radiotherapy for the Palliation of Thoracic Symptoms Changed Between 1999 and 2006 at the Rapid Response Radiotherapy Program?

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

Fairchild, Alysa; Goh, Philiz; Sinclair, Emily

2008-03-01

Purpose: Eleven randomized controlled trials (RCT) comparing various radiotherapy (RT) schedules for locally advanced lung cancer published since 1991 found no difference in palliation of intrathoracic symptoms. The most commonly prescribed schedule by Canadian Radiation Oncologists (RO) (20 Gy in five fractions [20 Gy/5]), when first evaluated versus 10 Gy/1 in a 2002 RCT, showed a significant survival benefit. A subsequent RCT assessing 20 Gy/5 found worse survival versus 16 Gy/2. This study examines whether the RT prescription for lung cancer palliation in the Rapid Response Radiotherapy Program (RRRP) has changed over time. Methods and Materials: Chart review was conductedmore » for patients treated with palliative thoracic RT across three periods (1999-2006). Patient demographics, tumor, treatment, and organizational factors were analyzed descriptively. Chi-square test was used to detect differences in proportions between unordered categorical variables. Continuous variables were tested using analysis of variance. Multivariate logistic regression was used to identify independent predictors of RT schedule prescribed. Results: A total of 117 patients received 121 courses of palliative thoracic RT. The most common dose (20 Gy/5) comprised 65% of courses in 1999, 68% in 2003, and 60% in 2005-2006 (p = 0.76). The next most common dose was 30 Gy/10 (13%). Overall, the median survival was 14.9 months, independent of RT schedule (p = 0.68). Multivariate analysis indicated palliative chemotherapy and certification year of RO were significant predictors of prescription of 20 Gy/5. Conclusion: RT schedule for palliation of intrathoracic symptoms did not mirror the results of sequential, conflicting RCTs, suggesting that factors other than the literature influenced practice patterns in palliative thoracic RT.« less

A double-dose hepatitis B vaccination schedule in travelers presenting for late consultation.

PubMed

Wong, Jason; Payne, Michael; Hollenberg, Susan

2014-01-01

Vaccination against hepatitis B virus (HBV) is recommended for all travelers visiting HBV-endemic countries. However, travelers often present with insufficient time for the standard HBV vaccine schedule (SVS). We examined seroprotection against HBV following an alternative two-visit vaccination schedule (TVS) with currently available vaccine products, and completion rates with this TVS. A retrospective cohort study was conducted in three travel clinics in British Columbia, Canada. Adults ≥20 years old traveling to an HBV-endemic country, and unable to complete the standard or rapid HBV vaccination schedule before departure, were offered a TVS that consisted of a double dose of HBV vaccine at day 0, followed by a single dose in 4 to 12 months. Immunity to HBV [anti-HBV surface antigen (HBs) ≥10 mIU/mL] was determined 1 to 6 months following the final dose of HBV vaccine. Logistic regression modeling was used to assess correlates of seroprotection. We also determined completion rate with this TVS at two clinics. In total, 117 participants (age range, 21-81 years, median age 57) met the inclusion criteria. Of these, 97 (82.9%) were immune after the TVS. Immunity was demonstrated in 93.1% of patients <50 years old and 79.5% of patients ≥50 years old. Increasing age was associated with reduced odds of developing immunity to HBV using the TVS [adjusted odds ratio = 0.954, 95% confidence interval (CI): 0.904, 1.008]. The completion rate of the TVS was 32.6% over a 12-month period. Completion rates varied between clinics (23.5% vs 48.4%, p < 0.001), suggesting that clinic-specific follow-up policies were important. Seroprotection with completion of this TVS was similar to or exceeded that published in the literature for the SVS by age. However, even with a TVS, completion rates were low, underscoring the importance of follow-up. Further research is needed to determine whether travelers are protected prior to completion of this TVS. © 2014 International Society of Travel Medicine.

Immediate effects of different schedules of somatostatin on portal pressure in patients with liver cirrhosis.

PubMed

Zhang, C; Xu, J-M; Kong, D-R; Min, X-K; Chen, R

2013-06-01

Somatostatin (SST) is used for the treatment of acute variceal bleeding based on its ability to decrease portal pressure and collateral blood flow. To date, no studies have focused on the immediate-early effects (between 1 and 30 min) of SST. The aim of this study was to compare the efficacy of different schedules of SST therapy with placebo on portal pressure in patients with portal hypertension treated with portal-azygous disconnection and to test whether an increase in bolus or infusion dose can improve the clinical efficacy of SST therapy.   Patients were treated with four different schedules: (a) standard dose (n = 11): one 250 μg bolus + a continuous infusion of 250 μg/h; (b) medium dose (n = 10): 500 μg bolus + a continuous infusion of 250 μg/h; (c) high dose (n = 10): 250 μg bolus + a continuous infusion of 500 μg/h; (d) control (n = 10): an injection of placebo (saline) followed by a placebo infusion. Following SST or placebo administration, portal pressure, central venous pressure (CVP), systemic blood pressure and heart rate (HR) were measured at 1, 3, 5, 7, 10 and 30 min.   The three schedules of SST induced a marked, rapid and highly significant decrease in portal pressure. The decline in portal pressure was moderate at 1 min (P < 0·040), achieved a peak effect at 5 min (P < 0·009) and remained decreased at 30 min. The effect of SST on portal pressure was significantly greater than placebo from 1 min after administration. There were no significant differences in portal pressure decrease between the three schedules of SST. The three schedules of SST and the placebo schedule did not induce significant changes in HR, systemic blood pressure and CVP.   This study shows that SST is effective in decreasing portal pressure within 30 min of administration in patients with liver cirrhosis. The clinical schedule used in this study was reasonable and safe. © 2013 Blackwell Publishing Ltd.

Reduced schedules of 4CMenB vaccine in infants and catch-up series in children: Immunogenicity and safety results from a randomised open-label phase 3b trial.

PubMed

Martinón-Torres, Federico; Safadi, Marco Aurelio P; Martinez, Alfonso Carmona; Marquez, Pilar Infante; Torres, Juan Carlos Tejedor; Weckx, Lily Yin; Moreira, Edson Duarte; Mensi, Ilhem; Calabresi, Marco; Toneatto, Daniela

2017-06-16

This study evaluated the immunogenicity and safety of a licensed meningococcal serogroup B vaccine (4CMenB) administered alone according to reduced schedules in infants or catch-up series in children. In this open-label, multicentre, phase 3b study (NCT01339923), infants randomised 1:1:1 received 4CMenB: 2+1 doses at 3½-5-11months or 6-8-11months of age, 3+1 doses at ages 2½-3½-5-11months. Children aged 2-10years received 2 catch-up doses administered 2months apart. Immune responses were measured by hSBA assays against 4 strains specific for vaccine components fHbp, NadA, PorA and NHBA. Sufficiency of immune responses was defined in groups with 2+1 doses schedules as a lower limit ≥70% for the 97.5% confidence interval of the percentage of infants with hSBA titres ≥4, 1month post-dose 2 for fHbp, NadA, PorA. Adverse events were collected for 7days post-vaccination; serious adverse events (SAEs) throughout the study. 754 infants and 404 children were enrolled. Post-primary vaccination, 98-100% of infants across all groups developed hSBA titres ≥4 for fHbp, NadA, PorA, and 48-77% for NHBA. Sufficiency of immune responses in infants receiving 2+1 schedules was demonstrated for fHbp, NadA, PorA after 2 doses of 4CMenB, as pre-specified criteria were met. Following receipt of 2 catch-up doses, 95-99% of children developed hSBA titres ≥4 for 4CMenB components. Similar safety profiles were observed across groups. A total of 45 SAEs were reported, 3 of which were related to vaccination. Reduced infant schedules and catch-up series in children were immunogenic and safe, having the potential to widen 4CMenB vaccine coverage. GlaxoSmithKline Biologicals SA. Copyright © 2017. Published by Elsevier Ltd.

Anthrax vaccine adsorbed: further evidence supporting continuing the vaccination series rather than restarting the series when doses are delayed.

PubMed

Pittman, Phillip R; Cavicchia, M A; Kingsbury, J L; Johnson, N A; Barrera-Oro, J G; Schmader, T; Korman, L; Quinn, X; Ranadive, M

2014-09-03

Whether to restart or continue the series when anthrax vaccine doses are missed is a frequent medical management problem. We applied the noninferiority analysis model to this prospective study comparing the Bacillus anthracis protective antigen (PA) IgG antibody response and lethal toxin neutralization activity at day 28 to the anthrax vaccine adsorbed (AVA) (Biothrax®) administered on schedule or delayed. A total of 600 volunteers were enrolled: 354 in the on-schedule cohort; 246 in the delayed cohort. Differences were noted in immune responses between cohorts (p<0.0001) and among the racial categories (p<0.0001). Controlling for covariates, the delayed cohort was non-inferior to the on-schedule cohort for the rate of 4-fold rise in both anti-PA IgG concentration (p<0.0001) and TNA ED50 titers (p<0.0001); as well as the mean log10-transformed anti-PA IgG concentration (p<0.0001) and the mean log10-transformed TNA ED50 titers (p<0.0001). Providing a missed AVA dose after a delay as long as 5-7 years, elicits anti-PA IgG antibody and TNA ED50 responses that are robust and non-inferior to the responses observed when the 6-month dose is given on-schedule. These important data suggest it is not necessary to restart the series when doses of the anthrax vaccine are delayed as long as 5 or more years. Published by Elsevier Ltd.

Biologically effective dose in fractionated molecular radiotherapy—application to treatment of neuroblastoma with 131I-mIBG

NASA Astrophysics Data System (ADS)

Mínguez, Pablo; Gustafsson, Johan; Flux, Glenn; Sjögreen Gleisner, Katarina

2016-03-01

In this work, the biologically effective dose (BED) is investigated for fractionated molecular radiotherapy (MRT). A formula for the Lea-Catcheside G-factor is derived which takes the possibility of combinations of sub-lethal damage due to radiation from different administrations of activity into account. In contrast to the previous formula, the new G-factor has an explicit dependence on the time interval between administrations. The BED of tumour and liver is analysed in MRT of neuroblastoma with 131I-mIBG, following a common two-administration protocol with a mass-based activity prescription. A BED analysis is also made for modified schedules, when due to local regulations there is a maximum permitted activity for each administration. Modifications include both the simplistic approach of delivering this maximum permitted activity in each of the two administrations, and also the introduction of additional administrations while maintaining the protocol-prescribed total activity. For the cases studied with additional (i.e. more than two) administrations, BED of tumour and liver decreases at most 12% and 29%, respectively. The decrease in BED of the tumour is however modest compared to the two-administration schedule using the maximum permitted activity, where the decrease compared to the original schedule is 47%.

Quinine-induced tinnitus in rats.

PubMed

Jastreboff, P J; Brennan, J F; Sasaki, C T

1991-10-01

Quinine ingestion reportedly induces tinnitus in humans. To expand our salicylate-based animal model of tinnitus, a series of conditioned suppression experiments was performed on 54 male-pigmented rats using quinine injections to induce tinnitus. Quinine induced changes in both the extent of suppression and recovery of licking, which followed a pattern that paralleled those produced after salicylate injections, and which may be interpreted as the result of tinnitus perception in animals. These changes depended on the dose and time schedule of quinine administration. Additionally, the calcium channel blocker, nimodipine, abolished the quinine-induced effect in a dose-dependent manner.

Survival efficacy of the PEGylated G-CSFs Maxy-G34 and neulasta in a mouse model of lethal H-ARS, and residual bone marrow damage in treated survivors.

PubMed

Chua, Hui Lin; Plett, P Artur; Sampson, Carol H; Katz, Barry P; Carnathan, Gilbert W; MacVittie, Thomas J; Lenden, Keith; Orschell, Christie M

2014-01-01

In an effort to expand the worldwide pool of available medical countermeasures (MCM) against radiation, the PEGylated G-CSF (PEG-G-CSF) molecules Neulasta and Maxy-G34, a novel PEG-G-CSF designed for increased half-life and enhanced activity compared to Neulasta, were examined in a murine model of the Hematopoietic Syndrome of the Acute Radiation Syndrome (H-ARS), along with the lead MCM for licensure and stockpiling, G-CSF. Both PEG-G-CSFs were shown to retain significant survival efficacy when administered as a single dose 24 h post-exposure, compared to the 16 daily doses of G-CSF required for survival efficacy. Furthermore, 0.1 mg kg of either PEG-G-CSF affected survival of lethally-irradiated mice that was similar to a 10-fold higher dose. The one dose/low dose administration schedules are attractive attributes of radiation MCM given the logistical challenges of medical care in a mass casualty event. Maxy-G34-treated mice that survived H-ARS were examined for residual bone marrow damage (RBMD) up to 9 mo post-exposure. Despite differences in Sca-1 expression and cell cycle position in some hematopoietic progenitor phenotypes, Maxy-G34-treated mice exhibited the same degree of hematopoietic stem cell (HSC) insufficiency as vehicle-treated H-ARS survivors in competitive transplantation assays of 150 purified Sca-1+cKit+lin-CD150+cells. These data suggest that Maxy-G34, at the dose, schedule, and time frame examined, did not mitigate RBMD but significantly increased survival from H-ARS at one-tenth the dose previously tested, providing strong support for advanced development of Maxy-G34, as well as Neulasta, as MCM against radiation.

Cycle control with an extended-regimen oral contraceptive combining levonorgestrel and ethinyl estradiol that includes continuous low-dose ethinyl estradiol instead of the traditional hormone-free interval.

PubMed

Nappi, Rossella E; Lobo Abascal, Paloma; Hsieh, Jennifer; Micheletti, Marie-Christine

2017-01-01

To evaluate scheduled and unscheduled bleeding and spotting over 1 year of treatment with 91-day extended-regimen combined oral contraception (COC) providing continuous low-dose ethinyl estradiol (EE) in place of the traditional 7-day hormone-free interval (HFI). This post hoc analysis of a multicenter, open-label, 1-year, Phase 3 study of extended-regimen COC with 30 µg EE/150 µg levonorgestrel (LNG) for 84 days and EE 10 µg for 7 days included 799 sexually active, adult women who completed at least one 91-day cycle of therapy. Subjects recorded bleeding and spotting episodes daily using electronic diaries. Logistic regression analyses are reported as ORs with 95% CIs. There was a 10% increase (OR =1.102; 95% CI: 1.006-1.206) in the likelihood of reporting no scheduled bleeding for each additional 91-day cycle completed. From the third 91-day cycle, more than one fifth of women reported no scheduled bleeding (third cycle =23% [121/533]; fourth cycle =22% [97/446]). Among women who reported no scheduled bleeding at Cycle 1 (136/758 [18%]), ≥45% showed sustained lack of scheduled bleeding in later cycles. There were increases of 53% (OR =1.531; 95% CI: 1.393-1.683) and 31% (OR =1.307; 95% CI: 1.205-1.418) in the likelihood of reporting 0 to ≤6 days vs >6 days of unscheduled bleeding and spotting, respectively, for each additional 91-day cycle. By Cycle 2, more than 80% of women reported no unscheduled bleeding or ≤6 days of unscheduled bleeding during each 91-day cycle. Improved cycle control with decreased bleeding over time was shown during extended-regimen COC with 30 µg EE/150 µg LNG for 84 days and continuous low-dose EE instead of the traditional 7-day HFI. Women considering this regimen should be informed that those who complete at least one 91-day COC cycle will likely experience less bleeding/spotting in future cycles.

Cycle control with an extended-regimen oral contraceptive combining levonorgestrel and ethinyl estradiol that includes continuous low-dose ethinyl estradiol instead of the traditional hormone-free interval

PubMed Central

Nappi, Rossella E; Lobo Abascal, Paloma; Hsieh, Jennifer; Micheletti, Marie-Christine

2017-01-01

Purpose To evaluate scheduled and unscheduled bleeding and spotting over 1 year of treatment with 91-day extended-regimen combined oral contraception (COC) providing continuous low-dose ethinyl estradiol (EE) in place of the traditional 7-day hormone-free interval (HFI). Patients and methods This post hoc analysis of a multicenter, open-label, 1-year, Phase 3 study of extended-regimen COC with 30 µg EE/150 µg levonorgestrel (LNG) for 84 days and EE 10 µg for 7 days included 799 sexually active, adult women who completed at least one 91-day cycle of therapy. Subjects recorded bleeding and spotting episodes daily using electronic diaries. Logistic regression analyses are reported as ORs with 95% CIs. Results There was a 10% increase (OR =1.102; 95% CI: 1.006–1.206) in the likelihood of reporting no scheduled bleeding for each additional 91-day cycle completed. From the third 91-day cycle, more than one fifth of women reported no scheduled bleeding (third cycle =23% [121/533]; fourth cycle =22% [97/446]). Among women who reported no scheduled bleeding at Cycle 1 (136/758 [18%]), ≥45% showed sustained lack of scheduled bleeding in later cycles. There were increases of 53% (OR =1.531; 95% CI: 1.393–1.683) and 31% (OR =1.307; 95% CI: 1.205–1.418) in the likelihood of reporting 0 to ≤6 days vs >6 days of unscheduled bleeding and spotting, respectively, for each additional 91-day cycle. By Cycle 2, more than 80% of women reported no unscheduled bleeding or ≤6 days of unscheduled bleeding during each 91-day cycle. Conclusion Improved cycle control with decreased bleeding over time was shown during extended-regimen COC with 30 µg EE/150 µg LNG for 84 days and continuous low-dose EE instead of the traditional 7-day HFI. Women considering this regimen should be informed that those who complete at least one 91-day COC cycle will likely experience less bleeding/spotting in future cycles. PMID:29042818

A primer on the hormone-free interval for combined oral contraceptives.

PubMed

Hauck, Brian A; Brown, Vivien

2015-01-01

The dosing, schedules, and other aspects of combined oral contraceptive (COC) design have evolved in recent years to address a variety of issues including short- and long-term safety, bleeding profiles, and contraceptive efficacy. In particular, several newer formulations have altered the length of the hormone-free interval (HFI), in order to minimize two key undesired effects that occur during this time: hormone-withdrawal-associated symptoms (HWaS) and follicular development. This primer reviews our current understanding of the key biological processes that occur during the HFI and how this understanding has led to changes in the dosing and schedule of newer COC formulations. In brief, HWaS are common, underappreciated, and a likely contributor to COC discontinuation; because of this, shortening the HFI and/or supplementing with estrogen during the progestin-free interval may provide relief from these symptoms and improve adherence. A short HFI (with or without estrogen supplementation) may also help maintain effective follicular suppression and contraceptive efficacy, even when the overall dose of estrogen throughout the cycle is low. Taken together, the available data about HWaS and follicular activity during the HFI support the rationale for recent COC designs that use a low estrogen dose and a short HFI. The availability of a variety of COC regimens gives physicians a range of choices when selecting the most appropriate COC for each woman's particular priorities and needs.

Advisory Committee on Immunization Practices Recommended Immunization Schedule for Adults Aged 19 Years or Older--United States, 2016.

PubMed

Kim, David K; Bridges, Carolyn B; Harriman, Kathleen H

2016-02-05

In October 2015, the Advisory Committee on Immunization Practices (ACIP)* approved the Recommended Immunization Schedule for Adults Aged 19 Years or Older, United States, 2016. This schedule provides a summary of ACIP recommendations for the use of vaccines routinely recommended for adults aged 19 years or older in two figures, footnotes for each vaccine, and a table that describes primary contraindications and precautions for commonly used vaccines for adults. Although the figures in the adult immunization schedule illustrate recommended vaccinations that begin at age 19 years, the footnotes contain information on vaccines that are recommended for adults that may begin at age younger than age 19 years. The footnotes also contain vaccine dosing, intervals between doses, and other important information and should be read with the figures.

Phase I clinical and pharmacokinetic study of kahalalide F administered weekly as a 1-hour infusion to patients with advanced solid tumors.

PubMed

Pardo, Beatriz; Paz-Ares, Luis; Tabernero, Josep; Ciruelos, Eva; García, Margarita; Salazar, Ramón; López, Ana; Blanco, María; Nieto, Antonio; Jimeno, José; Izquierdo, Miguel Angel; Trigo, José Manuel

2008-02-15

A dose-escalation, phase I study evaluated the safety, pharmacokinetics, and efficacy of a weekly 1-h regimen of kahalalide F, a cyclic depsipeptide isolated from the marine mollusk Elysia rufescens, in adult patients with advanced solid tumors and no standard treatment available. Patients received an i.v. 1-h infusion of kahalalide F once weekly until disease progression or unacceptable toxicity. The starting kahalalide F dose was 266 microg/m(2), and dose escalation proceeded based on the worst toxicity found in the previous cohort. Thirty-eight patients were enrolled at three Spanish institutions and received once-weekly kahalalide F 1-h infusions at doses between 266 and 1,200 microg/m(2). Dose-limiting toxicities consisted of transient grade 3/4 increases in transaminase blood levels. The maximum tolerated dose for this kahalalide F schedule was 800 microg/m(2), and the recommended dose for phase II studies was 650 microg/m(2). No accumulated toxicity was found. One patient with malignant melanoma had unconfirmed partial response, one patient with metastatic lung adenocarcinoma had minor response, and six patients with different types of metastatic solid tumors had stable disease for 2.8 to 12.7 months. The noncompartmental pharmacokinetics of this kahalalide F schedule was linear and showed a narrow distribution and short body residence. The transaminitis associated with kahalalide F was dose dependent. The maximum tolerated dose was 800 microg/m(2). Dose-limiting toxicities with weekly kahalalide F 1-h i.v. infusions were transient grade 3/4 increases in blood transaminase levels, and 650 microg/m(2) was declared the recommended dose for phase II studies. This schedule showed a favorable safety profile and hints of antitumor activity.

Effect of dose timing in relation to food intake on systemic exposure to blonanserin.

PubMed

Saruwatari, Junji; Yasui-Furukori, Norio; Inoue, Yoshimasa; Kaneko, Sunao

2010-09-01

Blonanserin is a novel potent dopamine D(2) and serotonin 5-HT(2) antagonist for treating schizophrenia. The aim of this study was to investigate prandial effects on systemic exposure to blonanserin in healthy volunteers, with particular attention paid to the effect of dose timing relative to meal intake. Volunteers received a single 2-mg oral dose of blonanserin under the following conditions: fasting, 30 min before eating a standard meal; or 30 min or 2 or 4 h after eating the meal. Plasma concentrations of blonanserin were measured using validated high-performance liquid chromatography coupled with tandem mass spectrometry. Ratios and 90% confidence intervals of the geometric means compared with the fasting condition indicated that the maximum concentrations of blonanserin (C(max)) significantly increased with dosing 30 min before meal intake, and 30 min and 2 and 4 h after meal intake, yielding by 330%, 239%, 272%, and 138%, respectively. The truncated area under the concentration-time curve (AUC(last)) also increased by 386%, 201%, 256%, and 155%, respectively. There was no difference in values of the time to reach maximum concentration between the fasting and the four fed states. Food intake increased the systemic exposure to blonanserin for all time intervals investigated in this study. The marked effect of food on the bioavailability of blonanserin should be taken into account in its dosing schedules.

The impact of overtime and long work hours on occupational injuries and illnesses: new evidence from the United States

PubMed Central

Dembe, A; Erickson, J; Delbos, R; Banks, S

2005-01-01

Aims: To analyse the impact of overtime and extended working hours on the risk of occupational injuries and illnesses among a nationally representative sample of working adults from the United States. Methods: Responses from 10 793 Americans participating in the National Longitudinal Survey of Youth (NLSY) were used to evaluate workers' job histories, work schedules, and occurrence of occupational injury and illness between 1987 and 2000. A total of 110 236 job records were analysed, encompassing 89 729 person-years of accumulated working time. Aggregated incidence rates in each of five exposure categories were calculated for each NLSY survey period. Multivariate analytical techniques were used to estimate the relative risk of long working hours per day, extended hours per week, long commute times, and overtime schedules on reporting a work related injury or illness, after adjusting for age, gender, occupation, industry, and region. Results: After adjusting for those factors, working in jobs with overtime schedules was associated with a 61% higher injury hazard rate compared to jobs without overtime. Working at least 12 hours per day was associated with a 37% increased hazard rate and working at least 60 hours per week was associated with a 23% increased hazard rate. A strong dose-response effect was observed, with the injury rate (per 100 accumulated worker-years in a particular schedule) increasing in correspondence to the number of hours per day (or per week) in the workers' customary schedule. Conclusions: Results suggest that job schedules with long working hours are not more risky merely because they are concentrated in inherently hazardous industries or occupations, or because people working long hours spend more total time "at risk" for a work injury. Strategies to prevent work injuries should consider changes in scheduling practices, job redesign, and health protection programmes for people working in jobs involving overtime and extended hours. PMID:16109814

The impact of overtime and long work hours on occupational injuries and illnesses: new evidence from the United States.

PubMed

Dembe, A E; Erickson, J B; Delbos, R G; Banks, S M

2005-09-01

To analyse the impact of overtime and extended working hours on the risk of occupational injuries and illnesses among a nationally representative sample of working adults from the United States. Responses from 10,793 Americans participating in the National Longitudinal Survey of Youth (NLSY) were used to evaluate workers' job histories, work schedules, and occurrence of occupational injury and illness between 1987 and 2000. A total of 110,236 job records were analysed, encompassing 89,729 person-years of accumulated working time. Aggregated incidence rates in each of five exposure categories were calculated for each NLSY survey period. Multivariate analytical techniques were used to estimate the relative risk of long working hours per day, extended hours per week, long commute times, and overtime schedules on reporting a work related injury or illness, after adjusting for age, gender, occupation, industry, and region. After adjusting for those factors, working in jobs with overtime schedules was associated with a 61% higher injury hazard rate compared to jobs without overtime. Working at least 12 hours per day was associated with a 37% increased hazard rate and working at least 60 hours per week was associated with a 23% increased hazard rate. A strong dose-response effect was observed, with the injury rate (per 100 accumulated worker-years in a particular schedule) increasing in correspondence to the number of hours per day (or per week) in the workers' customary schedule. Results suggest that job schedules with long working hours are not more risky merely because they are concentrated in inherently hazardous industries or occupations, or because people working long hours spend more total time "at risk" for a work injury. Strategies to prevent work injuries should consider changes in scheduling practices, job redesign, and health protection programmes for people working in jobs involving overtime and extended hours.

Tumor Induction in Mice After Localized Single- or Fractionated-Dose Irradiation: Differences in Tumor Histotype and Genetic Susceptibility Based on Dose Scheduling

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

Edmondson, Elijah F., E-mail: elijah.edmondson@colostate.edu; Hunter, Nancy R.; Weil, Michael M.

2015-07-15

Purpose: To investigate differences in tumor histotype, incidence, latency, and strain susceptibility in mice exposed to single-dose or clinically relevant, fractioned-dose γ-ray radiation. Methods and Materials: C3Hf/Kam and C57BL/6J mice were locally irradiated to the right hindlimb with either single large doses between 10 and 70 Gy or fractionated doses totaling 40 to 80 Gy delivered at 2-Gy/d fractions, 5 d/wk, for 4 to 8 weeks. The mice were closely evaluated for tumor development in the irradiated field for 800 days after irradiation, and all tumors were characterized histologically. Results: A total of 210 tumors were induced within the radiation field in 788 mice. Anmore » overall decrease in tumor incidence was observed after fractionated irradiation (16.4%) in comparison with single-dose irradiation (36.1%). Sarcomas were the predominant postirradiation tumor observed (n=201), with carcinomas occurring less frequently (n=9). The proportion of mice developing tumors increased significantly with total dose for both single-dose and fractionated schedules, and latencies were significantly decreased in mice exposed to larger total doses. C3Hf/Kam mice were more susceptible to tumor induction than C57BL/6J mice after single-dose irradiation; however, significant differences in tumor susceptibilities after fractionated radiation were not observed. For both strains of mice, osteosarcomas and hemangiosarcomas were significantly more common after fractionated irradiation, whereas fibrosarcomas and malignant fibrous histiocytomas were significantly more common after single-dose irradiation. Conclusions: This study investigated the tumorigenic effect of acute large doses in comparison with fractionated radiation in which both the dose and delivery schedule were similar to those used in clinical radiation therapy. Differences in tumor histotype after single-dose or fractionated radiation exposures provide novel in vivo evidence for differences in tumor susceptibility among stromal cell populations.« less

Model-based optimization of G-CSF treatment during cytotoxic chemotherapy.

PubMed

Schirm, Sibylle; Engel, Christoph; Loibl, Sibylle; Loeffler, Markus; Scholz, Markus

2018-02-01

Although G-CSF is widely used to prevent or ameliorate leukopenia during cytotoxic chemotherapies, its optimal use is still under debate and depends on many therapy parameters such as dosing and timing of cytotoxic drugs and G-CSF, G-CSF pharmaceuticals used and individual risk factors of patients. We integrate available biological knowledge and clinical data regarding cell kinetics of bone marrow granulopoiesis, the cytotoxic effects of chemotherapy and pharmacokinetics and pharmacodynamics of G-CSF applications (filgrastim or pegfilgrastim) into a comprehensive model. The model explains leukocyte time courses of more than 70 therapy scenarios comprising 10 different cytotoxic drugs. It is applied to develop optimized G-CSF schedules for a variety of clinical scenarios. Clinical trial results showed validity of model predictions regarding alternative G-CSF schedules. We propose modifications of G-CSF treatment for the chemotherapies 'BEACOPP escalated' (Hodgkin's disease), 'ETC' (breast cancer), and risk-adapted schedules for 'CHOP-14' (aggressive non-Hodgkin's lymphoma in elderly patients). We conclude that we established a model of human granulopoiesis under chemotherapy which allows predictions of yet untested G-CSF schedules, comparisons between them, and optimization of filgrastim and pegfilgrastim treatment. As a general rule of thumb, G-CSF treatment should not be started too early and patients could profit from filgrastim treatment continued until the end of the chemotherapy cycle.

Day-On, Day-Off emtricitabine, tenofovir disoproxil fumarate and efavirenz single tablet regimen (DODO) as maintenance therapy in HIV-infected patients.

PubMed

Costantini, Andrea; Tontini, Chiara; Rocchi, Monia; Martini, Matteo; Butini, Luca

2018-06-01

Reduced dose schedules may be feasible options to simplify antiretroviral therapy (ART) in selected HIV-1-infected individuals. Efficacy and safety of a Day-on, Day-off (DODO) schedule of tenofovir disoproxil fumarate, emtricitabine and efavirenz (FTC/TDF/EFV) single tablet regimen (STR) was assessed. Twenty-seven patients were prescribed the DODO schedule and were monitored for 48 weeks. Switching criteria were: no previous ART failure, no AIDS-defining illnesses, T CD4 cell nadir >200/mmc, and HIV-RNA below detection limit (40 copies/mL) for at least six months. Clinical and laboratory data, including plasma HIV-RNA levels, T CD4 and CD8 counts, liver and kidney function, lipid levels and ultrasensitive C-reactive protein (us-CRP) were assessed at baseline, week 4, 12, 24, and 48. Statistical analysis was performed by paired Student's T-test for comparison between baseline and each time point and Chi square test for CD4/CD8 ratio comparison. In all, 26 out of 27 patients maintained plasma HIV-RNA levels below the detection limit through the entire follow-up. One patient experienced low level plasma HIV-RNA rebound at week 36 (47 copies/ml) and immediately reverted to the conventional dose schedule of FTC/TDF/EFV; plasma HIV-RNA was undetectable after four weeks. No major changes on liver and kidney function tests, lipid levels and us-CRP were observed. Although no profound modifications of T CD4 count were observed during follow-up, the CD4/CD8 ratio increased significantly at week 48 compared to the baseline (p<0.05). In conclusion, 48-week DODO administration of the fixed dose FTC/TDF/EFV STR combination was safe and effective in maintaining HIV viral replication below the detection limit in a selected group of HIV-1-infected individuals.

A Prospective Cohort Study to Compare Treatment Results Between 2 Fractionation Schedules of High-Dose-Rate Intracavitary Brachytherapy (HDR-ICBT) in Patients With Cervical Cancer

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

Huang, Eng-Yen; School of Traditional Chinese Medicine, Chang Gung University College of Medicine, Taiwan; Sun, Li-Min

Purpose: To compare the treatment results of 2 fractionation schedules for high-dose-rate intracavitary brachytherapy (HDR-ICBT) in patients with cervical cancer. Methods and Materials: From June 2001 through January 2008, 267 patients with stage IB-IVA cervical cancer were enrolled in the study. All patients underwent 4-field pelvic irradiation and HDR-ICBT. The median central and parametrial doses were 39.6 Gy and 45 Gy, respectively. Patient underwent either 6 Gy Multiplication-Sign 4 (HDR-4) (n=144) or 4.5 Gy Multiplication-Sign 6 (HDR-6) (n=123) to point A of ICBT using {sup 192}Ir isotope twice weekly. The rates of overall survival, locoregional failure, distant metastasis, proctitis, cystitis,more » and enterocolitis were compared between HDR-4 and HDR-6. Results: There were no significant differences in the demographic data between HDR-4 and HDR-6 except for total treatment time. The 5-year proctitis rates were 23.0% and 21.5% in HDR-4 and HDR-6 (P=.399), respectively. The corresponding rates of grade 2-4 proctitis were 18.7% and 9.6% (P=.060). The corresponding rates of grades 3-4 proctitis were 5.2% and 1.3% (P=.231). Subgroup analysis revealed that HDR-4 significantly increased grade 2-4 proctitis in patients aged {>=}62 years old (P=.012) but not in patients aged <62 years (P=.976). The rates of overall survival, locoregional failure, distant metastasis, cystitis, and enterocolitis were not significantly different between HDR-4 and HDR-6 schedules. Conclusion: The small fraction size of HDR-ICBT is associated with grade 2 proctitis without compromise of prognosis in elderly patients. This schedule is suggested for patients who tolerate an additional 2 applications of HDR-ICBT.« less

Adjuvant chemotherapy with 5-fluorouracil, L-folinic acid and levamisole for patients with colorectal cancer: non-randomised comparison of weekly versus four-weekly schedules--less pain, same gain. QUASAR Colorectal Cancer Study Group.

PubMed

Kerr, D J; Gray, R; McConkey, C; Barnwell, J

2000-08-01

QUASAR is a large trial of adjuvant chemotherapy for colorectal cancer in which clinicians could choose to deliver a standard adjuvant cytotoxic chemotherapy regimen, 5-fluorouracil (5-FU) and L-folinic acid (L-FA), in either a once-weekly or a four-weekly schedule. We report results of a non-randomised comparison between these schedules with respect to survival, recurrence and differential toxicity. In a factorial (2 x 2) trial design, QUASAR compared high-dose (175 mg) versus low-dose (25 mg) L-FA and levamisole versus placebo. The dose of 5-FU was fixed at 370 mg/m2 and although the recommended schedule was i.v. bolus delivery, daily for 5 days repeated four-weekly for 6 months, a significant proportion of randomising clinicians were constrained to deliver once-weekly 5-FU-L-FA for 30 weeks. Four thousand nine hundred twenty-seven patients were entered into QUASAR between May 1994 and October 1997, eighteen hundred twenty-nine of whom have recurred and sixteen hundred eighty-nine died. Similar numbers 2370 vs. 2559 were treated with the once-weekly and four-weekly schedules and the demographic features of the 2 groups were well balanced: stage C, 73.3% once-weekly vs. 71.0% four-weekly; colon, 68.0% vs. 68.3%; high-dose FA, 50.1% vs. 49.9%; levamisole, 49.3% vs. 49.3%; females, 40.2% vs. 41.7%; median age (years) 62 vs. 61. The risk of recurrence and survival were similar regardless of schedule: three-year survival was 70.6% once-weekly vs. 71.0% four-weekly; three-year recurrence risk was 35.6% once-weekly vs. 35.5% four-weekly; But, the once-weekly regimen was much less toxic: number of patients for whom toxicity was reported (once-weekly: four-weekly), stomatitis, 37 vs. 337; diarrhoea, 260 vs. 440; neutropenia, 20 vs. 153. The once-weekly regimen is much less toxic than and, apparently, about as effective as the four-weekly schedule. This suggests that the toxicity of 5-FU-L-FA adjuvant chemotherapy could be reduced substantially by weekly scheduling without compromising efficacy. Alternatively, efficacy might be enhanced with equal toxicity by more dose-intense weekly FU-L-FA regimens. However, this conclusion from a non-randomised comparison needs confirmation in prospective randomised studies.

Stereotactic Body Radiotherapy in the Management of Oligometastatic Disease.

PubMed

Ahmed, Kamran A; Torres-Roca, Javier F

2016-01-01

The treatment of oligometastatic disease has become common as imaging techniques have advanced and the management of systemic disease has improved. Use of highly targeted, hypofractionated regimens of stereotactic body radiotherapy (SBRT) is now a primary management option for patients with oligometastatic disease. The properties of SBRT are summarized and the results of retrospective and prospective studies of SBRT use in the management of oligometastases are reviewed. Future directions of SBRT, including optimizing dose and fractionation schedules, are also discussed. SBRT can deliver highly conformal, dosed radiation treatments for ablative tumors in a few treatment sessions. Phase 1/2 trials and retrospective institutional results support use of SBRT as a treatment option for oligometastatic disease metastasized to the lung, liver, and spine, and SBRT offers adequate toxicity profiles with good rates of local control. Future directions will involve optimizing dose and fractionation schedules for select histologies to improve rates of local control while limiting toxicity to normal structures. SBRT offers an excellent management option for patients with oligometastases. However, additional research is still needed to optimize dose and fractionation schedules.

Cumulative cisplatin dose in concurrent chemoradiotherapy for head and neck cancer: A systematic review.

PubMed

Strojan, Primož; Vermorken, Jan B; Beitler, Jonathan J; Saba, Nabil F; Haigentz, Missak; Bossi, Paolo; Worden, Francis P; Langendijk, Johannes A; Eisbruch, Avraham; Mendenhall, William M; Lee, Anne W M; Harrison, Louis B; Bradford, Carol R; Smee, Robert; Silver, Carl E; Rinaldo, Alessandra; Ferlito, Alfio

2016-04-01

The optimal cumulative dose and timing of cisplatin administration in various concurrent chemoradiotherapy protocols for nonmetastatic head and neck squamous cell carcinoma (HNSCC) has not been determined. The absolute survival benefit at 5 years of concurrent chemoradiotherapy protocols versus radiotherapy alone observed in prospective randomized trials reporting on the use of cisplatin monochemotherapy for nonnasopharyngeal HNSCC was extracted. In the case of nonrandomized studies, the outcome results at 2 years were compared between groups of patients receiving different cumulative cisplatin doses. Eleven randomized trials and 7 nonrandomized studies were identified. In 6 definitive radiotherapy phase III trials, a statistically significant association (p = .027) between cumulative cisplatin dose, independent of the schedule, and overall survival benefit was observed for higher doses. Results support the conclusion that the cumulative dose of cisplatin in concurrent chemoradiation protocols for HNSCC has a significant positive correlation with survival. © 2015 Wiley Periodicals, Inc. Head Neck 38: E2151-E2158, 2016. © 2015 Wiley Periodicals, Inc.

Docetaxel chronopharmacology in mice.

PubMed

Tampellini, M; Filipski, E; Liu, X H; Lemaigre, G; Li, X M; Vrignaud, P; François, E; Bissery, M C; Lévi, F

1998-09-01

Docetaxel tolerance and antitumor efficacy could be enhanced if drug administration was adapted to circadian rhythms. This hypothesis was investigated in seven experiments involving a total of 626 male B6D2F1 mice, synchronized with an alternation of 12 h of light and 12 h of darkness (12:12), after i.v. administration of docetaxel. In experiment (Exp) 1, the drug was given once a week (wk) for 6 wks (20 mg/kg/wk) or for 5 wks (30 mg/kg/wk) at one of six circadian times, during light when mice were resting [3, 7, or 11 hours after light onset (HALO)], or during darkness, when mice were active (15, 19, or 23 HALO). Endpoints were survival and body weight change. In Exp 2 and 3, docetaxel (30 mg/kg/wk) was administered twice, 1 wk apart, at one of four circadian stages (7, 11, 19, or 23 HALO). Endpoints were hematological and intestinal toxicities. In Exp 4, circadian changes in cell cycle phase distribution and BCL-2 immunofluorescence were investigated in bone marrow as possible mechanisms of docetaxel tolerability rhythm. In Exp 5 to 7, docetaxel was administered to mice bearing measurable P03 pancreatic adenocarcinoma (270-370 mg), with tumor weight and survival as endpoints. Mice from Exp 5 and 6 received a weekly schedule of docetaxel at one of six circadian stages (20 or 30 mg/kg/wk at 3, 7, 11, 15, 19, or 23 HALO). In Exp 7, docetaxel (30 mg/kg) was given every 2 days (day 1, 3, 5 schedule) at 7, 11, 19, or 23 HALO. Docetaxel dosing in the second half of darkness (19 or 23 HALO) resulted in significantly worse toxicity than its administration during the light span (3, 7, or 11 HALO). The survival rate ranged from 56.3% in the mice treated at 23 HALO to 93.8 or 87.5% in those injected at 3 or 11 HALO, respectively (Exp 1, P < 0.01). Granulocytopenia at nadir was -49 +/- 14% at 7 HALO compared with -84 +/- 3% at 19 HALO (Exp 2 and 3, P < 0.029), and severe jejunal mucosa necrosis occurred in 5 of 8 mice treated at 23 HALO as opposed to 2 of 18 receiving docetaxel at 7, 11, or 19 HALO (Exp 2 and 3, P < 0.02). The time of least docetaxel toxicity corresponded to the circadian nadir in S or G2-M phase and to the circadian maximum in BCL-2 immunofluorescence in bone marrow. Docetaxel increased the median survival of tumor-bearing mice in a dose-dependent manner (controls: 24 days; 20 mg/kg weekly, 33 days; 30 mg/kg weekly or day 1, 3, 5 schedule, 44 or 46 days, respectively; Exp 5-7). Survival curves of treated mice differed significantly according to dosing time for each dose and schedule (P from log rank <0.003 to P < 0.03). In Exp 5 and 6, the percentage of increase in life span was largest if docetaxel was administered weekly at 7 HALO (20 mg/kg, 220%; 30 mg/kg, 372%) and lowest after docetaxel dosing at 19 HALO (80% with 20 mg/kg) or at 15 HALO (78% with 30 mg/kg). In Exp 7, (day 1, 3, 5 schedule), docetaxel was most active at 11 HALO (percentage increase in life span, 390%) and least active at 23 HALO (210%). Docetaxel tolerability and antitumor efficacy were simultaneously enhanced by drug dosing in the light span, when mice were resting. Mechanisms underlying the tolerability rhythm likely involved the circadian organization of cell cycle regulation. Docetaxel therapeutic index may be improved with an administration at night in cancer patients, when fewest bone marrow cells are in S or G2-M phase.

Rabies neutralizing antibody response to different schedules of serum and vaccine inoculations in non-exposed persons

PubMed Central

Atanasiu, P.; Cannon, D. A.; Dean, D. J.; Fox, J. P.; Habel, K.; Kaplan, M. M.; Kissling, R. E.; Koprowski, H.; Lépine, P.; Gallardo, F. Pérez

1961-01-01

This study is the third in a series on virus-neutralizing antibody response to different schedules of antirabies serum and vaccines in previously non-exposed persons. Three types of vaccine were studied—phenolized (Semple), duck embryo and high-egg-passage (HEP) chicken embryo. Reduced schedules of vaccine, consisting of 2-7 inoculations given at various intervals, did not give results comparable in efficacy (time of appearance, level and persistence of antibody) with schedules comprising at least 14 daily inoculations of vaccine as determined in previous trials. The effectiveness of a booster dose in previously sensitized individuals was confirmed with a demonstration that a rise in serum antibody appears between 4 and 8 days after the booster inoculation. Effective sensitization appears to be as much a function of spacing of inoculations as of total dosage of vaccine antigen. Interference by immune serum with the antigenicity of subsequently administered vaccine, noted previously by the present authors and by other workers, was again confirmed. This interference could be overcome by the administration of a sufficient amount of vaccine. PMID:13863061

A phase I and pharmacokinetic study of the quinoxaline antitumour Agent R(+)XK469 in patients with advanced solid tumours

PubMed Central

Undevia, Samir D.; Innocenti, Federico; Ramirez, Jacqueline; House, Larry; Desai, Apurva A.; Skoog, Linda A.; Singh, Deepti A.; Karrison, Theodore; Kindler, Hedy L.; Ratain, Mark J.

2009-01-01

Purpose To investigate the safety and pharmacokinetics of R(+)XK469, a quinoxaline analogue, in patients with advanced refractory solid tumours. Preclinical studies suggested that efficacy was independent of schedule but that toxicity was decreased by dividing the dose. Methods R(+)XK469 was initially administered as a 30 min intravenous infusion on days 1–5 of a 21-d cycle. Based on the demonstration of a long half-life, the dosing schedule was subsequently amended to infusion on days 1, 3 and 5 of a 21-d cycle. An alternate single-dose schedule of once every 21 d was also explored. Blood samples were collected for pharmaco-kinetic studies. Results Dose-limiting toxicity (DLT) was neutropaenia. There was significant interindividual variability in clearance as evidenced by a coefficient of variation of 46%. A flat-dosing scheme (not based on body surface area) was justified by the absence of correlation between clearance and body surface area. A partial response was observed in a patient with nasopharyngeal carcinoma. Conclusions The recommended phase II doses are 850–1100 mg/d on days 1, 3 and 5 of a 21-d cycle and 2500 mg on day 1 of a 21-d cycle. The observed interpatient pharmacokinetic variability should prompt investigation into the presence of genetic polymorphism in relevant metabolizing enzymes. PMID:18650079

Impact of the introduction of rotavirus vaccine on the timeliness of other scheduled vaccines: the Australian experience.

PubMed

Hull, Brynley P; Menzies, Robert; Macartney, Kristine; McIntyre, Peter B

2013-04-08

Strict age limits for receipt of rotavirus vaccines and simultaneous use of vaccines requiring two (Rotarix(®)) and three (RotaTeq(®)) doses in Australia may impact on coverage and timeliness of other vaccines in the infant schedule. Using data from the Australian Childhood Immunisation Register (ACIR), coverage and timeliness of rotavirus vaccines and changes in timeliness of other infant vaccines following rotavirus vaccine introduction was examined, with particular emphasis on Indigenous infants in whom coverage is less optimal. Final dose rotavirus coverage reached 83% within 21 months of program commencement but remained 7% lower than other vaccines due in infancy. Coverage was 11-17% lower in Indigenous infants. Adherence to the first dose upper age limits for rotavirus vaccine was high with >97% of children vaccinated by the recommended age, but for subsequent rotavirus doses, receipt beyond the upper age limits was more common, especially in Indigenous children. Following rotavirus vaccine introduction, there were improvements in timeliness of receipt of all doses of DTPa-containing and 7-valent pneumococcal conjugate vaccines. High population coverage can be attained with rotavirus vaccines, even with adherence to strict upper age restrictions for vaccine dose administration. Rotavirus vaccine introduction appears to have impacted upon the timeliness of other concomitantly scheduled vaccines. These factors should be considered when rotavirus programs are introduced. Copyright © 2013 Elsevier Ltd. All rights reserved.

Immunogenicity of quadrivalent HPV and combined hepatitis A and B vaccine when co-administered or administered one month apart to 9-10 year-old girls according to 0-6 month schedule.

PubMed

Gilca, Vladimir; Sauvageau, Chantal; Boulianne, Nicole; De Serres, Gaston; Couillard, Michel; Krajden, Mel; Ouakki, Manale; Murphy, Donald; Trevisan, Andrea; Dionne, Marc

2014-01-01

No immunogenicity data has been reported after a single dose of the quadrivalent HPV vaccine (qHPV-Gardasil®) and no data are available on co-administration of this vaccine with the HAV/HBV vaccine (Twinrix-Junior®). Two pre-licensure studies reported similar anti-HPV but lower anti-HBs titers when co-administering HPV and HBV vaccines. To assess the immunogenicity of the qHPV and HAV/HBV vaccine when co-administered (Group-Co-adm) or given one month apart (Group-Sep) and to measure the persistence of HPV antibodies three years post-second dose of qHPV vaccine in both study groups. 416 9-10 year-old girls were enrolled. Vaccination schedule was 0-6 months. Anti-HAV and anti-HBs were measured in all subjects 6 months post-first dose and 1 month post-second dose. Anti-HPV were measured 6 months post-first dose in Group-Co-adm and in all subjects 1 and 36 months post-second dose. Six months post-first dose: 100% of subjects had detectable anti-HAV and 56% and 73% had detectable anti-HBs in Group-Co-Adm and Group-Sep, respectively. In Group-Co-adm 94, 100, 99 and 96% had detectable antibodies to HPV 6, 11, 16 and 18, respectively. One month post-second dose of qHPV and HAV/HBV vaccine, in both study groups 99.5-100% of subjects had an anti-HAV titer ≥ 20IU/L, 97.5-97.6% an anti-HBs level ≥ 10IU/L, and 100% had an anti-HPV titer ≥ 3LU. Thirty-six months post-second dose of qHPV all but four subjects (99%) had antibodies to HPV18 and 100% had antibodies to HPV6, 11 and 16. The great majority (97-100%) had an anti-HPV titer ≥ 3 LU. Post-second dose administration of qHPV and HAV/HBV, no meaningful difference was observed in the immune response in the two study groups to any component of vaccines. The results indicate that qHPV and HAV/HBV can be given during the same vaccination session. Two doses of of qHPV and HAV/HBV vaccines induce a strong immune response. Three years post-second dose of qHPV, the great majority of subjects had antibodies to HPV types included in the vaccine. A two-dose schedule for pre-adolescents might be a reasonable alternative to the currently approved three-dose schedules.

Characterization of a Cynomolgus Macaque Model of Pneumonic Plague for Evaluation of Vaccine Efficacy.

PubMed

Fellows, Patricia; Price, Jessica; Martin, Shannon; Metcalfe, Karen; Krile, Robert; Barnewall, Roy; Hart, Mary Kate; Lockman, Hank

2015-09-01

The efficacy of a recombinant plague vaccine (rF1V) was evaluated in cynomolgus macaques (CMs) to establish the relationship among vaccine doses, antibody titers, and survival following an aerosol challenge with a lethal dose of Yersinia pestis strain Colorado 92. CMs were vaccinated with a range of rF1V doses on a three-dose schedule (days 0, 56, and 121) to provide a range of survival outcomes. The humoral immune response following vaccination was evaluated with anti-rF1, anti-rV, and anti-rF1V bridge enzyme-linked immunosorbent assays (ELISAs). Animals were challenged via aerosol exposure on day 149. Vaccine doses and antibody responses were each significantly associated with the probability of CM survival (P < 0.0001). Vaccination also decreased signs of pneumonic plague in a dose-dependent manner. There were statistically significant correlations between the vaccine dose and the time to onset of fever (P < 0.0001), the time from onset of fever to death (P < 0.0001), the time to onset of elevated respiratory rate (P = 0.0003), and the time to onset of decreased activity (P = 0.0251) postinfection in animals exhibiting these clinical signs. Delays in the onset of these clinical signs of disease were associated with larger doses of rF1V. Immunization with ≥ 12 μg of rF1V resulted in 100% CM survival. Since both the vaccine dose and anti-rF1V antibody titers correlate with survival, rF1V bridge ELISA titers can be used as a correlate of protection. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Effects of 14-day treatment with the schedule III anorectic phendimetrazine on choice between cocaine and food in rhesus monkeys.

PubMed

Banks, Matthew L; Blough, Bruce E; Negus, S Stevens

2013-08-01

The clinical utility of monoamine releasers such as phenmetrazine or d-amphetamine as candidate agonist medications for cocaine dependence is hindered by their high abuse liability. Phendimetrazine is a clinically available schedule III anorectic that functions as a prodrug for phenmetrazine and thus may have lower abuse liability. This study determined the effects of continuous 14-day treatment with phendimetrazine on cocaine vs. food choice in rhesus monkeys (N=4). Responding was maintained under a concurrent schedule of food delivery (1-g pellets, fixed-ratio 100 schedule) and cocaine injections (0-0.1mg/kg/injection, fixed-ratio 10 schedule). Cocaine choice dose-effect curves were determined daily before and during 14-day periods of continuous intravenous treatment with saline or (+)-phendimetrazine (0.32-1.0mg/kg/h). Effects of 14-day treatment with (+)-phenmetrazine (0.1-0.32 mg/kg/h; N=5) and d-amphetamine (0.032-0.1mg/kg/h; N=6) were also examined for comparison. During saline treatment, food was primarily chosen during availability of low cocaine doses (0, 0.0032, and 0.01 mg/kg/injection), and cocaine was primarily chosen during availability of higher cocaine doses (0.032 and 0.1mg/kg/injection). Phendimetrazine initially decreased overall responding without significantly altering cocaine choice. Over the course of 14 days, tolerance developed to rate decreasing effects, and phendimetrazine dose-dependently decreased cocaine choice (significant at 0.032 mg/kg/injection cocaine). Phenmetrazine and d-amphetamine produced qualitatively similar effects. These results demonstrate that phendimetrazine can produce significant, though modest, reductions in cocaine choice in rhesus monkeys. Phendimetrazine may be especially suitable as a candidate medication for human studies because of its schedule III clinical availability. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Pharmacokinetic profile of Mitoguazone (MGBG) in patients with AIDS related non-Hodgkin's lymphoma.

PubMed

Rizzo, J; Levine, A M; Weiss, G R; Pearce, T; Kraynak, M; Mueck, R; Smith, S; Von Hoff, D D; Kuhn, J G

1996-01-01

Mitoguazone is a unique chemotherapeutic agent whose activity is believed to result primarily from the competitive inhibition of S-adenosyl-methionine decarboxylase leading to a disruption in polyamine biosynthesis. Initial clinical trials demonstrated that the dose-limiting toxicities (mucositis and myelosuppression) of Mitoguazone were both dose and schedule dependent. Early pharmacokinetic studies of Mitoguazone in man revealed a prolonged half-life. Concurrent with a recent Phase II trial of Mitoguazone in patients with AIDS related non-Hodgkin's lymphoma, the single dose pharmacokinetics of Mitoguazone were characterized. Twelve patients received 600 mg/m2 of intravenous Mitoguazone over 30 minutes on an intermittent every 2 week schedule. Blood, urine, cerebrospinal fluid (CSF), pleural fluid and tissue samples were collected and analyzed by HPLC. Mitoguazone was cleared from the plasma triexponentially with a harmonic mean terminal half-life of 175 hours and a mean residence time of 192 hours. Peak plasma levels occurred immediately post-infusion, ranged from 6.47 to 42.8 micrograms/ml, and remained (for an extended period) well above the reported concentration for inhibition of polyamine biosynthesis. Plasma clearance averaged 4.73 l/hr/m2 with a relatively large apparent volume of distribution at steady-state of 1012 l/m2 indicating tissue sequestration. Renal excretion of unchanged Mitoguazone accounted for an average of 15.8% of the dose within 48 to 72 hours post-administration. Detectable levels of drug were present in random voided samples eight days post-dose. Mitoguazone levels in CSF ranged from 22 to 186 ng/ml post-dose with CSF/plasma ratios ranging from 0.6% to 7%. The pleural fluid/plasma ratio was approximately 1. Tissue levels of Mitoguazone were highest in the liver followed by lymph node, spleen and the brain.

High-Dose Infusional Gemcitabine Combined with Busulfan and Melphalan with Autologous Stem-Cell Transplant in Patients with Refractory Lymphoid Malignancies

PubMed Central

Nieto, Y; Thall, P; Valdez, B; Andersson, B; Popat, U; Anderlini, P; Shpall, EJ; Bassett, R; Alousi, A; Hosing, C; Kebriaei, P; Qazilbash, M; Gulbis, A; Chancoco, C; Bashir, Q; Ciurea, S; Khouri, I; Parmar, S; Shah, N; Worth, L; Rondon, G; Champlin, R; Jones, RB

2014-01-01

We developed a new high-dose combination of infusional gemcitabine with busulfan/melphalan for lymphoid tumors. Gemcitabine dose was escalated by extending infusions at a fixed rate of 10 mg/m2/min in sequential cohorts, in daily, 3-dose or 2-dose schedules. Each dose immediately preceded busulfan (adjusted targeting AUC 4,000 μM.min−1/day × 4 days) or melphalan (60 mg/m2/day × 2 days). We enrolled 133 patients (80 Hodgkin’s lymphoma (HL), 46 non-Hodgkin’s lymphoma (NHL), 7 myeloma), median 3 prior regimens; primary refractory disease in 63% HL/45% NHL and PET-positive tumors at transplant in 50% patients. Two patients died from early posttransplant infections. The major toxicity was mucositis. The daily and 3-dose schedules caused substantial cutaneous toxicity. In contrast, the 2-dose schedule was better tolerated, which allowed us to extend the infusions from 15 to 270 minutes. Pretransplant values of C-reactive protein, b-type natriuretic peptide, ferritin or haptoglobin did not correlate with toxicity. Overall response and complete response rates were 87%/62% (HL), 100%/69% (B-LCL), 66%/66% (T-NHL), and 71%/57% (myeloma). At median follow-up of 24 months (3–63), the event-free/overall survival rates are 54%/72% (HL), 60%/89% (B-LCL), 70%/70% (T-NHL) and 43%/43% (myeloma). In conclusion, gemcitabine/busulfan/melphalan is a feasible regimen with substantial activity against a range of lymphoid malignancies. This regimen merits further evaluation in phase II and III trials. PMID:22643322

Artemether-lumefantrine dosing for malaria treatment in young children and pregnant women: A pharmacokinetic-pharmacodynamic meta-analysis.

PubMed

Kloprogge, Frank; Workman, Lesley; Borrmann, Steffen; Tékété, Mamadou; Lefèvre, Gilbert; Hamed, Kamal; Piola, Patrice; Ursing, Johan; Kofoed, Poul Erik; Mårtensson, Andreas; Ngasala, Billy; Björkman, Anders; Ashton, Michael; Friberg Hietala, Sofia; Aweeka, Francesca; Parikh, Sunil; Mwai, Leah; Davis, Timothy M E; Karunajeewa, Harin; Salman, Sam; Checchi, Francesco; Fogg, Carole; Newton, Paul N; Mayxay, Mayfong; Deloron, Philippe; Faucher, Jean François; Nosten, François; Ashley, Elizabeth A; McGready, Rose; van Vugt, Michele; Proux, Stephane; Price, Ric N; Karbwang, Juntra; Ezzet, Farkad; Bakshi, Rajesh; Stepniewska, Kasia; White, Nicholas J; Guerin, Philippe J; Barnes, Karen I; Tarning, Joel

2018-06-01

The fixed dose combination of artemether-lumefantrine (AL) is the most widely used treatment for uncomplicated Plasmodium falciparum malaria. Relatively lower cure rates and lumefantrine levels have been reported in young children and in pregnant women during their second and third trimester. The aim of this study was to investigate the pharmacokinetic and pharmacodynamic properties of lumefantrine and the pharmacokinetic properties of its metabolite, desbutyl-lumefantrine, in order to inform optimal dosing regimens in all patient populations. A search in PubMed, Embase, ClinicalTrials.gov, Google Scholar, conference proceedings, and the WorldWide Antimalarial Resistance Network (WWARN) pharmacology database identified 31 relevant clinical studies published between 1 January 1990 and 31 December 2012, with 4,546 patients in whom lumefantrine concentrations were measured. Under the auspices of WWARN, relevant individual concentration-time data, clinical covariates, and outcome data from 4,122 patients were made available and pooled for the meta-analysis. The developed lumefantrine population pharmacokinetic model was used for dose optimisation through in silico simulations. Venous plasma lumefantrine concentrations 7 days after starting standard AL treatment were 24.2% and 13.4% lower in children weighing <15 kg and 15-25 kg, respectively, and 20.2% lower in pregnant women compared with non-pregnant adults. Lumefantrine exposure decreased with increasing pre-treatment parasitaemia, and the dose limitation on absorption of lumefantrine was substantial. Simulations using the lumefantrine pharmacokinetic model suggest that, in young children and pregnant women beyond the first trimester, lengthening the dose regimen (twice daily for 5 days) and, to a lesser extent, intensifying the frequency of dosing (3 times daily for 3 days) would be more efficacious than using higher individual doses in the current standard treatment regimen (twice daily for 3 days). The model was developed using venous plasma data from patients receiving intact tablets with fat, and evaluations of alternative dosing regimens were consequently only representative for venous plasma after administration of intact tablets with fat. The absence of artemether-dihydroartemisinin data limited the prediction of parasite killing rates and recrudescent infections. Thus, the suggested optimised dosing schedule was based on the pharmacokinetic endpoint of lumefantrine plasma exposure at day 7. Our findings suggest that revised AL dosing regimens for young children and pregnant women would improve drug exposure but would require longer or more complex schedules. These dosing regimens should be evaluated in prospective clinical studies to determine whether they would improve cure rates, demonstrate adequate safety, and thereby prolong the useful therapeutic life of this valuable antimalarial treatment.

Dose dependency of time of onset of radiation-induced growth hormone deficiency

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

Clayton, P.E.; Shalet, S.M.

1991-02-01

Growth hormone (GH) secretion during insulin-induced hypoglycemia was assessed on 133 occasions in 82 survivors of childhood malignant disease. All had received cranial irradiation with a dose range to the hypothalamic-pituitary axis of 27 to 47.5 Gy (estimated by a schedule of 16 fractions over 3 weeks) and had been tested on one or more occasions between 0.2 and 18.9 years after treatment. Results of one third of the GH tests were defined as normal (GH peak response, greater than 15 mU/L) within the first 5 years, in comparison with 16% after 5 years. Stepwise multiple linear regression analysis showedmore » that dose (p = 0.007) and time from irradiation (p = 0.03), but not age at therapy, had a significant influence on peak GH responses. The late incidence of GH deficiency was similar over the whole dose range (4 of 26 GH test results normal for less than 30 Gy and 4 of 25 normal for greater than or equal to 30 Gy after 5 years), but the speed of onset over the first years was dependent on dose. We conclude that the requirement for GH replacement therapy and the timing of its introduction will be influenced by the dose of irradiation received by the hypothalamic-pituitary axis.« less

A phase II study of sunitinib in patients with recurrent epithelial ovarian and primary peritoneal carcinoma: an NCIC Clinical Trials Group Study.

PubMed

Biagi, J J; Oza, A M; Chalchal, H I; Grimshaw, R; Ellard, S L; Lee, U; Hirte, H; Sederias, J; Ivy, S P; Eisenhauer, E A

2011-02-01

Sunitinib is a multitargeted receptor tyrosine kinase inhibitor. We conducted a two-stage phase II study to evaluate the objective response rate of oral sunitinib in recurrent epithelial ovarian cancer. Eligibility required measurable disease and one or two prior chemotherapies, at least one platinum based. Platinum-sensitive or -resistant disease was allowed. Initial dose schedule was sunitinib 50 mg daily, 4 of 6 weeks. Observation of fluid accumulations during off-treatment periods resulted in adoption of continuous 37.5 mg daily dosing in the second stage of accrual. Of 30 eligible patients, most had serous histology (67%), were platinum sensitive (73%) and had two prior chemotherapies (60%). One partial response (3.3%) and three CA125 responses (10%) were observed, all in platinum-sensitive patients using intermittent dosing. Sixteen (53%) had stable disease. Five had >30% decrease in measurable disease. Overall median progression-free survival was 4.1 months. Common adverse events included fatigue, gastrointestinal symptoms, hand-foot syndrome and hypertension. No gastrointestinal perforation occurred. Single-agent sunitinib has modest activity in recurrent platinum-sensitive ovarian cancer, but only at the 50 mg intermittent dose schedule, suggesting that dose and schedule may be vital considerations in further evaluation of sunitinib in this cancer setting.

Double-blind, placebo-controlled immunotherapy with mixed grass-pollen allergoids. IV. Comparison of the safety and efficacy of two dosages of a high-molecular-weight allergoid.

PubMed

Bousquet, J; Hejjaoui, A; Soussana, M; Michel, F B

1990-02-01

Specific immunotherapy is still widely used in grass-pollen allergy, but its side effects may limit its use. We tested the safety and efficacy of a formalinized high-molecular-weight allergoid prepared from a mixed grass-pollen extract with two injection schedules in a double-blind, placebo-controlled study. Eighteen patients received placebo, 19 received the low-dose schedule (maximal dose: 2000 PNU) and 20 received the high-dose schedule (maximal dose: 10,000 PNU). Only one patient presented a systemic reaction of moderate severity for a dose of 1200 PNU. Before the onset of the pollen season, patients had a nasal challenge with orchard grass-pollen grains, a skin test titration, and the titration of serum-specific IgG. Both groups of patients presented a significant reduction in nasal and skin sensitivities and a significant increase in IgG compared to placebo. Symptoms and medications for rhinitis and asthma were studied during the season, and both groups receiving allergoids had a significant reduction of symptom-medication scores for nasal and bronchial symptoms. There was a highly significant correlation between nasal symptom-medication scores during the season and the results of nasal challenges. High-molecular-weight allergoids are safe and effective.

Canadian supportive care recommendations for the management of neutropenia in patients with cancer.

PubMed

Kouroukis, C T; Chia, S; Verma, S; Robson, D; Desbiens, C; Cripps, C; Mikhael, J

2008-01-01

Hematologic toxicities of cancer chemotherapy are common and often limit the ability to provide treatment in a timely and dose-intensive manner. These limitations may be of utmost importance in the adjuvant and curative intent settings. Hematologic toxicities may result in febrile neutropenia, infections, fatigue, and bleeding, all of which may lead to additional complications and prolonged hospitalization. The older cancer patient and patients with significant comorbidities may be at highest risk of neutropenic complications. Colony-stimulating factors (csfs) such as filgrastim and pegfilgrastim can effectively attenuate most of the neutropenic consequences of chemotherapy, improve the ability to continue chemotherapy on the planned schedule, and minimize the risk of febrile neutropenia and infectious morbidity and mortality. The present consensus statement reviews the use of csfs in the management of neutropenia in patients with cancer and sets out specific recommendations based on published international guidelines tailored to the specifics of the Canadian practice landscape. We review existing international guidelines, the indications for primary and secondary prophylaxis, the importance of maintaining dose intensity, and the use of csfs in leukemia, stem-cell transplantation, and radiotherapy. Specific disease-related recommendations are provided related to breast cancer, non-Hodgkin lymphoma, lung cancer, and gastrointestinal cancer. Finally, csf dosing and schedules, duration of therapy, and associated acute and potential chronic toxicities are examined.

Feasibility of Dose-escalated Hypofractionated Chemoradiation in Human Papilloma Virus-negative or Smoking-associated Oropharyngeal Cancer.

PubMed

Meade, S; Gaunt, P; Hartley, A; Robinson, M; Harrop, V; Cashmore, J; Wagstaff, L; Babrah, J; Bowden, S J; Mehanna, H; Sanghera, P

2018-06-01

Oropharyngeal squamous cell carcinoma (OPSCC) can be divided into favourable and poor prognostic groups by association with human papilloma virus (HPV) and smoking. This study prospectively investigated a dose-intensified schedule in poor/intermediate prognosis OPSCC. Patients with p16/HPV-negative or p16-positive N2b OPSCC with a greater than 10 pack-year smoking history were eligible. Patients were planned to receive 64 Gy in 25 fractions with cisplatin. The primary end point was absence of grade 3 mucositis at 3 months. Fifteen patients were recruited over 14 months. All patients completed a minimum of 2 years of follow-up. All patients completed full-dose radiotherapy within a median treatment time of 32 days (31-35). Grade 3 mucositis was absent in all patients at 3 months. There was one grade 4 toxicity event due to cisplatin (hypokalaemia). Complete response rates at 3 months were 100% and 93% for local disease and lymph nodes, respectively. One patient developed metastatic disease and subsequently died. Overall survival at 2 years was 93% (95% confidence interval 61-99%). The schedule of 64 Gy in 25 fractions with concomitant chemotherapy is tolerable in patients with poor and intermediate prognosis OPSCC. Copyright © 2018. Published by Elsevier Ltd.

Buprenorphine dose induction in non-opioid-tolerant pre-release prisoners.

PubMed

Vocci, Frank J; Schwartz, Robert P; Wilson, Monique E; Gordon, Michael S; Kinlock, Timothy W; Fitzgerald, Terrence T; O'Grady, Kevin E; Jaffe, Jerome H

2015-11-01

In a previously reported randomized controlled trial, formerly opioid-dependent prisoners were more likely to enter community drug abuse treatment when they were inducted in prison onto buprenorphine/naloxone (hereafter called buprenorphine) than when they received counseling without buprenorphine in prison (47.5% vs. 33.7%, p=0.012) (Gordon et al., 2014). In this communication we report on the results of the induction schedule and the adverse event profile seen in pre-release prisoners inducted onto buprenorphine. This paper examines the dose induction procedure, a comparison of the proposed versus actual doses given per week, and side effects reported for 104 adult participants who were randomized to buprenorphine treatment in prison. Self-reported side effects were analyzed using generalized estimated equations to determine changes over time in side effects. Study participants were inducted onto buprenorphine at a rate faster than the induction schedule. Of the 104 (72 males, 32 females) buprenorphine recipients, 64 (37 males, 27 females) remained on medication at release from prison. Nine participants (8.6%) discontinued buprenorphine because of unpleasant opioid side effects. There were no serious adverse events reported during the in-prison phase of the study. Constipation was the most frequent symptom reported (69 percent). Our findings suggest that buprenorphine administered to non-opioid-tolerant adults should be started at a lower, individualized dose than customarily used for adults actively using opioids, and that non-opioid-tolerant pre-release prisoners can be successfully inducted onto therapeutic doses prior to release. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Immunization Schedule

MedlinePlus

... third dose may be needed, depending on the brand of vaccine used in previous Hib immunizations. PCV ... third dose may be needed, depending on the brand of vaccine used in previous RV immunizations. 6 ...

Oral low-dose chemotherapy: successful treatment of an alveolar rhabdomyosarcoma during pregnancy.

PubMed

Siepermann, Meinolf; Koscielniak, Ewa; Dantonello, Tobias; Klee, Dirk; Boos, Joachim; Krefeld, Barbara; Borkhardt, Arndt; Hoehn, Thomas; Asea, Alexzander; Wessalowski, Rüdiger

2012-01-01

We report for the first time the impact of neoadjuvant oral low-dose chemotherapy consisting of oral trofosfamide, idarubicin, and etoposide (O-TIE) in the case of alveolar rhabdomyosarcoma (RMS) in the lower jaw of an 18-year-old woman at 27 weeks of gestation, without fetal complications and a highly efficient anti-tumor response. Our study suggests the possible application of O-TIE treatment in a neoadjuvant setting during pregnancy and recommends a schedule that can be considered for the treatment of patients with high-risk sarcomas who cannot be treated with intensive chemotherapy for various reasons. Copyright © 2011 Wiley Periodicals, Inc.

Oral Low-Dose Chemotherapy: Successful Treatment of an Alveolar Rhabdomyosarcoma during Pregnancy

PubMed Central

Siepermann, Meinolf; Koscielniak, Ewa; Dantonello, Tobias; Klee, Dirk; Boos, Joachim; Krefeld, Barbara; Borkhardt, Arndt; Hoehn, Thomas; Asea, Alexzander; Wessalowski, Rüdiger

2011-01-01

We report for the first time the impact of neoadjuvant oral low-dose chemotherapy consisting of oral trofosfamide, idarubicin, and etoposide (O-TIE) in the case of alveolar Rhabdomyosarcoma (RMS) in the lower jaw of an 18-year-old woman at 27-weeks of gestation, without fetal complications and a highly efficient anti-tumor response. Our study suggests the possible application of O-TIE treatment in a neoadjuvant setting during pregnancy and recommends a schedule that can be considered for the treatment of patients with high-risk sarcomas who cannot be treated with intensive chemotherapy for various reasons. PMID:22076833

Role of gamma-aminobutyric acid type A (GABAA) receptor subtypes in acute benzodiazepine physical dependence-like effects: evidence from squirrel monkeys responding under a schedule of food presentation

PubMed Central

Fischer, Bradford D.; Teixeira, Laura P.; van Linn, Michael L.; Namjoshi, Ojas A.; Cook, James M.; Rowlett, James K.

2013-01-01

Rationale Assays of schedule-controlled responding can be used to characterize the pharmacology of benzodiazepines and other GABAA receptor modulators, and are sensitive to changes in drug effects that are related to physical dependence. Objective The present study used this approach to investigate the role of GABAA receptor subtypes in mediating dependence-like effects following benzodiazepine administration. Methods Squirrel monkeys (n=6) were trained on a fixed-ratio schedule of food reinforcement. Initially, the response rate-decreasing effects of chlordiazepoxide (0.1–10 mg/kg; nonselective GABAA receptor agonist), zolpidem (0.032–1.0 mg/kg; α1 subunit-containing GABAA subtype-preferring agonist) and HZ-166 (0.1–10 mg/kg; functionally selective α2 and α3 subunit-containing GABAA receptor agonist) were assessed. Next, acute dependence-like effects following single injections of chlordiazepoxide, zolpidem and HZ-166 were assessed with flumazenil (0.1–3.2 mg/kg; nonselective GABAA receptor antagonist). Finally, acute dependence-like effects following zolpidem administration were assessed with βCCt and 3-PBC (0.1–3.2 mg/kg and 0.32–10 mg/kg, respectively; α1 subunit-containing GABAA receptor antagonists). Results Chlordiazepoxide, zolpidem and HZ-166 produced dose- and time-dependent decreases in response rates, whereas flumazenil, βCCt and 3-PBC were ineffective. After the drug effects waned, flumazenil produced dose-dependent decreases in response rates following administration of 10 mg/kg chlordiazepoxide and 1.0 mg/kg zolpidem, but not following any dose of HZ-166. Further, both βCCt and 3-PBC produced dose-dependent decreases in response rates when administered after 1.0 mg/kg zolpidem. Conclusions These data raise the possibility that α1 subunit-containing GABAA receptors play a major role in physical dependence-related behaviors following a single injection of a benzodiazepine. PMID:23354533

Role of gamma-aminobutyric acid type A (GABAA) receptor subtypes in acute benzodiazepine physical dependence-like effects: evidence from squirrel monkeys responding under a schedule of food presentation.

PubMed

Fischer, Bradford D; Teixeira, Laura P; van Linn, Michael L; Namjoshi, Ojas A; Cook, James M; Rowlett, James K

2013-05-01

Assays of schedule-controlled responding can be used to characterize the pharmacology of benzodiazepines and other GABAA receptor modulators, and are sensitive to changes in drug effects that are related to physical dependence. The present study used this approach to investigate the role of GABAA receptor subtypes in mediating dependence-like effects following benzodiazepine administration. Squirrel monkeys (n = 6) were trained on a fixed-ratio schedule of food reinforcement. Initially, the response rate-decreasing effects of chlordiazepoxide (0.1-10 mg/kg; nonselective GABAA receptor agonist), zolpidem (0.032-1.0 mg/kg; α1 subunit-containing GABAA subtype-preferring agonist), and HZ-166 (0.1-10 mg/kg; functionally selective α2 and α3 subunit-containing GABAA receptor agonist) were assessed. Next, acute dependence-like effects following single injections of chlordiazepoxide, zolpidem, and HZ-166 were assessed with flumazenil (0.1-3.2 mg/kg; nonselective GABAA receptor antagonist). Finally, acute dependence-like effects following zolpidem administration were assessed with βCCt and 3-PBC (0.1-3.2 mg/kg and 0.32-10 mg/kg, respectively; α1 subunit-containing GABAA receptor antagonists). Chlordiazepoxide, zolpidem, and HZ-166 produced dose- and time-dependent decreases in response rates, whereas flumazenil, βCCT, and 3-PBC were ineffective. After the drug effects waned, flumazenil produced dose-dependent decreases in response rates following administration of 10 mg/kg chlordiazepoxide and 1.0 mg/kg zolpidem, but not following any dose of HZ-166. Further, both βCCT and 3-PBC produced dose-dependent decreases in response rates when administered after 1.0 mg/kg zolpidem. These data raise the possibility that α1 subunit-containing GABAA receptors play a major role in physical dependence-related behaviors following a single injection of a benzodiazepine.

Intravenous nicotine self-administration and cue-induced reinstatement in mice: Effects of nicotine dose, rate of drug infusion and prior instrumental training

PubMed Central

Fowler, Christie D.; Kenny, Paul J.

2011-01-01

Intravenous nicotine self-administration is the most direct measure of nicotine reinforcement in laboratory animals, but this procedure has proven difficult to establish in mice. We found that stable responding for nicotine in C57BL6/J mice was facilitated by prior instrumental training for food reward, initial exposure of mice to a lower unit dose of nicotine (0.03 mg/kg/infusion) before access to higher doses, a slower rate of drug delivery (3-sec versus 1-sec infusion), consistency in schedule of daily testing, and low extraneous noise during testing. Under these conditions, we found that mice lever-pressing for nicotine (0.03–0.4 mg/kg/infusion; 60-min test sessions) under a fixed-ratio 5 time-out 20-sec (FR5TO20) reinforcement schedule consumed the drug according to an inverted ‘U’-shaped dose-response curve. Mice switched their responding onto a previously non-reinforced lever to continue earning nicotine infusions when the active/inactive lever assignment was reversed. The nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine decreased responding for nicotine, but not food rewards, verifying that nAChRs regulate nicotine self-administration in mice. The cue-light paired with nicotine delivery did not support responding when delivered independently of nicotine infusions, further verifying that mice responded selectivity for the drug. Nicotine-seeking responses extinguished when nicotine infusions and the cue-light were withheld, and exposure to the cue-light reinstated responding. Finally, mice without prior instrumental food training acquired stable responding for nicotine under the FR5TO20 schedule, but required a greater number of sessions. These data demonstrate that nicotine is an effective reinforcer in mice and establish conditions under which the drug is reliably self-administered by mice. PMID:21640128

Evaluation of BGJ398, a Fibroblast Growth Factor Receptor 1-3 Kinase Inhibitor, in Patients With Advanced Solid Tumors Harboring Genetic Alterations in Fibroblast Growth Factor Receptors: Results of a Global Phase I, Dose-Escalation and Dose-Expansion Study.

PubMed

Nogova, Lucia; Sequist, Lecia V; Perez Garcia, Jose Manuel; Andre, Fabrice; Delord, Jean-Pierre; Hidalgo, Manuel; Schellens, Jan H M; Cassier, Philippe A; Camidge, D Ross; Schuler, Martin; Vaishampayan, Ulka; Burris, Howard; Tian, G Gary; Campone, Mario; Wainberg, Zev A; Lim, Wan-Teck; LoRusso, Patricia; Shapiro, Geoffrey I; Parker, Katie; Chen, Xueying; Choudhury, Somesh; Ringeisen, Francois; Graus-Porta, Diana; Porter, Dale; Isaacs, Randi; Buettner, Reinhard; Wolf, Jürgen

2017-01-10

Purpose This two-part, first-in-human study was initiated in patients with advanced solid tumors harboring genetic alterations in fibroblast growth factor receptors (FGFRs) to determine the maximum tolerated dose (MTD), the recommended phase II dose (RP2D), and the schedule, safety, pharmacokinetics, pharmacodynamics, and antitumor activity of oral BGJ398, a selective FGFR1-3 tyrosine kinase inhibitor. Patients and Methods Adult patients were treated with escalating dosages of BGJ398 5 to 150 mg once daily or 50 mg twice daily continuously in 28-day cycles. During expansion at the MTD, patients with FGFR1-amplified squamous cell non-small-cell lung cancer (sqNSCLC; arm 1) or other solid tumors with FGFR genetic alterations (mutations/amplifications/fusions) received BGJ398 daily on a continuous schedule (arm 2), or on a 3-weeks-on/1-week-off schedule (arm 3). Results Data in 132 patients from the escalation and expansion arms are reported (May 15, 2015, cutoff). The MTD, 125 mg daily, was determined on the basis of dose-limiting toxicities in four patients (100 mg, grade 3 aminotransferase elevations [n = 1]; 125 mg, hyperphosphatemia [n = 1]; 150 mg, grade 1 corneal toxicity [n = 1] and grade 3 aminotransferase elevations [n = 1]). Common adverse events in patients treated at the MTD (n = 57) included hyperphosphatemia (82.5%), constipation (50.9%), decreased appetite (45.6%), and stomatitis (45.6%). A similar safety profile was observed using the 3-weeks-on/1-week-off schedule (RP2D). However, adverse event-related dose adjustments/interruptions were less frequent with the 3-weeks-on/1-week-off (50.0%) versus the continuous (73.7%) schedule. Antitumor activity (seven partial responses [six confirmed]) was demonstrated with BGJ398 doses ≥ 100 mg in patients with FGFR1-amplified sqNSCLC and FGFR3-mutant bladder/urothelial cancer. Conclusion BGJ398 at the MTD/RP2D had a tolerable and manageable safety profile and showed antitumor activity in several tumor types, including FGFR1-amplified sqNSCLC and FGFR3-mutant bladder/urothelial cancers.

Deflazacort

MedlinePlus

... eyelid or eye surface); cataracts (clouding of the lens of the eye); glaucoma (an eye disease); high blood pressure; heart ... regular dosing schedule. Do not take a double dose to make up for a missed one.

Dose-time relationships for post-irradiation cutaneous telangiectasia

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

Cohen, L.; Ubaldi, S.E.

1977-01-01

Seventy-five patients who had received electron beam radiation a year or more previously were studied. The irradiated skin portals were photographed and late reactions graded in terms of the number and severity of telangiectatic lesions observed. The skin dose, number of fractions, overall treatment time and irradiated volume were recorded in each case. A Strandqvist-type iso-effect line was derived for this response. A multi-probit search program also was used to derive best-fitting cell population kinetic parameters for the same data. From these parameters a comprehensive iso-effect table could be computed for a wide range of treatment schedules including daily treatmentmore » as well as fractionation at shorter and longer intervals; this provided a useful set of normal tissue tolerance limits for late effects.« less

Licensure strategy for pre- and post-exposure prophylaxis of biothrax vaccine: the first vaccine licensed using the FDA animal rule.

PubMed

Longstreth, Janice; Skiadopoulos, Mario H; Hopkins, Robert J

2016-12-01

The availability of a licensed anthrax vaccine that is safe, effective, and easy to administer for both pre- and post-exposure prophylaxis is critical to successfully manage and prevent potential anthrax attacks. BioThrax® (Anthrax Vaccine Adsorbed; AVA) is the only licensed anthrax vaccine in the US. Areas covered: Recent licensed improvements to BioThrax vaccine for pre-exposure prophylaxis (PrEP) have included an intramuscular (IM) five-dose schedule (in 2008) and a three-dose IM primary series at 0, 1 and 6 months (in 2012). Post-exposure prophylaxis (PEP) - three doses given subcutaneously (SC) at 0, 2, and 4 weeks - was licensed in 2015. We review the anthrax disease and vaccine literature that supported these licensure efforts. Expert commentary: This PEP licensure is the first time the FDA's Animal Rule has been used to license a vaccine. Additional improvements such as fewer vaccine doses and reduced time to protection are desirable for a PEP vaccine and are being pursued with next generation vaccine candidates.

PEGylated G-CSF (BBT-015), GM-CSF (BBT-007), and IL-11 (BBT-059) analogs enhance survival and hematopoietic cell recovery in a mouse model of the hematopoietic syndrome of the acute radiation syndrome.

PubMed

Plett, Paul Artur; Chua, Hui Lin; Sampson, Carol H; Katz, Barry P; Fam, Christine M; Anderson, Lana J; Cox, George N; Orschell, Christie M

2014-01-01

Hematopoietic growth factors (HGF) are recommended therapy for high dose radiation exposure, but unfavorable administration schedules requiring early and repeat dosing limit the logistical ease with which they can be used. In this report, using a previously described murine model of H-ARS, survival efficacy and effect on hematopoietic recovery of unique PEGylated HGF were investigated. The PEGylated-HGFs possess longer half-lives and more potent hematopoietic properties than corresponding non-PEGylated-HGFs. C57BL/6 mice underwent single dose lethal irradiation (7.76-8.72 Gy, Cs, 0.62-1.02 Gy min) and were treated with various dosing regimens of 0.1, 0.3, and 1.0 mg kg of analogs of human PEG-G-CSF, murine PEG-GM-CSF, or human PEG-IL-11. Mice were administered one of the HGF analogs at 24-28 h post irradiation, and in some studies, additional doses given every other day (beginning with the 24-28 h dose) for a total of three or nine doses. Thirty-day (30 d) survival was significantly increased with only one dose of 0.3 mg kg of PEG-G-CSF and PEG-IL-11 or three doses of 0.3 mg kg of PEG-GM-CSF (p ≤ 0.006). Enhanced survival correlated with consistently and significantly enhanced WBC, NE, RBC, and PLT recovery for PEG-G- and PEG-GM-CSF, and enhanced RBC and PLT recovery for PEG-IL-11 (p ≤ 0.05). Longer administration schedules or higher doses did not provide a significant additional survival benefit over the shorter, lower dose, schedules. These data demonstrate the efficacy of BBT's PEG-HGF to provide significantly increased survival with fewer injections and lower drug doses, which may have significant economic and logistical value in the aftermath of a radiation event.

Assessing the cost-effectiveness of different measles vaccination strategies for children in the Democratic Republic of Congo.

PubMed

Doshi, Reena H; Eckhoff, Philip; Cheng, Alvan; Hoff, Nicole A; Mukadi, Patrick; Shidi, Calixte; Gerber, Sue; Wemakoy, Emile Okitolonda; Muyembe-Tafum, Jean-Jacques; Kominski, Gerald F; Rimoin, Anne W

2017-10-27

One of the goals of the Global Measles and Rubella Strategic Plan is the reduction in global measles mortality, with high measles vaccination coverage as one of its core components. While measles mortality has been reduced more than 79%, the disease remains a major cause of childhood vaccine preventable disease burden globally. Measles immunization requires a two-dose schedule and only countries with strong, stable immunization programs can rely on routine services to deliver the second dose. In the Democratic Republic of Congo (DRC), weak health infrastructure and lack of provision of the second dose of measles vaccine necessitates the use of supplementary immunization activities (SIAs) to administer the second dose. We modeled three vaccination strategies using an age-structured SIR (Susceptible-Infectious-Recovered) model to simulate natural measles dynamics along with the effect of immunization. We compared the cost-effectiveness of two different strategies for the second dose of Measles Containing Vaccine (MCV) to one dose of MCV through routine immunization services over a 15-year time period for a hypothetical birth cohort of 3 million children. Compared to strategy 1 (MCV1 only), strategy 2 (MCV2 by SIA) would prevent a total of 5,808,750 measles cases, 156,836 measles-related deaths and save U.S. $199 million. Compared to strategy 1, strategy 3 (MCV2 by RI) would prevent a total of 13,232,250 measles cases, 166,475 measles-related deaths and save U.S. $408 million. Vaccination recommendations should be tailored to each country, offering a framework where countries can adapt to local epidemiological and economical circumstances in the context of other health priorities. Our results reflect the synergistic effect of two doses of MCV and demonstrate that the most cost-effective approach to measles vaccination in DRC is to incorporate the second dose of MCV in the RI schedule provided that high enough coverage can be achieved. Published by Elsevier Ltd.

Changes in the retreatment radiation tolerance of the spinal cord with time after the initial treatment.

PubMed

Woolley, Thomas E; Belmonte-Beitia, Juan; Calvo, Gabriel F; Hopewell, John W; Gaffney, Eamonn A; Jones, Bleddyn

2018-06-01

To estimate, from experimental data, the retreatment radiation 'tolerances' of the spinal cord at different times after initial treatment. A model was developed to show the relationship between the biological effective doses (BEDs) for two separate courses of treatment with the BED of each course being expressed as a percentage of the designated 'retreatment tolerance' BED value, denoted [Formula: see text] and [Formula: see text]. The primate data of Ang et al. ( 2001 ) were used to determine the fitted parameters. However, based on rodent data, recovery was assumed to commence 70 days after the first course was complete, and with a non-linear relationship to the magnitude of the initial BED (BED init ). The model, taking into account the above processes, provides estimates of the retreatment tolerance dose after different times. Extrapolations from the experimental data can provide conservative estimates for the clinic, with a lower acceptable myelopathy incidence. Care must be taken to convert the predicted [Formula: see text] value into a formal BED value and then a practical dose fractionation schedule. Used with caution, the proposed model allows estimations of retreatment doses with elapsed times ranging from 70 days up to three years after the initial course of treatment.

Varicella prevention in Costa Rica: impact of a one-dose schedule universal vaccination.

PubMed

Avila-Aguero, María L; Ulloa-Gutierrez, Rolando; Camacho-Badilla, Kattia; Soriano-Fallas, Alejandra; Arroba-Tijerino, Roberto; Morice-Trejos, Ana

2017-03-01

To describe the impact following a 1-dose Varicella vaccination schedule introduced in Costa Rica in September 2007. Areas covered: This is a retrospective review using epidemiologic surveillance national databases of varicella cases and hospitalizations, period 2000-2015. We analyzed age-related varicella incidence cases and hospitalization trends before and after the vaccine introduction. Expert commentary: Varicella vaccine coverage among children 16 months age increased from 76% in 2008 to 95% in 2015. During this period Costa Rica reached a 73.8% reduction of Varicella reported cases and 85.9% reduction of hospitalizations in the general population. Among children under 5 years of age, that reduction was 79.1% and 87%, respectively. Varicella complications in hospitalized patients decreased 98%, from n = 53 in 2008 to n = 1 in 2014. After 8-years post implementation of a 1-dose schedule of universal varicella vaccination, a dramatic overall disease reduction in incidence, hospitalizations and complicated cases has been observed in all age groups.

[Comparative immunogenicity of 2 antirabies vaccines in a 2-1-1 post-exposure vaccination schedule].

PubMed

Landry, P; Lazzaro, M; Darioli, R

1998-09-09

Few trials have compared the Purified Duck Embryo Vaccine (PDEV) and the Human Diploid Cell Vaccine (HDCV) in a post-exposure immunization schedule of 4 shots (2 on day 0 and 1 each on day 7 and 21, or 2-1-1 schedule). A retrospective analysis compared 10 patients with PEDV and 20 with HDCV, who had received the 2-1-1 schedule as well as 20 UI mg/kg of immune globulins on day 0. The median neutralizing antibody titers on day 21 (after 3 doses) and the median of maximum titers until day 90 were higher for HDCV than for PEDV (0.6 IU/ml versus 3.5 IU/ml [p < 0.04] and 2.5 IU/ml versus 5.8 IU/ml [p < 0.03] respectively). Seven patients had not reached the seroconversion titer of 0.5 IU/ml after 3 doses (day 21). These results differ from previous studies showing a 100% seroconversion rate on day 21, and suggest that more studies are required before these 2 vaccines can be used in the 2-1-1 schedule after severe exposure.

Impact of Abbreviated Filgrastim Schedule on Survival and Hematopoietic Recovery after Irradiation in Four Mouse Strains with Different Radiosensitivity

PubMed Central

Satyamitra, Merriline; Kumar, Vidya P.; Biswas, Shukla; Cary, Lynnette; Dickson, Leonora; Venkataraman, Srinivasan; Ghosh, Sanchita P.

2017-01-01

Filgrastim (Neupogen®, granulocyte-colony stimulating factor) is among the few countermeasures recommended for management of patients in the event of lethal total-body irradiation. Despite the plethora of studies using filgrastim as a radiation countermeasure, relatively little is known about the optimal dose schedule of filgrastim to mitigate radiation lethality. We evaluated the efficacy of filgrastim in improving 30-day survival of CD2F1 mice irradiated with a lethal dose (LD70/30) in the AFRRI cobalt-60 facility. We tested different schedules of 1, 3, 5,10 or 16 once-daily injections of filgrastim initiated one day after irradiation. Time optimization studies with filgrastim treatment were also performed, beginning 6–48 h postirradiation. Maximum survival was observed with 3 daily doses of 0.17 mg/kg filgrastim. Survival efficacy of the 3-day treatment was compared against the conventional 16-day filgrastim treatment after irradiation in four mouse strains with varying radiation sensitivities: C3H/HeN, C57BL/6, B6C3F1 and CD2F1. Blood indices, bone marrow histopathology and colony forming unit assays were also evaluated. Filgrastim significantly increased 30-day survival (P < 0.001) with a 3-day treatment compared to 16-day treatment. Filgrastim did not prevent cytopenia nadirs, but facilitated faster recovery of white blood cells, neutrophils, red blood cells, platelets, lymphocytes and hematocrits in all four strains. Accelerated hematopoietic recovery was also reflected in faster bone marrow reconstitution and significant increase in hematopoietic progenitors (P < 0.001) in all four mouse strains. These data indicate that prompt and abbreviated filgrastim treatment has potential benefit for triage in the event of a radiological incident for treating acute hematopoietic syndrome. PMID:28362168

Adjuvant breast cancer therapy: current status and future strategies--growth kinetics and the improved drug therapy of breast cancer.

PubMed

Norton, L

1999-02-01

It is well-established that the adjuvant treatment of breast cancer is effective in prolonging both disease-free and overall survival. The pressing questions are how to improve on existing treatment, whether new agents should be incorporated into adjuvant regimens, and, if so, how they should best be utilized. The application of log-kill principles to the sigmoid growth curve characteristic of human cancers suggests that the chances of eradicating tumor will be increased by dose-dense schedules. If the tumor is composed of several cell lines with different sensitivities, the optimum therapy is likely to consist of several drugs given in sequence at a good dose and on a dense schedule. Such sequential chemotherapy, rather than the use of drugs given in combination at longer intervals, should maximize log-kill at the same time as minimizing tumor regrowth. There is now evidence that the actions of chemotherapy may involve Ras, tyrosine kinases (epidermal growth factor receptor, HER2), TC21, or similar molecules. This concept may provide important clues for optimizing the clinical applications of drug therapy and for designing new therapeutic approaches. It might also explain the reason why dose density may be more effective than other schedules of administration. New blood vessel formation is an obligatory step in the establishment of a tumor in its sigmoid growth course and there is evidence that taxanes adversely affect this process. Major practical advances in the curative drug therapy of cancer should follow the demonstration of better ways to maximize cell kill, the development of predictive in vitro methods of selecting active agents, the discovery of techniques to minimize both drug resistance and host-cell toxicity, and the improved understanding of cancer-stromal interactions and their therapeutic perturbation.

A Pilot Study of Cerebral and Hemodynamic Changes During Sedation with Low Dose of Thiopental Sodium or Propofol in Patients with Acute Brain Injury.

PubMed

Yaghoobi, Siamak; Khezri, Marzieh Beigom; Alamouti, Azam Mohammadi

2015-08-01

One of the most important therapeutic maneuvers in head injury patients is to maintain Intracranial Pressure (ICP) and Cerebral Perfusion Pressure (CPP) within normal levels. To compare the effects of low dose of thiopental sodium and propofol on reducing ICP and CPP in patients with head injury that scheduled for neurosurgical interventions. Using a randomized, crossover pilot study, we enrolled patients with head injury that scheduled for neurosurgical interventions admitted to ICU unit of a teaching hospital during 2010 to 2011. In this pilot study, patients randomized into two equal groups. The first group received bolus injection of thiopental sodium 2 mg/kg and a maintenance dose of 2 mg/kg/h and the second group was given a bolus dose of propofol 0.5 mg/kg followed by propofol infusion 20 μg/kg/min. All of patients were given dexamethasone 8 mg at time of catheter insertion. ICP measurement catheter was inserted for each patient and ICP, CPP, SPO2 and MAP were recorded hourly for a period of 6 hours. There was no significant difference in sex and age between the two study groups (p>0.05). The mean ICP, CPP, SPO2 and arterial blood pressure were found to be similar with no significant difference between both groups (p>0.05). Both propofol and thiopental sodium were equally effective in monitoring and maintaining CPP and MAP and eventually an ideal SPO2.

Indian Academy of Pediatrics (IAP) recommended immunization schedule for children aged 0 through 18 years--India, 2014 and updates on immunization.

PubMed

Vashishtha, Vipin M; Choudhury, Panna; Kalra, Ajay; Bose, Anuradha; Thacker, Naveen; Yewale, Vijay N; Bansal, C P; Mehta, Pravin J

2014-10-01

There is a need to review/revise recommendations about existing vaccines in light of recent developments in the field of vaccinology. Following an IAP ACVIP meeting on April 19 and 20, 2014, a draft of revised recommendations for the year 2014 and updates on certain vaccine formulations was prepared and circulated among the meeting participants to arrive at a consensus. To review and revise recommendations for 2014 Immunization timetable for pediatricians in office practice and issue statements on certain new and existing vaccine formulations. The major changes in the 2014 Immunization Timetable include two doses of MMR vaccine at 9 and 15 months of age, single dose recommendation for administration of live attenuated H2 strain hepatitis A vaccine, inclusion of two new situations in high-risk category of children in context with pre-exposure prophylaxis of rabies, creation of a new slot at 9-12 months of age for typhoid conjugate vaccine for primary immunization, and recommendation of two doses of human papilloma virus vaccines with a minimum interval of 6 months between doses for primary schedule of adolescent/preadolescent girls aged 9-14 years. There would not be any change to the committee's last year's (2013) recommendations on pertussis vaccination and administration schedule of monovalent human rotavirus vaccine. There is no need of providing additional doses of whole-cell pertussis vaccine to children who have earlier completed their primary schedule with acellular pertussis vaccine-containing products. A brief update on the new Indian Rotavirus vaccine, 116E is also provided. The committee has reviewed and offered its recommendations on the currently available pentavalent vaccine (DTwP+Hib+Hepatitis-B) combinations in Indian market. The comments and footnotes for several vaccines are also updated and revised.

[Immunisation schedule of the Spanish Association of Paediatrics: 2015 recommendations].

PubMed

Moreno-Pérez, D; Álvarez García, F J; Arístegui Fernández, J; Cilleruelo Ortega, M J; Corretger Rauet, J M; García Sánchez, N; Hernández Merino, A; Hernández-Sampelayo Matos, T; Merino Moína, M; Ortigosa Del Castillo, L; Ruiz-Contreras, J

2015-01-01

The Advisory Committee on Vaccines of the Spanish Association of Paediatrics updates the immunisation schedule every year, taking into account epidemiological data as well as evidence on the safety, effectiveness and efficiency of current vaccines, including levels of recommendation. In our opinion, this is the optimal vaccination calendar for all children resident in Spain. Regarding the vaccines included in the official unified immunization schedule, the Committee emphasizes the administration of the first dose of hepatitis B either at birth or at 2 months of life; the recommendation of the first dose of MMR and varicella vaccine at the age of 12 months, with the second dose at the age of 2-3 years; DTaP or Tdap vaccine at the age of 6 years, followed by another Tdap booster dose at 11-12 years old; Tdap strategies for pregnant women and household contacts of the newborn, and immunization against human papillomavirus in girls aged 11-12 years old with a 2 dose scheme (0, 6 months). The Committee reasserts its recommendation to include vaccination against pneumococcal disease in the routine immunisation schedule, the same as it is being conducted in Western European countries. The recently authorised meningococcal B vaccine, currently blocked in Spain, exhibits the profile of a universal vaccine. The Committe insists on the need of having the vaccine available in communitary pharmacies. It has also proposed the free availability of varicella vaccines. Their efectiveness and safety have been confirmed when they are administred from the second year of life. Vaccination against rotavirus is recommended in all infants. The Committee stresses the need to vaccinate population groups considered at risk against influenza and hepatitis A. Copyright © 2014. Published by Elsevier Espana.

Guadecitabine (SGI-110) in treatment-naive patients with acute myeloid leukaemia: phase 2 results from a multicentre, randomised, phase 1/2 trial.

PubMed

Kantarjian, Hagop M; Roboz, Gail J; Kropf, Patricia L; Yee, Karen W L; O'Connell, Casey L; Tibes, Raoul; Walsh, Katherine J; Podoltsev, Nikolai A; Griffiths, Elizabeth A; Jabbour, Elias; Garcia-Manero, Guillermo; Rizzieri, David; Stock, Wendy; Savona, Michael R; Rosenblat, Todd L; Berdeja, Jesus G; Ravandi, Farhad; Rock, Edwin P; Hao, Yong; Azab, Mohammad; Issa, Jean-Pierre J

2017-10-01

The hypomethylating drugs azacitidine and decitabine have shown efficacy in myelodysplastic syndromes and acute myeloid leukaemia, but complete tumour responses are infrequent and of short duration, possibly because of the short half-lives and suboptimal bone marrow exposure of the drugs. Guadecitabine, a next-generation hypomethylating drug, has a longer half-life and exposure than its active metabolite decitabine. A phase 1 study established 60 mg/m 2 guadecitabine for 5 days as an effective treatment schedule. In this phase 2 study, we aimed to assess the safety and activity of two doses and schedules of guadecitabine in older (≥65 years) patients with treatment-naive acute myeloid leukaemia who were not candidates for intensive chemotherapy. We did a multicentre, randomised, open-label, phase 1/2 study of guadecitabine in cohorts of patients with treatment-naive acute myeloid leukaemia, relapsed or refractory acute myeloid leukaemia, and myelodysplastic syndromes; here we report the phase 2 results from the cohort of treatment-naive patients with acute myeloid leukaemia. We included patients aged at least 65 years from 14 US medical centres (hospitals and specialist cancer clinics) who were not candidates for intensive chemotherapy and randomly assigned them (1:1) using a computer algorithm (for dynamic randomisation) to guadecitabine 60 or 90 mg/m 2 on days 1-5 (5-day schedule) of a 28-day treatment cycle. Treatment allocation was not masked. We also assigned additional patients to guadecitabine 60 mg/m 2 in a 10-day schedule in a 28-day treatment cycle after a protocol amendment. The primary endpoint was composite complete response (complete response, complete response with incomplete platelet recovery, or complete response with incomplete neutrophil recovery regardless of platelets). Response was assessed in all patients (as-treated) who received at least one dose of guadecitabine. We present the final analysis, although at the time of the database lock, 15 patients were still in follow-up for overall survival. This study is registered with ClinicalTrials.gov, number NCT01261312. Between Aug 24, 2012, and Sept 15, 2014, 107 patients were enrolled: 54 on the 5-day schedule (26 randomly assigned to 60 mg/m 2 and 28 to 90 mg/m 2 ) and 53 were assigned to the 10-day schedule. Median age was 77 years (range 62-92), and median follow-up was 953 days (IQR 721-1040). All treated patients were assessable for a response. The number of patients who achieved a composite complete response did not differ between dose groups or schedules (13 [54%, 95% CI 32·8-74·4] with 60 mg/m 2 on the 5-day schedule; 16 [59%; 38·8-77·6] with 90 mg/m 2 on the 5-day schedule; and 26 [50%, 35·8-64·2] with 60 mg/m 2 on the 10-day schedule). The most frequent grade 3 or worse adverse events, regardless of relationship to treatment, were febrile neutropenia (31 [61%] of 51 patients on the 5-day schedule vs 36 [69%] of 52 patients on the 10-day schedule), thrombocytopenia (25 [49%] vs 22 [42%]), neutropenia (20 [39%] vs 18 [35%]), pneumonia (15 [29%] vs 19 [37%]), anaemia (15 [29%] vs 12 [23%]), and sepsis (eight [16%] vs 14 [27%]). The most common serious adverse events, regardless of relationship to treatment, for the 5-day and 10-day schedules, respectively, were febrile neutropenia (27 [53%] vs 25 [48%]), pneumonia (14 [27%] vs 16 [31%]), and sepsis (eight [16%] vs 14 [27%]). 23 (22%) patients died because of adverse events (mainly from sepsis, eight [8%]; and pneumonia, five [5%]); four deaths were from adverse events deemed treatment-related (pneumonia, two [2%]; multiorgan failure, one [1%]; and sepsis, one [1%], all in the 10-day cohort). More than half of older treatment-naive patients with acute myeloid leukaemia achieved a composite complete response with guadecitabine at all drug doses and schedules investigated, with tolerable toxicity. The recommended guadecitabine regimen for this population is 60 mg/m 2 in a 5-day schedule. A phase 3 study in this patient population is ongoing (NCT02348489) to assess guadecitabine 60 mg/m 2 in a 5-day schedule versus standard of care. Astex Pharmaceuticals and Stand Up To Cancer. Copyright © 2017 Elsevier Ltd. All rights reserved.

Barriers to HIV Medication Adherence as a Function of Regimen Simplification.

PubMed

Chen, Yiyun; Chen, Kun; Kalichman, Seth C

2017-02-01

Barriers to HIV medication adherence may differ by levels of dosing schedules. The current study examined adherence barriers associated with medication regimen complexity and simplification. A total of 755 people living with HIV currently taking anti-retroviral therapy were recruited from community services in Atlanta, Georgia. Participants completed audio-computer-assisted self-interviews that assessed demographic and behavioral characteristics, provided their HIV viral load obtained from their health care provider, and completed unannounced phone-based pill counts to monitor medication adherence over 1 month. Participants taking a single-tablet regimen (STR) were more likely to be adherent than those taking multi-tablets in a single-dose regimen (single-dose MTR) and those taking multi-tablets in a multi-dose regimen (multi-dose MTR), with no difference between the latter two. Regarding barriers to adherence, individuals taking STR were least likely to report scheduling issues and confusion as reasons for missing doses, but they were equally likely to report multiple lifestyle and logistical barriers to adherence. Adherence interventions may need tailoring to address barriers that are specific to dosing 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).

Phase I Study of Oral Vinorelbine in Combination with Erlotinib in Advanced Non-Small Cell Lung Cancer (NSCLC) Using Two Different Schedules

PubMed Central

Sutiman, Natalia; Zhang, Zhenxian; Tan, Eng Huat; Ang, Mei Kim; Tan, Shao-Weng Daniel; Toh, Chee Keong; Ng, Quan Sing; Chowbay, Balram; Lim, Wan-Teck

2016-01-01

Purpose This study aimed to evaluate the safety, tolerability and pharmacokinetics of the combination of oral vinorelbine with erlotinib using the conventional (CSV) and metronomic (MSV) dosing schedules in patients with advanced non-small cell lung cancer (NSCLC). Methods This was an open-label, multiple dose-escalation phase I study. An alternating 3+3 phase I design was employed to allow each schedule to enroll three patients sequentially at each dose level. Thirty patients with Stage IIIB/IV NSCLC were treated with escalating doses of oral vinorelbine starting at 40 mg/m2 on day 1 and 8 in the CSV group (N = 16) and at 100 mg/week in the MSV group (N = 14). Erlotinib was administered orally daily. Results The maximum tolerated dose was vinorelbine 80 mg/m2 with erlotinib 100 mg in the CSV group and vinorelbine 120 mg/week with erlotinib 100 mg in the MSV group. Grade 3/4 toxicities included neutropenia (N = 2; 13%) and hyponatremia (N = 1; 6%) in the CSV group, and neutropenia (N = 5; 36%) in the MSV group. Objective response was achieved in 38% and 29% in the CSV and MSV groups respectively. Vinorelbine co-administration did not significantly affect the pharmacokinetics of erlotinib and OSI-420 after initial dose. However, at steady-state, significantly higher Cmax, higher Cmin and lower CL/F of erlotinib were observed with increasing dose levels of vinorelbine in the CSV group. Significantly higher steady-state Cmin, Cavg and AUCss of erlotinib were observed with increasing dose levels of vinorelbine in the MSV group. Conclusions Combination of oral vinorelbine with erlotinib is feasible and tolerable in both the CSV and MSV groups. Trial Registration ClinicalTrials.gov NCT00702182 PMID:27135612

A phase I and pharmacologic study of sequences of the proteasome inhibitor, bortezomib (PS-341, Velcade), in combination with paclitaxel and carboplatin in patients with advanced malignancies.

PubMed

Ma, Cynthia; Mandrekar, Sumithra J; Alberts, Steven R; Croghan, Gary A; Jatoi, Aminah; Reid, Joel M; Hanson, Lorelei J; Bruzek, Laura; Tan, Angelina D; Pitot, Henry C; Erlichman, Charles; Wright, John J; Adjei, Alex A

2007-02-01

Bortezomib, a selective inhibitor of the 20S proteasome with activity in a variety of cancers, exhibits sequence-dependent synergistic cytotoxicity with taxanes and platinum agents. Two different treatment schedules of bortezomib in combination with paclitaxel and carboplatin were tested in this phase I study to evaluate the effects of scheduling on toxicities, pharmacodynamics and clinical activity. Patients with advanced malignancies were alternately assigned to receive (schedule A) paclitaxel and carboplatin (IV d1) followed by bortezomib (IV d2, d5, d8) or (schedule B) bortezomib (IV d1, d4, d8) followed by paclitaxel and carboplatin (IV d2) on a 21-day cycle. Fifty-three patients (A 25, B 28) were treated with a median of 3 cycles (range 1-8) for schedule A and 3.5 cycles (range 1-10) for schedule B. Grade 3 or higher treatment related hematologic adverse events in all cycles of treatment included neutropenia (A 52%, B 50%), anemia (A 12%, B 7.1%) and thrombocytopenia (A 16%, B 17.9%). Non-hematologic treatment related adverse events were fairly mild (primarily grades 1 and 2). The maximum tolerated dose and the recommended doses for future phase II trials are bortezomib 1.2 mg/m2, paclitaxel 135 mg/m2 and carboplatin AUC = 6 for schedule A and bortezomib 1.2 mg/m2, paclitaxel 175 mg/m2 and carboplatin AUC = 6 for schedule B. Six (21.4%) partial responses (PR) were seen with schedule B. In contrast, only 1 (4%) PR was achieved with schedule A. Similar proteasome inhibition was achieved at MTD for both schedules. Administration of sequential bortezomib followed by chemotherapy (schedule B) was well tolerated and associated with an encouraging number of objective responses in this small group of patients. Further studies with this administration schedule are warranted.

Alcohol withdrawal syndrome: symptom-triggered versus fixed-schedule treatment in an outpatient setting.

PubMed

Elholm, Bjarne; Larsen, Klaus; Hornnes, Nete; Zierau, Finn; Becker, Ulrik

2011-01-01

To investigate whether, in the treatment with chlordiazepoxide for outpatient alcohol withdrawal, there are advantages of symptom-triggered self-medication over a fixed-schedule regimen. A randomized controlled trial in outpatient clinics for people suffering from alcohol dependence (AD) and alcohol-related problems; 165 adult patients in an outpatient setting in a specialized alcohol treatment unit were randomized 1:1 to either a symptom-triggered self-medication or tapered dose, using chlordiazepoxide. Alcohol withdrawal symptoms, amount of medication, duration of symptoms, time to relapse and patient satisfaction were measured. Patients assessed their symptoms using the Short Alcohol Withdrawal Scale (SAWS). Patient satisfaction was monitored by the Diabetes Treatment Satisfaction Questionnaire. We used the Well-Being Index and the European addiction severity index for the 1-year follow-up. We found no differences in the quantity of medication consumed, time to relapse, well being or treatment satisfaction. Symptom-triggered self-medication was as safe as fixed-schedule medication in treating outpatients with AD and mild to moderate symptoms of AWS. The SAWS is a powerful monitoring tool, because it is brief and permits the subject to log the withdrawal symptoms.

Evaluation of different infant vaccination schedules incorporating pneumococcal vaccination (The Vietnam Pneumococcal Project): protocol of a randomised controlled trial

PubMed Central

Temple, Beth; Toan, Nguyen Trong; Uyen, Doan Y; Balloch, Anne; Bright, Kathryn; Cheung, Yin Bun; Licciardi, Paul; Nguyen, Cattram Duong; Phuong, Nguyen Thi Minh; Satzke, Catherine; Smith-Vaughan, Heidi; Vu, Thi Que Huong; Huu, Tran Ngoc; Mulholland, Edward Kim

2018-01-01

Introduction WHO recommends the use of pneumococcal conjugate vaccine (PCV) as a priority. However, there are many countries yet to introduce PCV, especially in Asia. This trial aims to evaluate different PCV schedules and to provide a head-to-head comparison of PCV10 and PCV13 in order to generate evidence to assist with decisions regarding PCV introduction. Schedules will be compared in relation to their immunogenicity and impact on nasopharyngeal carriage of Streptococcus pneumoniae and Haemophilus influenzae. Methods and analysis This randomised, single-blind controlled trial involves 1200 infants recruited at 2 months of age to one of six infant PCV schedules: PCV10 in a 3+1, 3+0, 2+1 or two-dose schedule; PCV13 in a 2+1 schedule; and controls that receive two doses of PCV10 and 18 and 24 months. An additional control group of 200 children is recruited at 18 months that receive one dose of PCV10 at 24 months. All participants are followed up until 24 months of age. The primary outcome is the post-primary series immunogenicity, expressed as the proportions of participants with serotype-specific antibody levels ≥0.35 µg/mL for each serotype in PCV10. Ethics and dissemination Ethical approval has been obtained from the Human Research Ethics Committee of the Northern Territory Department of Health and Menzies School of Health Research (EC00153) and the Vietnam Ministry of Health Ethics Committee. The results, interpretation and conclusions will be presented to parents and guardians, at national and international conferences, and published in peer-reviewed open access journals. Trial registration number NCT01953510; Pre-results. PMID:29884695

Long-term Impact of a "3 + 0" Schedule for 7- and 13-Valent Pneumococcal Conjugate Vaccines on Invasive Pneumococcal Disease in Australia, 2002-2014.

PubMed

Jayasinghe, Sanjay; Menzies, Rob; Chiu, Clayton; Toms, Cindy; Blyth, Christopher C; Krause, Vicki; McIntyre, Peter

2017-01-15

Australia introduced universal 7-valent pneumococcal conjugate vaccine (PCV7) from 2005, replaced by 13-valent PCV (PCV13) in 2011, uniquely among high-income countries giving doses at 2, 4, and 6 months (3 + 0 schedule). Data on impact of a timely 3 + 0 PCV schedule with high coverage are sparse, with none for PCV13. We used national surveillance of invasive pneumococcal disease (IPD) from 2002 for baseline and appropriate later comparison periods to calculate incidence rate ratios (IRRs) by serotype and age using a Poisson model. PCV coverage was assessed from the Australian Childhood Immunisation Register. After 9 years of timely 3-dose PCV coverage of >92%, all-age IPD in Australia almost halved (IRR, 0.53; 95% confidence interval [CI], .50-.57), but differed by PCV era. Reductions in IPD due to vaccine serotypes from PCV7 (IRR, 0.20; CI, .17-.22) were about 2-fold greater than for IPD due to extra serotypes in PCV13 (13v-non7v) in a similar period (IRR, 0.58; CI, .51-.66). Post-PCV13 declines in serotype 19A IPD in persons aged <2 years (IRR, 0.23; CI, .13-.35) and ≥2 years (IRR, 0.35; CI, .28-.44) differed from other 13v-non7v IPD (IRR, 0.73; CI, .35-1.48 for those aged <2 years and IRR, 0.96; CI, .81-1.15 for those ≥2 years). Meningitis due to vaccine serotypes nearly disappeared in children eligible for 3 PCV13 doses. IPD due to non-PCV13 serotypes increased by 30% compared with 76% for non-PCV7 serotypes in equivalent period of vaccine use. Reductions in vaccine-type IPD post-PCV13 were inferior to Australian experience with PCV7 and reports from high-income countries giving a PCV booster dose. Applicability of findings to other settings would depend on age of IPD onset, serotype profile, and timeliness of vaccination. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Low completion rate of hepatitis B vaccination in female sex workers.

PubMed

Magalhães, Rosilane de Lima Brito; Teles, Sheila Araújo; Reis, Renata Karina; Galvão, Marli Teresinha Gimeniz; Gir, Elucir

2017-01-01

to assess predictive factors for noncompletion of the hepatitis B vaccination schedule in female sex workers in the city of Teresina, Northeastern Brazil. 402 women were interviewed and, for those who did not wish to visit specialized sites, or did not know their hepatitis B vaccination status, the vaccine was offered at their workplaces. Bi- and multivariate analyses were performed to identify potential predictors for noncompletion of the vaccination schedule. of the 284 women eligible for vaccination, 258 (90.8%) received the second dose, 157/258 (60.8%) and 68/258 (26.3%) received the second and third doses, respectively. Working at clubs and consuming illicit drugs were predictors for noncompletion of the vaccination schedule. the high acceptability of the vaccine's first dose, associated with low completion rates of the vaccination schedule in sex workers, shows the need for more persuasive strategies that go beyond offering the vaccine at their workplaces. avaliar fatores preditores de não completude do esquema vacinal contra hepatite B em mulheres que se prostituem em Teresina, Nordeste do Brasil. Um total de 402 mulheres foi entrevistado e, para as que se negaram a irem a lugares especializados, ou desconheciam sua situação vacinal contra hepatite B, a vacina foi oferecida no local do trabalho. Análises bi e multivariadas foram realizadas para identificar potenciais preditores de não completude do esquema vacinal. Das 284 mulheres elegíveis para vacinação, 258 (90,8%) receberam a primeira dose, 157/258 (60,8%) e 68/258 (26,3%) receberam a segunda e terceira doses. Trabalhar em boates e consumir drogas ilícitas foram preditores de não completude do esquema vacinal (p<0,05). A elevada aceitabilidade da primeira dose da vacina, associada à baixa completude do esquema vacinal em profissionais do sexo, evidencia a necessidade de estratégia mais persuasiva que vá além da oferta da vacina no local de trabalho.

Immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine administered to older infants and children naïve to pneumococcal vaccination.

PubMed

Wysocki, Jacek; Brzostek, Jerzy; Szymański, Henryk; Tetiurka, Bogusław; Toporowska-Kowalska, Ewa; Wasowska-Królikowska, Krystyna; Sarkozy, Denise A; Giardina, Peter C; Gruber, William C; Emini, Emilio A; Scott, Daniel A

2015-03-30

Streptococcus pneumoniae infections are a major cause of morbidity and mortality in children <5 years old worldwide. To increase serotype coverage globally, a 13-valent pneumococcal conjugate vaccine (PCV13) has been developed and approved in many countries worldwide. Assess the safety and immunogenicity of PCV13 in healthy older infants and children naïve to previous pneumococcal vaccination. This was a phase 3, open-label, multicenter study conducted in Polish children (N=354) who were vaccinated according to 3 age-appropriate catch-up schedules: Group 1 (aged 7 to <12 months) received two PCV13 doses with a booster at 12-16 months of age; Group 2 (aged 12 to <24 months) received two vaccine doses only; and Group 3 (aged 24 to <72 months) received a single dose of PCV13. Statistical analyses were descriptive. The proportion of immunological "responders" achieving serotype-specific antipneumococcal polysaccharide concentrations ≥0.35μg/mL, 1-month after the last dose of vaccine, was determined for each vaccine serotype. In addition, antipolysaccharide immunoglobulin (Ig) G geometric mean concentrations (GMCs) were calculated. Safety assessments included systemic and local reactions, and adverse events. The proportion of immunological responders was ≥88% across groups for all serotypes. Antipolysaccharide IgG GMCs were generally similar across groups. Each schedule elicited immune response levels against all 13 serotypes comparable to or greater than levels previously reported in infants after a 3-dose series. The 3 catch-up schedules had similar tolerability and safety profiles; a trend was present towards greater local tenderness with increasing age and subsequent dose administration. Immunological responses and safety results support the use of PCV13 for catch-up schedules in older infants and children naïve to pneumococcal vaccination. Copyright © 2015. Published by Elsevier Ltd.

Neurological Adverse Effects in Patients of Advanced Colorectal Carcinoma Treated with Different Schedules of FOLFOX

PubMed Central

Najam, Rahila; Mateen, Ahmed

2013-01-01

The study is designed to assess the frequency and severity of few dose limiting neurological adverse effects of four different schedules of FOLFOX. Patients with histologically confirmed advanced colorectal carcinoma (CRC) were included in the study. Toxicity was graded according to CTC v 2.0. The frequency of grade 3 and 4 adverse effects was comparatively assessed in each treatment arm. The difference in the pattern of toxicity between the treatment schedule was evaluated. The most frequent adverse symptom of neurological adverse effect was grade 1 paresthesia in the patients treated with FOLFOX4 schedule. Grade 4 peripheral neuropathy was reported in few patients of FOLFOX7 treatment arm. Frequency and onset of neurological adverse effects like paresthesia, dizziness, and hypoesthesia were significantly different (P < 0.05), whereas frequency and onset of peripheral neuropathy were highly significant (P < 0.01) in each treatment arm of FOLFOX. Peripheral neuropathy was associated with electrolyte imbalance and diabetes in few patients. Frequency of symptoms, for example, paresthesia, is associated with increased number of recurrent exposure to oxaliplatin (increased number of cycles) even at low doses (85 mg/m2), whereas severity of symptoms, for example, peripheral neuropathy, is associated with higher dose (130 mg/m2) after few treatment cycles. PMID:24187619

Safety and Immunogenicity of Influenza A H5 Subunit Vaccines: Effect of Vaccine Schedule and Antigenic Variant

PubMed Central

Frey, Sharon E.; Graham, Irene; Mulligan, Mark J.; Edupuganti, Srilatha; Jackson, Lisa A.; Wald, Anna; Poland, Gregory; Jacobson, Robert; Keyserling, Harry L.; Spearman, Paul; Hill, Heather; Wolff, Mark

2011-01-01

Background. The current US national stockpile of influenza H5 vaccine was produced using the antigen from the strain A/Vietnam/1203/2004 (a clade 1 H5 virus). Recent H5 disease has been caused by antigenically divergent H5 viruses, including A/Indonesia/05/2005 (a clade 2 H5 virus). Methods. The influence of schedule on the antibody response to 2 doses of H5 vaccines (one a clade 1 hemagglutinin protein [HA] vaccine and one a clade 2 HA vaccine) containing 90 μg of antigen was evaluated in healthy adults 18–49 years of age. Results. Two doses of vaccine were required to induce antibody titers ≥1:10 in most subjects. Accelerated schedules were immunogenic, and antibody developed after vaccinations on days 0 and 7, 0 and 14, and 0 and 28, with the day 0 and 7 schedule inducing lower titers than those induced with the other schedules. With mixed vaccine schedules of clade 1 followed by clade 2 vaccine administration, the first vaccination primed for a heterologous boost. The heterologous response was improved when the second vaccination was given 6 months after the first, compared with the response when the second vaccination was given after an interval of 1 month. Conclusions. An accelerated vaccine schedule of injections administered at days 0 and 14 was as immunogenic as a vaccine schedule of injections at days 0 and 28, but both schedules were inferior to a vaccine schedule of injections administered at 0 and 6 months for priming for heterologous vaccine boosting. Clinical Trial Registry Number: NCT00703053 PMID:21282194

Efficacy and safety of sunitinib alternate day regimen in patients with metastatic renal cell carcinoma in Japan: Comparison with standard 4/2 schedule.

PubMed

Ohba, Kojiro; Miyata, Yasuyoshi; Yasuda, Takuji; Asai, Akihiro; Mitsunari, Kensuke; Matsuo, Tomohiro; Mochizuki, Yasushi; Matsunaga, Noriko; Sakai, Hideki

2018-06-01

Sunitinib is a standard agent for metastatic renal cell carcinoma (mRCC). The standard schedule, 4 weeks-on followed by 2 weeks-off (4/2 schedule), often does not maintain an adequate dosage because of the severe adverse events (AEs). We compared the efficacy and safety of an alternative every other day (q.a.d.) dosing with that of the 4/2 schedule in mRCC patients. Of the 55 Japanese patients, 32 and 23 were administered 4/2 (standard group) and q.a.d. schedules (50 or 37.5 mg, every other day; experimental groups), respectively. The AEs, anticancer effects, and trough plasma concentrations of sunitinib were compared between them. The most common AE in the standard group was thrombocytopenia (43.2%), but it was observed in only two patients in the experimental group (8.7%). Although leukopenia and hand-foot syndrome were both detected in six patients (18.8%) in the standard group, no patients had these AEs in the experimental group. The incidence of dose interruption in the experimental group (21.7%) was significantly lower than that in the standard group was (59.4%, P = 0.005). Time to progression (TTP) and overall survival (OS) of the experimental group were better than those of the standard group (P < 0.001 and P = 0.002, respectively). Mean plasma levels in the experimental group (64.83 ng/mL) were significantly lower than those in the standard group (135.82 ng/mL, P < 0.001) were. Sunitinib administered q.a.d. was safe and effective for mRCC patients. We speculate that the persistent optimal drug plasma concentrations contributed to these effects. © 2018 The Authors. Asia-Pacific Journal of Clinical Oncology Published by John Wiley & Sons Australia, Ltd.

Leveraging Hypoxia-Activated Prodrugs to Prevent Drug Resistance in Solid Tumors.

PubMed

Lindsay, Danika; Garvey, Colleen M; Mumenthaler, Shannon M; Foo, Jasmine

2016-08-01

Experimental studies have shown that one key factor in driving the emergence of drug resistance in solid tumors is tumor hypoxia, which leads to the formation of localized environmental niches where drug-resistant cell populations can evolve and survive. Hypoxia-activated prodrugs (HAPs) are compounds designed to penetrate to hypoxic regions of a tumor and release cytotoxic or cytostatic agents; several of these HAPs are currently in clinical trial. However, preliminary results have not shown a survival benefit in several of these trials. We hypothesize that the efficacy of treatments involving these prodrugs depends heavily on identifying the correct treatment schedule, and that mathematical modeling can be used to help design potential therapeutic strategies combining HAPs with standard therapies to achieve long-term tumor control or eradication. We develop this framework in the specific context of EGFR-driven non-small cell lung cancer, which is commonly treated with the tyrosine kinase inhibitor erlotinib. We develop a stochastic mathematical model, parametrized using clinical and experimental data, to explore a spectrum of treatment regimens combining a HAP, evofosfamide, with erlotinib. We design combination toxicity constraint models and optimize treatment strategies over the space of tolerated schedules to identify specific combination schedules that lead to optimal tumor control. We find that (i) combining these therapies delays resistance longer than any monotherapy schedule with either evofosfamide or erlotinib alone, (ii) sequentially alternating single doses of each drug leads to minimal tumor burden and maximal reduction in probability of developing resistance, and (iii) strategies minimizing the length of time after an evofosfamide dose and before erlotinib confer further benefits in reduction of tumor burden. These results provide insights into how hypoxia-activated prodrugs may be used to enhance therapeutic effectiveness in the clinic.

The Peroxisome Proliferator-Activated Receptor Alpha Agonist Fenofibrate Attenuates Alcohol Self-administration in Rats

PubMed Central

Haile, Colin N.; Kosten, Therese A.

2017-01-01

Fibrates are a class of medications used to treat hypercholesterolemia and dyslipidemia that target nuclear peroxisome proliferator-activated receptors (PPARs). Studies have shown the PPARα agonist fenofibrate decreases voluntary EtOH consumption however its impact on the reinforcing and motivational effects of EtOH is unknown. We evaluated the ability of fenofibrate (25, 50 and 100mg/kg), to alter EtOH (10%, w/v) and sucrose (2%, w/v) operant self-administration in rats under a FR2 schedule of reinforcement over four days and under a progressive ratio (PR) schedule on day five of treatment. Results showed fenofibrate dose-dependently decreased EtOH self-administration under both schedules of reinforcement with the greatest effects seen after four to five days of treatment. Fenofibrate decreased responding for sucrose only under the PR schedule of reinforcement and this effect was not dose-dependent. These findings provide further evidence for fenofibrate as a potential treatment for alcohol use disorder in humans. PMID:28088358

Introduction of Sequential Inactivated Polio Vaccine–Oral Polio Vaccine Schedule for Routine Infant Immunization in Brazil’s National Immunization Program

PubMed Central

Domingues, Carla Magda Allan S.; de Fátima Pereira, Sirlene; Marreiros, Ana Carolina Cunha; Menezes, Nair; Flannery, Brendan

2015-01-01

In August 2012, the Brazilian Ministry of Health introduced inactivated polio vaccine (IPV) as part of sequential polio vaccination schedule for all infants beginning their primary vaccination series. The revised childhood immunization schedule included 2 doses of IPV at 2 and 4 months of age followed by 2 doses of oral polio vaccine (OPV) at 6 and 15 months of age. One annual national polio immunization day was maintained to provide OPV to all children aged 6 to 59 months. The decision to introduce IPV was based on preventing rare cases of vaccine-associated paralytic polio, financially sustaining IPV introduction, ensuring equitable access to IPV, and preparing for future OPV cessation following global eradication. Introducing IPV during a national multivaccination campaign led to rapid uptake, despite challenges with local vaccine supply due to high wastage rates. Continuous monitoring is required to achieve high coverage with the sequential polio vaccine schedule. PMID:25316829

Compliance with birth dose of Hepatitis B vaccine in high endemic and hard to reach areas in the Colombian amazon: results from a vaccination survey.

PubMed

Choconta-Piraquive, Luz Angela; De la Hoz-Restrepo, Fernando; Sarmiento-Limas, Carlos Arturo

2016-07-21

Hepatitis B vaccination was introduced into the Expanded Program of Immunization in Colombia in 1992, in response to WHO recommendations on hepatitis B immunization. Colombia is a low endemic country for Hepatitis B virus infection (HBV) but it has several high endemic areas like the Amazon basin where more than 70 % of adults had been infected. A cross- sectional study was carried out in three rural areas of the Colombian Amazon to evaluate compliance with the recommended schedule for hepatitis B vaccine in Colombian children (one monovalent dose given in the first 24 h after birth + 3 doses of a pentavalent containing Hepatitis B. (DPT + Hib + Hep B). A household survey was conducted in order to collect vaccination data from children aged from 6 months to <8 years. Vaccination status was related to sociodemographic data obtained from children caretakers. Among 938 children above 6 months and < 8 years old studied, 79 % received a monovalent dose of hepatitis B vaccine, but only 30.7 % were vaccinated in the first 24 h after birth. This proportion did not increase by age or subsequent birth cohorts. Coverage with three doses of a DTP-Hib-HepB vaccine was 98 %, but most children did not receive them according to the recommended schedule. Being born in a health facility was the strongest predictor of receiving a timely birth dose. This study suggests that more focused strategies on improving compliance with hepatitis B birth dose should be implemented in rural areas of the Amazon, if elimination of perinatal transmission of HBV is to be achieved. Increasing the proportion of newborns delivered at health facilities should be one of the priorities to reach that goal.

SURVIVAL EFFICACY OF THE PEGYLATED G-CSFS MAXY-G34 AND NEULASTA IN A MOUSE MODEL OF LETHAL H-ARS, AND RESIDUAL BONE MARROW DAMAGE IN TREATED SURVIVORS

PubMed Central

Chua, Hui Lin; Plett, P. Artur; Sampson, Carol H.; Katz, Barry P.; Carnathan, Gilbert W.; MacVittie, Thomas J.; Lenden, Keith; Orschell, Christie M.

2013-01-01

In an effort to expand the worldwide pool of available medical countermeasures (MCM) against radiation, the PEGylated G-CSF (PEG-G-CSF) molecules Neulasta and Maxy-G34, a novel PEG-G-CSF designed for increased half-life and enhanced activity compared to Neulasta, were examined in a murine model of the Hematopoietic Syndrome of the Acute Radiation Syndrome (H-ARS), along with the lead MCM for licensure and stockpiling, G-CSF. Both PEG-G-CSFs were shown to retain significant survival efficacy when administered as a single dose 24hr post-exposure, compared to the 16 daily doses of G-CSF required for survival efficacy. Furthermore, 0.1 mg kg−1 of either PEG-G-CSF effected survival of lethally-irradiated mice that was similar to a 10-fold higher dose. The one dose/low dose administration schedules are attractive attributes of radiation MCM given the logistical challenges of medical care in a mass casualty event. Maxy-G34-treated mice that survived H-ARS were examined for residual bone marrow damage (RBMD) up to 9mo post-exposure. Despite differences in Sca-1 expression and cell cycle position in some hematopoietic progenitor phenotypes, Maxy-G34-treated mice exhibited the same degree of hematopoietic stem cell (HSC) insufficiency as vehicle treated H-ARS survivors in competitive transplantation assays of 150 purified Sca-1+cKit+lin-CD150+ cells. These data suggest that Maxy-G34, at the dose, schedule, and time frame examined, did not mitigate RBMD, but significantly increased survival from H-ARS at one-tenth the dose previously tested, providing strong support for advanced development of Maxy-G34, as well as Neulasta, as MCM against radiation. PMID:24276547

Difluprednate Ophthalmic

MedlinePlus

... tell you that you should not wear contact lenses during your treatment with difluprednate eye drops.you should know that difluprednate eye drops ... your regular dosing schedule. Do not apply extra eye drops to make up for a missed dose.

76 FR 17617 - Changes to Treatments for Citrus Fruit From Australia

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-30

... from Australia into the United States. We also proposed to establish an approved irradiation dose for... Manual to include the new treatment schedules for sweet cherries and the revised irradiation dose for...

Tailored interventions for screening mammography among a sample of initially non-adherent women: when is a booster dose important?

PubMed

Skinner, Celette Sugg; Kobrin, Sarah C; Monahan, Patrick O; Daggy, Joanne; Menon, Usha; Todora, Helen Smith; Champion, Victoria L

2007-01-01

To assess added value of a booster dose of a tailored mammography intervention. Participants, non-adherent at baseline, were randomly assigned to usual care or one of three tailored interventions. Intervention group members (n=657) were further randomly assigned to receive/not receive a booster intervention dose. Electronic record mammography data were collected following initial intervention and at 6 and 15 months post-booster. Booster had no effect among women not screened after first intervention dose (n=337). Among women screened after initial dose (n=320), booster predicted re-screening at 6 but not 15 months. A boosterxrace interaction showed a booster effect at 6 months for African Americans (OR=4.66, p=.0005) but not Caucasians (OR=0.74, p=.44). Findings suggest if a first-dose intervention does not facilitate screening, neither will a booster dose. However, among women for whom a first dose is effective, boosters can facilitate timely repeat adherence, especially among African Americans. At 6 months booster recipients were less likely to be off-schedule but, by 15 months, the groups were similar. Boosters may effect when, but not whether, women continue screening.

Intrathecal morphine for analgesia in children undergoing selective dorsal rhizotomy.

PubMed

Dews, T E; Schubert, A; Fried, A; Ebrahim, Z; Oswalt, K; Paranandi, L

1996-03-01

Selective dorsal root rhizotomy is performed for relief of spasticity in children with cerebral palsy. Postoperative pain relief can be provided by intrathecal morphine administered at the time of the procedure. We sought to define an optimal dose of intrathecal morphine in children undergoing selective rhizotomy, through a randomized, double-blinded prospective trial. After institutional approval and parental written informed consent, 27 patients, ages 3-10 years, were randomized to receive 10, 20, or 30 micrograms.kg-1 (Groups A, B, and C, respectively) of preservative-free morphine administered intrathecally by the surgeon after dural closure. Postoperatively, vital signs, pulse oximetry, and pain intensity scores were recorded hourly for 24 hr. Supplemental intravenous morphine was administered postoperatively according to a predetermined schedule based on pain scores. There was considerable individual variability in the time to initial morphine dosing and cumulative supplemental morphine dose. Time to first supplemental morphine dose was not different between groups. When compared to Groups A and B, cumulative 6-hr supplemental morphine dose was significantly lower in Group C (38.6 +/- 47 micrograms versus 79.1 +/- 74 and 189.6 +/- 126 for Groups A and B, respectively). By 12 hr, cumulative supplemental morphine dose was similar in Groups A and C. Group B consistently had a higher supplemental dose requirement than Groups A and C at 6, 12, and 18 hr. By 24 hr, there was no difference in cumulative dose among groups. Postoperative pain scores and the incidence of respiratory events, nausea, vomiting and pruritus were comparable among groups. These data suggest that intrathecal morphine at 30 micrograms.kg-1 provides the most intense analgesia at 6 hr following selective dorsal root rhizotomy, but was otherwise comparable to the 10 micrograms.kg-1 dose.

Feasibility and antitumor efficacy in vivo, of simultaneously targeting glycolysis, glutaminolysis and fatty acid synthesis using lonidamine, 6-diazo-5-oxo-L-norleucine and orlistat in colon cancer.

PubMed

Cervantes-Madrid, Diana; Dominguez-Gomez, Guadalupe; Gonzalez-Fierro, Aurora; Perez-Cardenas, Enrique; Taja-Chayeb, Lucia; Trejo-Becerril, Catalina; Duenas-Gonzalez, Alfonso

2017-03-01

The aim of the present study was to investigate in vivo the feasibility and efficacy of the combination of lonidamine (LND), 6-diazo-5-oxo-L-norleucine (DON) and orlistat to simultaneously target glycolysis, glutaminolysis and de novo synthesis of fatty acids, respectively. The doses of LND and DON used in humans were translated to mouse doses (77.7 mg/kg and 145.5 mg/kg, respectively) and orlistat was used at 240 mg/kg. Three schedules of LND, DON and orlistat at different doses were administered by intraperitoneal injection to BALB/c mice in a 21-day cycle (schedule 1: LND, 0.5 mg/day; DON, 0.25 mg/day 1, 5 and 9; orlistat, 240 mg/kg/day; schedule 2: LND, 0.1 mg/day; DON, 0.5 mg/day 1, 5 and 9; orlistat, 240 mg/kg/day; schedule 3: LND, 0.5 mg/day; DON, 0.08 mg/day 1, 5 and 9; orlistat, 360 mg/kg/day) to assess tolerability. To determine the antitumor efficacy, a syngeneic tumor model in BALB/c mice was created using colon cancer CT26.WT cells, and a xenogeneic tumor model was created in nude mice using the human colon cancer SW480 cell line. Mice were treated with schedule 1. Animals were weighed, clinically inspected during the experiment and the tumor volume was measured at day 21. The 3 schedules assessed in the tolerability experiments were well tolerated, as mice maintained their weight and no evident clinical signs of toxicity were observed. Combination treatment with schedule 1 significantly decreased tumor growth in each mouse model. No evident signs of toxicity were observed and mice maintained their weight during treatment. The triple metabolic blockade of the malignant phenotype appears feasible and promising for cancer therapy.

Feasibility and antitumor efficacy in vivo, of simultaneously targeting glycolysis, glutaminolysis and fatty acid synthesis using lonidamine, 6-diazo-5-oxo-L-norleucine and orlistat in colon cancer

PubMed Central

Cervantes-Madrid, Diana; Dominguez-Gomez, Guadalupe; Gonzalez-Fierro, Aurora; Perez-Cardenas, Enrique; Taja-Chayeb, Lucia; Trejo-Becerril, Catalina; Duenas-Gonzalez, Alfonso

2017-01-01

The aim of the present study was to investigate in vivo the feasibility and efficacy of the combination of lonidamine (LND), 6-diazo-5-oxo-L-norleucine (DON) and orlistat to simultaneously target glycolysis, glutaminolysis and de novo synthesis of fatty acids, respectively. The doses of LND and DON used in humans were translated to mouse doses (77.7 mg/kg and 145.5 mg/kg, respectively) and orlistat was used at 240 mg/kg. Three schedules of LND, DON and orlistat at different doses were administered by intraperitoneal injection to BALB/c mice in a 21-day cycle (schedule 1: LND, 0.5 mg/day; DON, 0.25 mg/day 1, 5 and 9; orlistat, 240 mg/kg/day; schedule 2: LND, 0.1 mg/day; DON, 0.5 mg/day 1, 5 and 9; orlistat, 240 mg/kg/day; schedule 3: LND, 0.5 mg/day; DON, 0.08 mg/day 1, 5 and 9; orlistat, 360 mg/kg/day) to assess tolerability. To determine the antitumor efficacy, a syngeneic tumor model in BALB/c mice was created using colon cancer CT26.WT cells, and a xenogeneic tumor model was created in nude mice using the human colon cancer SW480 cell line. Mice were treated with schedule 1. Animals were weighed, clinically inspected during the experiment and the tumor volume was measured at day 21. The 3 schedules assessed in the tolerability experiments were well tolerated, as mice maintained their weight and no evident clinical signs of toxicity were observed. Combination treatment with schedule 1 significantly decreased tumor growth in each mouse model. No evident signs of toxicity were observed and mice maintained their weight during treatment. The triple metabolic blockade of the malignant phenotype appears feasible and promising for cancer therapy. PMID:28454342

Application of biological effective dose (BED) to estimate the duration of symptomatic relief and repopulation dose equivalent in palliative radiotherapy and chemotherapy.

PubMed

Jones, Bleddyn; Cominos, Matilda; Dale, Roger G

2003-03-01

To investigate the potential for mathematic modeling in the assessment of symptom relief in palliative radiotherapy and cytotoxic chemotherapy. The linear quadratic model of radiation effect with the overall treatment time and the daily dose equivalent of repopulation is modified to include the regrowth time after completion of therapy. The predicted times to restore the original tumor volumes after treatment are dependent on the biological effective dose (BED) delivered and the repopulation parameter (K); it is also possible to estimate K values from analysis of palliative treatment response durations. Hypofractionated radiotherapy given at a low total dose may produce long symptom relief in slow-growing tumors because of their low alpha/beta ratios (which confer high fraction sensitivity) and their slow regrowth rates. Cancers that have high alpha/beta ratios (which confer low fraction sensitivity), and that are expected to repopulate rapidly during therapy, are predicted to have short durations of symptom control. The BED concept can be used to estimate the equivalent dose of radiotherapy that will achieve the same duration of symptom relief as palliative chemotherapy. Relatively simple radiobiologic modeling can be used to guide decision-making regarding the choice of the most appropriate palliative schedules and has important implications in the design of radiotherapy or chemotherapy clinical trials. The methods described provide a rationalization for treatment selection in a wide variety of tumors.

CORTISONE IN TREATMENT OF BRONCHIAL ASTHMA

PubMed Central

Harris, Marvin S.

1951-01-01

Twenty patients with intractable asthma were treated with cortisone on various dosage schedules. Results indicated that a rapid improvement in the asthmatic state may be expected in four to five days with high level dosage of the hormone—usually a total dose exceeding 200 mg. per day at the beginning. If treatment is discontinued after a week, relapse usually will occur within a period of eight days. If small doses are given two or three times weekly, following initial response, relapse may not occur for 20 or 30 days. The interspersed administration of ACTH during an attempt to discontinue cortisone apparently was of no value. It therefore appears that cortisone control of intractable asthma is dependent on large dosage until clinical improvement is obtained, then approximately 100 mg. two or three times a week for maintenance of a reasonable state of health. PMID:14848726

Steady-state serum salicylate levels in hospitalized patients with rheumatoid arthritis. Comparison of two dosage schedules of choline magnesium trisalicylate.

PubMed

Cassell, S; Furst, D; Dromgoole, S; Paulus, H

1979-04-01

When the total daily drug dose was individualized to produce a steady-state serum salicylate concentration between 20 and 35 mg/dl, clinically acceptable fluctuations of serum concentrations occurred during both twice daily and three times daily administration. In 6 rheumatoid arthritis patients receiving choline magnesium trisalicylate, mean steady-state serum levels were the same, and the ranges of hourly mean concentrations during 8 and 12 hour dosage intervals were 19 to 27 mg/dl and 17 to 30 mg/dl, respectively. Changing the dosing interval from 8 to 12 hours required a 50% increase in the fractional doses, but resulted in an increase of only 3 mg/dl in mean peak concentration and a ddecrease of 1 mg/dl in mean minimum concentration.

Inadequacy of Plasma Acyclovir Levels at Delivery in Patients with Genital Herpes Receiving Oral Acyclovir Suppressive Therapy in Late Pregnancy

PubMed Central

Leung, Daniel T.; Henning, Paul A.; Wagner, Emily C.; Blasig, Audrey; Wald, Anna; Sacks, Stephen L.; Corey, Lawrence; Money, Deborah M.

2009-01-01

Objective: Acyclovir therapy in late pregnancy among women with recurrent genital herpes is effective in decreasing genital lesion frequency and subclinical viral shedding rates at delivery, thereby decreasing the need for caesarean delivery. Despite good adherence and increased dosing schedules, breakthrough lesions and viral shedding are still observed in some women at or near delivery. Anecdotal data suggests that low levels of HSV replication at delivery may result in transmission to the neonate. Therefore, defining optimal acyclovir dosing during labor and delivery is warranted. Our objectives were to determine actual acyclovir levels at delivery, and explore associations between acyclovir levels, duration of labour and time since last acyclovir dose. Methods: Twenty-seven patients were prescribed oral acyclovir 400 mg three times daily from 36 weeks gestation. Cord blood (venous and arterial) and maternal venous blood samples were collected at delivery, and acyclovir levels measured using capillary electrophoresis. Correlations between duration of labour and time since last acyclovir dose with acyclovir blood levels were calculated. Results: Acyclovir levels were below the published mean steady-state trough value (180 ng/ml) in 52% of venous cord, 55% of arterial cord, and 36% of maternal samples. There was a significant inverse correlation between time since last dose and venous cord (rs19=−0.57, p<0.015), arterial cord (rs16=−0.63, p<0.01), and maternal acyclovir levels (r10=−0.69, p<0.03). Conclusions: Oral dosing of acyclovir in late pregnancy may result in insufficient levels at delivery to prevent viral shedding. Alternative approaches should evaluate dosing through labor, perhaps intravenously, and its effect on viral shedding. PMID:20085679

An In-home Advanced Robotic System to Manage Elderly Home-care Patients' Medications: A Pilot Safety and Usability Study.

PubMed

Rantanen, Pekka; Parkkari, Timo; Leikola, Saija; Airaksinen, Marja; Lyles, Alan

2017-05-01

We examined the safety profile and usability of an integrated advanced robotic device and telecare system to promote medication adherence for elderly home-care patients. There were two phases. Phase I aimed to verify under controlled conditions in a single nursing home (n = 17 patients) that no robotic malfunctions would hinder the device's safe use. Phase II involved home-care patients from 3 sites (n = 27) who were on long-term medication. On-time dispensing and missed doses were recorded by the robotic system. Patients' and nurses' experiences were assessed with structured interviews. The 17 nursing home patients had 457 total days using the device (Phase I; mean, 26.9 per patient). On-time sachet retrieval occurred with 97.7% of the alerts, and no medication doses were missed. At baseline, Phase II home-dwelling patients reported difficulty remembering to take their medicines (23%), and 18% missed at least 2 doses per week. Most Phase II patients (78%) lived alone. The device delivered and patients retrieved medicine sachets for 99% of the alerts. All patients and 96% of nurses reported the device was easy to use. This trial demonstrated the safety profile and usability of an in-home advanced robotic device and telecare system and its acceptability to patients and nurses. It supports individualized patient dosing schedules, patient-provider communications, and on-time, in-home medication delivery to promote adherence. Real time dose-by-dose monitoring and communication with providers if a dose is missed provide oversight generally not seen in home care. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Evaluation of relative dose intensity during the early phase of first-line sunitinib treatment using a 2-week-on/1-week-off regimen for metastatic renal cell carcinoma.

PubMed

Iwamoto, Kana; Ishihara, Hiroki; Takagi, Toshio; Kondo, Tsunenori; Yoshida, Kazuhiko; Iizuka, Junpei; Tanabe, Kazunari

2018-04-23

Sunitinib treatment with a 2-week-on/1-week-off schedule (Schedule 2/1) is a common alternative regimen with high relative dose intensity (RDI) and superior tolerability for patients with metastatic renal cell carcinoma (mRCC). The prognostic impact of RDI is reported only in 4-week-on/2-week-off or mixed regimens. Herein, we evaluated the prognostic impact of RDI during early-phase sunitinib treatment using Schedule 2/1. Seventy-four patients who received first-line sunitinib treatment using Schedule 2/1 were evaluated. Endpoints were progression-free survival (PFS) and overall survival (OS). We assessed RDI within the initial two cycles (2c-RDI), and its prognostic impact. Predictive factors for 2c-RDI deterioration were also evaluated. The cut-off value of 2c-RDI was set at 65%. Based on this cut-off, 31 patients (42.0%) were classified into the low 2c-RDI group (< 65%). PFS and OS were significantly shorter in the low-2c-RDI patients, compared with the high 2c-RDI patients (median PFS: 6.15 vs. 18.4 months, p = 0.0005; OS 11.0 vs. 39.3 months, p = 0.0002). Furthermore, multivariate analyses showed that the development of dose-limiting toxicities (DLTs) within the initial two cycles, as well as low initial dose, were independent factors for low 2c-RDI (DLTs: OR 18.6, 95% CI 3.27-105.30, p = 0.0010; initial dose: OR 9.26, 95% CI 1.42-60.40, p = 0.020). The most common adverse event was thrombocytopenia (any grade: 24.3%; grade ≥ 3: 8.1%). More than 65% of 2c-RDI should be maintained for optimal therapeutic effect of sunitinib treatment using Schedule 2/1. To achieve the appropriate 2c-RDI, careful follow-up for patient tolerability is needed to avoid early DLT development.

Introduction of inactivated poliovirus vaccine leading into the polio eradication endgame strategic plan; Hangzhou, China, 2010-2014.

PubMed

Liu, Yan; Wang, Jun; Liu, Shijun; Du, Jian; Wang, Liang; Gu, Wenwen; Xu, Yuyang; Zuo, Shuyan; Xu, Erping; An, Zhijie

2017-03-01

China's Expanded Program on Immunization (EPI) has provided 4 doses of oral poliovirus vaccine (OPV) since the 1970s. Inactivated poliovirus vaccine (IPV) became available in 2010 in Hangzhou as a private-sector, parent-chosen alternative to OPV. In 2015, WHO recommended that countries with all-OPV vaccination schedules introduce at least one dose of IPV, to mitigate risk associated with the withdrawal of type 2 OPV. We analyzed polio vaccine coverage and utilization in Hangzhou to determine patterns of IPV use and the occurrence of vaccine-associated paralytic polio (VAPP) in the various patterns identified. Children born between 2010 and 2014 and registered in Hangzhou's Immunization Information System (HZIIS) were included. VAPP cases were detected through the acute flaccid paralysis surveillance system. We used descriptive epidemiological methods to determine IPV and OPV usage patterns and VAPP occurrence. HZIIS data from 566,894 children were analyzed. Coverage levels of polio vaccine were greater than 92% for each birth cohort. Percentages of children using OPV-only, IPV-only, and IPV/OPV sequential schedules were 70.57%, 27.01% and 2.41%, respectively. IPV-only schedule utilization increased by birth cohort regardless of geographical area or whether the child was locally-born. The highest use of an all-IPV schedule (79.85%) was among urban, locally-born children in the 2014 birth cohort. Five VAPP cases were identified during the study years; all cases occurred following the first polio vaccine dose, which was always OPV for the cases. Type 2 vaccine virus was isolated from 2 VAPP cases, and type 2 and type 3 vaccine virus was isolated from one VAPP case. The incidence of VAPP in the 2010-2014 birth cohorts was 3.76 per 1million doses of OPV. Children in Hangzhou had high polio vaccination coverage. IPV-only schedule use increased by year, and was highest in urban areas among locally-born children. All cases of VAPP were associated with the first dose of OPV. Copyright © 2017 Elsevier Ltd. All rights reserved.

The effect of methylphenidate and rearing environment on behavioral inhibition in adult male rats.

PubMed

Hill, Jade C; Covarrubias, Pablo; Terry, Joel; Sanabria, Federico

2012-01-01

The ability to withhold reinforced responses-behavioral inhibition-is impaired in various psychiatric conditions including Attention Deficit Hyperactivity Disorder (ADHD). Methodological and analytical limitations have constrained our understanding of the effects of pharmacological and environmental factors on behavioral inhibition. To determine the effects of acute methylphenidate (MPH) administration and rearing conditions (isolated vs. pair-housed) on behavioral inhibition in adult rats. Inhibitory capacity was evaluated using two response-withholding tasks, differential reinforcement of low rates (DRL) and fixed minimum interval (FMI) schedules of reinforcement. Both tasks made sugar pellets contingent on intervals longer than 6 s between consecutive responses. Inferences on inhibitory and timing capacities were drawn from the distribution of withholding times (interresponse times, or IRTs). MPH increased the number of intervals produced in both tasks. Estimates of behavioral inhibition increased with MPH dose in FMI and with social isolation in DRL. Nonetheless, burst responding in DRL and the divergence of DRL data relative to past studies, among other limitations, undermined the reliability of DRL data as the basis for inferences on behavioral inhibition. Inhibitory capacity was more precisely estimated from FMI than from DRL performance. Based on FMI data, MPH, but not a socially enriched environment, appears to improve inhibitory capacity. The highest dose of MPH tested, 8 mg/kg, did not reduce inhibitory capacity but reduced the responsiveness to waiting contingencies. These results support the use of the FMI schedule, complemented with appropriate analytic techniques, for the assessment of behavioral inhibition in animal models.

Radiotherapy Dose Fractionation under Parameter Uncertainty

NASA Astrophysics Data System (ADS)

Davison, Matt; Kim, Daero; Keller, Harald

2011-11-01

In radiotherapy, radiation is directed to damage a tumor while avoiding surrounding healthy tissue. Tradeoffs ensue because dose cannot be exactly shaped to the tumor. It is particularly important to ensure that sensitive biological structures near the tumor are not damaged more than a certain amount. Biological tissue is known to have a nonlinear response to incident radiation. The linear quadratic dose response model, which requires the specification of two clinically and experimentally observed response coefficients, is commonly used to model this effect. This model yields an optimization problem giving two different types of optimal dose sequences (fractionation schedules). Which fractionation schedule is preferred depends on the response coefficients. These coefficients are uncertainly known and may differ from patient to patient. Because of this not only the expected outcomes but also the uncertainty around these outcomes are important, and it might not be prudent to select the strategy with the best expected outcome.

[Immunisation schedule of the Spanish Association of Paediatrics: 2013 recommendations].

PubMed

Moreno-Pérez, D; Álvarez García, F J; Arístegui Fernández, J; Barrio Corrales, F; Cilleruelo Ortega, M J; Corretger Rauet, J M; González-Hachero, J; Hernández-Sampelayo Matos, T; Merino Moína, M; Ortigosa Del Castillo, L; Ruiz-Contreras, J

2013-01-01

The Advisory Committee on Vaccines of the Spanish Association of Paediatrics (CAV-AEP) updates the immunisation schedule every year, taking into account epidemiological data as well as evidence on the safety, effectiveness and efficiency of vaccines. The present schedule includes levels of recommendation. We have graded as routine vaccinations those that the CAV-AEP consider all children should receive; as recommended those that fit the profile for universal childhood immunisation and would ideally be given to all children, but that can be prioritised according to the resources available for their public funding; and as risk group vaccinations those that specifically target individuals in situations of risk. Immunisation schedules tend to be dynamic and adaptable to ongoing epidemiological changes. Nevertheless, the achievement of a unified immunisation schedule in all regions of Spain is a top priority for the CAV-AEP. Based on the latest epidemiological trends, CAV-AEP follows the innovations proposed in the last year's schedule, such as the administration of the first dose of the MMR and the varicella vaccines at age 12 months and the second dose at age 2-3 years, as well as the administration of the Tdap vaccine at age 4-6 years, always followed by another dose at 11-14 years of age, preferably at 11-12 years. The CAV-AEP believes that the coverage of vaccination against human papillomavirus in girls aged 11-14 years, preferably at 11-12 years, must increase. It reasserts its recommendation to include vaccination against pneumococcal disease in the routine immunisation schedule. Universal vaccination against varicella in the second year of life is an effective strategy and therefore a desirable objective. Vaccination against rotavirus is recommended in all infants due to the morbidity and elevated healthcare burden of the virus. The Committee stresses the need to vaccinate population groups considered at risk against influenza and hepatitis A. Finally, it emphasizes the need to bring incomplete vaccinations up to date following the catch-up immunisation schedule. Copyright © 2012 Asociación Española de Pediatría. Published by Elsevier España, S.L. All rights reserved.

Controlled Administration of Penicillamine Reduces Radiation Exposure in Critical Organs during 64Cu-ATSM Internal Radiotherapy: A Novel Strategy for Liver Protection

PubMed Central

Yoshii, Yukie; Matsumoto, Hiroki; Yoshimoto, Mitsuyoshi; Furukawa, Takako; Morokoshi, Yukie; Sogawa, Chizuru; Zhang, Ming-Rong; Wakizaka, Hidekatsu; Yoshii, Hiroshi; Fujibayashi, Yasuhisa; Saga, Tsuneo

2014-01-01

Purpose 64Cu-diacetyl-bis (N 4-methylthiosemicarbazone) (64Cu-ATSM) is a promising theranostic agent that targets hypoxic regions in tumors related to malignant characteristics. Its diagnostic usefulness has been recognized in clinical studies. Internal radiotherapy (IRT) with 64Cu-ATSM is reportedly effective in preclinical studies; however, for clinical applications, improvements to reduce radiation exposure in non-target organs, particularly the liver, are required. We developed a strategy to reduce radiation doses to critical organs while preserving tumor radiation doses by controlled administration of copper chelator penicillamine during 64Cu-ATSM IRT. Methods Biodistribution was evaluated in HT-29 tumor-bearing mice injected with 64Cu-ATSM (185 kBq) with or without oral penicillamine administration. The appropriate injection interval between 64Cu-ATSM and penicillamine was determined. Then, the optimal penicillamine administration schedule was selected from single (100, 300, and 500 mg/kg) and fractionated doses (100 mg/kg×3 at 1- or 2-h intervals from 1 h after 64Cu-ATSM injection). PET imaging was performed to confirm the effect of penicillamine with a therapeutic 64Cu-ATSM dose (37 MBq). Dosimetry analysis was performed to estimate human absorbed doses. Results Penicillamine reduced 64Cu accumulation in the liver and small intestine. Tumor uptake was not affected by penicillamine administration at 1 h after 64Cu-ATSM injection, when radioactivity was almost cleared from the blood and tumor uptake had plateaued. Of the single doses, 300 mg/kg was most effective. Fractionated administration at 2-h intervals further decreased liver accumulation at later time points. PET indicated that penicillamine acts similarly with the therapeutic 64Cu-ATSM dose. Dosimetry demonstrated that appropriately scheduled penicillamine administration reduced radiation doses to critical organs (liver, ovaries, and red marrow) below tolerance levels. Laxatives reduced radiation doses to the large intestine. Conclusions We developed a novel strategy to reduce radiation exposure in critical organs during 64Cu-ATSM IRT, thus promoting its clinical applications. This method could be beneficial for other 64Cu-labeled compounds. PMID:24466309

Safety and immunogenicity of different doses and schedules of a live attenuated tetravalent dengue vaccine (TDV) in healthy adults: A Phase 1b randomized study.

PubMed

Rupp, Richard; Luckasen, Gary Joseph; Kirstein, Judith Lee; Osorio, Jorge E; Santangelo, Joseph D; Raanan, Marsha; Smith, Mary Kathryn; Wallace, Derek; Gordon, Gilad S; Stinchcomb, Dan T

2015-11-17

A safe, effective dengue vaccine that can simultaneously induce immunity to all four dengue virus serotypes (DENV-1-4) is a public health priority. A chimeric tetravalent dengue vaccine (TDV) based on an attenuated DENV-2 serotype backbone was evaluated in healthy, flavivirus-seronegative adults. In this randomized, multicenter, Phase 1b study conducted in the United States, the safety and immunogenicity of TDV were evaluated in 140 participants aged 18-45 years in six dosing regimen study groups. Participants were injected subcutaneously on Days 0 and 90; placebo (saline) was injected where appropriate to maintain double blinding. Three different TDV dosages (TDV, a vaccine in which TDV-4 had been increased three-fold, and a one-tenth TDV dose), and single or double dosing were evaluated in one and/or both arms. Primary endpoints were solicited and unsolicited adverse events (AEs) and seroconversion rates to DENV-1-4 at Day 120. The severity of all AEs was generally mild. The most common unsolicited AEs were headache (52%), fatigue (43%) and myalgia (29%). The incidence of injection site pain ranged from 29 to 64% and 5 to 52% among study groups after the first and second doses, respectively. At Day 120, the ranges of seroconversion rates among the groups were DEN-1: 84-100%; DEN-2: 96-100%; DEN-3: 83-100%; and DEN-4: 33-77%. More than 80% of participants in each group seroconverted to at least three dengue serotypes. Substantial GMT increases from baseline were observed for DEN-1-3 at all time points from Day 30 onward; DEN-4 GMT increases were lower. Increasing TDV-4 slightly increased DEN-4 GMT, did not impact DEN-2 and DEN-3 GMT, but reduced DEN-1 GMT. Neither multiple dosing in both arms, nor one-tenth TDV dosing meaningfully impacted GMT increases relative to TDV. All TDV doses and dosing schedules were well tolerated and immunogenic in healthy flavivirus-naive adults (ClinicalTrials.gov NCT01511250). Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Artemether-lumefantrine dosing for malaria treatment in young children and pregnant women: A pharmacokinetic-pharmacodynamic meta-analysis

PubMed Central

Borrmann, Steffen; Tékété, Mamadou; Lefèvre, Gilbert; Hamed, Kamal; Piola, Patrice; Ursing, Johan; Kofoed, Poul Erik; Mårtensson, Andreas; Ngasala, Billy; Björkman, Anders; Friberg Hietala, Sofia; Aweeka, Francesca; Parikh, Sunil; Mwai, Leah; Davis, Timothy M. E.; Karunajeewa, Harin; Newton, Paul N.; Mayxay, Mayfong; Deloron, Philippe; van Vugt, Michele; Karbwang, Juntra; Ezzet, Farkad; Bakshi, Rajesh; Stepniewska, Kasia; Barnes, Karen I.

2018-01-01

Background The fixed dose combination of artemether-lumefantrine (AL) is the most widely used treatment for uncomplicated Plasmodium falciparum malaria. Relatively lower cure rates and lumefantrine levels have been reported in young children and in pregnant women during their second and third trimester. The aim of this study was to investigate the pharmacokinetic and pharmacodynamic properties of lumefantrine and the pharmacokinetic properties of its metabolite, desbutyl-lumefantrine, in order to inform optimal dosing regimens in all patient populations. Methods and findings A search in PubMed, Embase, ClinicalTrials.gov, Google Scholar, conference proceedings, and the WorldWide Antimalarial Resistance Network (WWARN) pharmacology database identified 31 relevant clinical studies published between 1 January 1990 and 31 December 2012, with 4,546 patients in whom lumefantrine concentrations were measured. Under the auspices of WWARN, relevant individual concentration-time data, clinical covariates, and outcome data from 4,122 patients were made available and pooled for the meta-analysis. The developed lumefantrine population pharmacokinetic model was used for dose optimisation through in silico simulations. Venous plasma lumefantrine concentrations 7 days after starting standard AL treatment were 24.2% and 13.4% lower in children weighing <15 kg and 15–25 kg, respectively, and 20.2% lower in pregnant women compared with non-pregnant adults. Lumefantrine exposure decreased with increasing pre-treatment parasitaemia, and the dose limitation on absorption of lumefantrine was substantial. Simulations using the lumefantrine pharmacokinetic model suggest that, in young children and pregnant women beyond the first trimester, lengthening the dose regimen (twice daily for 5 days) and, to a lesser extent, intensifying the frequency of dosing (3 times daily for 3 days) would be more efficacious than using higher individual doses in the current standard treatment regimen (twice daily for 3 days). The model was developed using venous plasma data from patients receiving intact tablets with fat, and evaluations of alternative dosing regimens were consequently only representative for venous plasma after administration of intact tablets with fat. The absence of artemether-dihydroartemisinin data limited the prediction of parasite killing rates and recrudescent infections. Thus, the suggested optimised dosing schedule was based on the pharmacokinetic endpoint of lumefantrine plasma exposure at day 7. Conclusions Our findings suggest that revised AL dosing regimens for young children and pregnant women would improve drug exposure but would require longer or more complex schedules. These dosing regimens should be evaluated in prospective clinical studies to determine whether they would improve cure rates, demonstrate adequate safety, and thereby prolong the useful therapeutic life of this valuable antimalarial treatment. PMID:29894518

Effects of ethanol on cocaine self-administration in monkeys responding under a second-order schedule of reinforcement.

PubMed

John, William S; Nader, Michael A

2017-01-01

Concurrent alcohol use among cocaine abusers is common but the behavioral variables that promote co-abuse are not well understood. The present study examined the effects of intragastric (i.g.) ethanol (EtOH) administration in monkeys responding under a schedule of cocaine reinforcement in which extensive drug seeking was maintained by conditioned stimuli. Four adult male cynomolgus monkeys (Macaca fascicularis) were trained to respond under a second-order fixed-interval (FI) 600s (fixed-ratio (FR) 30:S) schedule of cocaine (0.003-0.56mg/kg/injection) presentation. Sessions ended after 5 injections or 90min had elapsed. Different EtOH doses (0.5-2.0g/kg, i.g.) were administered 30min before the session, typically on Tuesdays and Fridays. Blood ethanol concentrations (BECs) were also assessed. Pattern of FI responding was assessed by determining quarter-life (QL) values. Cocaine self-administration was characterized as an inverted U-shaped function of dose; QL values increased monotonically with dose. EtOH pretreatments dose-dependently decreased self-administration at several cocaine doses in 3 of 4 monkeys. In one animal, EtOH increased low-dose cocaine-maintained responding. For all monkeys, QL values were increased by EtOH when low- and high-cocaine doses were self-administered, suggesting additive effects of EtOH and cocaine. Furthermore, BECs were not altered following cocaine self-administration. The reductions in cocaine self-administration and the increases in QL values following EtOH, suggest that EtOH was enhancing cocaine-related conditioned reinforcement. A better understanding of the behavioral mechanisms that mediate the co-abuse of alcohol and cocaine will lead to improved treatments for both drugs. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Interrogating two schedules of the AKT inhibitor MK-2206 in patients with advanced solid tumors incorporating novel pharmacodynamic and functional imaging biomarkers

PubMed Central

Yap, Timothy A.; Yan, Li; Patnaik, Amita; Tunariu, Nina; Biondo, Andrea; Fearen, Ivy; Papadopoulos, Kyriakos P.; Olmos, David; Baird, Richard; Delgado, Liliana; Tetteh, Ernestina; Beckman, Robert A.; Lupinacci, Lisa; Riisnaes, Ruth; Decordova, Shaun; Heaton, Simon P.; Swales, Karen; deSouza, Nandita M; Leach, Martin O.; Garrett, Michelle D.; Sullivan, Daniel M.; de Bono, Johann S.; Tolcher, Anthony W.

2014-01-01

Purpose Multiple cancers harbor genetic aberrations that impact AKT signaling. MK-2206 is a potent pan-AKT inhibitor with a maximum tolerated dose (MTD) previously established at 60mg on alternate days (QOD). Due to a long half-life (60-80h), a weekly (QW) MK-2206 schedule was pursued to compare intermittent QW and continuous QOD dosing. Experimental Design Patients with advanced cancers were enrolled onto a QW dose-escalation phase I study to investigate the safety and pharmacokinetic-pharmacodynamic profiles of tumor and platelet-rich plasma (PRP). The QOD MTD of MK-2206 was also assessed in patients with ovarian and castration-resistant prostate cancers, and patients with advanced cancers undergoing multiparametric functional magnetic resonance imaging (MRI) studies, including dynamic contrast-enhanced MRI, diffusion-weighted imaging, magnetic resonance spectroscopy and intrinsic susceptibility-weighted MRI. Results Seventy-one patients were enrolled; 38 patients had 60mg MK-2206 QOD, while 33 received MK-2206 at 90mg, 135mg, 150mg, 200mg, 250mg, and 300mg QW. The QW MK-2206 MTD was established at 200mg following dose-limiting rash at 250mg and 300mg. QW dosing appeared to be similarly tolerated to QOD, with toxicities including rash, gastrointestinal symptoms, fatigue, and hyperglycemia. Significant AKT pathway blockade was observed with both continuous QOD and intermittent QW dosing of MK-2206 in serially-obtained tumor and PRP specimens. The functional imaging studies demonstrated that complex multiparametric MRI protocols may be effectively implemented in a phase I trial. Conclusions MK-2206 safely results in significant AKT pathway blockade in QOD and QW schedules. The intermittent dose of 200mg QW is currently used in phase II MK-2206 monotherapy and combination studies. PMID:25239610

Interrogating two schedules of the AKT inhibitor MK-2206 in patients with advanced solid tumors incorporating novel pharmacodynamic and functional imaging biomarkers.

PubMed

Yap, Timothy A; Yan, Li; Patnaik, Amita; Tunariu, Nina; Biondo, Andrea; Fearen, Ivy; Papadopoulos, Kyriakos P; Olmos, David; Baird, Richard; Delgado, Liliana; Tetteh, Ernestina; Beckman, Robert A; Lupinacci, Lisa; Riisnaes, Ruth; Decordova, Shaun; Heaton, Simon P; Swales, Karen; deSouza, Nandita M; Leach, Martin O; Garrett, Michelle D; Sullivan, Daniel M; de Bono, Johann S; Tolcher, Anthony W

2014-11-15

Multiple cancers harbor genetic aberrations that impact AKT signaling. MK-2206 is a potent pan-AKT inhibitor with a maximum tolerated dose (MTD) previously established at 60 mg on alternate days (QOD). Due to a long half-life (60-80 hours), a weekly (QW) MK-2206 schedule was pursued to compare intermittent QW and continuous QOD dosing. Patients with advanced cancers were enrolled in a QW dose-escalation phase I study to investigate the safety and pharmacokinetic-pharmacodynamic profiles of tumor and platelet-rich plasma (PRP). The QOD MTD of MK-2206 was also assessed in patients with ovarian and castration-resistant prostate cancers and patients with advanced cancers undergoing multiparametric functional magnetic resonance imaging (MRI) studies, including dynamic contrast-enhanced MRI, diffusion-weighted imaging, magnetic resonance spectroscopy, and intrinsic susceptibility-weighted MRI. A total of 71 patients were enrolled; 38 patients had 60 mg MK-2206 QOD, whereas 33 received MK-2206 at 90, 135, 150, 200, 250, and 300 mg QW. The QW MK-2206 MTD was established at 200 mg following dose-limiting rash at 250 and 300 mg. QW dosing appeared to be similarly tolerated to QOD, with toxicities including rash, gastrointestinal symptoms, fatigue, and hyperglycemia. Significant AKT pathway blockade was observed with both continuous QOD and intermittent QW dosing of MK-2206 in serially obtained tumor and PRP specimens. The functional imaging studies demonstrated that complex multiparametric MRI protocols may be effectively implemented in a phase I trial. Treatment with MK-2206 safely results in significant AKT pathway blockade in QOD and QW schedules. The intermittent dose of 200 mg QW is currently used in phase II MK-2206 monotherapy and combination studies (NCT00670488). ©2014 American Association for Cancer Research.

Self-administration of nicotine and cigarette smoke extract in adolescent and adult rats.

PubMed

Gellner, Candice A; Belluzzi, James D; Leslie, Frances M

2016-10-01

Although smoking initiation typically occurs during adolescence, most preclinical studies of tobacco use involve adult animals. Furthermore, their focus is largely on nicotine alone, even though cigarette smoke contains thousands of constituents. The present study therefore aimed to determine whether aqueous constituents in cigarette smoke affect acquisition of nicotine self-administration during adolescence in rats. Adolescent and adult male rats, aged postnatal day (P) 25 and 85, respectively, were food trained on a fixed ratio 1 (FR1) schedule, then allowed to self-administer one of 5 doses of nicotine (0, 3.75, 7.5, 15, or 30 μg/kg) or aqueous cigarette smoke extract (CSE) with equivalent nicotine content. Three progressively more difficult schedules of reinforcement, FR1, FR2, and FR5, were used. Both adolescent and adult rats acquired self-administration of nicotine and CSE. Nicotine and CSE similarly increased non-reinforced responding in adolescents, leading to enhanced overall drug intake as compared to adults. When data were corrected for age-dependent alterations in non-reinforced responding, adolescents responded more for low doses of nicotine and CSE than adults at the FR1 reinforcement schedule. No differences in adolescent responding for the two drugs were seen at this schedule, whereas adults had fewer responses for CSE than for nicotine. However, when the reinforcement schedule was increased to FR5, animals dose-dependently self-administered both nicotine and CSE, but no drug or age differences were observed. These data suggest that non-nicotine tobacco smoke constituents do not influence the reinforcing effect of nicotine in adolescents. Published by Elsevier Ltd.

76 FR 42771 - Medicare Program; Payment Policies Under the Physician Fee Schedule and Other Revisions to Part B...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-07-19

...--Association of Freestanding Radiation Oncology Centers AFS--Ambulance Fee Schedule AHA--American Heart...) Update Committee AMA-DE--American Medical Association Drug Evaluations AMI--Acute Myocardial Infarction.../Low-density lipoprotein HDRT--High dose radiation therapy HEMS--Helicopter Emergency Medical Services...

Optimization of Catheter Based rtPA Thrombolysis in a Novel In Vitro Clot Model for Intracerebral Hemorrhage

PubMed Central

Masomi-Bornwasser, Julia; Müller-Werkmeister, Hendrik; Kantelhardt, Sven Rainer; König, Jochem; Kempski, Oliver; Giese, Alf

2017-01-01

Hematoma lysis with recombinant tissue plasminogen activator (rtPA) has emerged as an alternative therapy for spontaneous intracerebral hemorrhage (ICH). Optimal dose and schedule are still unclear. The aim of this study was to create a reliable in vitro blood clot model for investigation of optimal drug dose and timing. An in vitro clot model was established, using 25 mL and 50 mL of human blood. Catheters were placed into the clots and three groups, using intraclot application of rtPA, placebo, and catheter alone, were analyzed. Dose-response relationship, repetition, and duration of rtPA treatment and its effectiveness in aged clots were investigated. A significant relative end weight difference was found in rtPA treated clots compared to catheter alone (p = 0.002) and placebo treated clots (p < 0.001). Dose-response analysis revealed 95% effective dose around 1 mg rtPA in 25 and 50 mL clots. Approximately 80% of relative clot lysis could be achieved after 15 min incubation. Lysis of aged clots was less effective. A new clot model for in vitro investigation was established. Our data suggest that current protocols for rtPA based ICH therapy may be optimized by using less rtPA at shorter incubation times. PMID:28459065

Optimization of Catheter Based rtPA Thrombolysis in a Novel In Vitro Clot Model for Intracerebral Hemorrhage.

PubMed

Keric, Naureen; Masomi-Bornwasser, Julia; Müller-Werkmeister, Hendrik; Kantelhardt, Sven Rainer; König, Jochem; Kempski, Oliver; Giese, Alf

2017-01-01

Hematoma lysis with recombinant tissue plasminogen activator (rtPA) has emerged as an alternative therapy for spontaneous intracerebral hemorrhage (ICH). Optimal dose and schedule are still unclear. The aim of this study was to create a reliable in vitro blood clot model for investigation of optimal drug dose and timing. An in vitro clot model was established, using 25 mL and 50 mL of human blood. Catheters were placed into the clots and three groups, using intraclot application of rtPA, placebo, and catheter alone, were analyzed. Dose-response relationship, repetition, and duration of rtPA treatment and its effectiveness in aged clots were investigated. A significant relative end weight difference was found in rtPA treated clots compared to catheter alone ( p = 0.002) and placebo treated clots ( p < 0.001). Dose-response analysis revealed 95% effective dose around 1 mg rtPA in 25 and 50 mL clots. Approximately 80% of relative clot lysis could be achieved after 15 min incubation. Lysis of aged clots was less effective. A new clot model for in vitro investigation was established. Our data suggest that current protocols for rtPA based ICH therapy may be optimized by using less rtPA at shorter incubation times.

[A seroconversion study of the measles component of the MMR vaccine in adolescents of the town of Sabrosa].

PubMed

Gonçalves, G; Tavares, F; de Andrade, H R

1998-12-01

The Portuguese national programme of vaccination has instituted a two-dose MMR vaccine schedule. The second dose of MMR (measles-mumps-rubella combined vaccine) is given at 11-13 years of age, for both sexes. This study was conducted to evaluate the duration of immunity of the monovalent measles vaccine, and the efficacy of a second dose given as MMR. MMR (Triviraten Berna with the strain Edmonston-Zagreb) was given to the 38 participants. Blood samples were collected before and after vaccination. Thirty-six participants had been vaccinated with measles monovalent vaccine during childhood. To measure anti-measles IgG (mIgG), an enzyme immunoassay was used. Participants were classified as "susceptible" or "immune", using 200 mIU/ml (milli international units per millilitre) as the threshold for "immune". Geometric mean concentration (GMC) of mIgG was 1401 mIU/ml in prevaccination sera (n = 38). Thirty-five (92%) of the adolescents were "immune". Only the two unvaccinated had a positive measles history. GMC in the sera of the 36 vaccinated participants was 1301 mIU/ml. Neither the time since measles vaccination nor age at vaccination were correlated with the levels of mIgG. After receiving MMR, all adolescents became "immune". GMC of mIgG was 2879 mIU/ml in postvaccination sera (n = 38). In 28 (74%) participants, mIgG levels increased after receiving MMR. Mean concentration increase was 1082 mIU/ml. For measles, results support the use of a two-dose MMR vaccine schedule in Portugal.

Dose escalation methods in phase I cancer clinical trials.

PubMed

Le Tourneau, Christophe; Lee, J Jack; Siu, Lillian L

2009-05-20

Phase I clinical trials are an essential step in the development of anticancer drugs. The main goal of these studies is to establish the recommended dose and/or schedule of new drugs or drug combinations for phase II trials. The guiding principle for dose escalation in phase I trials is to avoid exposing too many patients to subtherapeutic doses while preserving safety and maintaining rapid accrual. Here we review dose escalation methods for phase I trials, including the rule-based and model-based dose escalation methods that have been developed to evaluate new anticancer agents. Toxicity has traditionally been the primary endpoint for phase I trials involving cytotoxic agents. However, with the emergence of molecularly targeted anticancer agents, potential alternative endpoints to delineate optimal biological activity, such as plasma drug concentration and target inhibition in tumor or surrogate tissues, have been proposed along with new trial designs. We also describe specific methods for drug combinations as well as methods that use a time-to-event endpoint or both toxicity and efficacy as endpoints. Finally, we present the advantages and drawbacks of the various dose escalation methods and discuss specific applications of the methods in developmental oncotherapeutics.

[Vaccination schedule of the Spanish Association of Pediatrics: recommendations 2004].

PubMed

2004-05-01

The Vaccine Assessment Committee of the Spanish Association of Pediatrics discusses vaccine developments in 2003 and recommends some modifications to the vaccination schedule. The recommendation of substituting the oral polio vaccine for the inactivated polio vaccine, suppressing the fifth dose, is maintained. The introduction of the conjugate pneumococcal vaccine and the varicella vaccine is stressed. Concerning the meningococcal C vaccine, the improvement introduced by being able to immunize with just two doses is discussed. In agreement with the information received from the European Medicines Agency, there appear to be no well-founded reasons to abandon hexavalent preparations.

Effects of Pharmacokinetic Processes and Varied Dosing Schedules on the Dynamics of Acquired Resistance to Erlotinib in EGFR-Mutant Lung Cancer

PubMed Central

Foo, Jasmine; Chmielecki, Juliann; Pao, William; Michor, Franziska

2013-01-01

Introduction Erlotinib (Tarceva) is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, which effectively targets EGFR-mutant driven non–small-cell lung cancer. However, the evolution of acquired resistance because of a second-site mutation (T790M) within EGFR remains an obstacle to successful treatment. Methods We used mathematical modeling and available clinical trial data to predict how different pharmacokinetic parameters (fast versus slow metabolism) and dosing schedules (low dose versus high dose; missed doses with and without make-up doses) might affect the evolution of T790M-mediated resistance in mixed populations of tumor cells. Results We found that high-dose pulses with low-dose continuous therapy impede the development of resistance to the maximum extent, both pre- and post-emergence of resistance. The probability of resistance is greater in fast versus slow drug metabolizers, suggesting a potential mechanism, unappreciated to date, influencing acquired resistance in patients. In case of required dose modifications because of toxicity, little difference is observed in terms of efficacy and resistance dynamics between the standard daily dose (150 mg/d) and 150 mg/d alternating with 100 mg/d. Missed doses are expected to lead to resistance faster, even if make-up doses are attempted. Conclusions For existing and new kinase inhibitors, this novel framework can be used to rationally and rapidly design optimal dosing strategies to minimize the development of acquired resistance. PMID:22982659

A comparison of dehydroepiandrosterone and 7-keto dehydroepiandrosterone with other drugs that modulate ethanol intake in rats responding under a multiple schedule

PubMed Central

Amato, Russell J.; Hulin, Mary W.; Winsauer, Peter J.

2012-01-01

Dehydroepiandrosterone (DHEA), 7-keto DHEA, and several comparison drugs (ethanol, chlordiazepoxide, rauwolscine, and RO15-4513) were administered to male rats responding under a multiple schedule of food and ethanol presentation to determine their selectively for decreasing ethanol-maintained responding. DHEA and 7-keto DHEA significantly decreased both ethanol- and food-maintained responding, compared to control, while also decreasing blood ethanol concentration (BEC). Acute ethanol administration also decreased responding for both food and ethanol; however, ethanol-maintained responding was more potently decreased than food-maintained responding. BEC remained relatively stable after increasing ethanol doses. Among the other drugs tested, RO15-4513 was the most selective for decreasing ethanol-maintained responding compared to food-maintained responding, and it decreased BECs as ethanol-maintained responding decreased. The largest dose of rauwolscine significantly decreased responding for food, while not affecting ethanol-maintained responding compared to control. Low to intermediate doses of rauwolscine produced small, non-significant increases in ethanol-maintained responding and BECs. Chlordiazepoxide produced significant decreases in food-maintained responding and the dose of ethanol presented, but only at the highest dose tested. Although DHEA and 7-keto DHEA did not decrease ethanol-maintained responding as selectively as ethanol or RO15-4513 under the multiple schedule, these neurosteroids may be valuable pharmacological tools in the development of new treatments for alcohol abuse and dependence. PMID:22473025

Using Six Sigma to improve once daily gentamicin dosing and therapeutic drug monitoring performance.

PubMed

Egan, Sean; Murphy, Philip G; Fennell, Jerome P; Kelly, Sinead; Hickey, Mary; McLean, Carolyn; Pate, Muriel; Kirke, Ciara; Whiriskey, Annette; Wall, Niall; McCullagh, Eddie; Murphy, Joan; Delaney, Tim

2012-12-01

Safe, effective therapy with the antimicrobial gentamicin requires good practice in dose selection and monitoring of serum levels. Suboptimal therapy occurs with breakdown in the process of drug dosing, serum blood sampling, laboratory processing and level interpretation. Unintentional underdosing may result. This improvement effort aimed to optimise this process in an academic teaching hospital using Six Sigma process improvement methodology. A multidisciplinary project team was formed. Process measures considered critical to quality were defined, and baseline practice was examined through process mapping and audit. Root cause analysis informed improvement measures. These included a new dosing and monitoring schedule, and standardised assay sampling and drug administration timing which maximised local capabilities. Three iterations of the improvement cycle were conducted over a 24-month period. The attainment of serum level sampling in the required time window improved by 85% (p≤0.0001). A 66% improvement in accuracy of dosing was observed (p≤0.0001). Unnecessary dose omission while awaiting level results and inadvertent disruption to therapy due to dosing and monitoring process breakdown were eliminated. Average daily dose administered increased from 3.39 mg/kg to 4.78 mg/kg/day. Using Six Sigma methodology enhanced gentamicin usage process performance. Local process related factors may adversely affect adherence to practice guidelines for gentamicin, a drug which is complex to use. It is vital to adapt dosing guidance and monitoring requirements so that they are capable of being implemented in the clinical environment as a matter of routine. Improvement may be achieved through a structured localised approach with multidisciplinary stakeholder involvement.

Preventing radiation retinopathy with hyperfractionation

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

Monroe, Alan T.; Bhandare, Niranjan; Morris, Christopher G.

2005-03-01

Purpose: The purpose of this study was to determine factors associated with the development of radiation retinopathy in a large series of patients with head-and-neck cancer. In particular, we addressed whether the use of hyperfractionated radiation therapy was effective in reducing the risk of retinopathy. Methods and materials: One hundred eighty-six patients received a significant dose to the retina as part of curative radiotherapy. Primary sites included: nasopharynx, 46; paranasal sinus, 64; nasal cavity, 69; and palate, 7. Prescription doses varied depending on primary site and histology. Hyperfractionated (twice-daily) radiation was delivered to 42% of the patients in this study,more » typically at 1.10 to 1.20 Gy per fraction. The remainder were treated once-daily. Retinal doses were determined from computerized dosimetry plans when available. For all other patients, retinal doses were retrospectively calculated using reconstructed off-axis dosimetry taken from contours through the center of the globes. Retinal dose was defined as the minimum dose received by at least 25% of the globe. The median retinal dose was 56.85 Gy. Patients were followed for a median of 7.6 years. Results: Thirty-one eyes in 30 patients developed radiation retinopathy, resulting in monocular blindness in 25, bilateral blindness in 1, and decreased visual acuity in 4. The median time to the diagnosis of retinopathy was 2.6 years (range, 11 months to 5.3 years). The actuarial incidence of developing radiation retinopathy was 20% at both 5 and 10 years. The incidence of developing ipsilateral blindness due to retinopathy was 16% at 5 years and 17% at 10 years. Site-specific incidences varied considerably, with ethmoid sinus (9 of 25, 36%), nasal cavity (13 of 69, 19%), and maxillary sinus (6 of 35, 17%) being the most common sites associated with radiation retinopathy. Three of 72 patients (4%) receiving retinal doses less than 50 Gy developed retinopathy. Higher retinal doses resulted in a steady increase in the incidence of retinopathy, with 25 of the 30 cases occurring after 60 Gy or more. Of the patients receiving more than 50 Gy to the retina, hyperfractionation was associated with a significantly lower incidence of radiation retinopathy (37% vs. 13%; p = 0.0037). On multivariate analysis, retinal dose (p < 0.0001), fractionation schedule (p = 0.0003), age (p = 0.0365), and prolonged overall treatment time (p = 0.0213) were significant predictors of radiation retinopathy. Conclusion: The incidence of ipsilateral radiation retinopathy after treatment of nasal cavity/paranasal tumors is 20% at 5 and 10 years. Retinal dose and fractionation schedule are the strongest predictors of retinopathy. Hyperfractionated radiotherapy is associated with a significant reduction in the incidence of radiation retinopathy, especially when the retina receives more than 50 Gy.« less

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

Jeong, J; Deasy, J O

Purpose: Concurrent chemo-radiation therapy (CCRT) has become a more common cancer treatment option with a better tumor control rate for several tumor sites, including head and neck and lung cancer. In this work, possible optimal chemotherapy schedules were investigated by implementing chemotherapy cell-kill into a tumor response model of RT. Methods: The chemotherapy effect has been added into a published model (Jeong et al., PMB (2013) 58:4897), in which the tumor response to RT can be simulated with the effects of hypoxia and proliferation. Based on the two-compartment pharmacokinetic model, the temporal concentration of chemotherapy agent was estimated. Log cell-killmore » was assumed and the cell-kill constant was estimated from the observed increase in local control due to concurrent chemotherapy. For a simplified two cycle CCRT regime, several different starting times and intervals were simulated with conventional RT regime (2Gy/fx, 5fx/wk). The effectiveness of CCRT was evaluated in terms of reduction in radiation dose required for 50% of control to find the optimal chemotherapy schedule. Results: Assuming the typical slope of dose response curve (γ50=2), the observed 10% increase in local control rate was evaluated to be equivalent to an extra RT dose of about 4 Gy, from which the cell-kill rate of chemotherapy was derived to be about 0.35. Best response was obtained when chemotherapy was started at about 3 weeks after RT began. As the interval between two cycles decreases, the efficacy of chemotherapy increases with broader range of optimal starting times. Conclusion: The effect of chemotherapy has been implemented into the resource-conservation tumor response model to investigate CCRT. The results suggest that the concurrent chemotherapy might be more effective when delayed for about 3 weeks, due to lower tumor burden and a larger fraction of proliferating cells after reoxygenation.« less

SU-D-BRB-06: Treating Glioblastoma Multiforme (GBM) as a Chronic Disease: Implication of Temporal-Spatial Dose Fractionation Optimization Including Cancer Stem Cell Dynamics

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

Yu, V; Nguyen, D; Pajonk, F

Purpose: To explore the feasibility of improving GBM treatment outcome with temporal-spatial dose optimization of an ordinary differential equation (ODE) that models the differentiation and distinct radiosensitivity between cancer stem cells (CSC) and differentiated cancer cells (DCC). Methods: The ODE was formulated into a non-convex optimization problem with the objective to minimize remaining total cancer cells 500 days from the onset of radiotherapy when the total cancer cell number was 3.5×10{sup 7}, while maintaining normal tissue biological effective dose (BED) of 100Gy resulted from standard prescription of 2Gyx30. Assuming spatially separated CSC and DCC, optimization was also performed to exploremore » the potential benefit from dose-painting the two compartments. Dose escalation to a sub-cell-population in the GTV was also examined assuming that a 2 cm margin around the GTV allows sufficient dose drop-off to 100Gy BED. The recurrence time was determined as the time at which the total cancer cell number regrows to 10{sup 9} cells. Results: The recurrence time with variable fractional doses administered once per week, bi-week and month for one year were found to be 615, 593 and 570 days, superior to the standard-prescription recurrence time of 418 days. The optimal dose-fraction size progression for both uniform and dose-painting to the tumor is low and relatively constant in the beginning and gradually increases to more aggressive fractions at end of the treatment course. Dose escalation to BED of 200Gy to the whole tumor alongside with protracted weekly treatment was found to further delay recurrence to 733 days. Dose-painting of 200 and 500Gy BED to CSC on a year-long weekly schedule further extended recurrence to 736 and 1076 days, respectively. Conclusion: GBM treatment outcome can possibly be improved with a chronic treatment approach. Further dose escalation to the entire tumor or CSC targeted killing is needed to achieve total tumor control. This work is supported by the NSF Graduate Research Fellowship (DGE-1144087)« less

Significant reduction in notification and seroprevalence rates of hepatitis B virus infection among the population of Zhejiang Province, China, aged between 1 and 29years from 2006 to 2014.

PubMed

Zhou, Yang; He, Hanqing; Deng, Xuan; Yan, Rui; Tang, Xuewen; Xie, Shuyun; Yao, Jun

2017-08-03

The Chinese government integrated hepatitis B vaccination into the national immunization program in 1992, when the hepatitis B birth dose was introduced in China. Zhejiang province is a relatively developed area in eastern China and was an area with high endemicity for hepatitis B virus (HBV) infection via mother-to-child transmission. The hepatitis B vaccine vaccination rates for the birth dose and 3- dose schedule in Zhejiang Province since 1992 have both remained above 90% [1]. The results of two hepatitis B seroepidemiological surveys conducted in 2006 and 2014, respectively, to evaluate the rates of notification and seroprevalence of HBV infection among the population of Zhejiang Province, China, aged between 1 and 29years. Data on the notification rates of HBV infection in Zhejiang province from 2006 to 2014 were obtained from the National Notifiable Disease Reporting System (NNDRS). The prevalence rate of HBV serological markers and the rate of immunization coverage were compared between surveys. The reported notification rates in people aged between 1 and 29years according to the NNDRS decreased approximately 4.88 times from 2006 to 2014. The prevalence of HBsAg decreased from 2.16% in 2006 to 1.05% in 2014, while the prevalence of anti-HBc decreased from 7.13% to 5.49%. The anti-HBc seroprevalence in the 15-29-year-old age group was significantly higher than that in all the other age groups both in the 2006 and 2014 serosurveys. The rate of anti-HBs seroprevalence in those aged between 1 and 14years was maintained at a high level between 2006 and 2014. The rate of hepatitis B reported and the rate of HBsAg positivity decreased significantly in Zhejiang province by maintaining the high-level coverage rate of the hepatitis B timely birth dose and three-dose schedule. While additional efforts are needed to achieve the goal of elimination. Copyright © 2017 Elsevier Ltd. All rights reserved.

Metronomic chemotherapy: An attractive alternative to maximum tolerated dose therapy that can activate anti-tumor immunity and minimize therapeutic resistance

DOE PAGES

Kareva, Irina; Waxman, David J.; Klement, Giannoula Lakka

2014-12-23

The administration of chemotherapy at reduced doses given at regular, frequent time intervals, termed ‘metronomic’ chemotherapy, presents an alternative to standard maximal tolerated dose (MTD) chemotherapy. The primary target of metronomic chemotherapy was originally identified as endothelial cells supporting the tumor vasculature, and not the tumor cells themselves, consistent with the emerging concept of cancer as a systemic disease involving both tumor cells and their microenvironment. While anti-angiogenesis is an important mechanism of action of metronomic chemotherapy, other mechanisms, including activation of anti-tumor immunity and a decrease in acquired therapeutic resistance, have also been identified. In this paper, we presentmore » evidence supporting a mechanistic explanation for the improved activity of cancer chemotherapy when administered on a metronomic, rather than an MTD schedule and discuss the implications of these findings for further translation into the clinic.« less

Metronomic chemotherapy: A potent macerator of cancer by inducing angiogenesis suppression and antitumor immune activation.

PubMed

Biziota, Eirini; Mavroeidis, Leonidas; Hatzimichael, Eleftheria; Pappas, Periklis

2017-08-01

Metronomic chemotherapy is a low dosing treatment strategy that attracts growing scientific and clinical interest. It refers to dense and uninterrupted administration of low doses of chemotherapeutic agents (without prolonged drug free intervals) over extended periods of time. Cancer chemotherapy is conventionally given in cycles of maximum tolerated doses (MTD) with the aim of inducing maximum cancer cell apoptosis. In contrast, the primary target of metronomic chemotherapy is the tumor's neovasculature. This is relevant to the emerging concept that tumors exist in a complex microenvironment of cancer cells, stromal cells and supporting vessels. In addition to its anti-angiogenetic properties, metronomic chemotherapy halts tumor growth by activating anti-tumor immunity, thus decreasing the acquired resistance to conventional chemotherapy. Herein, we present a review of the literature that provides a scientific basis for the merits of chemotherapy when administered on a metronomic schedule. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Metronomic chemotherapy: an attractive alternative to maximum tolerated dose therapy that can activate anti-tumor immunity and minimize therapeutic resistance.

PubMed

Kareva, Irina; Waxman, David J; Lakka Klement, Giannoula

2015-03-28

The administration of chemotherapy at reduced doses given at regular, frequent time intervals, termed 'metronomic' chemotherapy, presents an alternative to standard maximal tolerated dose (MTD) chemotherapy. The primary target of metronomic chemotherapy was originally identified as endothelial cells supporting the tumor vasculature, and not the tumor cells themselves, consistent with the emerging concept of cancer as a systemic disease involving both tumor cells and their microenvironment. While anti-angiogenesis is an important mechanism of action of metronomic chemotherapy, other mechanisms, including activation of anti-tumor immunity and a decrease in acquired therapeutic resistance, have also been identified. Here we present evidence supporting a mechanistic explanation for the improved activity of cancer chemotherapy when administered on a metronomic, rather than an MTD schedule and discuss the implications of these findings for further translation into the clinic. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Serum IgG antibody response to the protective antigen (PA) of Bacillus anthracis induced by Anthrax Vaccine Adsorbed (AVA) among U.S. military personnel

PubMed Central

Singer, Darrell E.; Schneerson, Rachel; Bautista, Christian T.; Rubertone, Mark V.; Robbins, John B.; Taylor, David N.

2008-01-01

The seroconversion rates and geometric mean concentrations (GMC) of IgG anti-PA for stored sera from U.S. military personnel immunized 3, 4, and 6 times with the U.S. licensed anthrax vaccine adsorbed were studied. Anti-PA IgG concentrations were measured by ELISA. All 246 vaccinees had low but detectable pre-immunization anti-PA IgG (GMC 1.83μg/mL). Three doses elicited a GMC of 60 μg/mL and a seroconversion rate of 85.3%, four doses elicited a GMC of 157 μg/mL and 67.9% and the sixth of 277 μg/mL and 45.5% respectively. The forth dose elicited 100% seroconversion compared to the pre-immunization level. These results should facilitate comparison between different immunization schedules and new vaccines. PMID:18206278

Toxic adenoma of the thyroid gland and Wolff-Parkinson-White syndrome

PubMed Central

Naço, M; Çeliku, E; Llukaçaj, A; Shehaj, J; Kameniku, R

2009-01-01

We report the case of a 17-year-old girl with toxic adenoma scheduled for surgery right lobectomy and isthmectomy of thyroid gland. During the examination before surgery, patient was diagnosed for the first time as having with Wolff – Parkinson – White (WPW) syndrome. In the operating room, after the induction of anesthesia, the electrocardiogram showed wide QRS complex tachycardia with a rate of 180 beats/min, which was diagnosed as paroxysmal supraventricular tachycardia. The patient was treated immediately with antiarrhythmic drugs: adenosine iv three times (at doses of 6 mg, 12mg, 12mg bolus) and esmolol iv twice (at doses 28.5 mg). This approach resulted in disappearance of the delta wave and tachycardia for the whole surgery period. In this case report we discuss the role of induction of anesthesia and presence of toxic adenoma in a patient with WPW. PMID:19561784

Evaluation of a multidrug chemotherapy protocol with mitoxantrone based maintenance (CHOP-MA) for the treatment of canine lymphoma.

PubMed

Daters, A T; Mauldin, G E; Mauldin, G N; Brodsky, E M; Post, G S

2010-03-01

The purpose of this study was to evaluate the efficacy of adding mitoxantrone to a cyclophosphamide, doxorubicin, vincristine, L-asparaginase and prednisone containing protocol. Sixty-five dogs with multicentric lymphoma were evaluated for overall remission and survival times. Remission and survival time versus stage, substage, pretreatment hypercalcaemia and pretreatment steroid administration were also evaluated. Overall median remission for dogs with multicentric lymphoma was 302 days and overall median survival was 622 days. Of the dogs with multicentric lymphoma, 23 (35%) received all scheduled mitoxantrone doses. Only median survival versus substage was found to be significant (substage a median survival was 679 days and substage b median survival was 302 days, P = 0.025). Increasing the total combined dose of doxorubicin and mitoxantrone may improve remission times when compared with historical controls, and further studies are needed to determine how best to utilize mitoxantrone in multidrug chemotherapy protocols for canine multicentric lymphoma.

Lecture: fotemustine in brain tumors.

PubMed

Silvani, A; Gaviani, P; Lamperti, E; Botturi, A; Ferrari, D; Simonetti, G; Salmaggi, A

2011-11-01

Fotemustine (FTMS) is a third-generation nitrosourea, in preclinical studies, FTMS compared favorably with carmustine (BCNU) and lomustine (CCNU) against several human tumor cell lines. In conventional schedule, FTMS is administered at a dose of 100 mg/sqm/week for three consecutive weeks as induction (I) treatment, followed by 100 mg/sqm every three weeks, after a 5-week rest, as maintenance (M). Several Italian groups reported the results using FTMS in malignant glioma patients recurring after temozolomide standard treatment. In these papers, the 6-progression free survival are ranging from 20 to 52%. With the schedule (I + M) myelosuppression is observed in more than 30% of patients, and thrombocytopenia and leukopenia are more frequent and significant in Temozolomide pretreated patients. On the bases of the hematological toxicities several authors experimented new schedules of FTMS administrated at low doses. Recently, some authors reported the interesting results of a multicenter study on recurrent glioblastoma multiforme patients combining FTMS with new antiangiogentic agent bevacizumab.

Estimated UV doses to psoriasis patients during climate therapy at Gran Canaria in March 2006

NASA Astrophysics Data System (ADS)

Nilsen, L. T. N.; Søyland, E.; Krogstad, A. L.

2008-01-01

Psoriasis is a chronic inflammatory disease involving about 2-3% of the Norwegian population. Sun exposure has a positive effect on most psoriasis lesions, but ultraviolet (UV) radiation also causes a direct DNA damage in the skin cells and comprises a carcinogenic potential. UV exposure on the skin causes a local as well as a systemic immune suppressive effect, but the relation between sun exposure and these biological effects is not well known. In March 2006 a study was carried out to investigate possible therapeutic outcome mechanisms in 20 psoriasis patients receiving climate therapy at Gran Canaria. This paper presents estimates of their individual skin UV-doses based on UV measurements and the patients' diaries with information on time spent in the sun. On the first day of exposure the patients received on average 5.1 Standard Erythema Doses (SED: median=4.0 SED, range 2.6-10.3 SED) estimated to the skin. During the 15 days study they received 165.8 SED (range 104.3-210.1 SED). The reduction in PASI score was 72.8% on average, but there was no obvious relation between the improvement and the UV dose. The UV doses were higher than those found from climate therapy studies at other locations. It seems beneficial to use more strict exposure schedules that consider the available UV irradiance, depending on time of the day, time of the year and weather conditions.

Radiosurgery with flattening-filter-free techniques in the treatment of brain metastases : Plan comparison and early clinical evaluation.

PubMed

Rieber, J; Tonndorf-Martini, E; Schramm, O; Rhein, B; Stefanowicz, S; Kappes, J; Hoffmann, H; Lindel, K; Debus, J; Rieken, S

2016-11-01

Radiosurgical treatment of brain metastases is well established in daily clinical routine. Utilization of flattening-filter-free beams (FFF) may allow for more rapid delivery of treatment doses and improve clinical comfort. Hence, we compared plan quality and efficiency of radiosurgery in FFF mode to FF techniques. Between November 2014 and June 2015, 21 consecutive patients with 25 brain metastases were treated with stereotactic radiosurgery (SRS) in FFF mode. Brain metastases received dose-fractionation schedules of 1 × 20 Gy or 1 × 18 Gy, delivered to the conformally enclosing 80 % isodose. Three patients with critically localized or large (>3 cm) brain metastases were treated with 6 × 5 Gy. Plan quality and efficiency were evaluated by analyzing conformity, dose gradients, dose to healthy brain tissue, treatment delivery time, and number of monitor units. FFF plans were compared to those using the FF method, and early clinical outcome and toxicity were assessed. FFF mode resulted in significant reductions in beam-on time (p < 0.001) and mean brain dose (p = 0.001) relative to FF-mode comparison plans. Furthermore, significant improvements in dose gradients and sharper dose falloffs were found for SRS in FFF mode (-1.1 %, -29.6 %; p ≤ 0.003), but conformity was slightly superior in SRS in FF mode (-1.3 %; p = 0.001). With a median follow-up time of 5.1 months, 6‑month overall survival was 63.3 %. Local control was observed in 24 of 25 brain metastases (96 %). SRS in FFF mode is time efficient and provides similar plan quality with the opportunity of slightly reduced dose exposure to healthy brain tissue when compared to SRS in FF mode. Clinical outcomes appear promising and show only modest treatment-related toxicity.

[Immunisation schedule of the Spanish Association of Paediatrics: 2016 recommendations].

PubMed

Moreno-Pérez, D; Álvarez García, F J; Arístegui Fernández, J; Cilleruelo Ortega, M J; Corretger Rauet, J M; García Sánchez, N; Hernández Merino, A; Hernández-Sampelayo Matos, T; Merino Moína, M; Ortigosa del Castillo, L; Ruiz-Contreras, J

2016-01-01

The Advisory Committee on Vaccines of the Spanish Association of Paediatrics (CAV-AEP) annually publishes the immunisation schedule which, in our opinion, estimates optimal for children resident in Spain, considering available evidence on current vaccines. We acknowledge the effort of the Ministry of Health during the last year in order to optimize the funded unified Spanish vaccination schedule, with the recent inclusion of pneumococcal and varicella vaccination in early infancy. Regarding the funded vaccines included in the official unified immunization schedule, taking into account available data, CAV-AEP recommends 2+1 strategy (2, 4 and 12 months) with hexavalent (DTPa-IPV-Hib-HB) vaccines and 13-valent pneumococcal conjugate vaccine. Administration of Tdap and poliomyelitis booster dose at the age of 6 is recommended, as well as Tdap vaccine for adolescents and pregnant women, between 27-36 weeks gestation. The two-dose scheme should be used for MMR (12 months and 2-4 years) and varicella (15 months and 2-4 years). Coverage of human papillomavirus vaccination in girls aged 11-12 with a two dose scheme (0, 6 months) should be improved. Information for male adolescents about potential beneficial effects of this immunisation should be provided as well. Regarding recommended unfunded immunisations, CAV-AEP recommends the administration of meningococcal B vaccine, due to the current availability in Spanish communitary pharmacies, with a 3+1 scheme (3, 5, 7 and 13-15 months). CAV-AEP requests the incorporation of this vaccine in the funded unified schedule. Vaccination against rotavirus is recommended in all infants. Annual influenza immunisation and vaccination against hepatitis A are indicated in population groups considered at risk. Copyright © 2015 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.

Stimulant effects of adenosine antagonists on operant behavior: differential actions of selective A2A and A1 antagonists

PubMed Central

Randall, Patrick A.; Nunes, Eric J.; Janniere, Simone L.; Stopper, Colin M.; Farrar, Andrew M.; Sager, Thomas N.; Baqi, Younis; Hockemeyer, Jörg; Müller, Christa E.

2012-01-01

Rationale Adenosine A2A antagonists can reverse many of the behavioral effects of dopamine antagonists, including actions on instrumental behavior. However, little is known about the effects of selective adenosine antagonists on operant behavior when these drugs are administered alone. Objective The present studies were undertaken to investigate the potential for rate-dependent stimulant effects of both selective and nonselective adenosine antagonists. Methods Six drugs were tested: two nonselective adenosine antagonists (caffeine and theophylline), two adenosine A1 antagonists (DPCPX and CPT), and two adenosine A2A antagonists (istradefylline (KW6002) and MSX-3). Two schedules of reinforcement were employed; a fixed interval 240-s (FI-240 sec) schedule was used to generate low baseline rates of responding and a fixed ratio 20 (FR20) schedule generated high rates. Results Caffeine and theophylline produced rate-dependent effects on lever pressing, increasing responding on the FI-240 sec schedule but decreasing responding on the FR20 schedule. The A2A antagonists MSX-3 and istradefylline increased FI-240 sec lever pressing but did not suppress FR20 lever pressing in the dose range tested. In fact, there was a tendency for istradefylline to increase FR20 responding at a moderate dose. A1 antagonists failed to increase lever pressing rate, but DPCPX decreased FR20 responding at higher doses. Conclusions These results suggest that adenosine A2A antagonists enhance operant response rates, but A1 antagonists do not. The involvement of adenosine A2A receptors in regulating aspects of instrumental response output and behavioral activation may have implications for the treatment of effort-related psychiatric dysfunctions, such as psychomotor slowing and anergia in depression. PMID:21347642

The effects of the novel DA D3 receptor antagonist SR 21502 on cocaine reward, cocaine seeking and cocaine-induced locomotor activity in rats.

PubMed

Galaj, E; Ananthan, S; Saliba, M; Ranaldi, Robert

2014-02-01

There is a focus on developing D3 receptor antagonists as cocaine addiction treatments. We investigated the effects of a novel selective D3 receptor antagonist, SR 21502, on cocaine reward, cocaine-seeking, food reward, spontaneous locomotor activity and cocaine-induced locomotor activity in rats. In Experiment 1, rats were trained to self-administer cocaine under a progressive ratio (PR) schedule of reinforcement and tested with vehicle or one of three doses of SR 21502. In Experiment 2, animals were trained to self-administer cocaine under a fixed ratio schedule of reinforcement followed by extinction of the response. Then, animals were tested with vehicle or one of the SR 21502 doses on cue-induced reinstatement of responding. In Experiment 3, animals were trained to lever press for food under a PR schedule and tested with vehicle or one dose of the compound. In Experiments 4 and 5, in separate groups of animals, the vehicle and three doses of SR 21502 were tested on spontaneous or cocaine (10 mg/kg, IP)-induced locomotor activity, respectively. SR 21502 produced significant, dose-related (3.75, 7.5 and 15 mg/kg) reductions in breakpoint for cocaine self-administration, cue-induced reinstatement (3.75, 7.5 and 15 mg/kg) and cocaine-induced locomotor activity (3.75, 7.5 and 15 mg/kg) but failed to reduce food self-administration and spontaneous locomotor activity. SR 21502 decreases cocaine reward, cocaine-seeking and locomotor activity at doses that have no effect on food reward or spontaneous locomotor activity. These data suggest SR 21502 may selectively inhibit cocaine's rewarding, incentive motivational and stimulant effects.

A comparison of traditional vs. Canadian tailored prophylaxis dosing of prophylactic factor infusions in children with haemophilia A and B in a single hemophilia treatment center.

PubMed

Dodd, C; Watts, R G

2012-07-01

Prophylactic infusion of clotting factor concentrates is a developing standard of care for individuals with haemophilia. The ideal schedule and techniques of prophylactic infusions remain incompletely defined. Our aim was to determine the optimal techniques and schedules for factor prophylaxis in paediatric patients. A retrospective electronic medical record review of all children treated with prophylactic factor infusions in a single Haemophilia Treatment Center was conducted. Comparison of traditional vs. Canadian dosing regimens and primary vs. secondary prophylaxis was made. Failure of prophylaxis was defined as the first serious bleed. A total of 58 children were identified for review. Five cases were excluded (four due to high titre inhibitors and one due to repeated non-compliance), thus there were 53 total cases: 46 with severe haemophilia, 2 with moderate haemophilia, 5 with mild haemophilia, 44 with haemophilia A and 9 with haemophilia B; 32 Traditional dosing and 21 Canadian dosing regimens. Patients on primary prophylaxis had a decreased failure rate (25%) compared to children treated with secondary prophylaxis (67%) regardless of technique of prophylaxis. When compared to a 'Traditional' factor prophylaxis schedule, the 'Canadian' tailored prophylaxis protocol was comparable with the exception of a decreased use of implanted venous devices in the 'Canadian' group. Ongoing bleeding (primarily joint bleeds) occurs with all prophylactic regimens. The lowest incidence of treatment failure was noted in children who began primary prophylaxis at a young age and before initial joint bleeds. Primary prophylaxis is superior to secondary prophylaxis regardless of dosing regimen. Traditional and Canadian dosing regimens were equivalent in outcome when measured over several years of follow-up. © 2012 Blackwell Publishing Ltd.

The RTS,S/AS01 malaria vaccine in children 5 to 17 months of age at first vaccination.

PubMed

Vandoolaeghe, Pascale; Schuerman, Lode

2016-12-01

The RTS,S/AS01 malaria vaccine received a positive scientific opinion from the European Medicines Agency in July 2015. The World Health Organization recommended pilot implementation of the vaccine in children at least 5 months of age according to an initial 3-dose schedule given at least 1 month apart, and a 4th dose 15-18 months post-dose 3. Clinical trials and mathematical modeling demonstrated that the partial protection provided by RTS,S/AS01 against malaria has the potential to provide substantial public health benefit when used in parallel with other malaria interventions, especially in highly endemic regions. The highest impact was seen with 4 vaccine doses in children aged 5 months or older. The vaccine will be evaluated in real-life settings to further assess its impact on mortality, vaccine safety in the context of routine immunization, and programmatic feasibility of delivering a 4-dose vaccination schedule requiring new immunization contacts. If successful, this will pave the way for larger-scale implementation.

Dose-dense weekly chemotherapy in advanced ovarian cancer: An updated meta-analysis of randomized controlled trials.

PubMed

Marchetti, C; De Felice, F; Di Pinto, A; D'Oria, O; Aleksa, N; Musella, A; Palaia, I; Muzii, L; Tombolini, V; Benedetti Panici, P

2018-05-01

The use of dose-dense weekly chemotherapy in the management of advanced ovarian cancer (OC) remains controversial. The aim of this meta-analysis was to evaluate the efficacy of dose-dense regimen to improve clinical outcomes in OC patients with the inclusion of new trials. For this updated meta-analysis, PubMed Medline and Scopus databases and meeting proceedings were searched for eligible studies with the limitation of randomized controlled trials, comparing dose-dense chemotherapy versus standard treatment. Trials were grouped in two types of dose-dense chemotherapy: weekly dose-dense (both paclitaxel and carboplatin weekly administration) and semi-weekly dose-dense (weekly paclitaxel and three weekly carboplatin administration). Data were extracted independently and were analyzed using RevMan statistical software version 5.3 (http://www.cochrane.org). Primary end-point was progression-free survival (PFS). Four randomized controlled trials comprising 3698 patients were identified as eligible. Dose-dense chemotherapy had not a significant benefit on PFS (HR 0.92, 95% CI 0.81-1.04, p = 0.20). When the analysis was restricted to both weekly and semi-weekly dose-dense data, a no significant interaction between dose-dense and standard regimen was confirmed (HR 1.01, 95% CI 0.93-1.10 and HR 0.82, 95% CI 0.63-1.08, respectively). In the absence of PFS superiority of dose-dense schedule, three weekly schedule should remain the standard of care for advanced OC. Copyright © 2018 Elsevier B.V. All rights reserved.

Immunogenicity to poliovirus type 2 following two doses of fractional intradermal inactivated poliovirus vaccine: A novel dose sparing immunization schedule.

PubMed

Anand, Abhijeet; Molodecky, Natalie A; Pallansch, Mark A; Sutter, Roland W

2017-05-19

The polio eradication endgame strategic plan calls for the sequential removal of Sabin poliovirus serotypes from the trivalent oral poliovirus vaccine (tOPV), starting with type 2, and the introduction of ≥1 dose of inactivated poliovirus vaccine (IPV), to maintain an immunity base against poliovirus type 2. The global removal of oral poliovirus type 2 was successfully implemented in May 2016. However, IPV supply constraints has prevented introduction in 21 countries and led to complete stock-out in >20 countries. We conducted a literature review and contacted corresponding authors of recent studies with fractional-dose IPV (fIPV), one-fifth of intramuscular dose administered intradermally, to conduct additional type 2 immunogenicity analyses of two fIPV doses compared with one full-dose IPV. Four studies were identified that assessed immunogenicity of two fIPV doses compared to one full-dose IPV. Two fractional doses are more immunogenic than 1 full-dose, with type 2 seroconversion rates improving between absolute 19-42% (median: 37%, p<0.001) and relative increase of 53-125% (median: 82%), and antibody titer to type 2 increasing by 2-32-fold (median: 10-fold). Early age of administration and shorter intervals between doses were associated with lower immunogenicity. Overall, two fIPV doses are more immunogenic than a single full-dose, associated with significantly increased seroconversion rates and antibody titers. Two fIPV doses together use two-fifth of the vaccine compared to one full-dose IPV. In response to the current IPV shortage, a schedule of two fIPV doses at ages 6 and 14weekshas been endorsed by technical oversight committees and has been introduced in some affected countries. Copyright © 2017. Published by Elsevier Ltd.

Individual differences in the reinforcing and punishing effects of nicotine in rhesus monkeys.

PubMed

Koffarnus, Mikhail N; Winger, Gail

2015-07-01

The relatively weak reinforcing effects of nicotine in experimental studies have been attributed to possible aversive effects or the need to space nicotine administrations over time to expose reinforcing effects. This study was designed to determine if the response-maintaining effects of nicotine are increased when availability is spaced through time, and whether nicotine is an effective punisher of remifentanil-maintained responding. Compared to a cocaine reference dose, nicotine dose and timeout (TO) value were varied in eight rhesus monkeys responding for intravenous (i.v.) nicotine on varying fixed-ratio (FR) schedules of reinforcement.The aversive effects of nicotine were evaluated in four animals choosing between a standard dose of remifentanil alone or in combination with one of several doses of nicotine. In three of eight self-administration monkeys, 0.01 mg/kg/inj nicotine did not maintain responding at any FR value. In the other five animals, nicotine-maintained response rates increased with either FR or TO values to a certain point, and then slowed. Maximum nicotine-maintained response rates were much slower than those maintained by cocaine, and demand for nicotine was less than demand for cocaine. Nicotine was an effective punisher of remifentanil-maintained responding at doses ranging from 0.01 to 0.3 mg/kg/inj. Lower punishing dose seemed to be related to the absence of reinforcing effects within subject. There are an order of magnitude individual differences in sensitivity to both the reinforcing and punishing effects of nicotine, and this drug may be unique in being a weak positive reinforcer in small doses and aversive in large doses.

Repeated Post- or Presession Cocaine Administration: Roles of Dose and Fixed-Ratio Schedule

ERIC Educational Resources Information Center

Pinkston, Jonathan W.; Branch, Marc N.

2004-01-01

Effects of repeated administration of cocaine to animals behaving under operant contingencies have depended on when the drug is given. Moderate doses given presession have generally led to a decrease in the drug's effect, an outcome usually referred to as tolerance. When these same doses have been given after sessions, the usual result has been no…

Fentanyl, but not haloperidol, entrains persisting circadian activity episodes when administered at 24- and 31-hour intervals

PubMed Central

Leffel, Joseph K.; Kosobud, Ann E; Timberlake, William

2009-01-01

Administration of several drugs of abuse on a 24-hour schedule has been shown to entrain both pre-drug (anticipatory) and post-drug (evoked) circadian activity episodes that persist for several days when the drug is withheld. The present tested the entrainment effects of fentanyl, an opioid agonist with a noted abuse liability, and haloperidol, an antipsychotic dopamine antagonist without apparent abuse liability. Adult female Sprague-Dawley rats housed under constant light in cages with attached running wheels received repeated low, medium, or high doses of either fentanyl or haloperidol on a 24-hour administration schedule followed by a 31-hour schedule (Experiment 1) or solely on a 31-hour schedule (Experiment 2). The results showed that all three doses of fentanyl entrained both pre-drug and post-drug episodes of wheel running when administered every 24░hours, and the combined pre- and post-fentanyl activity episodes persist for at least 3 days when the drug is withheld during test days. On the 31-hour schedule, fentanyl produced an ``ensuing" activity episode approximately 24░hours post-administration, but failed to produce an anticipatory episode 29–31░hours post-administration. In contrast, haloperidol injections failed to produce both pre-drug episodes on the 24-hour schedule and circadian ensuing episodes on the 31-hour schedule, and post-haloperidol suppression of activity appeared to mask the freerunning activity rhythm. Taken together, these results provide additional evidence that drugs of abuse share a common ability to entrain circadian activity episodes. PMID:19595707

Naltrexone at low doses upregulates a unique gene expression not seen with normal doses: Implications for its use in cancer therapy.

PubMed

Liu, Wai M; Scott, Katherine A; Dennis, Jayne L; Kaminska, Elwira; Levett, Alan J; Dalgleish, Angus G

2016-08-01

It has been reported that lower doses of the opioid antagonist naltrexone are able to reduce tumour growth by interfering with cell signalling as well as by modifying the immune system. We have evaluated the gene expression profile of a cancer cell line after treatment with low-dose naltrexone (LDN), and assessed the effect that adapting treatment schedules with LDN may have on enhancing efficacy. LDN had a selective impact on genes involved with cell cycle regulation and immune modulation. Similarly, the pro-apoptotic genes BAD and BIK1 were increased only after LDN. Continuous treatment with LDN had little effect on growth in different cell lines; however, altering the treatment schedule to include a phase of culture in the absence of drug following an initial round of LDN treatment, resulted in enhanced cell killing. Furthermore, cells pre-treated with LDN were more sensitive to the cytotoxic effects of a number of common chemotherapy agents. For example, priming HCT116 with LDN before treatment with oxaliplatin significantly increased cell killing to 49±7.0 vs. 14±2.4% in cultures where priming was not used. Interestingly, priming with NTX before oxaliplatin resulted in just 32±1.8% cell killing. Our data support further the idea that LDN possesses anticancer activity, which can be improved by modifying the treatment schedule.

Discovery of cryptophycin-1 and BCN-183577: examples of strategies and problems in the detection of antitumor activity in mice.

PubMed

Corbett, T H; Valeriote, F A; Demchik, L; Lowichik, N; Polin, L; Panchapor, C; Pugh, S; White, K; Kushner, J; Rake, J; Wentland, M; Golakoti, T; Hetzel, C; Ogino, J; Patterson, G; Moore, R

1997-01-01

Historically, many new anticancer agents were first detected in a prescreen; usually consisting of a molecular/biochemical target or a cellular cytotoxicity assay. The agent then progressed to in vivo evaluation against transplanted human or mouse tumors. If the investigator had a large drug supply and ample resources, multiple tests were possible, with variations in tumor models, tumor and drug routes, dose-decrements, dose-schedules, number of groups, etc. However, in most large programs involving several hundred in vivo tests yearly, resource limitations and drug supply limitations have usually dictated a single trial. Under such restrictive conditions, we have implemented a flexible in vivo testing protocol. With this strategy, the tumor model is dictated by in vitro cellular sensitivity; drug route by water solubility (with water soluble agents injected intravenously); dosage decrement by drug supply, dose-schedule by toxicities encountered, etc. In this flexible design, many treatment parameters can be changed during the course of treatment (e.g., dose and schedule). The discovery of two active agents are presented (Cryptophycin-1, and Thioxanthone BCN 183577). Both were discovered by the intravenous route of administration. Both would have been missed if they were tested intraperitoneally, the usual drug route used in discovery protocols. It is also likely that they would have been missed with an easy to execute fixed protocol design, even if injected i.v.

Major bleeding risks of different low-molecular-weight heparin agents: a cohort study in 12 934 patients treated for acute venous thrombosis.

PubMed

van Rein, N; Biedermann, J S; van der Meer, F J M; Cannegieter, S C; Wiersma, N; Vermaas, H W; Reitsma, P H; Kruip, M J H A; Lijfering, W M

2017-07-01

Essentials Low-molecular-weight-heparins (LMWH) kinetics differ which may result in different bleeding risks. A cohort of 12 934 venous thrombosis patients on LMWH was followed until major bleeding. The absolute major bleeding risk was low among patients registered at the anticoagulation clinic. Once-daily dosing was associated with a lower bleeding risk as compared with twice-daily. Background Low-molecular-weight heparins (LMWHs) are considered members of a class of drugs with similar anticoagulant properties. However, pharmacodynamics and pharmacokinetics between LMWHs differ, which may result in different bleeding risks. As these agents are used by many patients, small differences may lead to a large effect on numbers of major bleeding events. Objectives To determine major bleeding risks for different LMWH agents and dosing schedules. Methods A cohort of acute venous thrombosis patients from four anticoagulation clinics who used an LMWH and a vitamin K antagonist were followed until they ceased LMWH treatment or until major bleeding. Exposures were classified according to different types of LMWHs and for b.i.d. and o.d. use. Cumulative incidences for major bleeding per 1000 patients and risk ratios were calculated and adjusted for study center. Results The study comprised 12 934 patients with a mean age of 59 years; 6218 (48%) were men. The cumulative incidence of major bleeding was 2.5 per 1000 patients (95% confidence interval [CI], 1.7-3.5). Enoxaparin b.i.d. or o.d. was associated with a relative bleeding risk of 1.7 (95% CI, 0.2-17.5) compared with nadroparin o.d. In addition, a nadroparin b.i.d. dosing schedule was associated with a 2.0-fold increased major bleeding risk (95% CI, 0.8-5.1) as compared with a nadroparin o.d. dosing schedule. Conclusions Absolute major bleeding rates were low for all LMWH agents and dosing schedules in a large unselected cohort. Nevertheless, twice-daily dosing with nadroparin appeared to be associated with an increased major bleeding risk as compared with once-daily dosing, as also suggested in a meta-analysis of controlled clinical trials. © 2017 International Society on Thrombosis and Haemostasis.

[Vaccination schedule of the Spanish Association of Pediatrics: recommendations 2005].

PubMed

2005-02-01

The Advisory Committee on Vaccines of the Spanish Association of Pediatrics provides information and comments on the new developments in vaccines that have taken place in 2004 and recommends a few modifications to the Immunization Schedule for 2005. Concerning the meningococcal C vaccine, no change is made to the possibility of administering two doses for the first vaccination with one of the available formulations. The existence of immunization failure in children who have received a first vaccination with three vaccine doses before the age of 12 months is discussed, and the health authorities will probably include a booster dose in the second year of life throughout 2005. The recommendations of the European Medicines Evaluation Agency (EMEA) on hexavalent vaccines continue to be valid and consequently the use of these vaccines should not be stopped. This year the need for adolescents to receive a booster dose of the pertussis vaccine, with administration of an acellular, low antigenic load preparation together with the adult diphtheria and tetanus vaccine is stressed.

Twice-daily dosing of temozolomide in combination with fotemustine for the treatment of patients with refractory glioblastoma.

PubMed

Santoni, M; Paccapelo, A; Burattini, L; Onofri, A; Cascinu, S

2012-03-01

Alkylating agents, such as temozolomide (TMZ) and fotemustine (FTM) are widely used in recurrent glioblastoma (GBM) regimes. Several strategies have been proposed to prevent resistance to these agents, by combining or sequencing them. We report the results of a pilot study of patients with refractory GBM receiving a regime of twice-daily dosing of temozolomide administered on day 1, (with an initial oral dose of 200 mg/m(2) and a second oral dose of 75 mg/m(2) 12 h later), followed by fotemustine in a single i.v. infusion at 75 mg/m(2) on day 2, repeated every four weeks. Enrolment was stopped at 15 patients due to lack of effectiveness of this schedule for patients with GBM. Toxicity was mild, with no grade 4 side effects reported. Results indicate that our temozolomide -FTM combined schedule is not effective, although well tolerated, in non responsive patients with GBM. Further strategies are required to improve the outcome of these patients.

Reinforcing effectiveness of nicotine in nonhuman primates: effects of nicotine dose and history of nicotine self-administration.

PubMed

Kohut, Stephen J; Bergman, Jack

2016-07-01

Despite the high prevalence of nicotine use in humans, robust nicotine self-administration has been difficult to demonstrate in laboratory animals. A parametric analysis of nicotine self-administration was conducted to study its reinforcing effects in nonhuman primates. Adult rhesus macaques (N = 6) self-administered intravenous (IV) nicotine (0.001-0.1 mg/kg) under a fixed-ratio (FR)1 schedule of reinforcement during daily 90-min sessions. Next, the demand function relating drug intake and response cost was determined by increasing the FR across sessions during the availability of each of several unit doses of nicotine (0.0032-0.032 mg/kg/inj). The reinforcing effects of 0.01 mg/kg/inj cocaine and 1 g banana-flavored food pellets were also determined under similar testing conditions. Finally, the nicotine demand function was re-determined after approximately 8 months of daily IV nicotine self-administration. IV nicotine self-administration followed an inverted U-shaped pattern, with the peak number of injections maintained by 0.0032 mg/kg/inj. Self-administration of each reinforcer (food pellets, IV cocaine, and IV nicotine) decreased as FR size increased. Application of the exponential model of demand showed that demand elasticity for nicotine was (1) dose-dependent and lowest for 0.0032 mg/kg/inj; (2) for 0.0032 mg/kg/inj, similar to that of food pellets and significantly higher than cocaine; and (3) decreased after 8 months of daily nicotine self-administration. These data show that, though high levels of nicotine self-administration can be achieved under simple FR schedules in nonhuman primates, its reinforcing effectiveness is dose-related but limited and may increase over time.

Uptake and timeliness of rotavirus vaccination in Norway: The first year post-introduction.

PubMed

Valcarcel Salamanca, Beatriz; Hagerup-Jenssen, Maria Elisabeth; Flem, Elmira

2016-09-07

To minimise vaccine-associated risk of intussusception following rotavirus vaccination, Norway adopted very strict age limits for initiating and completing the vaccine series at the time rotavirus vaccination was included in the national immunisation programme, October 2014. Although Norway has a high coverage for routine childhood vaccines, these stringent age limits could negatively affect rotavirus coverage. We documented the status and impact of rotavirus vaccination on other infant vaccines during the first year after its introduction. We used individual vaccination data from the national immunisation register to calculate coverage for rotavirus and other vaccines and examine adherence with the recommended schedules. We identified factors associated with completing the full rotavirus series by performing multiple logistic regression analyses. We also evaluated potential changes in uptake and timeliness of other routine vaccines after the introduction of rotavirus vaccine using the Kaplan-Meier method. The national coverage for rotavirus vaccine achieved a year after the introduction was 89% for one dose and 82% for two doses, respectively. Among fully rotavirus-vaccinated children, 98% received both doses within the upper age limit and 90% received both doses according to the recommended schedule. The child's age at the initiation of rotavirus series and being vaccinated with diphtheria, tetanus, pertussis, polio and Haemophilus influenzae type b (DTaP/IPV/Hib) and pneumococcal vaccines were the strongest predictors of completing the full rotavirus series. No major changes in uptake and timeliness of other paediatric vaccines were observed after introduction of rotavirus vaccine. Norway achieved a high national coverage and excellent adherence with the strict age limits for rotavirus vaccine administration during the first year of introduction, indicating robustness of the national immunisation programme. Rotavirus vaccination did not impact coverage or timeliness of other infant vaccines. Copyright © 2016. Published by Elsevier Ltd.

Assessment of normal tissue complications following prostate cancer irradiation: Comparison of radiation treatment modalities using NTCP models

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

Takam, Rungdham; Bezak, Eva; Yeoh, Eric E.

2010-09-15

Purpose: Normal tissue complication probability (NTCP) of the rectum, bladder, urethra, and femoral heads following several techniques for radiation treatment of prostate cancer were evaluated applying the relative seriality and Lyman models. Methods: Model parameters from literature were used in this evaluation. The treatment techniques included external (standard fractionated, hypofractionated, and dose-escalated) three-dimensional conformal radiotherapy (3D-CRT), low-dose-rate (LDR) brachytherapy (I-125 seeds), and high-dose-rate (HDR) brachytherapy (Ir-192 source). Dose-volume histograms (DVHs) of the rectum, bladder, and urethra retrieved from corresponding treatment planning systems were converted to biological effective dose-based and equivalent dose-based DVHs, respectively, in order to account for differences inmore » radiation treatment modality and fractionation schedule. Results: Results indicated that with hypofractionated 3D-CRT (20 fractions of 2.75 Gy/fraction delivered five times/week to total dose of 55 Gy), NTCP of the rectum, bladder, and urethra were less than those for standard fractionated 3D-CRT using a four-field technique (32 fractions of 2 Gy/fraction delivered five times/week to total dose of 64 Gy) and dose-escalated 3D-CRT. Rectal and bladder NTCPs (5.2% and 6.6%, respectively) following the dose-escalated four-field 3D-CRT (2 Gy/fraction to total dose of 74 Gy) were the highest among analyzed treatment techniques. The average NTCP for the rectum and urethra were 0.6% and 24.7% for LDR-BT and 0.5% and 11.2% for HDR-BT. Conclusions: Although brachytherapy techniques resulted in delivering larger equivalent doses to normal tissues, the corresponding NTCPs were lower than those of external beam techniques other than the urethra because of much smaller volumes irradiated to higher doses. Among analyzed normal tissues, the femoral heads were found to have the lowest probability of complications as most of their volume was irradiated to lower equivalent doses compared to other tissues.« less

Prediction of Normal Organ Absorbed Doses for [177Lu]Lu-PSMA-617 Using [44Sc]Sc-PSMA-617 Pharmacokinetics in Patients With Metastatic Castration Resistant Prostate Carcinoma.

PubMed

Khawar, Ambreen; Eppard, Elisabeth; Sinnes, Jean Phlippe; Roesch, Frank; Ahmadzadehfar, Hojjat; Kürpig, Stefan; Meisenheimer, Michael; Gaertner, Florian C; Essler, Markus; Bundschuh, Ralph A

2018-04-23

In vivo pharmacokinetic analysis of [Sc]Sc-PSMA-617 was used to determine the normal organ-absorbed doses that may result from therapeutic activity of [Lu]Lu-PSMA-617 and to predict the maximum permissible activity of [Lu]Lu-PSMA-617 for patients with metastatic castration-resistant prostate carcinoma. Pharmacokinetics of [Sc]Sc-PSMA-617 was evaluated in 5 patients with metastatic castration-resistant prostate carcinoma using dynamic PET/CT, followed by 3 static PET/CT acquisitions and blood sample collection over 19.5 hours, as well as urine sample collection at 2 time points. Total activity measured in source organs by PET imaging, as well as counts per milliliter measured in blood and urine samples, was decay corrected back to the time of injection using the half-life of Sc. Afterward, forward decay correction using the half-life of Lu was performed, extrapolating the pharmacokinetics of [Sc]Sc-PSMA-617 to that of [Lu]Lu-PSMA-617. Source organs residence times and organ-absorbed doses for [Lu]Lu-PSMA-617 were calculated using OLINDA/EXM software. Bone marrow self-dose was determined with indirect blood-based method, and urinary bladder contents residence time was estimated by trapezoidal approximation. The maximum permissible activity of [Lu]Lu-PSMA-617 was calculated for each patient considering external beam radiotherapy toxicity limits for radiation absorbed doses to kidneys, bone marrow, salivary glands, and whole body. The predicted mean organ-absorbed doses were highest in the kidneys (0.44 mSv/MBq), followed by the salivary glands (0.23 mSv/MBq). The maximum permissible activity was highly variable among patients; limited by whole body-absorbed dose (1 patient), marrow-absorbed dose (1 patient), and kidney-absorbed dose (3 patients). [Sc]Sc-PSMA-617 PET/CT imaging is feasible and allows theoretical extrapolation of the pharmacokinetics of [Sc]Sc-PSMA-617 to that of [Lu]Lu-PSMA-617, with the intent of predicting normal organ-absorbed doses and maximum permissible activity in patients scheduled for therapy with [Lu]Lu-PSMA-617.

Retrospective Mining of Toxicology Data to Discover ...

EPA Pesticide Factsheets

In vivo toxicology data is subject to multiple sources of uncertainty: observer severity bias (a pathologist may record only more severe effects and ignore less severe ones); dose spacing issues (this can lead to missing data, e.g. if a severe effect has a less severe precursor, but both occur at the same tested dose); imperfect control of key independent variables (in databases, one can rarely control key input variables such as animal strain or dosing schedules); effect description heterogeneity (terminology changes over time which can lead to information loss); statistical issues (too few chemicals with a given phenotype, or too few animals in dose groups). These issues directly contribute to uncertainties in models built from the data. We are investigating the use of collections of endpoints (toxicity syndromes) to address these issues. These are identical in concept to medical syndromes which allow a physician to diagnose an underlying disease more accurately than can be done when relying on examination of one symptom at a time. Our test case is anemia, for several reasons: most of the phenotypes (e.g. cell counts) are quantitative; related effects are measured in an automated way; anemia is relatively common, at least at high doses (~30% of chemicals in our database show significant drops in red cell count); the causes of anemia are well understood; and, there is a standard clinical decision tree to classify anemia. Using a database of 658 chemicals, we ha

Impact of the addition of new vaccines in the early childhood schedule on vaccine coverage by 24 months of age from 2006 to 2016 in Quebec, Canada.

PubMed

Kiely, Marilou; Boulianne, Nicole; Talbot, Denis; Ouakki, Manale; Guay, Maryse; Landry, Monique; Zafack, Joseline; Sauvageau, Chantal; De Serres, Gaston

2018-07-05

Between 2004 and 2016, in the province of Quebec (Canada), 4 new antigens were added in the early childhood vaccine schedule from birth to 18 months, increasing the number of injections or doses needed from 7 to 12. These additions may have decreased the proportion of children who had received all recommended vaccines. To assess the impact of the introduction of new vaccines to the childhood schedule on the 24-month vaccine coverage from 2006 to 2016 and identify factors associated with incomplete vaccination status by 24 months of age. We used the data from six cross-sectional vaccine coverage surveys conducted every two years which included a total of 3515 children aged 2 years old and randomly selected from the Quebec public health insurance database. Factors associated with an incomplete vaccine status by 24 months were identified with multivariable logistic regression. Despite the addition of 4 new vaccine antigens since 2004, the vaccine coverage remained high from 2006 (82.4%) through 2016 (88.3%) for vaccines present in the schedule since 2006. In 2016, vaccine coverage was 78.2% for all vaccines included in the schedule. The vaccine coverage of new vaccines increases rapidly within 2 years of their introduction. For both new and older vaccines, incomplete vaccine status by 24 months of age is associated with a delay of 30 days or more in receiving the vaccines scheduled at 2 and 12 months of age. Increasing to 12 the number of doses in the recommended schedule has slightly reduced the vaccine coverage by 24 months of age and the vaccine coverage of vaccines already in the schedule remained stable over the years. Future additions to the vaccine schedule may not be similarly accepted by the population and this will require continuing the monitoring of vaccine coverage. Copyright © 2018 Elsevier Ltd. All rights reserved.

Efficacy, immunogenicity, and safety of two doses of a tetravalent rotavirus vaccine RRV-TV in Ghana with the first dose administered during the neonatal period.

PubMed

Armah, George E; Kapikian, Albert Z; Vesikari, Timo; Cunliffe, Nigel; Jacobson, Robert M; Burlington, D Bruce; Ruiz, Leonard P

2013-08-01

Oral rhesus/rhesus-human reassortant rotavirus tetravalent vaccine (RRV-TV) was licensed in 1998 but withdrawn in 1999 due to a rare association with intussusception, which occurred disproportionately in infants receiving their first dose at ≥90 days of age. This study examined RRV-TV for the prevention of rotavirus gastroenteritis (RV-GE) in Ghana, West Africa, with infants receiving the first dose during the neonatal period and the second before 60 days of age. In a double-blinded, randomized, placebo-controlled trial in Navrongo, Ghana, we recruited neonates to receive 2 doses of RRV-TV or placebo and followed them to age 12 months. In the intention-to-treat population of 998 infants, we measured a vaccine efficacy of 63.1% against RV-GE of any severity associated with any of the 4 serotypes represented in the vaccine and 60.7% against RV-GE associated with any rotavirus serotype. RRV-TV in a 2-dose schedule with the first dose during the neonatal period is efficacious in preventing RV-GE in rural Ghana. Neonatal dosing results in early protection and may be the optimum schedule to avoid or significantly reduce intussusception, now reported to be associated in international settings with the 2 most widely marketed, licensed, live virus, oral rotavirus vaccines.

Influence of fatigue time and level on increases in postural sway.

PubMed

Pline, Kevin M; Madigan, Michael L; Nussbaum, Maury A

2006-12-15

The purpose of this study was to investigate the influence of fatigue time and fatigue level on the increases in postural sway during quiet standing. Centre of pressure-based measures of postural sway were collected both before and after fatiguing participants using three different fatigue levels and two different fatigue times. Results showed increasing fatigue time increased sway velocity and sway area, and increasing fatigue level increased sway velocity. Fatigue time effects are important to consider when applying laboratory-based findings to the field given that the fatigue time can differ substantially between the two. Fatigue level effects imply a dose - response relationship between localized muscle fatigue and risk of falling that can have important implications in work/rest cycle scheduling for occupations at risk of injurious falls.

Daytime Sleepiness Increases With Age in Early Adolescence: A Sleep Restriction Dose-Response Study.

PubMed

Campbell, Ian G; Burright, Christopher S; Kraus, Amanda M; Grimm, Kevin J; Feinberg, Irwin

2017-05-01

Daytime sleepiness increases across adolescence. This increase is commonly attributed to insufficient sleep durations resulting from increasingly limited time in bed. We tested the effects of 3 sleep schedules on daytime sleepiness and whether these effects changed with age in early adolescence. In 77 children ranging in age from 9.9 to 14 years, objective (multiple sleep latency test [MSLT]) and subjective (Karolinska sleepiness scale [KSS]) sleepiness was measured following 4 consecutive nights of either 7, 8.5, or 10 hours in bed. All participants completed all 3 sleep schedules. The order in which they completed the schedules was not randomized but was accounted for in all statistical analyses. Time in bed restriction decreased sleep duration and increased objective and subjective daytime sleepiness. Although the sleep durations did not change with age, the likelihood of falling asleep during the MSLT increased with age. Nevertheless, sleep restriction produced a greater increase in MSLT-measured sleepiness in younger participants. Subjective sleepiness measured with the KSS increased with shorter sleep duration, but this effect did not change with age. Increasing objective daytime sleepiness in early adolescence cannot simply be attributed to reduced sleep due to restricted sleep schedules. We propose that some of the increased daytime sleepiness of adolescents is a consequence of adolescent brain reorganization driven by synaptic pruning which decreases the intensity of waking brain activity. © Sleep Research Society 2017. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.

The seroepidemiology of pertussis in Australia during an epidemic period.

PubMed

Cagney, M; MacIntyre, C R; McIntyre, P; Puech, M; Giammanco, A

2006-12-01

Studying the epidemiology of pertussis and impact of differing vaccine schedules is difficult because of differing methods of case ascertainment. The advent of internationally standardized serological diagnosis for recent infection has allowed comparison of age-specific pertussis infection among European countries and was applied in Australia at the time of a major national epidemic. In 1997 and 1998, a nationally representative serum bank using residual sera from diagnostic laboratories was established. Measurement of pertussis toxin (PT) IgG level was conducted by a reference laboratory using an enzyme-linked immunosorbent assay standardized for a number of European countries. A titre of 125 EU/ml was interpreted as indicative of recent pertussis infection. The serological data were correlated with age, gender, region and disease epidemiology in Australia. The highest prevalence of recent pertussis infection was in the 5-9 years age group, and the lowest in 1-4 and 25-64 years age groups. In the 5-14 years age group, 29.7% (5-9 years) and 14.6% (10-14 years) of the sample had serological evidence of recent infection, correlating with the pattern of epidemic notifications. The 15- to 24-year-olds had similar high titres but the same notification rate as 25- to 44-year-olds, suggesting ascertainment bias may result in under-notification in the former age group. The prevalence of high titres observed was up to 20-fold higher than some European countries during a similar time period. Although vaccination has reduced the transmission of pertussis in the youngest and most vulnerable age group, pertussis is still endemic in Australia, particularly in older children and the elderly. The Australian vaccination schedule has been changed in an attempt to address this problem, by spacing doses more widely, with the fifth dose at 15-17 years of age. Seroepidemiology for pertussis offers the potential to compare patterns of pertussis between countries and examine the impact of vaccine schedule changes independent of notification and diagnostic bias.

Durable antibody responses following one dose of the bivalent human papillomavirus L1 virus-like particle vaccine in the Costa Rica Vaccine Trial.

PubMed

Safaeian, Mahboobeh; Porras, Carolina; Pan, Yuanji; Kreimer, Aimee; Schiller, John T; Gonzalez, Paula; Lowy, Douglas R; Wacholder, Sholom; Schiffman, Mark; Rodriguez, Ana C; Herrero, Rolando; Kemp, Troy; Shelton, Gloriana; Quint, Wim; van Doorn, Leen-Jan; Hildesheim, Allan; Pinto, Ligia A

2013-11-01

The Costa Rica HPV16/18 Vaccine Trial (CVT) showed that four-year vaccine efficacy against 12-month HPV16/18 persistent infection was similarly high among women who received one, two, or the recommended three doses of the bivalent HPV16/18 L1 virus-like particle (VLP) vaccine. Live-attenuated viral vaccines, but not simple-subunit vaccines, usually induce durable lifelong antibody responses after a single dose. It is unclear whether noninfectious VLP vaccines behave more like live-virus or simple-subunit vaccines in this regard. To explore the likelihood that efficacy will persist longer term, we investigated the magnitude and durability of antibodies to this vaccine by measuring HPV16- and HPV18-specific antibodies by VLP-ELISA using serum from enrollment, vaccination, and annual visits through four years in four vaccinated groups; one-dose (n = 78), two-doses separated by one month (n = 140), two doses separated by six months (n = 52), and three scheduled doses (n = 120, randomly selected). We also tested enrollment sera from n = 113 HPV16- or HPV18 L1-seropositive women prevaccination, presumably from natural infection. At four years, 100% of women in all groups remained HPV16/18 seropositive; both HPV16/18 geometric mean titers (GMT) among the extended two-dose group were non-inferior to the three-dose group, and ELISA titers were highly correlated with neutralization titers in all groups. Compared with the natural infection group, HPV16/18 GMTs were, respectively, at least 24 and 14 times higher among the two-dose and 9 and 5 times higher among one-dose vaccinees. Antibody levels following one-dose remained stable from month 6 through month 48. Results raise the possibility that even a single dose of HPV VLPs will induce long-term protection. ©2013 AACR.

Radiobiology of hypofractionated stereotactic radiotherapy: what are the optimal fractionation schedules?

PubMed Central

Shibamoto, Yuta; Miyakawa, Akifumi; Otsuka, Shinya; Iwata, Hiromitsu

2016-01-01

In hypofractionated stereotactic radiotherapy (SRT), high doses per fraction are usually used and the dose delivery pattern is different from that of conventional radiation. The daily dose is usually given intermittently over a longer time compared with conventional radiotherapy. During prolonged radiation delivery, sublethal damage repair takes place, leading to the decreased effect of radiation. In in vivo tumors, however, this decrease in effect may be counterbalanced by rapid reoxygenation. Another issue related to hypofractionated SRT is the mathematical model for dose evaluation and conversion. The linear–quadratic (LQ) model and biologically effective dose (BED) have been suggested to be incorrect when used for hypofractionation. The LQ model overestimates the effect of high fractional doses of radiation. BED is particularly incorrect when used for tumor responses in vivo, since it does not take reoxygenation into account. Correction of the errors, estimated at 5–20%, associated with the use of BED is necessary when it is used for SRT. High fractional doses have been reported to exhibit effects against tumor vasculature and enhance host immunity, leading to increased antitumor effects. This may be an interesting topic that should be further investigated. Radioresistance of hypoxic tumor cells is more problematic in hypofractionated SRT, so trials of hypoxia-targeted agents are encouraged in the future. In this review, the radiobiological characteristics of hypofractionated SRT are summarized, and based on the considerations, we would like to recommend 60 Gy in eight fractions delivered three times a week for lung tumors larger than 2 cm in diameter. PMID:27006380

Morphine Tolerance as a Function of Ratio Schedule: Response Requirement or Unit Price?

ERIC Educational Resources Information Center

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

2005-01-01

Key pecking by 3 pigeons was maintained by a multiple fixed-ratio 10, fixed-ratio 30, fixed-ratio 90 schedule of food presentation. Components differed with respect to amount of reinforcement, such that the unit price was 10 responses per 1-s access to food. Acute administration of morphine, "l"-methadone, and cocaine dose-dependently decreased…

Clinical trial tests new schedule of radiation therapy for recurring prostate cancer | Center for Cancer Research

Cancer.gov

In order to find the most compressed schedule of radiation that prostate cancer patients can tolerate without strong side effects, Deborah Citrin, M.D., of the Radiation Oncology Branch wants to see if giving higher doses of radiation over 2–4 weeks can be as effective at killing cancer cells. Read more… 

Introduction of sequential inactivated polio vaccine-oral polio vaccine schedule for routine infant immunization in Brazil's National Immunization Program.

PubMed

Domingues, Carla Magda Allan S; de Fátima Pereira, Sirlene; Cunha Marreiros, Ana Carolina; Menezes, Nair; Flannery, Brendan

2014-11-01

In August 2012, the Brazilian Ministry of Health introduced inactivated polio vaccine (IPV) as part of sequential polio vaccination schedule for all infants beginning their primary vaccination series. The revised childhood immunization schedule included 2 doses of IPV at 2 and 4 months of age followed by 2 doses of oral polio vaccine (OPV) at 6 and 15 months of age. One annual national polio immunization day was maintained to provide OPV to all children aged 6 to 59 months. The decision to introduce IPV was based on preventing rare cases of vaccine-associated paralytic polio, financially sustaining IPV introduction, ensuring equitable access to IPV, and preparing for future OPV cessation following global eradication. Introducing IPV during a national multivaccination campaign led to rapid uptake, despite challenges with local vaccine supply due to high wastage rates. Continuous monitoring is required to achieve high coverage with the sequential polio vaccine schedule. Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.

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

SU-E-T-776: Use of Quality Metrics for a New Hypo-Fractionated Pre-Surgical Mesothelioma Protocol

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

Richardson, S; Mehta, V

Purpose: The “SMART” (Surgery for Mesothelioma After Radiation Therapy) approach involves hypo-fractionated radiotherapy of the lung pleura to 25Gy over 5 days followed by surgical resection within 7. Early clinical results suggest that this approach is very promising, but also logistically challenging due to the multidisciplinary involvement. Due to the compressed schedule, high dose, and shortened planning time, the delivery of the planned doses were monitored for safety with quality metric software. Methods: Hypo-fractionated IMRT treatment plans were developed for all patients and exported to Quality Reports™ software. Plan quality metrics or PQMs™ were created to calculate an objective scoringmore » function for each plan. This allows for an objective assessment of the quality of the plan and a benchmark for plan improvement for subsequent patients. The priorities of various components were incorporated based on similar hypo-fractionated protocols such as lung SBRT treatments. Results: Five patients have been treated at our institution using this approach. The plans were developed, QA performed, and ready within 5 days of simulation. Plan Quality metrics utilized in scoring included doses to OAR and target coverage. All patients tolerated treatment well and proceeded to surgery as scheduled. Reported toxicity included grade 1 nausea (n=1), grade 1 esophagitis (n=1), grade 2 fatigue (n=3). One patient had recurrent fluid accumulation following surgery. No patients experienced any pulmonary toxicity prior to surgery. Conclusion: An accelerated course of pre-operative high dose radiation for mesothelioma is an innovative and promising new protocol. Without historical data, one must proceed cautiously and monitor the data carefully. The development of quality metrics and scoring functions for these treatments allows us to benchmark our plans and monitor improvement. If subsequent toxicities occur, these will be easy to investigate and incorporate into the metrics. This will improve the safe delivery of large doses for these patients.« less

Percutaneous Bone Biopsies: Comparison between Flat-Panel Cone-Beam CT and CT-Scan Guidance

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

Tselikas, Lambros, E-mail: lambros.tselikas@gmail.com; Joskin, Julien, E-mail: j.joskin@gmail.com; Roquet, Florian, E-mail: florianroquet@hotmail.com

2015-02-15

PurposeThis study was designed to compare the accuracy of targeting and the radiation dose of bone biopsies performed either under fluoroscopic guidance using a cone-beam CT with real-time 3D image fusion software (FP-CBCT-guidance) or under conventional computed tomography guidance (CT-guidance).MethodsSixty-eight consecutive patients with a bone lesion were prospectively included. The bone biopsies were scheduled under FP-CBCT-guidance or under CT-guidance according to operating room availability. Thirty-four patients underwent a bone biopsy under FP-CBCT and 34 under CT-guidance. We prospectively compared the two guidance modalities for their technical success, accuracy, puncture time, and pathological success rate. Patient and physician radiation doses also were compared.ResultsAll biopsiesmore » were technically successful, with both guidance modalities. Accuracy was significantly better using FP-CBCT-guidance (3 and 5 mm respectively: p = 0.003). There was no significant difference in puncture time (32 and 31 min respectively, p = 0.51) nor in pathological results (88 and 88 % of pathological success respectively, p = 1). Patient radiation doses were significantly lower with FP-CBCT (45 vs. 136 mSv, p < 0.0001). The percentage of operators who received a dose higher than 0.001 mSv (dosimeter detection dose threshold) was lower with FP-CBCT than CT-guidance (27 vs. 59 %, p = 0.01).ConclusionsFP-CBCT-guidance for bone biopsy is accurate and reduces patient and operator radiation doses compared with CT-guidance.« less

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

Kareva, Irina; Waxman, David J.; Klement, Giannoula Lakka

The administration of chemotherapy at reduced doses given at regular, frequent time intervals, termed ‘metronomic’ chemotherapy, presents an alternative to standard maximal tolerated dose (MTD) chemotherapy. The primary target of metronomic chemotherapy was originally identified as endothelial cells supporting the tumor vasculature, and not the tumor cells themselves, consistent with the emerging concept of cancer as a systemic disease involving both tumor cells and their microenvironment. While anti-angiogenesis is an important mechanism of action of metronomic chemotherapy, other mechanisms, including activation of anti-tumor immunity and a decrease in acquired therapeutic resistance, have also been identified. In this paper, we presentmore » evidence supporting a mechanistic explanation for the improved activity of cancer chemotherapy when administered on a metronomic, rather than an MTD schedule and discuss the implications of these findings for further translation into the clinic.« less

Towards real-time photon Monte Carlo dose calculation in the cloud

NASA Astrophysics Data System (ADS)

Ziegenhein, Peter; Kozin, Igor N.; Kamerling, Cornelis Ph; Oelfke, Uwe

2017-06-01

Near real-time application of Monte Carlo (MC) dose calculation in clinic and research is hindered by the long computational runtimes of established software. Currently, fast MC software solutions are available utilising accelerators such as graphical processing units (GPUs) or clusters based on central processing units (CPUs). Both platforms are expensive in terms of purchase costs and maintenance and, in case of the GPU, provide only limited scalability. In this work we propose a cloud-based MC solution, which offers high scalability of accurate photon dose calculations. The MC simulations run on a private virtual supercomputer that is formed in the cloud. Computational resources can be provisioned dynamically at low cost without upfront investment in expensive hardware. A client-server software solution has been developed which controls the simulations and transports data to and from the cloud efficiently and securely. The client application integrates seamlessly into a treatment planning system. It runs the MC simulation workflow automatically and securely exchanges simulation data with the server side application that controls the virtual supercomputer. Advanced encryption standards were used to add an additional security layer, which encrypts and decrypts patient data on-the-fly at the processor register level. We could show that our cloud-based MC framework enables near real-time dose computation. It delivers excellent linear scaling for high-resolution datasets with absolute runtimes of 1.1 seconds to 10.9 seconds for simulating a clinical prostate and liver case up to 1% statistical uncertainty. The computation runtimes include the transportation of data to and from the cloud as well as process scheduling and synchronisation overhead. Cloud-based MC simulations offer a fast, affordable and easily accessible alternative for near real-time accurate dose calculations to currently used GPU or cluster solutions.

Towards real-time photon Monte Carlo dose calculation in the cloud.

PubMed

Ziegenhein, Peter; Kozin, Igor N; Kamerling, Cornelis Ph; Oelfke, Uwe

2017-06-07

Near real-time application of Monte Carlo (MC) dose calculation in clinic and research is hindered by the long computational runtimes of established software. Currently, fast MC software solutions are available utilising accelerators such as graphical processing units (GPUs) or clusters based on central processing units (CPUs). Both platforms are expensive in terms of purchase costs and maintenance and, in case of the GPU, provide only limited scalability. In this work we propose a cloud-based MC solution, which offers high scalability of accurate photon dose calculations. The MC simulations run on a private virtual supercomputer that is formed in the cloud. Computational resources can be provisioned dynamically at low cost without upfront investment in expensive hardware. A client-server software solution has been developed which controls the simulations and transports data to and from the cloud efficiently and securely. The client application integrates seamlessly into a treatment planning system. It runs the MC simulation workflow automatically and securely exchanges simulation data with the server side application that controls the virtual supercomputer. Advanced encryption standards were used to add an additional security layer, which encrypts and decrypts patient data on-the-fly at the processor register level. We could show that our cloud-based MC framework enables near real-time dose computation. It delivers excellent linear scaling for high-resolution datasets with absolute runtimes of 1.1 seconds to 10.9 seconds for simulating a clinical prostate and liver case up to 1% statistical uncertainty. The computation runtimes include the transportation of data to and from the cloud as well as process scheduling and synchronisation overhead. Cloud-based MC simulations offer a fast, affordable and easily accessible alternative for near real-time accurate dose calculations to currently used GPU or cluster solutions.

Pharmacokinetic/pharmacodynamic modeling and simulation of neutropenia during phase I development of liposome-entrapped paclitaxel.

PubMed

Fetterly, Gerald J; Grasela, Thaddeus H; Sherman, Jeffrey W; Dul, Jeanne L; Grahn, Amy; Lecomte, Diane; Fiedler-Kelly, Jill; Damjanov, Nevena; Fishman, Mayer; Kane, Michael P; Rubin, Eric H; Tan, Antoinette R

2008-09-15

To evaluate the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of liposome-entrapped paclitaxel easy-to-use (LEP-ETU) and to characterize the relationship between LEP-ETU concentrations and the time course of neutropenia in cancer patients. LEP-ETU was administered to 88 patients and 63 were evaluable for pharmacokinetic/pharmacodynamic (PK/PD) analysis following 1.5- and 3-h infusions every 3 weeks (q3w; dose range, 135-375 mg/m(2)). MTD was identified using a 3 + 3, up-and-down dose-finding algorithm. PK/PD modeling was done to describe the temporal relationship between paclitaxel concentrations and neutrophil count. Simulations assessed the influence of dose and schedule on neutropenia severity to help guide dose selection. The MTD of LEP-ETU was identified as 325 mg/m(2). DLTs occurring at 375 mg/m(2) consisted of febrile neutropenia and neuropathy. The C(max) and area under the plasma concentration-time curve of LEP-ETU were less than proportional with increasing dose. The PK/PD model showed that LEP-ETU inhibition of neutrophil proliferation was 9.1% per 10 mug/mL of total paclitaxel concentration. The incidence of grade 4 neutropenia increased from 33% to 42% across the dose range of 275 to 325 mg/m(2) q3w. For a dose of 110 mg/m(2) given weekly, grade 4 neutropenia was estimated to be 16% compared with 42% for the same total dose administered q3w. LEP-ETU can be administered safely at higher doses than Taxol. Modeling and simulation studies predict that 325 mg/m(2) LEP-ETU q3w provides acceptable neutropenic events relative to those observed at 175 mg/m(2) Taxol q3w. A 275 mg/m(2) dose may offer an improved therapeutic index.

Phase 2 trial of temozolomide using protracted low-dose and whole-brain radiotherapy for nonsmall cell lung cancer and breast cancer patients with brain metastases.

PubMed

Addeo, Raffaele; De Rosa, Carmine; Faiola, Vincenzo; Leo, Luigi; Cennamo, Gregorio; Montella, Liliana; Guarrasi, Rosario; Vincenzi, Bruno; Caraglia, Michele; Del Prete, Salvatore

2008-11-01

Temozolomide (TMZ), an oral methylating imidazotetrazinone, has antitumor activity against gliomas, malignant melanomas, and brain metastasis and is presently administered as a 5-day oral schedule every 4 weeks. A single-institution phase 2 clinical trial was conducted to determine the efficacy and the safety profile of a new regimen based on a dose-intensified, protracted course of TMZ after whole-brain radiotherapy (WBRT). Patients were eligible if they had at least 1 bidimensionally measurable brain metastasis from breast cancer and nonsmall cell lung cancer (NSCLC). Twenty-seven patients were treated with 30 grays (Gy) of WBRT with concomitant TMZ (75 mg/m(2)/day) for 10 days, and subsequent TMZ at a dose of 75 mg/m(2) per day for 21 days every 4 weeks, for up to 12 cycles. Two complete responses (7.4%) and 11 partial responses (40.7%) were achieved. The schedule appeared to be well tolerated, with grade 3 toxicity (graded according to National Cancer Institute Common Toxicity Criteria) observed in only 2 patients. The overall median survival was 8.8 months and the median progression-free survival was 6 months. The concomitant use of WBRT and protracted low-dose TMZ appears to be an active, well-tolerated regimen. The observed antitumor activity suggests the need for further investigation of this schedule in combination with other anticancer agents for the concomitant treatment of brain metastases and primary cancers.

Interaction between behavioral and pharmacological treatment strategies to decrease cocaine choice in rhesus monkeys.

PubMed

Banks, Matthew L; Blough, Bruce E; Negus, S Stevens

2013-02-01

Behavioral and pharmacotherapeutic approaches constitute two prominent strategies for treating cocaine dependence. This study investigated interactions between behavioral and pharmacological strategies in a preclinical model of cocaine vs food choice. Six rhesus monkeys, implanted with a chronic indwelling double-lumen venous catheter, initially responded under a concurrent schedule of food delivery (1-g pellets, fixed-ratio (FR) 100 schedule) and cocaine injections (0-0.1 mg/kg/injection, FR 10 schedule) during continuous 7-day treatment periods with saline or the agonist medication phenmetrazine (0.032-0.1 mg/kg/h). Subsequently, the FR response requirement for cocaine or food was varied (food, FR 100; cocaine, FR 1-100; cocaine, FR 10; food, FR 10-300), and effects of phenmetrazine on cocaine vs food choice were redetermined. Decreases in the cocaine FR or increases in the food FR resulted in leftward shifts in the cocaine choice dose-effect curve, whereas increases in the cocaine FR or decreases in the food FR resulted in rightward shifts in the cocaine choice dose-effect curve. The efficacy of phenmetrazine to decrease cocaine choice varied systematically as a function of the prevailing response requirements, such that phenmetrazine efficacy was greatest when cocaine choice was maintained by relatively low unit cocaine doses. These results suggest that efficacy of pharmacotherapies to modulate cocaine use can be influenced by behavioral contingencies of cocaine availability. Agonist medications may be most effective under contingencies that engender choice of relatively low cocaine doses.

Multiresource allocation and scheduling for periodic soft real-time applications

NASA Astrophysics Data System (ADS)

Gopalan, Kartik; Chiueh, Tzi-cker

2001-12-01

Real-time applications that utilize multiple system resources, such as CPU, disks, and network links, require coordinated scheduling of these resources in order to meet their end-to-end performance requirements. Most state-of-the-art operating systems support independent resource allocation and deadline-driven scheduling but lack coordination among multiple heterogeneous resources. This paper describes the design and implementation of an Integrated Real-time Resource Scheduler (IRS) that performs coordinated allocation and scheduling of multiple heterogeneous resources on the same machine for periodic soft real-time application. The principal feature of IRS is a heuristic multi-resource allocation algorithm that reserves multiple resources for real-time applications in a manner that can maximize the number of applications admitted into the system in the long run. At run-time, a global scheduler dispatches the tasks of the soft real-time application to individual resource schedulers according to the precedence constraints between tasks. The individual resource schedulers, which could be any deadline based schedulers, can make scheduling decisions locally and yet collectively satisfy a real-time application's performance requirements. The tightness of overall timing guarantees is ultimately determined by the properties of individual resource schedulers. However, IRS maximizes overall system resource utilization efficiency by coordinating deadline assignment across multiple tasks in a soft real-time application.

Absorption and chemopreventive targets of sulforaphane in humans following consumption of broccoli sprouts or a myrosinase-treated broccoli sprout extract

PubMed Central

Atwell, Lauren L.; Hsu, Anna; Wong, Carmen P.; Stevens, Jan F.; Bella, Deborah; Yu, Tian-Wei; Pereira, Clifford B.; Löhr, Christiane V.; Christensen, John Mark; Dashwood, Roderick H.; Williams, David E.; Shannon, Jackilen; Ho, Emily

2015-01-01

Scope Sulforaphane (SFN), an isothiocyanate derived from crucifers, has numerous health benefits. SFN bioavailability from dietary sources is a critical determinant of its efficacy in humans. A key factor in SFN absorption is the release of SFN from its glucosinolate precursor, glucoraphanin, by myrosinase. Dietary supplements are used in clinical trials to deliver consistent SFN doses, but myrosinase is often inactivated in available supplements. We evaluated SFN absorption from a myrosinase-treated broccoli sprout extract (BSE) and are the first to report effects of twice daily, oral dosing on SFN exposure in healthy adults. Methods and results Subjects consumed fresh broccoli sprouts or the BSE, each providing 200 μmol SFN daily, as a single dose and as two 100-μmol doses taken 12 h apart. Using HPLC-MS/MS, we detected ~3 x higher SFN metabolite levels in plasma and urine of sprout consumers, indicating enhanced SFN absorption from sprouts. Twelve-hour dosing retained higher plasma SFN metabolite levels at later time points than 24-hour dosing. No dose responses were observed for molecular targets of SFN (i.e. heme oxygenase-1, histone deacetylase activity, p21). Conclusion We conclude that the dietary form and dosing schedule of SFN may impact SFN absorption and efficacy in human trials. PMID:25522265

Rapid-infusion rituximab in lymphoma treatment: 2-year experience in a single institution.

PubMed

Atay, Sevcan; Barista, Ibrahim; Gundogdu, Fatma; Akgedik, Kiymet; Arpaci, Afey

2012-05-01

Rituximab is a chimeric anti-CD20 monoclonal antibody. We aimed to explore the safety and tolerability of rapid infusion rituximab, (over 90 minutes) in patients with non-Hodgkin's lymphoma at Hacettepe University Department of Medical Oncology. Adult patients diagnosed with non-Hodgkin's lymphoma who were to receive rituximab were included in the study. The schedule of administration for cycle 1 was unaltered and delivered according to the product monograph. All subsequent cycles were administered over a total infusion time of 90 minutes (20% of the dose in the first 30 minutes, then the remaining 80% over 60 minutes, total dose delivered in 500 mL). All patients were observed for infusion-related reactions during the rituximab infusion, and vital signs were recorded every 15 minutes. From July 2006 to December 2008, 75 patients with non-Hodgkin's lymphoma were treated with rituximab-based chemotherapy. A total of 372 infusions were administered. The majority of patients were treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone, or rituximab only. The 90-minute rituximab infusion schedule was well tolerated, with no grade 3 or 4 infusion-related adverse events observed. A rapid infusion rituximab over 90 minutes is well tolerated and safe when administered as the second and subsequent infusions in the course of therapy.

The GLP-1 agonist exendin-4 attenuates self-administration of sweetened fat on fixed and progressive ratio schedules of reinforcement

PubMed Central

Bernosky-Smith, Kimberly A.; Stanger, David B.; Trujillo, Alexandria J.; Mitchell, Luke R.; Espana, Rodrigo A.; Bass, Caroline E.

2016-01-01

GLP-1 agonists such as exendin-4 (EX4) are used in the treatment of type 2 diabetes and have the additional benefit of promoting weight loss. GLP-1 agonists decrease feeding through peripheral affects, but recent evidence suggests they may also influence sweet or high fat preference, as well as the motivation to obtain these tastants. Yet it remains unclear how GLP-1 induced alterations in food preference influences the decrease in overall feeding. The current study sought to determine if EX4 affects the reinforcing strength and consumption of a highly palatable sweet/fat reinforcer. Rats were trained to self-administer sweetened vegetable shortening (SVS) under fixed (FR) and progressive ratio (PR) schedules of reinforcement. EX4 (0.3 - 2.4 μg/kg, IP) administered one hour prior to operant sessions significantly reduced responding for SVS under both FR and PR schedules (e.g. total reinforcers and breakpoints, respectively), although the lowest active dose (0.6 μg/kg) significantly suppressed FR responding only. EX4 also dose dependently decreased locomotor activity (0.6-2.4 μg/kg doses), but did not enhance acute kaolin intake, indicating that EX4-induced nausea did not influence the self-administration results. Analysis of ED50 values show that EX4 is more effective at inhibiting FR responding versus PR, indicating that EX4 may have more potent effects on consummatory versus appetitive feeding behaviors. Although EX4 caused generalized behavioral suppression, these results cannot fully explain the decreases in operant responding. For example, the 0.6 μg/kg dose inhibited only FR responding, even though the rats were physically capable of responding at a higher rate during PR sessions. In addition, the rate of intake was constant at the beginning of the sessions in both PR and FR schedules, regardless of the dose. Together these data suggest that EX4 inhibits consumption of a palatable high sweet/high fat reinforcer potentially through altering satiety. PMID:26701752

Safety and immunogenicity of a monovalent MF59®-adjuvanted A/H1N1 vaccine in HIV-infected children and young adults.

PubMed

Palma, Paolo; Romiti, Maria Luisa; Bernardi, Stefania; Pontrelli, Giuseppe; Mora, Nadia; Santilli, Veronica; Tchidjou, Hyppolite Kuekou; Aquilani, Angela; Cotugno, Nicola; Alghisi, Federico; Lucidi, Vincenzina; Rossi, Paolo; Douagi, Iyadh

2012-03-01

This Phase IV study evaluated the safety and immunogenicity of a two-dose, MF59®-adjuvanted (Novartis Vaccines, Marburg, Germany), monovalent, A/H1N1 pandemic influenza vaccination schedule in Human Immunodeficiency Virus (HIV) positive children and young adults. A total of 83 children infected with HIV-1, and 37 non-immunocompromised, age-matched controls were enrolled. All participants received two vaccine doses administered three weeks apart. Antibody responses were assessed by haemagglutination assay at baseline, three weeks after each vaccine dose, and six months after immunization. Vaccines were evaluated according to European influenza vaccine licensure criteria. The investigational vaccine was well tolerated. After the first vaccine dose, seroconversion rates were significantly lower in HIV-positive patients (60%) than controls (82%), with GMTs of 419 and 600, respectively. No significant differences in seroconversion rates were observed between the two study groups in response to the second vaccine dose. Persisting antibody titers were similar for both HIV-positive and non-infected controls, six months after immunization. One dose of MF59-adjuvanted vaccine was sufficient to provide adequate levels of seroprotection against A/H1N1 influenza disease in HIV-positive children. However, a two-dose vaccination schedule may be optimal for this population. Copyright © 2011 The International Alliance for Biological Standardization. Published by Elsevier Ltd. All rights reserved.

Patients' and physicians' perspectives on opioid therapy for chronic cancer and musculoskeletal pain in Germany, Italy, and Turkey: PAin RESearch (PARES) survey.

PubMed

Müller-Schwefe, Gerhard H H; Wimmer, Antonie M; Dejonckheere, Joachim; Eggers, Antje; Vellucci, Renato

2014-03-01

Under-treatment or lack of appropriate treatment for chronic pain remains an ongoing major healthcare problem. Opioids are being increasingly recognized as an effective option for chronic pain management. The objective of this survey was to understand the perspective of patients treated with opioids on quality of treatment, preferences, and possibilities to improve treatment and communication between patients and physicians. A large-scale PAin RESearch (PARES) survey of 2860 patients (Germany, Italy, and Turkey) with chronic cancer or musculoskeletal pain prescribed opioid therapy was conducted to assess various factors such as ease of use and compliance, sleep, quality-of-life, and polymedication. A physician component was also included. Relationships between variables and differences between groups were tested using Spearman and Wilcoxon signed-rank tests, respectively. Of the patients surveyed, 61% received strong opioids (WHO III) and 39% weak opioids (WHO II). Nearly 65% of the patients were currently on a twice daily or more dosing schedule; however, 61.5% of the patients responded that they considered once-daily dosing to be the most convenient schedule. Patients' responses indicated that different dosing schedules significantly influenced the occurrence of end-of-dose pain, feeling limited by the remaining level of pain, problems in falling asleep, and episodes of waking up at night or early in the morning. Physicians' responses showed that they were not surprised by 68.5% of patient responses; they also felt the need to change some aspect of pain treatment for a third of the patients, the commonest being pain medication (52.4%). The results of the survey suggest that patients prefer a convenient dosing scheme, which may have a positive impact on compliance. Physicians may have to communicate more closely with patients about their needs.

TH-302, a hypoxia-activated prodrug with broad in vivo preclinical combination therapy efficacy: optimization of dosing regimens and schedules.

PubMed

Liu, Qian; Sun, Jessica D; Wang, Jingli; Ahluwalia, Dharmendra; Baker, Amanda F; Cranmer, Lee D; Ferraro, Damien; Wang, Yan; Duan, Jian-Xin; Ammons, W Steve; Curd, John G; Matteucci, Mark D; Hart, Charles P

2012-06-01

Subregional hypoxia is a common feature of tumors and is recognized as a limiting factor for the success of radiotherapy and chemotherapy. TH-302, a hypoxia-activated prodrug selectively targeting hypoxic regions of solid tumors, delivers a cytotoxic warhead to the tumor, while maintaining relatively low systemic toxicity. The antitumor activity, different dosing sequences, and dosing regimens of TH-302 in combination with commonly used conventional chemotherapeutics were investigated in human tumor xenograft models. Seven chemotherapeutic drugs (docetaxel, cisplatin, pemetrexed, irinotecan, doxorubicin, gemcitabine, and temozolomide) were tested in combination with TH-302 in eleven human xenograft models, including non-small cell lung cancer (NSCLC), colon cancer, prostate cancer, fibrosarcoma, melanoma, and pancreatic cancer. The antitumor activity of docetaxel, cisplatin, pemetrexed, irinotecan, doxorubicin, gemcitabine, and temozolomide was increased when combined with TH-302 in nine out of eleven models tested. Administration of TH-302 2-8 h prior to the other chemotherapeutics yielded superior efficacy versus other sequences tested. Simultaneous administration of TH-302 and chemotherapeutics increased toxicity versus schedules with dosing separations. In a dosing optimization study, TH-302 administered daily at 50 mg/kg intraperitoneally for 5 days per week in the H460 NSCLC model showed the optimal response with minimal toxicity. TH-302 enhances the activity of a wide range of conventional anti-neoplastic agents in a broad panel of in vivo xenograft models. These data highlight in vivo effects of schedule and order of drug administration in regimen efficacy and toxicity and have relevance to the design of human regimens incorporating TH-302.

TH-302, a hypoxia-activated prodrug with broad in vivo preclinical combination therapy efficacy: optimization of dosing regimens and schedules

PubMed Central

Liu, Qian; Sun, Jessica D.; Wang, Jingli; Ahluwalia, Dharmendra; Baker, Amanda F.; Cranmer, Lee D.; Ferraro, Damien; Wang, Yan; Duan, Jian-Xin; Ammons, W. Steve; Curd, John G.; Matteucci, Mark D.

2014-01-01

Purpose Subregional hypoxia is a common feature of tumors and is recognized as a limiting factor for the success of radiotherapy and chemotherapy. TH-302, a hypoxia-activated prodrug selectively targeting hypoxic regions of solid tumors, delivers a cytotoxic warhead to the tumor, while maintaining relatively low systemic toxicity. The antitumor activity, different dosing sequences, and dosing regimens of TH-302 in combination with commonly used conventional chemotherapeutics were investigated in human tumor xenograft models. Methods Seven chemotherapeutic drugs (docetaxel, cisplatin, pemetrexed, irinotecan, doxorubicin, gemcitabine, and temozolomide) were tested in combination with TH-302 in eleven human xenograft models, including non-small cell lung cancer (NSCLC), colon cancer, prostate cancer, fibrosarcoma, melanoma, and pancreatic cancer. Results The antitumor activity of docetaxel, cisplatin, pemetrexed, irinotecan, doxorubicin, gemcitabine, and temozolomide was increased when combined with TH-302 in nine out of eleven models tested. Administration of TH-302 2–8 h prior to the other chemotherapeutics yielded superior efficacy versus other sequences tested. Simultaneous administration of TH-302 and chemotherapeutics increased toxicity versus schedules with dosing separations. In a dosing optimization study, TH-302 administered daily at 50 mg/kg intraperitoneally for 5 days per week in the H460 NSCLC model showed the optimal response with minimal toxicity. Conclusions TH-302 enhances the activity of a wide range of conventional anti-neoplastic agents in a broad panel of in vivo xenograft models. These data highlight in vivo effects of schedule and order of drug administration in regimen efficacy and toxicity and have relevance to the design of human regimens incorporating TH-302. PMID:22382881

[Immunisation schedule of the Spanish Association of Paediatrics: 2018 recommendations].

PubMed

Moreno-Pérez, David; Álvarez García, Francisco José; Álvarez Aldeán, Javier; Cilleruelo Ortega, María José; Garcés Sánchez, María; García Sánchez, Nuria; Hernández Merino, Ángel; Méndez Hernández, María; Merino Moína, Manuel; Montesdeoca Melián, Abián; Ruiz-Contreras, Jesús

2018-01-01

The Advisory Committee on Vaccines of the Spanish Association of Paediatrics annually publishes the immunisation schedule considered optimal for children resident in Spain, according to available evidence on current vaccines. Regarding funded immunisations, 2+1 strategy (2, 4, 11-12 months) with hexavalent (DTPa-IPV-Hib-HB) and 13-valent pneumococcal vaccines are recommended. Administration of the 6-year booster dose with DTPa is recommended, and a poliomyelitis dose for children who had received the 2+1 scheme, as well as Tdap vaccine for adolescents and pregnant women in every pregnancy between 27 and 32 weeks' gestation. The two-dose scheme should be used for MMR (12 months and 2-4 years) and varicella (15 months and 2-4 years). MMRV vaccine could be applied as the second dose if available. Coverage of human papillomavirus vaccination in girls aged 12 with a two dose scheme (0, 6 months) should be improved. Information and recommendation for male adolescents about potential beneficial effects of this immunisation should be provided as well. The new 9 genotypes vaccine is now available, expanding the coverage for both gender. Regarding non-funded immunisations, Committee on Vaccines of the Spanish Association of Paediatrics recommends meningococcal B vaccination, with a 3+1 schedule, and requests to be included in the National Immunisation Program. Tetravalent meningococcal vaccine (MenACWY) is recommended to adolescents (14-18 years) who are going to live in countries with systematic vaccination against ACWY serogroups, and people >6 weeks of age with risk factors or travellers to countries with very high incidence. Vaccination against rotavirus is recommended in all infants. Copyright © 2017 Asociación Española de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.

Intermittent high-dose ethanol exposures increase motivation for operant ethanol self-administration: possible neurochemical mechanism.

PubMed

Li, Zhimin; Zharikova, Alevtina; Vaughan, Cheryl H; Bastian, Jaime; Zandy, Shannon; Esperon, Leonardo; Axman, Elyssia; Rowland, Neil E; Peris, Joanna

2010-01-15

We investigated the neurochemical mechanism of how high-dose ethanol exposure may increase motivation for ethanol consumption. First, we developed an animal model of increased motivation for ethanol using a progressive ratio (PR) schedule. Sprague-Dawley rats were trained to administer 10% ethanol-containing gelatin or plain gelatin (on alternate weeks) in daily 30-min sessions under different fixed ratio (FR) and PR schedules. During FR schedules, rats self-administered about 1 g/kg ethanol, which was decreased to 0.4+/-0.03 g/kg under PR10. Rats then received four pairs of either 3 g/kg ethanol or saline injections during the weeks when the reinforcer was plain gelatin. During subsequent ethanol gel sessions, breakpoints and ethanol consumption rose 40% in the high-dose ethanol group by the fourth set of injections with no change in plain gel responding. Alterations in amino acids in the ventral striatum (VS) during PR10 responding for 10% ethanol gelatin and plain gelatin were measured using microdialysis sampling coupled with capillary electrophoresis and laser-induced fluorescence detection. There was greater release of taurine, glycine and glutamate in the NAC of the high-dose ethanol rats during 10% ethanol-containing gelatin responding, compared to the control rats or during plain gel responding. An increase in the release of glycine in this same brain region has recently been shown to be involved with anticipation of a reward. Thus, it appears that intermittent high-dose ethanol exposure not only increases motivation for ethanol responding but may also change neurotransmitter release that mediates anticipation of reinforcement, which may play a key role in the development of alcoholism. Copyright 2009 Elsevier B.V. All rights reserved.

[Vaccination schedule of the Spanish Association of Pediatrics: recommendations 2006].

PubMed

2006-01-01

Based on the evidence available, the Vaccines Advisory Committee (VAC) of the Spanish Association of Pediatrics reports and comments on the new developments in vaccines that have taken place in 2005 and recommends some modifications to the vaccination schedule for 2006. In agreement with changes in the product monographs for the meningococcal C vaccine, the VAC recommends two doses for the three commercially available preparations with a booster dose in the second year of life. The European Medicines Evaluation Agency (EMEA) has temporarily suspended the sale of the Hexavac vaccine due to doubts about its long-term protection against hepatitis B. The VAC continues to support the use of these combined vaccines. Currently only Infranrix Hexa is available in Spain. The recommendation of vaccinating adolescents with a booster dose of pertussis vaccine via the administration of an acellular preparation of low antigenic load together with the adult diphtheria and tetanus vaccine remains valid. Vaccination against chickenpox in susceptible children aged more than 12 months old continues to be recommended. There is wide coverage for the 7-valent pneumococcal conjugate vaccine in many areas of Spain. In view of the studies published, the VAC reiterates the need for universal immunization by introducing this vaccine in the official vaccination schedule. Finally, other vaccines not included in this schedule are discussed, with special mention of the advisability of influenza vaccination in children, according to the recommendations of the VAC available at the beginning of each season on the web site of the Spanish Association of Pediatrics www.aeped.es; www. vacunasaep.org.

Long-term efficacy and safety of certolizumab pegol in Japanese rheumatoid arthritis patients with an inadequate response to methotrexate: 52-week results from an open-label extension of the J-RAPID study

PubMed Central

Tanaka, Yoshiya; Yamamoto, Kazuhiko; Takeuchi, Tsutomu; Yamanaka, Hisashi; Ishiguro, Naoki; Eguchi, Katsumi; Watanabe, Akira; Origasa, Hideki; Shoji, Toshiharu; Miyasaka, Nobuyuki; Koike, Takao

2014-01-01

Abstract Objectives. To evaluate the long-term efficacy and safety of certolizumab pegol (CZP) plus methotrexate treatment and to assess the efficacy of two CZP maintenance dosing schedules in Japanese rheumatoid arthritis (RA) patients with an inadequate response to methotrexate. Methods. J-RAPID double-blind patients were entered into an open-label extension (OLE) study. Patients withdrawn due to lack of efficacy at 16 weeks and double-blind completers without a week-24 American College of Rheumatology (ACR) 20 response received CZP 200 mg every other week (Q2W) plus methotrexate. Double-blind completers with week-24 ACR20 responses were randomized to CZP 200 mg Q2W plus methotrexate or CZP 400 mg every 4 weeks plus methotrexate. Results. The ACR20/ACR50/ACR70 response rates of double-blind completers (n = 204) were 89.7%/67.2%/36.3% at OLE entry and 95.6%/84.8%/58.3% at 52 weeks, respectively. Other clinical, functional and radiographic outcomes were sustained with long-term CZP plus methotrexate. Long-term treatment with CZP was well-tolerated with no new unexpected adverse events observed. The efficacy and safety of CZP treatment were similar between the two dosing schedules. Conclusions. Continued CZP administration with methotrexate maintained efficacy over 52 weeks and was well-tolerated for Japanese RA patients. No obvious differences in clinical efficacy and safety were observed between the two dosing schedules, giving flexibility in maintenance administration schedules. PMID:24593170

Infusional 5-FU for advanced colorectal cancer.

PubMed

Lokich, J

1995-01-01

5-Fluorouracil (5-FU) has been studied over the past two decades in five prospective randomized trials comparing bolus with infusional schedules. Response rates and time to progression are improved with infusional schedules and survival as determined by the proportion of patients alive at 2 years is also superior for infusional administration. Biochemical modulation of infusional 5-FU by leucovorin or interferon does not increase the therapeutic effect (in contrast to the modulation of bolus delivery) but does effect the toxicity profile adversely. Time modulation of infusional 5-FU has been reported to improve response rates, and survival over constant or flat infusion and additional studies are ongoing. A proposed experimental design for a comparative trial in advanced colon cancer is presented to address the questions of the optimal infusion duration; the role of dose intensity; and the role of chronomodulation. The application of infusional 5-FU into the adjuvant setting seems to be a reasonable step, and such trials have been initiated in both the United States and the United Kingdom. Bolus single agent 5-FU should be abandoned as a treatment option for colon cancer.

Evaluation of Flexible Tacrolimus Drug Concentration Monitoring Approach in Patients Receiving Extended-Release Once-Daily Tacrolimus Tablets.

PubMed

Philosophe, Benjamin; Leca, Nicolae; West-Thielke, Patricia M; Horwedel, Timothy; Culkin-Gemmell, Christine; Kistler, Kristin; Stevens, Daniel R

2018-02-20

The majority of United States kidney transplant patients are treated with tacrolimus, a drug effective in preventing graft rejection, but with a narrow therapeutic range, necessitating close monitoring to avoid increased risks of transplant rejection or toxicity if the tacrolimus concentration is too low or too high, respectively. The trough drug concentration tests are time sensitive; patients treated on a twice-daily basis have blood draws exactly 12 hours after their previous dose. The schedule's rigidity causes problems for both patients and health care providers. Novel once-daily tacrolimus formulations such as LCPT (an extended-release tablet by Veloxis Pharmaceuticals, Inc., Cary, North Carolina) have allowed for blood draws on a once-daily basis; however, even that schedule can be restrictive. Results from tests taken either before or after that 24-hour target time may be discarded, or worse, may lead to inappropriate dose changes. Data from ASTCOFF, a phase 3B pharmacokinetic clinical trial (NCT02339246), demonstrated that the unique pharmacokinetic curve of LCPT may allow for a therapeutic monitoring window that extends for 3 hours before or after the 24-hour monitoring target. Furthermore, important tools to help clinicians interpret these levels, such as formulas to estimate the 24-hour trough level if an alternative monitoring time is used, were constructed from these data. These study results give treating clinicians access to data that allow them to safely use and monitor LCPT in their patients and expand the body of evidence surrounding differentiation and practical application of the novel LCPT tacrolimus formulation. © 2018, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Sustained immunogenicity of the HPV-16/18 AS04-adjuvanted vaccine administered as a two-dose schedule in adolescent girls: Five-year clinical data and modeling predictions from a randomized study

PubMed Central

Romanowski, Barbara; Schwarz, Tino F; Ferguson, Linda; Peters, Klaus; Dionne, Marc; Behre, Ulrich; Schulze, Karin; Hillemanns, Peter; Suryakiran, Pemmaraju; Thomas, Florence; Struyf, Frank

2016-01-01

In this randomized, partially-blind study (clinicaltrials.gov; NCT00541970), the licensed formulation of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine (20 μg each of HPV-16/18 antigens) was found highly immunogenic up to 4 y after first vaccination, whether administered as a 2-dose (2D) schedule in girls 9–14 y or 3-dose (3D) schedule in women 15–25 y. This end-of-study analysis extends immunogenicity and safety data until Month (M) 60, and presents antibody persistence predictions estimated by piecewise and modified power law models. Healthy females (age stratified: 9–14, 15–19, 20–25 y) were randomized to receive 2D at M0,6 (N = 240 ) or 3D at M0,1,6 (N = 239). Here, results are reported for girls 9–14 y (2D) and women 15–25 y (3D). Seropositivity rates, geometric mean titers (by enzyme-linked immunosorbent assay) and geometric mean titer ratios (GMRs; 3D/2D; post-hoc exploratory analysis) were calculated. All subjects seronegative pre-vaccination in the according-to-protocol immunogenicity cohort were seropositive for anti-HPV-16 and −18 at M60. Antibody responses elicited by the 2D and 3D schedules were comparable at M60, with GMRs close to 1 (anti-HPV-16: 1.13 [95% confidence interval: 0.82–1.54]; anti-HPV-18: 1.06 [0.74–1.51]). Statistical modeling predicted that in 95% of subjects, antibodies induced by 2D and 3D schedules could persist above natural infection levels for ≥ 21 y post-vaccination. The vaccine had a clinically acceptable safety profile in both groups. In conclusion, a 2D M0,6 schedule of the HPV-16/18 AS04-adjuvanted vaccine was immunogenic for up to 5 y in 9–14 y-old girls. Statistical modeling predicted that 2D-induced antibodies could persist for longer than 20 y. PMID:26176261

Dose dense cyclophosphamide, methotrexate, fluorouracil is feasible at 14-day intervals: a pilot study of every-14-day dosing as adjuvant therapy for breast cancer.

PubMed

Drullinsky, Pamela; Sugarman, Steven M; Fornier, Monica N; D'Andrea, Gabriella; Gilewski, Teresa; Lake, Diana; Traina, Tiffany; Wasserheit-Lieblich, Carolyn; Sklarin, Nancy; Atieh-Graham, Deena; Mills, Nancy; Troso-Sandoval, Tiffany; Seidman, Andrew D; Yuan, Jeffrey; Patel, Hamangi; Patil, Sujata; Norton, Larry; Hudis, Clifford

2010-12-01

Cyclophosphamide/methotrexate/fluorouracil (CMF) is a proven adjuvant option for patients with early-stage breast cancer. Randomized trials with other regimens demonstrate that dose-dense (DD) scheduling can offer greater efficacy. We investigated the feasibility of administering CMF using a DD schedule. Thirty-eight patients with early-stage breast cancer were accrued from March 2008 through June 2008. They were treated every 14 days with C 600, M 40, F 600 (all mg/m2) with PEG-filgrastim (Neulasta®) support on day 2 of each cycle. The primary endpoint was tolerability using a Simon's 2-stage optimal design. The design would effectively discriminate between true tolerability (as protocol-defined) rates of ≤ 60% and ≥ 80%. The median age was 52-years-old (range, 38-78 years of age). Twenty-nine of the 38 patients completed 8 cycles of CMF at 14-day intervals. Dose-dense adjuvant CMF is tolerable and feasible at 14-day intervals with PEG-filgrastim support.

Generating variable and random schedules of reinforcement using Microsoft Excel macros.

PubMed

Bancroft, Stacie L; Bourret, Jason C

2008-01-01

Variable reinforcement schedules are used to arrange the availability of reinforcement following varying response ratios or intervals of time. Random reinforcement schedules are subtypes of variable reinforcement schedules that can be used to arrange the availability of reinforcement at a constant probability across number of responses or time. Generating schedule values for variable and random reinforcement schedules can be difficult. The present article describes the steps necessary to write macros in Microsoft Excel that will generate variable-ratio, variable-interval, variable-time, random-ratio, random-interval, and random-time reinforcement schedule values.

Decorporation Approach after Rat Lung Contamination with Plutonium: Evaluation of the Key Parameters Influencing the Efficacy of a Protracted Chelation Treatment.

PubMed

Grémy, Olivier; Coudert, Sylvie; Renault, Daniel; Miccoli, Laurent

2017-11-01

While the efficacy of a protracted zinc (Zn)- or calcium (Ca)-diethylenetriaminepentaacetic acid (DTPA) treatment in reducing transuranic body burden has already been demonstrated, questions about therapeutic variables remain. In response to this, we designed animal experiments primarily to assess both the effect of fractionation of a given dose and the effect of the frequency of dose fraction, with the same total dose. In our study, rats were contaminated intravenously with plutonium (Pu) then treated several days later with Ca-DTPA given at once or in various split-dose regimens cumulating to the same total dose and spread over several days. Similar efficacies were induced by the injection of the total dose or by splitting the dose in several smaller doses, independent of the number of doses and the dose level per injection. In a second study, rats were pulmonary contaminated, and three weeks later they received a Ca-DTPA dose 11-fold higher than the maximal daily recommended dose, administered either as a single bolus or as numerous multiple injections cumulating to the same dose, based on different injection frequency schedules. Independent of frequency schedule, the various split-dose regimens spread over weeks/months were as efficient as single delivery of the total dose in mobilizing lung plutonium, and had a therapeutic advantage for removal of retained hepatic and bone plutonium burdens. We concluded that cumulative dose level was a therapeutic variable of greater importance than the distribution of split doses for the success of a repeated treatment regimen on retained tissue plutonium. In addition, pulmonary administration of clodronate, which aims at killing alveolar macrophages and subsequently releasing their plutonium content, and which is associated with a continuous Ca-DTPA infusion regimen, suggested that the efficacy of injected Ca-DTPA in decorporating lung deposit is limited, due to its restricted penetration into alveolar macrophages and not because plutonium, as a physicochemical form, is unavailable for chelation.

Immunogenicity and safety evaluation of bivalent types 1 and 3 oral poliovirus vaccine by comparing different poliomyelitis vaccination schedules in China: A randomized controlled non-inferiority clinical trial.

PubMed

Qiu, Jingjun; Yang, Yunkai; Huang, Lirong; Wang, Ling; Jiang, Zhiwei; Gong, Jian; Wang, Wei; Wang, Hongyan; Guo, Shaohong; Li, Chanjuan; Wei, Shuyuan; Mo, Zhaojun; Xia, Jielai

2017-06-03

The type 2 component of the oral poliovirus vaccine is targeted for global withdrawal through a switch from the trivalent oral poliovirus vaccine (tOPV) to a bivalent oral poliovirus vaccine (bOPV). The switch is intended to prevent paralytic polio caused by circulating vaccine-derived poliovirus type 2. We aimed to assess the immunogenicity and safety profile of 6 vaccination schedules with different sequential doses of inactivated poliovirus vaccine (IPV), tOPV, or bOPV. A randomized controlled trial was conducted in China in 2015. Healthy newborn babies randomly received one of the following 6 vaccination schedules: cIPV-bOPV-bOPV(I-B-B), cIPV-tOPV-tOPV(I-T-T), cIPV-cIPV-bOPV(I-I-B), cIPV-cIPV-tOPV(I-I-T), cIPV-cIPV-cIPV(I-I-I), or tOPV-tOPV-tOPV(T-T-T). Doses were administered sequentially at 4-6 week intervals after collecting baseline blood samples. Patients were proactively followed up for observation of adverse events after the first dose and 30 days after all doses. The primary study objective was to investigate the immunogenicity and safety profile of different vaccine schedules, evaluated by seroconversion, seroprotection and antibody titer against poliovirus types 1, 2, and 3 in the per-protocol population. Of 600 newborn babies enrolled, 504 (84.0%) were included in the per-protocol population. For type 1 poliovirus, the differences in the seroconversion were 1.17% (95% CI = -2.74%, 5.08%) between I-B-B and I-T-T and 0.00% (95% CI: -6.99%, 6.99%) between I-I-B and I-I-T; for type 3 poliovirus, differences in the seroconversion were 3.49% (95% CI: -1.50%, 8.48%) between I-B-B and I-T-T and -2.32% (95% CI: -5.51%, 0.86%) between I-I-B and I-I-T. The non-inferiority conclusion was achieved in both poliovirus type 1 and 3 with the margin of -10%. Of 24 serious adverse events reported, no one was vaccine-related. The vaccination schedules with bOPV followed by one or 2 doses of IPV were recommended to substitute for vaccinations involving tOPV without compromising the immunogenicity and safety in the Chinese population. The findings will be essential for policy formulation by national and global authorities to facilitate polio elimination.

Moderate Hypofractionated Protracted Radiation Therapy and Dose Escalation for Prostate Cancer: Do Dose and Overall Treatment Time Matter?

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

Kountouri, Melpomeni; Zilli, Thomas; Rouzaud, Michel

2016-02-01

Purpose: This was a retrospective study of 2 sequential dose escalation regimens of twice-weekly 4 Gy/fractions hypofractionated intensity modulated radiation therapy (IMRT): 56 Gy and 60 Gy delivered within a protracted overall treatment time (OTT) of 6.5 and 7 weeks, respectively. Methods and Materials: 163 prostate cancer patients with cT1c-T3a disease and nodal involvement risk ≤20% (Roach index) were treated twice weekly to the prostate ± seminal vesicles with 2 sequential dose-escalated IMRT schedules: 56 Gy (14 × 4 Gy, n=81) from 2003 to 2007 and 60 Gy (15 × 4 Gy, n=82) from 2006 to 2010. Patient repositioning was made with bone matching on portal images. Gastrointestinal (GI) and genitourinary (GU) toxicities weremore » scored according to the Common Terminology Criteria for Adverse Events version 3.0 grading scale. Results: There were no significant differences regarding the acute GU and GI toxicities in the 2 dose groups. The median follow-up times were 80.2 months (range, 4.5-121 months) and 56.5 months (range, 1.4-91.2 months) for patients treated to 56 and 60 Gy, respectively. The 5-year grade ≥2 late GU toxicity-free survivals with 56 Gy and 60 Gy were 96 ± 2.3% and 78.2 ± 5.1% (P=.001), respectively. The 5-year grade ≥2 late GI toxicity-free survivals with 56 Gy and 60 Gy were 98.6 ± 1.3% and 85.1 ± 4.5% (P=.005), respectively. Patients treated with 56 Gy showed a 5-year biochemical progression-free survival (bPFS) of 80.8 ± 4.7%, worse than patients treated with 60 Gy (93.2 ± 3.9%, P=.007). A trend for a better 5-year distant metastasis-free survival was observed among patients treated in the high-dose group (95.3 ± 2.7% vs 100%, P=.073, respectively). On multivariate analysis, only the 60-Gy group predicted for a better bPFS (P=.016, hazard ratio = 4.58). Conclusions: A single 4-Gy additional fraction in patients treated with a hypofractionated protracted IMRT schedule of 14 × 4 Gy resulted in a similar and minimal acute toxicity, in worse moderate to severe urinary and GI late effects, but a significantly better biochemical control.« less

Influence of titration schedule and maintenance dose on the tolerability of adjunctive eslicarbazepine acetate: An integrated analysis of three randomized placebo-controlled trials.

PubMed

Krauss, Gregory; Biton, Victor; Harvey, Jay H; Elger, Christian; Trinka, Eugen; Soares da Silva, Patrício; Gama, Helena; Cheng, Hailong; Grinnell, Todd; Blum, David

2018-01-01

To examine the influence of titration schedule and maintenance dose on the incidence and type of treatment-emergent adverse events (TEAEs) associated with adjunctive eslicarbazepine acetate (ESL). Data from three randomized, double-blind, placebo-controlled trials were analyzed. Patients with refractory partial-onset seizures were randomized to maintenance doses of ESL 400, 800, or 1200mg QD (dosing was initiated at 400 or 800mg QD) or placebo. The incidence of TEAEs was analyzed during the double-blind period (2-week titration phase; 12-week maintenance phase), according to the randomized maintenance dose and the titration schedule. 1447 patients were included in the analysis. During the first week of treatment, 62% of patients taking ESL 800mg QD had ≥1 TEAE, vs 35% of those taking 400mg QD and 32% of the placebo group; dizziness, somnolence, nausea, and headache were numerically more frequent in patients taking ESL 800mg than those taking ESL 400mg QD. During the double-blind period, the incidences of common TEAEs were lower in patients who initiated ESL at 400mg vs 800mg QD. For the 800 and 1200mg QD maintenance doses, rates of TEAEs leading to discontinuation were lower in patients who began treatment with 400mg than in those who began taking ESL 800mg QD. Initiation of ESL at 800mg QD is feasible. However, initiating treatment with ESL 400mg QD for 1 or 2 weeks is recommended, being associated with a lower incidence of TEAEs, and related discontinuations. For some patients, treatment may be initiated at 800mg QD, if the need for more immediate seizure reduction outweighs concerns about increased risk of adverse reactions during initiation. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Effectiveness of 7-Valent Pneumococcal Conjugate Vaccine Against Invasive Pneumococcal Disease in HIV-Infected and -Uninfected Children in South Africa: A Matched Case-Control Study

PubMed Central

Cohen, Cheryl; von Mollendorf, Claire; de Gouveia, Linda; Naidoo, Nireshni; Meiring, Susan; Quan, Vanessa; Nokeri, Vusi; Fortuin-de Smit, Melony; Malope-Kgokong, Babatyi; Moore, David; Reubenson, Gary; Moshe, Mamokgethi; Madhi, Shabir A.; Eley, Brian; Hallbauer, Ute; Kularatne, Ranmini; Conklin, Laura; O'Brien, Katherine L.; Zell, Elizabeth R.; Klugman, Keith; Whitney, Cynthia G.; von Gottberg, Anne; Moore, David; Verwey, Charl; Varughese, Sheeba; Archary, Moherndran; Naby, Fathima; Dawood, Khathija; Naidoo, Ramola; Elliott, Gene; Hallbauer, Ute; Eley, Brian; Nuttall, James; Cooke, Louise; Finlayson, Heather; Rabie, Helena; Whitelaw, Andrew; Perez, Dania; Jooste, Pieter; Naidoo, Dhamiran; Kularatne, Ranmini; Reubenson, Gary; Cohen, Cheryl; de Gouveia, Linda; du Plessis, Mignon; Govender, Nevashan; Meiring, Susan; Quan, Vanessa; von Mollendorf, Claire; Fortuin-de Smidt, Melony; Naidoo, Nireshni; Malope-Kgokong, Babatyi; Nokeri, Vusi; Ncha, Relebohile; Lindani, Sonwabo; von Gottberg, Anne; Spies, Barry; Sono, Lino; Maredi, Phasweni; Hamese, Ken; Moshe, Mamokgethi; Nchabeleng, Maphosane; Ngcobo, Ntombenhle; van den Heever, Johann; Madhi, Shabir; Conklin, Laura; Verani, Jennifer; Whitney, Cynthia; Zell, Elizabeth; Loo, Jennifer; Nelson, George; Klugman, Keith; O'Brien, Katherine

2014-01-01

Background. South Africa introduced 7-valent pneumococcal conjugate vaccine (PCV7) in April 2009 using a 2 + 1 schedule (6 and 14 weeks and 9 months). We estimated the effectiveness of ≥2 PCV7 doses against invasive pneumococcal disease (IPD) in human immunodeficiency virus (HIV)–infected and -uninfected children. Methods. IPD (pneumococcus identified from a normally sterile site) cases were identified through national laboratory-based surveillance. Specimens were serotyped by Quellung or polymerase chain reaction. Four controls, matched for age, HIV status, and hospital were sought for each case. Using conditional logistic regression, we calculated vaccine effectiveness (VE) as 1 minus the adjusted odds ratio for vaccination. Results. From March 2010 through November 2012, we enrolled 187 HIV-uninfected (48 [26%] vaccine serotype) and 109 HIV-infected (43 [39%] vaccine serotype) cases and 752 HIV-uninfected and 347 HIV-infected controls aged ≥16 weeks. Effectiveness of ≥2 PCV7 doses against vaccine-serotype IPD was 74% (95% confidence interval [CI], 25%–91%) among HIV-uninfected and −12% (95% CI, −449% to 77%) among HIV-infected children. Effectiveness of ≥3 doses against vaccine-serotype IPD was 90% (95% CI, 14%–99%) among HIV-uninfected and 57% (95% CI, −371% to 96%) among HIV-infected children. Among HIV-exposed but -uninfected children, effectiveness of ≥2 doses was 92% (95% CI, 47%–99%) against vaccine-serotype IPD. Effectiveness of ≥2 doses against all-serotype multidrug-resistant IPD was 96% (95% CI, 62%–100%) among HIV-uninfected children. Conclusions. A 2 + 1 PCV7 schedule was effective in preventing vaccine-serotype IPD in HIV-uninfected and HIV-exposed, uninfected children. This finding supports the World Health Organization recommendation for this schedule as an alternative to a 3-dose primary series among HIV-uninfected individuals. PMID:24917657

Evaluation of an Alcohol Withdrawal Protocol and a Preprinted Order Set at a Tertiary Care Hospital

PubMed Central

Ng, Karen; Dahri, Karen; Chow, Ivy; Legal, Michael

2011-01-01

Background: Alcohol withdrawal protocols involving symptom-triggered administration of benzodiazepine have been established to reduce the duration of treatment and the cumulative benzodiazepine dose (relative to usual care). However, the effects of a protocol combining fixed-schedule and symptom-triggered benzodiazepine dosing are less clear. Objective: To assess the efficacy and safety of a combination fixed-scheduled and symptom-triggered benzodiazepine dosing protocol for alcohol withdrawal, relative to usual care, for medical inpatients at a tertiary care hospital. Methods: A chart review of admissions to the internal medicine service for alcohol withdrawal was conducted to compare treatment outcomes before (October 2005 to April 2007) and after (October 2007 to April 2009) implementation of the combination protocol. The primary outcome was duration of benzodiazepine treatment for alcohol withdrawal. The secondary outcomes were cumulative benzodiazepine dose administered, safety implications, and use of adjunctive medications. Results: A total of 159 patients met the inclusion criteria. Assessable data were available for 71 charts from the pre-implementation period and 72 charts from the post-implementation period. The median duration of benzodiazepine treatment was 91 h before implementation and 57 h after implementation (p < 0.001). Use of the protocol was also associated with a significant reduction in severe complications of alcohol withdrawal (50% versus 33%, p = 0.019), median cumulative benzodiazepine dose (in lorazepam equivalents) (20.0 mg versus 15.5 mg, p = 0.026), and use of adjunctive medications (65% versus 38%, p = 0.001). The incidence of serious adverse outcomes of treatment with benzodiazepines was not significantly different between the 2 groups. Conclusions: Implementation of an alcohol withdrawal protocol with a combination of fixed-schedule and symptom-triggered benzodiazepine dosing in a medical ward was associated with a shorter duration of benzodiazepine use and a lower incidence of severe complications of alcohol withdrawal. PMID:22479099

Burden of rotavirus in India--is rotavirus vaccine an answer to it?

PubMed

Taneja, Davendra K; Malik, Akash

2012-01-01

Rotavirus is currently by far the most common cause of severe diarrhea in infants and young children worldwide and of diarrheal deaths in developing countries. Worldwide Rotavirus is responsible for 611,000 childhood deaths out of which more than 80% occur in low-income countries. The resistance of rotavirus to commonly used disinfectants and ineffectiveness of oral rehydration therapy due to severe vomiting indicates that if an effective vaccine is the preferred option. WHO has recommended inclusion of rotavirus vaccine in the National Schedules where under 5 mortality due to diarrheal diseases is ≥ 10%. Currently two vaccines are available against rotavirus. Rotarix (GlaxoSmithKline) is a monovalent vaccine recommended to be orally administered in two doses at 6-12 weeks. Rota Teq (Merck) is a pentavalent vaccine recommended to be orally administered in three doses starting at 6-12 weeks of age. Serodiversity of rotavirus in India and its regional variation favor either a monovalent vaccine that can induce heterotypic immunity or a polyvalent vaccine incorporating majority of serotypes prevalent in the country. However, the efficacy of available rotavirus vaccines is less in low-income countries. Both the candidate vaccines when coadministered with OPV, immune response to first dose of these vaccines is reduced. However, immune responses to subsequent rotavirus vaccine doses are not affected. In view of this, WHO recommends three doses of either vaccine to be given to children in developing countries to produce the optimum response. Indigenous vaccine, 116E (Bharat Biotech) based on human rotavirus of serotype G9P [11] is still under Phase 2 trials. Another multivalent vaccine is being developed by Shantha Biotechnics in India. The cost effectiveness of the three dose schedule of the available and the rsults of the field trials of the indigenous vaccines should be assessed before inclusion of rotavirus vaccine in the National Immunization Schedule.

Inflammatory Pain Promotes Increased Opioid Self-Administration: Role of Dysregulated Ventral Tegmental Area μ Opioid Receptors

PubMed Central

Hipólito, Lucia; Wilson-Poe, Adrianne; Campos-Jurado, Yolanda; Zhong, Elaine; Gonzalez-Romero, Jose; Virag, Laszlo; Whittington, Robert; Comer, Sandra D.; Carlton, Susan M.; Walker, Brendan M.; Bruchas, Michael R.

2015-01-01

Pain management in opioid abusers engenders ethical and practical difficulties for clinicians, often resulting in pain mismanagement. Although chronic opioid administration may alter pain states, the presence of pain itself may alter the propensity to self-administer opioids, and previous history of drug abuse comorbid with chronic pain promotes higher rates of opioid misuse. Here, we tested the hypothesis that inflammatory pain leads to increased heroin self-administration resulting from altered mu opioid receptor (MOR) regulation of mesolimbic dopamine (DA) transmission. To this end, the complete Freund's adjuvant (CFA) model of inflammation was used to assess the neurochemical and functional changes induced by inflammatory pain on MOR-mediated mesolimbic DA transmission and on rat intravenous heroin self-administration under fixed ratio (FR) and progressive ratio (PR) schedules of reinforcement. In the presence of inflammatory pain, heroin intake under an FR schedule was increased for high, but attenuated for low, heroin doses with concomitant alterations in mesolimbic MOR function suggested by DA microdialysis. Consistent with the reduction in low dose FR heroin self-administration, inflammatory pain reduced motivation for a low dose of heroin, as measured by responding under a PR schedule of reinforcement, an effect dissociable from high heroin dose PR responding. Together, these results identify a connection between inflammatory pain and loss of MOR function in the mesolimbic dopaminergic pathway that increases intake of high doses of heroin. These findings suggest that pain-induced loss of MOR function in the mesolimbic pathway may promote opioid dose escalation and contribute to opioid abuse-associated phenotypes. SIGNIFICANCE STATEMENT This study provides critical new insights that show that inflammatory pain alters heroin intake through a desensitization of MORs located within the VTA. These findings expand our knowledge of the interactions between inflammatory pain and opioid abuse liability, and should help to facilitate the development of novel and safer opioid-based strategies for treating chronic pain. PMID:26338332

Immunogenicity and Safety of Four Different Dosing Regimens of Anthrax Vaccine Adsorbed for Post-Exposure Prophylaxis for Anthrax in Adults

PubMed Central

Bernstein, David I.; Jackson, Lisa; Patel, Shital M.; El Sahly, Hana M.; Spearman, Paul; Rouphael, Nadine; Rudge, Thomas L.; Hill, Heather; Goll, Johannes B.

2014-01-01

Background Strategies to implement post exposure prophylaxis (PEP) in case of an anthrax bioterror event are needed. To increase the number of doses of vaccine available we evaluated reducing the amount of vaccine administered at each of the vaccinations, and reducing the number of doses administered. Methods Healthy male and non-pregnant female subjects between the ages of 18 and 65 were enrolled and randomized 1:1:1:1 to one of four study arms to receive 0.5 mL (standard dose) of vaccine subcutaneously (SQ) at: A) days 0, 14; B) days 0 and 28; C) days 0, 14, and 28; or D) 0.25 ml at days 0, 14, and 28. A booster was provided on day 180. Safety was assessed after each dose. Blood was obtained on days 0, 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 84, 100, 180, and 201 and both Toxin Neutralizing antibody and anti-PA IgG antibody measured. Results Almost all subjects developed some local reactions with 46% to 64% reported to be of moderate severity and 3.3% severe during the primary series. Vaccine groups that included a day 14 dose induced a ≥4 fold antibody rise in more subjects on days 21, 28 and 35 than the arm without a day 14 dose. However, schedules with a full day 28 dose induced higher peak levels of antibody that persisted longer. The half dose regimen did not induce antibody as well as the full dose study arms. Conclusion Depending on the extent of the outbreak, effectiveness of antibiotics and availability of vaccine, the full dose 0, 28 or 0, 14, 28 schedules may have advantages. PMID:25239484

Immunogenicity and safety of four different dosing regimens of anthrax vaccine adsorbed for post-exposure prophylaxis for anthrax in adults.

PubMed

Bernstein, David I; Jackson, Lisa; Patel, Shital M; El Sahly, Hana M; Spearman, Paul; Rouphael, Nadine; Rudge, Thomas L; Hill, Heather; Goll, Johannes B

2014-10-29

Strategies to implement post exposure prophylaxis (PEP) in case of an anthrax bioterror event are needed. To increase the number of doses of vaccine available we evaluated reducing the amount of vaccine administered at each of the vaccinations, and reducing the number of doses administered. Healthy male and non-pregnant female subjects between the ages of 18 and 65 were enrolled and randomized 1:1:1:1 to one of four study arms to receive 0.5 mL (standard dose) of vaccine subcutaneously (SQ) at: (A) days 0, 14; (B) days 0 and 28; (C) days 0, 14, and 28; or (D) 0.25 mL at days 0, 14, and 28. A booster was provided on day 180. Safety was assessed after each dose. Blood was obtained on days 0, 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 84, 100, 180, and 201 and both Toxin Neutralizing antibody and anti-PA IgG antibody measured. Almost all subjects developed some local reactions with 46-64% reported to be of moderate severity and 3.3% severe during the primary series. Vaccine groups that included a day 14 dose induced a ≥ 4 fold antibody rise in more subjects on days 21, 28, and 35 than the arm without a day 14 dose. However, schedules with a full day 28 dose induced higher peak levels of antibody that persisted longer. The half dose regimen did not induce antibody as well as the full dose study arms. Depending on the extent of the outbreak, effectiveness of antibiotics and availability of vaccine, the full dose 0, 28 or 0, 14, 28 schedules may have advantages. Copyright © 2014 Elsevier Ltd. All rights reserved.

The Effect of a Federal Controlled Substance Act Schedule Change on Hydrocodone Combination Products Claims in a Medicaid Population.

PubMed

Tran, Stephanie; Lavitas, Pavel; Stevens, Karen; Greenwood, Bonnie C; Clements, Karen; Alper, Caroline J; Lenz, Kimberly; Price, Mylissa; Hydery, Tasmina; Arnold, Jennifer L; Takeshita, Mito; Bacon, Rachel; Peristere, Justin P; Jeffrey, Paul L

2017-05-01

In 2012, hydrocodone combination products (HCPs) were the most prescribed medications in the United States. Under the Controlled Substance Act of 1970, hydrocodone alone was classified as a Schedule II drug, while HCPs were classified as Schedule III, indicating a lower risk for abuse and misuse. However, according to a Drug Enforcement Agency analysis, the addition of nonopioids has not been shown to diminish abuse potential of hydrocodone. In response to concerns for drug abuse and overdose, the Drug Enforcement Agency rescheduled HCPs to Schedule II in October 2014, with the intent of limiting overprescribing and increasing awareness of their abuse potential. However, it is unknown whether this has affected the overall claims for HCPs in a Medicaid population. To (a) compare the trend in HCP prescription claims with select non-HCP (opioid and nonopioid) analgesic claims before and after the HCP schedule change in the Massachusetts Medicaid fee-for-service/Primary Care Clinician plan population and (b) identify if there was a change in HCP new start member and claim characteristics before and after the HCP schedule change. This quasi-experimental, retrospective study used enrollment and pharmacy claims data to evaluate all members in the study population 1 year before and after the HCP schedule change. The number of claims for HCPs and select non-HCP analgesics was reported as the monthly rate per total population, and an interrupted time series analysis compared the change in the monthly rate of claims across groups. Members with 1 or more pharmacy claims for a new HCP prescription during a 5-month period before or after the HCP schedule change were analyzed to determine member demographics (age, gender, and number of claims) and claim characteristics (average daily dose, average quantity per claim, and days supply). The rate of HCP claims increased before and decreased after the HCP schedule change. Controlling for the trend during the period before the HCP schedule change, the rate of HCP claims per 1,000 members per month decreased at a greater rate than non-HCP analgesics in the period after the HCP schedule change (P < 0.001). The percentage of HCP claims for new start members decreased after the HCP schedule change (44.9% vs. 34.1% of all HCP claims pre- to post-schedule change; P < 0.001). In the group of new starts, there was not a significant difference in the average daily dose (26.3 mg vs. 26.4 mg; P = 0.69), while there was a decrease in average number of tablets dispensed per claim (from 37.1 to 20.3 tablets; P < 0.001) and an increase in the percentage of claims for a shorter days supply (from 57.7% to 81.6%; P < 0.001). The findings of this study suggest that the HCP schedule change may have contributed to the decrease in claims for HCPs in a Medicaid population. After the HCP schedule change, there was a trend towards decreased HCP use among new starts. No outside funding supported this study. The authors have nothing to disclose. Study concept and design were contributed by all authors except for Arnold and Clements. Tran, Arnold, and Clements took the lead in data collection, along with Peristere, and data interpretation was performed by all the authors, except Arnold. The manuscript was written primarily by Tran, along with Lavitas, Stevens, and Greenwood, and revised by all the authors except Arnold and Peristere. A poster of this research project was presented at the Academy of Managed Care Pharmacy's 2016 Annual Meeting in San Francisco, California, April 2016.

External-beam Co-60 radiotherapy for canine nasal tumors: a comparison of survival by treatment protocol.

PubMed

Yoon, J H; Feeney, D A; Jessen, C R; Walter, P A

2008-02-01

A retrospective analysis of survival times in dogs with intranasal tumors was performed comparing those treated using hypofractionated or full course Co-60 radiotherapy protocols alone or with surgical adjuvant therapy and those receiving no radiation treatment. One hundred thirty-nine dogs presented to the University of Minnesota Veterinary Medical Center for treatment of histologically-confirmed nasal neoplasia between July 1983 and October 2001 met the criteria for review. Statistically analyzed parameters included age at diagnosis, tumor histologic classification, fractionation schedule (number of treatments, and number of treatment days/week) (classified as hypofractionated if 2 or less treatments/week); calculated minimum tumor dose/fraction; calculated total minimum tumor dose (classified as hypofractionated if less than 37 Gy in six or fewer fractions); number of radiotherapy portals, a treatment gap of more than 7 days in a full course (3-5 treatments/week, 3-3.5 week treatment time) radiotherapy protocol, the influence of eye shields on survival following single portal DV fields, the survey radiographic extent of the disease, and the presence or absence of cytoreductive surgery. There was a significant relationship only between protocols using 3 or more treatments/week and at least 37 Gy cumulative minimum tumor dose and survival. However, there was no significant relationship between either total minimum tumor dose or dose/fraction and survival and there were no significant relationships between survival and any of the other variables analyzed including tumor histologic type.

Methods to model and predict the ViewRay treatment deliveries to aid patient scheduling and treatment planning.

PubMed

Liu, Shi; Wu, Yu; Wooten, H Omar; Green, Olga; Archer, Brent; Li, Harold; Yang, Deshan

2016-03-08

A software tool is developed, given a new treatment plan, to predict treatment delivery time for radiation therapy (RT) treatments of patients on ViewRay magnetic resonance image-guided radiation therapy (MR-IGRT) delivery system. This tool is necessary for managing patient treatment scheduling in our clinic. The predicted treatment delivery time and the assessment of plan complexities could also be useful to aid treatment planning. A patient's total treatment delivery time, not including time required for localization, is modeled as the sum of four components: 1) the treatment initialization time; 2) the total beam-on time; 3) the gantry rotation time; and 4) the multileaf collimator (MLC) motion time. Each of the four components is predicted separately. The total beam-on time can be calculated using both the planned beam-on time and the decay-corrected dose rate. To predict the remain-ing components, we retrospectively analyzed the patient treatment delivery record files. The initialization time is demonstrated to be random since it depends on the final gantry angle of the previous treatment. Based on modeling the relationships between the gantry rotation angles and the corresponding rotation time, linear regression is applied to predict the gantry rotation time. The MLC motion time is calculated using the leaves delay modeling method and the leaf motion speed. A quantitative analysis was performed to understand the correlation between the total treatment time and the plan complexity. The proposed algorithm is able to predict the ViewRay treatment delivery time with the average prediction error 0.22min or 1.82%, and the maximal prediction error 0.89 min or 7.88%. The analysis has shown the correlation between the plan modulation (PM) factor and the total treatment delivery time, as well as the treatment delivery duty cycle. A possibility has been identified to significantly reduce MLC motion time by optimizing the positions of closed MLC pairs. The accuracy of the proposed prediction algorithm is sufficient to support patient treatment appointment scheduling. This developed software tool is currently applied in use on a daily basis in our clinic, and could also be used as an important indicator for treatment plan complexity.

From total empiricism to a rational design of metronomic chemotherapy phase I dosing trials.

PubMed

Lam, Thomas; Hetherington, John W; Greenman, John; Maraveyas, Anthony

2006-02-01

'Metronomic chemotherapy' represents a novel anti-angiogenic strategy whereby low-dose chemotherapy is utilized in a continuous fashion in order to target tumor endothelium. There are many potential advantages of this strategy and clinical trials are already underway. However, although the scheduling of metronomic chemotherapy is relatively unequivocal, metronomic dosing principles are at present poorly defined. Arbitrarily, 10-33% of the maximum tolerated dose comprises 'the dose range'. We argue that this is too empirical and propose a set of phase I metronomic chemotherapy dosing strategies based on a principled approach which may help to reduce the problem of empiricism in dosing for metronomic chemotherapy trials.

Generating Variable and Random Schedules of Reinforcement Using Microsoft Excel Macros

PubMed Central

Bancroft, Stacie L; Bourret, Jason C

2008-01-01

Variable reinforcement schedules are used to arrange the availability of reinforcement following varying response ratios or intervals of time. Random reinforcement schedules are subtypes of variable reinforcement schedules that can be used to arrange the availability of reinforcement at a constant probability across number of responses or time. Generating schedule values for variable and random reinforcement schedules can be difficult. The present article describes the steps necessary to write macros in Microsoft Excel that will generate variable-ratio, variable-interval, variable-time, random-ratio, random-interval, and random-time reinforcement schedule values. PMID:18595286

The R-Shell approach - Using scheduling agents in complex distributed real-time systems

NASA Technical Reports Server (NTRS)

Natarajan, Swaminathan; Zhao, Wei; Goforth, Andre

1993-01-01

Large, complex real-time systems such as space and avionics systems are extremely demanding in their scheduling requirements. The current OS design approaches are quite limited in the capabilities they provide for task scheduling. Typically, they simply implement a particular uniprocessor scheduling strategy and do not provide any special support for network scheduling, overload handling, fault tolerance, distributed processing, etc. Our design of the R-Shell real-time environment fcilitates the implementation of a variety of sophisticated but efficient scheduling strategies, including incorporation of all these capabilities. This is accomplished by the use of scheduling agents which reside in the application run-time environment and are responsible for coordinating the scheduling of the application.

Postoperative analgesic efficacy of single high dose and low dose rectal acetaminophen in pediatric ophthalmic surgery

PubMed Central

Gandhi, Ranju; Sunder, Rani

2012-01-01

Background: Analgesic efficacy of rectal acetaminophen is variable in different surgical procedures. Little data is available on its efficacy in ophthalmic surgeries. We conducted this prospective, randomized, double blind study to evaluate and compare the efficacy of single high dose and low dose rectal acetaminophen in pediatric ophthalmic surgery over a 24 hour period. Materials and Methods: 135 children scheduled for elective ophthalmic surgery were randomly allocated to one of the three groups, high, low, or control (H, L, or N) and received rectal acetaminophen 40 mg/kg, 20 mg/kg or no rectal drug respectively after induction of general anesthesia. Postoperative observations included recovery score, hourly observational pain score (OPS) up to 8 hours, time to first analgesic demand, and requirement of rescue analgesics and antiemetics over a 24 hour period. Results: Nineteen of 30 (63%) of children in group N required postoperative rescue analgesic versus 5/48 (10%) of group H (P <0.0001) and 10/47 (23%) of group L (P =0.0005) during 24 hour period. Mean time to requirement of first analgesic was 206±185 min in group H, 189±203min in group L, and 196 ±170 min in group N (P=0.985). OPS was significantly lower in group H and L compared to group N during first 8 hours. Requirement of rescue antiemetic was 18.7% in group H as compared to 23% each in group L and group N (P >0.5). Conclusions: Single dose rectal acetaminophen can provide effective postoperative analgesia for pediatric ophthalmic surgery at both high dose (40 mg/kg) and low dose (20 mg/kg) both in early postoperative and over a 24 hour period. PMID:23225924

Objective Analysis of Poly-L-Lactic Acid Injection Efficacy in Different Settings.

PubMed

Byun, Sang-Young; Seo, Koo-Il; Shin, Jung-Won; Kwon, Soon-Hyo; Park, Mi-Sook; Lee, Joshua; Park, Kyoung-Chan; Na, Jung-Im; Huh, Chang-Hun

2015-12-01

Poly-L-lactic acid (PLLA) filler is known to have continuous volume effect. The objective of this study is to analyze objective volume effect of PLLA in different settings of injection schedule on the cheek. A split-face, evaluator-blind randomized study in 24 volunteers was conducted. One side was injected 3 times with 4 cc dose and the other side was injected 2 times with 6 cc dose per visit. Facial volume loss scale (FVLS) and Vectra were evaluated. Measured average FVLS showed statistically significant improvement both in 3 and 2 times injection sides and maintained efficacy until 12 months. Vectra showed volume difference (cc) between before and after injection. In 3 times injection side, it was increased 2.12 (after 1 month) to 3.17 (after 12 months). In 2 times injection side, it was increased 2.26 (after 1 month) to 3.19 (after 12 months). Gradual volume improvement over 12 months was statistically significant in both sides. There was no statistically significant difference between 3 and 2 times injection in FVLS and Vectra. There was no severe adverse event. Poly-L-lactic acid has continuous volume effect and there was no significant difference by injection times at the same total injection volume.

Efficiently Scheduling Multi-core Guest Virtual Machines on Multi-core Hosts in Network Simulation

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

Yoginath, Srikanth B; Perumalla, Kalyan S

2011-01-01

Virtual machine (VM)-based simulation is a method used by network simulators to incorporate realistic application behaviors by executing actual VMs as high-fidelity surrogates for simulated end-hosts. A critical requirement in such a method is the simulation time-ordered scheduling and execution of the VMs. Prior approaches such as time dilation are less efficient due to the high degree of multiplexing possible when multiple multi-core VMs are simulated on multi-core host systems. We present a new simulation time-ordered scheduler to efficiently schedule multi-core VMs on multi-core real hosts, with a virtual clock realized on each virtual core. The distinguishing features of ourmore » approach are: (1) customizable granularity of the VM scheduling time unit on the simulation time axis, (2) ability to take arbitrary leaps in virtual time by VMs to maximize the utilization of host (real) cores when guest virtual cores idle, and (3) empirically determinable optimality in the tradeoff between total execution (real) time and time-ordering accuracy levels. Experiments show that it is possible to get nearly perfect time-ordered execution, with a slight cost in total run time, relative to optimized non-simulation VM schedulers. Interestingly, with our time-ordered scheduler, it is also possible to reduce the time-ordering error from over 50% of non-simulation scheduler to less than 1% realized by our scheduler, with almost the same run time efficiency as that of the highly efficient non-simulation VM schedulers.« less

Collaborative Resource Allocation

NASA Technical Reports Server (NTRS)

Wang, Yeou-Fang; Wax, Allan; Lam, Raymond; Baldwin, John; Borden, Chester

2007-01-01

Collaborative Resource Allocation Networking Environment (CRANE) Version 0.5 is a prototype created to prove the newest concept of using a distributed environment to schedule Deep Space Network (DSN) antenna times in a collaborative fashion. This program is for all space-flight and terrestrial science project users and DSN schedulers to perform scheduling activities and conflict resolution, both synchronously and asynchronously. Project schedulers can, for the first time, participate directly in scheduling their tracking times into the official DSN schedule, and negotiate directly with other projects in an integrated scheduling system. A master schedule covers long-range, mid-range, near-real-time, and real-time scheduling time frames all in one, rather than the current method of separate functions that are supported by different processes and tools. CRANE also provides private workspaces (both dynamic and static), data sharing, scenario management, user control, rapid messaging (based on Java Message Service), data/time synchronization, workflow management, notification (including emails), conflict checking, and a linkage to a schedule generation engine. The data structure with corresponding database design combines object trees with multiple associated mortal instances and relational database to provide unprecedented traceability and simplify the existing DSN XML schedule representation. These technologies are used to provide traceability, schedule negotiation, conflict resolution, and load forecasting from real-time operations to long-range loading analysis up to 20 years in the future. CRANE includes a database, a stored procedure layer, an agent-based middle tier, a Web service wrapper, a Windows Integrated Analysis Environment (IAE), a Java application, and a Web page interface.

Long-Term Effectiveness of Accelerated Hepatitis B Vaccination Schedule in Drug Users

PubMed Central

Shah, Dimpy P.; Grimes, Carolyn Z.; Nguyen, Anh T.; Lai, Dejian

2015-01-01

Objectives. We demonstrated the effectiveness of an accelerated hepatitis B vaccination schedule in drug users. Methods. We compared the long-term effectiveness of accelerated (0–1–2 months) and standard (0–1–6 months) hepatitis B vaccination schedules in preventing hepatitis B virus (HBV) infections and anti-hepatitis B (anti-HBs) antibody loss during 2-year follow-up in 707 drug users (HIV and HBV negative at enrollment and completed 3 vaccine doses) from February 2004 to October 2009. Results. Drug users in the accelerated schedule group had significantly lower HBV infection rates, but had a similar rate of anti-HBs antibody loss compared with the standard schedule group over 2 years of follow-up. No chronic HBV infections were observed. Hepatitis C positivity at enrollment and age younger than 40 years were independent risk factors for HBV infection and antibody loss, respectively. Conclusions. An accelerated vaccination schedule was more preferable than a standard vaccination schedule in preventing HBV infections in drug users. To overcome the disadvantages of a standard vaccination schedule, an accelerated vaccination schedule should be considered in drug users with low adherence. Our study should be repeated in different cohorts to validate our findings and establish the role of an accelerated schedule in hepatitis B vaccination guidelines for drug users. PMID:25880946

Pharmacological validation of individual animal locomotion, temperature and behavioural analysis in group-housed rats using a novel automated home cage analysis system: A comparison with the modified Irwin test.

PubMed

Tse, Karen; Sillito, Rowland; Keerie, Amy; Collier, Rachel; Grant, Claire; Karp, Natasha A; Vickers, Cathy; Chapman, Kathryn; Armstrong, J Douglas; Redfern, William S

2018-04-01

The ActualHCA™ system continuously monitors the activity, temperature and behavior of group-housed rats without invasive surgery. The system was validated to detect the contrasting effects of sedative and stimulant test agents (chlorpromazine, clonidine and amphetamine), and compared with the modified Irwin test (mIT) with rectal temperature measurements. Six male Han Wistar rats per group were used to assess each test agent and vehicle controls in separate ActualHCA™ recordings and mIT. The mIT was undertaken at 15, 30 mins, 1, 2, 4 and 24 h post-dose. ActualHCA™ recorded continuously for 24 h post-dose under 3 experimental conditions: dosed during light phase, dark phase, and light phase with a scheduled cage change at the time of peak effects determined by mIT. ActualHCA™ detected an increase stimulated activity from the cage change at 1-2 h post-dose which was obliterated by chlorpromazine and clonidine. Amphetamine increased activity up to 4 h post-dose in all conditions. Temperature from ActualHCA™ was affected by all test agents in all conditions. The mIT showed effects on all 3 test agents up to 4 h post-dose, with maximal effects at 1-2 h post-dose. The maximal effects on temperature from ActualHCA™ differed from mIT. Delayed effects on activity were detected by ActualHCA™, but not on mIT. Continuous monitoring has the advantage of capturing effects over time that may be missed with manual tests using pre-determined time points. This automated behavioural system does not replace the need for conventional methods but could be implemented simultaneously to improve our understanding of behavioural pharmacology. Copyright © 2018 Elsevier Inc. All rights reserved.

Immunogenicity and safety of the human rotavirus vaccine Rotarix co-administered with routine infant vaccines following the vaccination schedules in Europe.

PubMed

Vesikari, Timo; Karvonen, Aino; Prymula, Roman; Schuster, Volker; Tejedor, Juan C; Thollot, Franck; Garcia-Corbeira, Pilar; Damaso, Silvia; Han, Htay-Htay; Bouckenooghe, Alain

2010-07-19

This study assessed the immunogenicity and safety of a human rotavirus vaccine RIX4414; the effect of co-administration of childhood vaccines on the immune responses was also assessed. Healthy infants aged 6-14 weeks received two doses of RIX4414/placebo concomitantly with the primary childhood vaccination (Infanrix hexa, Infanrix quinta,Meningitec and/or Prevnar), respecting the vaccination schedule of each country. Anti-rotavirus IgA seroconversion rate (ELISA cut-off 20 U/ml) was measured pre-vaccination and 1-2 months post-Dose 2. Immune response against diphtheria, tetanus, pertussis, hepatitis B, Haemophilus influenzae type b, inactivated polio virus, pneumococcal polysaccharide conjugate (France and Germany) and meningococcal group C conjugate vaccines (Spain) were measured approximately 1-month post-Dose 3. An overall anti-rotavirus IgA seroconversion rate of 86.5%(95% CI: 83.9-88.8) was observed in the RIX4414 group 1-month post-Dose 2. The seroconversion rate in Finland and Italy (3 and 5-month schedule) was 94.6%(95% CI: 90.0-97.5) and 92.3%(95% CI: 64.0-99.8), respectively. Immune response to the childhood vaccines was unaffected following co-administration with RIX4414. Reactogenicity profile was similar for RIX4414 and placebo groups. RIX4414 was immunogenic and well tolerated in European infants and the co-administration of routine childhood vaccines with RIX4414 did not negatively impact the immune responses to these vaccines. (c) 2010 Elsevier Ltd. All rights reserved.

High acceptability of HIV pre-exposure prophylaxis but challenges in adherence and use: qualitative insights from a phase I trial of intermittent and daily PrEP in at-risk populations in Kenya.

PubMed

Van der Elst, Elisabeth Maria; Mbogua, Judie; Operario, Don; Mutua, Gaudensia; Kuo, Caroline; Mugo, Peter; Kanungi, Jennifer; Singh, Sagri; Haberer, Jessica; Priddy, Frances; Sanders, Eduard Joachim

2013-07-01

This paper used qualitative methods to explore experiences of men who have sex with men and female sex workers in Nairobi and Mtwapa, Kenya, who used oral pre-exposure prophylaxis (PrEP) for HIV prevention as part of a four-month trial of safety, acceptability and adherence. Fifty-one of 72 volunteers who took part in a randomized, placebo-controlled, blinded trial that compared daily and intermittent dosage of PrEP underwent qualitative assessments after completing the trial. Analyses identified three themes: (i) acceptability of PrEP was high, i.e. side effects were experienced early in the study but diminished over time, however characteristics of pills could improve comfort and use; (ii) social impacts such as stigma, rumors, and relationship difficulties due to being perceived as HIV positive were prevalent; (iii) adherence was challenged by complexities of daily life, in particular post-coital dosing adherence suffered from alcohol use around time of sex, mobile populations, and transactional sex work. These themes resonated across dosing regimens and gender, and while most participants favored the intermittent dosing schedule, those in the intermittent group noted particular challenges in adhering to the post-coital dose. Culturally appropriate and consistent counseling addressing these issues may be critical for PrEP effectiveness.

Influence of control group therapy on the benefit from dose-dense chemotherapy in early breast cancer: a systemic review and meta-analysis.

PubMed

Goldvaser, Hadar; Majeed, Habeeb; Ribnikar, Domen; Šeruga, Boštjan; Ocaña, Alberto; Cescon, David W; Amir, Eitan

2018-06-01

Results from clinical trials of adjuvant dose-dense chemotherapy in patients with breast cancer are inconsistent. A systematic search of MEDLINE identified studies comparing the efficacy of dose-dense adjuvant chemotherapy to a standard treatment. The primary analysis included studies that used identical regimens in the experimental and control groups, but varied only dose density. A secondary analysis included studies that used either different drugs or doses in the experimental and the control groups. Hazard ratios (HRs) and 95% confidence intervals were computed for disease-free survival (DFS) and overall survival (OS) and pooled in a meta-analysis. Subgroup analyses and meta-regression explored drug schedules utilized in control groups and the influence of clinicopathologic variables on benefit from dose-dense therapy. The primary analysis included 5 studies comprising 9819 patients while the secondary analysis included 6 studies comprising 9679 patients. Dose-dense treatment significantly improved DFS (HR 0.85, p < 0.001) and OS (HR 0.86, p = 0.008) in the primary analysis. Similar results were observed in the secondary analysis. Dose-dense schedule was important primarily in studies utilizing paclitaxel every 3 weeks as the control group (interaction p = 0.04 for DFS interaction p = 0.001 for OS). A significantly greater relative magnitude of benefit was observed in pre-menopausal women and those with nodal involvement, but there was no influence of hormone receptor status on results. Adjuvant dose-dense regimens improve breast cancer outcomes. It remains uncertain whether the observed benefit reflects the impact of dose density or the inferiority of paclitaxel every 3 weeks as a control group.

Phase I study of continuous MKC-1 in patients with advanced or metastatic solid malignancies using the modified Time-to-Event Continual Reassessment Method (TITE-CRM) dose escalation design.

PubMed

Tevaarwerk, Amye; Wilding, George; Eickhoff, Jens; Chappell, Rick; Sidor, Carolyn; Arnott, Jamie; Bailey, Howard; Schelman, William; Liu, Glenn

2012-06-01

MKC-1 is an oral cell-cycle inhibitor with broad antitumor activity in preclinical models. Clinical studies demonstrated modest antitumor activity using intermittent dosing schedule, however additional preclinical data suggested continuous dosing could be efficacious with additional effects against the mTor/AKT pathway. The primary objectives were to determine the maximum tolerated dose (MTD) and response of continuous MKC-1. Secondary objectives included characterizing the dose limiting toxicities (DLTs) and pharmacokinetics (PK). Patients with solid malignancies were eligible, if they had measurable disease, ECOG PS ≤1, and adequate organ function. Exclusions included brain metastases and inability to receive oral drug. MKC-1 was dosed twice daily, continuously in 28-day cycles. Other medications were eliminated if there were possible drug interactions. Doses were assigned using a TITE-CRM algorithm following enrollment of the first 3 pts. Disease response was assessed every 8 weeks. Between 5/08-9/09, 24 patients enrolled (15 M/9 F, median 58 years, range 44-77). Patients 1-3 received 120 mg/d of MKC-1; patients 4-24 were dosed per the TITE-CRM algorithm: 150 mg [n = 1], 180 [2], 200 [1], 230 [1], 260 [5], 290 [6], 320 [5]. The median time on drug was 8 weeks (range 4-28). The only DLT occurred at 320 mg (grade 3 fatigue). Stable disease occurred at 150 mg/d (28 weeks; RCC) and 320 mg/d (16 weeks; breast, parotid). Escalation halted at 320 mg/d. Day 28 pharmacokinetics indicated absorption and active metabolites. Continuous MKC-1 was well-tolerated; there were no RECIST responses, although clinical benefit occurred in 3/24 pts. Dose escalation stopped at 320 mg/d, and this is the MTD as defined by the CRM dose escalation algorithm; this cumulative dose/cycle exceeds that determined from intermittent dosing studies. A TITE-CRM allowed for rapid dose escalation and was able to account for late toxicities with continuous dosing via a modified algorithm.

Real-time subway information for improving transit ridership.

DOT National Transportation Integrated Search

2016-08-01

In recent years, the standardization of transit schedule information has yielded a dramatic increase in the accessibility of computerized transit schedules and given rise to real-time service schedules. Two such real-time service schedules are the Ge...

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

Detilleux, Michel; Centner, Baudouin

The paper describes different methodologies and tools developed in-house by Tractebel Engineering to facilitate the engineering works to be carried out especially in the frame of decommissioning projects. Three examples of tools with their corresponding results are presented: - The LLWAA-DECOM code, a software developed for the radiological characterization of contaminated systems and equipment. The code constitutes a specific module of more general software that was originally developed to characterize radioactive waste streams in order to be able to declare the radiological inventory of critical nuclides, in particular difficult-to-measure radionuclides, to the Authorities. In the case of LLWAA-DECOM, deposited activitiesmore » inside contaminated equipment (piping, tanks, heat exchangers...) and scaling factors between nuclides, at any given time of the decommissioning time schedule, are calculated on the basis of physical characteristics of the systems and of operational parameters of the nuclear power plant. This methodology was applied to assess decommissioning costs of Belgian NPPs, to characterize the primary system of Trino NPP in Italy, to characterize the equipment of miscellaneous circuits of Ignalina NPP and of Kozloduy unit 1 and, to calculate remaining dose rates around equipment in the frame of the preparation of decommissioning activities; - The VISIMODELLER tool, a user friendly CAD interface developed to ease the introduction of lay-out areas in a software named VISIPLAN. VISIPLAN is a 3D dose rate assessment tool for ALARA work planning, developed by the Belgian Nuclear Research Centre SCK.CEN. Both softwares were used for projects such as the steam generators replacements in Belgian NPPs or the preparation of the decommissioning of units 1 and 2 of Kozloduy NPP; - The DBS software, a software developed to manage the different kinds of activities that are part of the general time schedule of a decommissioning project. For each activity, when relevant, algorithms allow to estimate, on the basis of local inputs, radiological exposures of the operators (collective and individual doses), production of primary, secondary and tertiary waste and their characterization, production of conditioned waste, release of effluents,... and enable the calculation and the presentation (histograms) of the global results for all activities together. An example of application in the frame of the Ignalina decommissioning project is given. (authors)« less

Phase II Study of Two Weeks on, One Week off Sunitinib Scheduling in Patients With Metastatic Renal Cell Carcinoma.

PubMed

Jonasch, Eric; Slack, Rebecca S; Geynisman, Daniel M; Hasanov, Elshad; Milowsky, Matthew I; Rathmell, W Kimryn; Stovall, Summer; Juarez, Donna; Gilchrist, Troy R; Pruitt, Lisa; Ornstein, Moshe C; Plimack, Elizabeth R; Tannir, Nizar M; Rini, Brian I

2018-06-01

Purpose Standard frontline treatment of patients with metastatic renal cell carcinoma currently includes sunitinib. A barrier to long-term treatment with sunitinib includes the development of significant adverse effects, including diarrhea, hand-foot syndrome (HFS), and fatigue. This trial assessed the effect of an alternate 2 weeks on, 1 week off (2/1) schedule of sunitinib on toxicity and efficacy in previously untreated patients with metastatic renal cell carcinoma. Methods Patients started with oral administration of 50 mg sunitinib on a 2/1 schedule and underwent schedule and dose alterations if toxicity developed. The primary end point was < 15% grade ≥ 3 fatigue, diarrhea, or HFS. With 60 patients, the upper bound of the CI would fall below the published 4/2 schedule grade ≥ 3 toxicity rate of 25% to 30%. Results Fifty-nine patients were treated between August 2014 and March 2016. Seventy-seven percent were intermediate or poor risk per Memorial Sloan Kettering Cancer Center criteria. With a median follow-up of 17 months, 25% of patients experienced grade 3 fatigue, HFS, or diarrhea; 37% required a dose reduction, and 10% discontinued because of toxicity. The overall response rate was 57%, median progression-free survival was 13.7 months, and median overall survival was not reached. At 12 weeks, Functional Assessment of Cancer Therapy-General scores dropped between 0% and 10% from baseline, with less reduction in patients who continued treatment longer. Conclusion The primary end point of decreased grade 3 toxicity was not met; however, treatment with a 2/1 sunitinib schedule is associated with a lack of grade 4 toxicity, a low patient discontinuation rate, and high efficacy.

[Intrathecal methotrexate in breast cancer meningeal carcinomatosis - Experience with a new administration schedule].

PubMed

Cochereau, Delphine; Da Costa, Sabrina; Le Maignan, Christine; Gauthier, Hélène; Cochereau, Jérôme; Espié, Marc; Giacchetti, Sylvie; Teixeira, Luis

2016-05-01

Methotrexate represents the standard intrathecal treatment of breast cancer meningeal carcinomatosis. However, its optimal schedule remains undefined. The aim of the present study was to evaluate results obtained with the methotrexate schedule used in Saint-Louis hospital (Paris). Patients followed in Saint-Louis hospital for breast cancer and who received intrathecal methotrexate were included in this retrospective monocentric study. Intrathecal treatment received contained methotrexate 12 mg/day (days: 1-5) and then 15 mg/week until progression or toxicity. Between 2003 and 2015, 41 patients were included. Primitive tumours were RH+/HER2-, HER2+ and triple-negative in respectively 66%, 14%, 5% and 15% of patients, 22% of them had meningeal carcinomatosis as metastatic disease initial manifestation. Objective response rate was 54%, median overall survival was 4.0 mois [CI 95%: 3-7.3] and 1-year survival rate was 15.2% (11.4%, 50% et 0% in RH+/HER2-, HER2+ and triple-negative subgroups; HR=0.45 [0.21-0.97] between HER2+ and RH+/HER2-). In univariate analysis, prognostic factors were brain involvement (p=0.049), initial cerebrospinal fluid protein level (p=0.0002) and concomitant systemic treatment received (p=0.049). This intrathecal methotrexate schedule demonstrates a similar median overall survival as the one obtained with a dose-dense schedule and an improved quality of life. Nevertheless, as the objective response and 1-year survival rates are slightly inferior, a dose-dense schedule remains still preferred in HER2+ patients or in those harboring a mainly meningeal progression. Copyright © 2016 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

Human neonatal rotavirus vaccine (RV3-BB) targets rotavirus from birth

PubMed Central

Thobari, Jarir At; Satria, Cahya Dewi; Handley, Amanda; Watts, Emma; Cowley, Daniel; Nirwati, Hera; Ackland, James; Standish, Jane; Justice, Frances; Byars, Gabrielle; Lee, Katherine J.; Barnes, Graeme L.; Bachtiar, Novilia S.; Icanervilia, Ajeng Viska; Boniface, Karen; Bogdanovic-Sakran, Nada; Pavlic, Daniel; Bishop, Ruth F.; Kirkwood, Carl D.; Buttery, Jim P.; Soenarto, Yati

2018-01-01

Background A birth dose strategy using a neonatal rotavirus vaccine to target early prevention of rotavirus disease may address remaining barriers to global vaccine implementation. Methods We conducted a randomized, placebo-controlled trial in Indonesia to evaluate the efficacy of an oral human neonatal rotavirus vaccine (RV3-BB) to prevent rotavirus gastroenteritis. Healthy newborns received three doses of RV3-BB administered in a neonatal schedule at 0-5 days, 8 and 14 weeks or infant schedule at 8, 14 and 18 weeks, or placebo. Laboratory-confirmed rotavirus gastroenteritis was graded using a modified Vesikari score. The primary analysis was efficacy against severe rotavirus gastroenteritis from two weeks after all doses to 18 months in the combined vaccine group (neonatal and infant schedule) compared with placebo. Results Vaccine efficacy against severe rotavirus gastroenteritis to 18 months was 63% in the combined vaccine group (95% CI 34, 80; p<0.001), 75% in the neonatal vaccine group (95% confidence interval [CI] 44, 91; p<0.001) and 51% in the infant vaccine group (95% CI 7, 76; p=0.03) in the per protocol analysis, with similar results in the intention-to-treat analysis. Vaccine efficacy to 12 months was 94% in the neonatal vaccine group (95%CI 56, 99; p=0.006). Vaccine take occurred in 78/83 (94%) in the neonatal vaccine group and 83/84 (99%) in the infant vaccine group. The vaccine was well tolerated, with similar incidence of adverse events in vaccine and placebo recipients. Conclusion RV3-BB was efficacious, immunogenic and well-tolerated when administered in a neonatal or infant schedule in Indonesia. PMID:29466164

Comparison of long-term (10 years) immunogenicity of two- and three-dose regimens of a combined hepatitis A and B vaccine in adolescents.

PubMed

Beran, Jiri; Kervyn, Diane; Wertzova, Veronika; Hobzova, Lenka; Tichy, Petr; Kuriyakose, Sherine; Leyssen, Maarten; Jacquet, Jeanne-Marie

2010-08-23

300 adolescents aged 12-15 years were randomised (1:1) into two groups to compare the long-term (10 years) immunogenicity profile of two doses of an Adult formulation [Group HAB_2D: 150; 0-6 months] vs. three doses of a Paediatric formulation [Group HAB_3D: 150; 0-1-6 months] of a combined hepatitis A and B (HAB) vaccine. At Year 10, anti-HAV seropositivity rate was 100% in both groups, while 85.9% and 85.1% subjects in the HAB_2D and HAB_3D groups, respectively, had anti-HBs antibody concentrations > or =10 mIU/mL. The anti-HAV antibody GMCs (HAB_2D: 429.3 mIU/mL; HAB_3D: 335.5 mIU/mL) and anti-HBs antibody GMCs (HAB_2D: 50.6 mIU/mL; HAB_3D: 60.1 mIU/mL) were similar in both groups. No vaccine-related serious adverse events were reported. Hence, with respect to long-term antibody persistence, the two-dose schedule of the combined HAB vaccine Adult formulation is an effective alternative to the conventional three-dose schedule of the Paediatric formulation in adolescents. Copyright 2010 Elsevier Ltd. All rights reserved.

Palonosetron as an anti-emetic and anti-nausea agent in oncology.

PubMed

Aapro, Matti S

2007-12-01

Palonosetron (Aloxi(®), Onicit(®), Paloxi(®)) is a second-generation 5-HT(3) receptor antagonist (RA) with an extended half-life of ~40 hours and high binding affinity for the 5-HT₃ receptor that is markedly different from other 5-HT(3) RAs. Phase III trials demonstrate that a single dose of palonosetron compared with traditional 5-HT₃ RAs is more effective in preventing chemotherapy-induced nausea and vomiting (CINV) during the first 24 hours following chemotherapy (acute CINV), and also exhibits prolonged efficacy to provide significantly better protection from CINV in the delayed and overall phases. This superior and extended protection from CINV conferred by palonosetron following a single intravenous dose before chemotherapy simplifies dosing schedules. Recent research has focused on optimization of palonosetron-based antiemetic regimens, particularly in combination with steroids and neurokinin-1 RAs. The available clinical data indicate high control rates for palonosetron, suggesting a synergistic potential for protection in patients scheduled to receive emetogenic drug regimens.

Drinking typography established by scheduled induction predicts chronic heavy drinking in a monkey model of ethanol self-administration.

PubMed

Grant, Kathleen A; Leng, Xiaoyan; Green, Heather L; Szeliga, Kendall T; Rogers, Laura S M; Gonzales, Steven W

2008-10-01

We have developed an animal model of alcohol self-administration that initially employs schedule-induced polydipsia (SIP) to establish reliable ethanol consumption under open access (22 h/d) conditions with food and water concurrently available. SIP is an adjunctive behavior that is generated by constraining access to an important commodity (e.g., flavored food). The induction schedule and ethanol polydipsia generated under these conditions affords the opportunity to investigate the development of drinking typologies that lead to chronic, excessive alcohol consumption. Adult male cynomolgus monkeys (Macaca fascicularis) were induced to drink water and 4% (w/v in water) ethanol by a Fixed-Time 300 seconds (FT-300 seconds) schedule of banana-flavored pellet delivery. The FT-300 seconds schedule was in effect for 120 consecutive sessions, with daily induction doses increasing from 0.0 to 0.5 g/kg to 1.0 g/kg to 1.5 g/kg every 30 days. Following induction, the monkeys were allowed concurrent access to 4% (w/v) ethanol and water for 22 h/day for 12 months. Drinking typographies during the induction of drinking 1.5 g/kg ethanol emerged that were highly predictive of the daily ethanol intake over the next 12 months. Specifically, the frequency in which monkeys ingested 1.5 g/kg ethanol without a 5-minute lapse in drinking (defined as a bout of drinking) during induction strongly predicted (correlation 0.91) subsequent ethanol intake over the next 12 months of open access to ethanol. Blood ethanol during induction were highly correlated with intake and with drinking typography and ranged from 100 to 160 mg% when the monkeys drank their 1.5 g/kg dose in a single bout. Forty percent of the population became heavy drinkers (mean daily intakes >3.0 g/kg for 12 months) characterized by frequent "spree" drinking (intakes >4.0 g/kg/d). This model of ethanol self-administration identifies early alcohol drinking typographies (gulping the equivalent of 6 drinks) that evolve into chronic heavy alcohol consumption in primates (drinking the equivalent of 16 to 20 drinks per day). The model may aid in identifying biological risks for establishing harmful alcohol drinking.

Drinking Typography Established by Scheduled Induction Predicts Chronic Heavy Drinking in a Monkey Model of Ethanol Self-Administration

PubMed Central

Grant, Kathleen A.; Leng, Xiaoyan; Green, Heather L.; Szeliga, Kendall T.; Rogers, Laura S. M.; Gonzales, Steven W.

2010-01-01

Background We have developed an animal model of alcohol self-administration that initially employs schedule-induced polydipsia (SIP) to establish reliable ethanol consumption under open access (22 h/d) conditions with food and water concurrently available. SIP is an adjunctive behavior that is generated by constraining access to an important commodity (e.g., flavored food). The induction schedule and ethanol polydipsia generated under these conditions affords the opportunity to investigate the development of drinking typologies that lead to chronic, excessive alcohol consumption. Methods Adult male cynomolgus monkeys (Macaca fascicularis) were induced to drink water and 4% (w/v in water) ethanol by a Fixed-Time 300 seconds (FT-300 seconds) schedule of banana-flavored pellet delivery. The FT-300 seconds schedule was in effect for 120 consecutive sessions, with daily induction doses increasing from 0.0 to 0.5 g/kg to 1.0 g/kg to 1.5 g/kg every 30 days. Following induction, the monkeys were allowed concurrent access to 4% (w/v) ethanol and water for 22 h/day for 12 months. Results Drinking typographies during the induction of drinking 1.5 g/kg ethanol emerged that were highly predictive of the daily ethanol intake over the next 12 months. Specifically, the frequency in which monkeys ingested 1.5 g/kg ethanol without a 5-minute lapse in drinking (defined as a bout of drinking) during induction strongly predicted (correlation 0.91) subsequent ethanol intake over the next 12 months of open access to ethanol. Blood ethanol during induction were highly correlated with intake and with drinking typography and ranged from 100 to 160 mg% when the monkeys drank their 1.5 g/kg dose in a single bout. Forty percent of the population became heavy drinkers (mean daily intakes >3.0 g/kg for 12 months) characterized by frequent “spree” drinking (intakes >4.0 g/kg/d). Conclusion This model of ethanol self-administration identifies early alcohol drinking typographies (gulping the equivalent of 6 drinks) that evolve into chronic heavy alcohol consumption in primates (drinking the equivalent of 16 to 20 drinks per day). The model may aid in identifying biological risks for establishing harmful alcohol drinking. PMID:18702645

Nicotine enhancement and reinforcer devaluation: Interaction with opioid receptors.

PubMed

Kirshenbaum, Ari P; Suhaka, Jesse A; Phillips, Jessie L; Voltolini de Souza Pinto, Maiary

In rats, nicotine enhances responding maintained by non-pharmacological reinforcers, and discontinuation of nicotine devalues those same reinforcers. The goal of this study was to assess the interaction of nicotine and opioid receptors and to evaluate the degree to which nicotine enhancement and nicotine-induced devaluation are related to opioid activation. Nicotine (0.4mg/kg), or nicotine plus naloxone (0.3 or 3.0mg/kg), was delivered to rats prior to progressive ratio (PR) schedule sessions in which sucrose was used as a reinforcer. PR-schedule responding was assessed during ten daily sessions of drug delivery, and for three post-dosing days/sessions. Control groups for this investigation included a saline-only condition, and naloxone-only (0.3 or 3.0mg/kg) conditions. When administered in conjunction with nicotine, both naloxone doses attenuated nicotine enhancement of the sucrose reinforcer, and the combination of the larger dose of naloxone (3.0mg/kg) with nicotine produced significant impairments in sucrose reinforced responding. When administered alone, neither dose of naloxone (0.3 & 3.0mg/kg) significantly altered responding in comparison to saline. Furthermore, when dosing was discontinued after ten once-daily doses, all nicotine groups (nicotine-only and nicotine+naloxone combination) demonstrated significant decreases in sucrose reinforcement compared to the saline group. Although opioid antagonism attenuated reinforcement enhancement by nicotine, it did not prevent reinforcer devaluation upon discontinuation of nicotine dosing, and the higher dose of naloxone (3.0mg/kg) produced decrements upon discontinuation on its own in the absence of nicotine. Copyright © 2016 Elsevier Inc. All rights reserved.

45 CFR 2551.52 - What factors are considered in determining a Senior Companion's service schedule?

Code of Federal Regulations, 2011 CFR

2011-10-01

... schedule? (a) Travel time between the Senior Companion's home and place of assignment is not part of the service schedule and is not stipended. (b) Travel time between individual assignments is a part of the service schedule and is stipended. (c) Meal time may be part of the service schedule and is stipended only...

45 CFR 2551.52 - What factors are considered in determining a Senior Companion's service schedule?

Code of Federal Regulations, 2010 CFR

2010-10-01

... schedule? (a) Travel time between the Senior Companion's home and place of assignment is not part of the service schedule and is not stipended. (b) Travel time between individual assignments is a part of the service schedule and is stipended. (c) Meal time may be part of the service schedule and is stipended only...

Real-time scheduling using minimum search

NASA Technical Reports Server (NTRS)

Tadepalli, Prasad; Joshi, Varad

1992-01-01

In this paper we consider a simple model of real-time scheduling. We present a real-time scheduling system called RTS which is based on Korf's Minimin algorithm. Experimental results show that the schedule quality initially improves with the amount of look-ahead search and tapers off quickly. So it sppears that reasonably good schedules can be produced with a relatively shallow search.

[Appropriate usage of antibiotics by therapeutic drug monitoring].

PubMed

Kokubun, Hideya; Kimura, Toshimi; Yago, Kazuo

2007-06-01

Aminoglycosides are mainly distributed in the extracellular fluid, so when they are given to neonates who have a large amount of extracellular fluid, their distribution is increased. In our data, the volume of distribution (Vd) of Arbekacin in the neonates was twice that of the adults, 0.54 l/kg. Therefore, the dose per weight of aminoglycosides to the neonates should be increased more than to the adults. In the renal function of the neonates, differentiation of the nephron is completed within 36 weeks after conception, but it is functionally immature. In our data, renal drug excretion increased rapidly in the post-conceptional ages (PCAs) of 34-35 weeks. Consequently, we based the Arbekacin administration schedule for the neonates on the PCAs. There is excellent correlation between serum level of vancomicin (VCM) and dose x serum creatinine (Scr)/weight in the haemodialysis patients, suggesting that we can use weight and Scr to set the VCM administration schedule for these patients. We also established on administration schedule of Teicoplanin for the haemodialysis patients. In this article, we present the TDM analysis result of the antibiotics in our hospital.

[Concurrent chemoradiation in lung cancer].

PubMed

Girard, Nicolas; Mornex, Françoise

2005-12-01

Concurrent chemoradiation has become for the 15 last years the standard treatment for locally advanced non-small cell lung cancer, either as a definite therapy in non resectable tumors, or in a neoadjuvant setting in potentially resectable tumors. Associating sequential and concurrent schedules, by administering chemotherapy before or after concurrent chemoradiation, has been recently investigated, but the best sequence remains a matter of controversy. Increasing local control and survival after definite chemoradiation seems possible not only by using optimized radiation fractionation schedules and escalated total doses, but also by associating more convenient and less toxic chemotherapy agents at the right cytotoxic or radio-sensitizing dose. Moreover, recent data have suggested that surgery following induction chemoradiation is feasible and effective in selected patients without mediastinal nodes involvement, if a complete resection can be performed. In patients with localized small cell lung cancer, early concurrent chemoradiation with platinium and etoposide has been recognized as the state-of-the-art treatment. The increasing number of ongoing trials including modern radiation schedules combined with newer chemotherapy agents shows that chemoradiation is one of the most promising therapeutic strategies in thoracic oncology.

Human coffee drinking: manipulation of concentration and caffeine dose.

PubMed Central

Griffiths, R R; Bigelow, G E; Liebson, I A; O'Keeffe, M; O'Leary, D; Russ, N

1986-01-01

In a residential research ward coffee drinking was studied in 9 volunteer human subjects with histories of heavy coffee drinking. A series of five experiments was undertaken to characterize adlibitum coffee consumption and to investigate the effects of manipulating coffee concentration, caffeine dose per cup, and caffeine preloads prior to coffee drinking. Manipulations were double-blind and scheduled in randomized sequences across days. When cups of coffee were freely available, coffee drinking tended to be rather regularly spaced during the day with intercup intervals becoming progressively longer throughout the day; experimental manipulations showed that this lengthening of intercup intervals was not due to accumulating caffeine levels. Number of cups of coffee consumed was an inverted U-shaped function of both coffee concentration and caffeine dose per cup; however, coffee-concentration and dose-per-cup manipulations did not produce similar effects on other measures of coffee drinking (intercup interval, time to drink a cup, within-day distribution of cups). Caffeine preload produced dose-related decreases in number of cups consumed. As a whole, these experiments provide some limited evidence for both the suppressive and the reinforcing effects of caffeine on coffee consumption. Examination of total daily coffee and caffeine intake across experiments, however, provides no evidence for precise regulation (i.e., titration) of coffee or caffeine intake. PMID:3958660

The comparison of predictive scheduling algorithms for different sizes of job shop scheduling problems

NASA Astrophysics Data System (ADS)

Paprocka, I.; Kempa, W. M.; Grabowik, C.; Kalinowski, K.; Krenczyk, D.

2016-08-01

In the paper a survey of predictive and reactive scheduling methods is done in order to evaluate how the ability of prediction of reliability characteristics influences over robustness criteria. The most important reliability characteristics are: Mean Time to Failure, Mean Time of Repair. Survey analysis is done for a job shop scheduling problem. The paper answers the question: what method generates robust schedules in the case of a bottleneck failure occurrence before, at the beginning of planned maintenance actions or after planned maintenance actions? Efficiency of predictive schedules is evaluated using criteria: makespan, total tardiness, flow time, idle time. Efficiency of reactive schedules is evaluated using: solution robustness criterion and quality robustness criterion. This paper is the continuation of the research conducted in the paper [1], where the survey of predictive and reactive scheduling methods is done only for small size scheduling problems.

Influences on cocaine tolerance assessed under a multiple conjunctive schedule of reinforcement.

PubMed

Yoon, Jin Ho; Branch, Marc N

2009-11-01

Under multiple schedules of reinforcement, previous research has generally observed tolerance to the rate-decreasing effects of cocaine that has been dependent on schedule-parameter size in the context of fixed-ratio (FR) schedules, but not under the context of fixed-interval (FI) schedules of reinforcement. The current experiment examined the effects of cocaine on key-pecking responses of White Carneau pigeons maintained under a three-component multiple conjunctive FI (10 s, 30 s, & 120 s) FR (5 responses) schedule of food presentation. Dose-effect curves representing the effects of presession cocaine on responding were assessed in the context of (1) acute administration of cocaine (2) chronic administration of cocaine and (3) daily administration of saline. Chronic administration of cocaine generally resulted in tolerance to the response-rate decreasing effects of cocaine, and that tolerance was generally independent of relative FI value, as measured by changes in ED50 values. Daily administration of saline decreased ED50 values to those observed when cocaine was administered acutely. The results show that adding a FR requirement to FI schedules is not sufficient to produce schedule-parameter-specific tolerance. Tolerance to cocaine was generally independent of FI-parameter under the present conjunctive schedules, indicating that a ratio requirement, per se, is not sufficient for tolerance to be dependent on FI parameter.

Low-dose cyclophosphamide administered as daily or single dose enhances the antitumor effects of a therapeutic HPV vaccine

PubMed Central

Peng, Shiwen; Lyford-Pike, Sofia; Akpeng, Belinda; Wu, Annie; Hung, Chien-Fu; Hannaman, Drew; Saunders, John R.; Wu, T.-C.

2012-01-01

Although therapeutic HPV vaccines are able to elicit systemic HPV-specific immunity, clinical responses have not always correlated with levels of vaccine-induced CD8+ T cells in human clinical trials. This observed discrepancy may be attributable to an immunosuppressive tumor microenvironment in which the CD8+ T cells are recruited. Regulatory T cells (Tregs) are cells that can dampen cytotoxic CD8+ T-cell function. Cyclophosphamide (CTX) is a systemic chemotherapeutic agent, which can eradicate immune cells, including inhibitory Tregs. The optimal dose and schedule of CTX administration in combination with immunotherapy to eliminate the Treg population without adversely affecting vaccine-induced T-cell responses is unknown. Therefore, we investigated various dosing and administration schedules of CTX in combination with a therapeutic HPV vaccine in a preclinical tumor model. HPV tumor-bearing mice received either a single preconditioning dose or a daily dose of CTX in combination with the pNGVL4a-CRT/E7(detox) DNA vaccine. Both single and daily dosing of CTX in combination with vaccine had a synergistic anti-tumor effect as compared to monotherapy alone. The potent antitumor responses were attributed to the reduction in Treg frequency and increased infiltration of HPV16 E7-specific CD8+ T cells, which led to higher ratios of CD8+/Treg and CD8+/CD11b+Gr-1+ myeloid-derived suppressor cells (MDSCs). There was an observed trend toward decreased vaccine-induced CD8+ T-cell frequency with daily dosing of CTX. We recommend a single, preconditioning dose of CTX prior to vaccination due to its efficacy, ease of administration, and reduced cumulative adverse effect on vaccine-induced T cells. PMID:23011589

Phase I Study of the Hedgehog Pathway Inhibitor IPI-926 in Adult Patients with Solid Tumors

PubMed Central

Jimeno, Antonio; Weiss, Glen J.; Miller, Wilson H.; Gettinger, Scott; Eigl, Bernard J.C.; Chang, Anne Lynne S.; Dunbar, Joi; Devens, Shannon; Faia, Kerrie; Skliris, Georgios; Kutok, Jeff; Lewis, Karl D.; Tibes, Raoul; Sharfman, William H.; Ross, Robert W.; Rudin, Charles M.

2013-01-01

Purpose To conduct a first-in-human phase I study to determine the dose-limiting toxicities (DLT), characterize the pharmacokinetic profile, and document the antitumor activity of IPI-926, a new chemical entity that inhibits the Hedgehog pathway (HhP). Experimental Design Patients with solid tumors refractory to standard therapy were given IPI-926 once daily (QD) by mouth in 28-day cycles. The starting dose was 20 mg, and an accelerated titration schedule was used until standard 3 + 3 dose-escalation cohorts were implemented. Pharmacokinetics were evaluated on day −7 and day 22 of cycle 1. Results Ninety-four patients (32F, 62M; ages, 39–87) received doses ranging from 20 to 210 mg QD. Dose levels up to and including 160 mg administered QD were well tolerated. Toxicities consisted of reversible elevations in aspartate aminotransferase (AST), alanine aminotransferase (ALT) and bilirubin, fatigue, nausea, alopecia, and muscle spasms. IPI-926 was not associated with hematologic toxicity. IPI-926 pharmacokinetics were characterized by a slow absorption (Tmax = 2–8 hours) and a terminal half-life (t1/2) between 20 and 40 hours, supporting QD dosing. Of those HhP inhibitor-naïve patients with basal cell carcinoma (BCC) who received more than one dose of IPI-926 and had a follow-up clinical or Response Evaluation Criteria in Solid Tumors (RECIST) assessment, nearly a third (8 of 28 patients) showed a response to IPI-926 at doses ≥130 mg. Conclusions IPI-926 was well tolerated up to 160 mg QD within 28-day cycles, which was established as the recommended phase II dose and schedule for this agent. Single-agent activity of IPI-926 was observed in HhP inhibitor–naïve patients with BCC. PMID:23575478

The activity of several newer antimicrobials against logarithmically multiplying M. leprae in mice.

PubMed

Burgos, Jasmin; de la Cruz, Eduardo; Paredes, Rose; Andaya, Cora Revelyn; Gelber, Robert H

2011-09-01

Moxifloxacin, rifampicin, rifapentine, linezolid, and PA 824, alone and in combination, have been previously administered, as single doses and five times daily doses, to M. leprae infected mice during lag phase multiplication and were each found to have some bactericidal activity. The fluroquinolones, ofloxacin, moxifloxacin and gatifloxacin, (50 mg/kg, 150 mg/kg and 300 mg/kg) and the rifamycins (5 mg/kg, 10 mg/kg, and 20 mg/kg), rifampicin and rifapentine, were evaluated alone and in combination for bactericidal activity against M. leprae using the mouse footpad model during logarithmic multiplication. Linezolid and PA 824 were similarly evaluated alone and linezolid in combination with rifampicin, minocycline and ofloxacin. The three fluroquinolones and rifamycins were found alone and in combination to be bactericidal at all dosage schedules. PA 824 had no activity against M. leprae, while linezolid at a dose of 25 mg/kg was bacteriostatic, and progressively more bactericidal at doses of 50 mg/kg and 100 mg/kg. No antagonisms were detected between any of these drugs when used in combinations. Moxifloxacin, gatifloxacin, rifapentine and linezolid were found bactericidal against rapidly multiplying M. leprae.

Biological properties and response to x-rays of first-generation transplants of spontaneous mammary carcinomas in C3H mice.

PubMed

Fowler, J F; Sheldon, P W; Begg, A C; Hill, S A; Smith, A M

1975-05-01

First-generation transplants of spontaneous mouse mammary carcinomas have been used extensively for radiobiological investigations of fractionated irradiation schedules, r.b.e. of fast neutrons and effectiveness of radiosensitizers, as reported elsewhere. The present work investigates the growth characteristics of the tumours; the criteria for the choice of end-points used in the definition of 'local control' of irradiated tumours; the reason for a decrease of 30 per cent in X-ray dose required to control tumours in females as compared with male mice; the proportion of hypoxic cells and its variation with time (reoxygenation) after a single dose of 1500 rad of X-rays; and the repair capacity of tumour cells within 24 hours after a substantial first dose of X-rays. Evidence is presented that the male-female difference was due to a higher proportion of hypoxic cells in tumours in male than in female mice. The repair of sub-lethal injury in tumour cells made hypoxic was slightly less than in skin made hypoxic but not significantly so. In the two-dose experiments on clamped tumours, no evidence of induced synchrony was found.

Symptom-Triggered vs. Fixed-Dosing Management of Alcohol Withdrawal Syndrome.

PubMed

Skinner, Reagan T

2014-01-01

A literature review was conducted with the objective of creating evidence-based recommendations for use of symptom-triggered therapy (STT) or fixed-schedule dosing in treating alcohol withdrawal syndrome in inpatients. Use of STT reduced duration of therapy as well as the number of patients requiring treatment or medication, potentially reducing costs and risk of adverse medication reactions.

Rapid-Infusion Rituximab in Lymphoma Treatment: 2-Year Experience in a Single Institution

PubMed Central

Atay, Sevcan; Barista, Ibrahim; Gundogdu, Fatma; Akgedik, Kiymet; Arpaci, Afey

2012-01-01

Purpose: Rituximab is a chimeric anti-CD20 monoclonal antibody. We aimed to explore the safety and tolerability of rapid infusion rituximab, (over 90 minutes) in patients with non-Hodgkin's lymphoma at Hacettepe University Department of Medical Oncology. Patients and Methods: Adult patients diagnosed with non-Hodgkin's lymphoma who were to receive rituximab were included in the study. The schedule of administration for cycle 1 was unaltered and delivered according to the product monograph. All subsequent cycles were administered over a total infusion time of 90 minutes (20% of the dose in the first 30 minutes, then the remaining 80% over 60 minutes, total dose delivered in 500 mL). All patients were observed for infusion-related reactions during the rituximab infusion, and vital signs were recorded every 15 minutes. Results: From July 2006 to December 2008, 75 patients with non-Hodgkin's lymphoma were treated with rituximab-based chemotherapy. A total of 372 infusions were administered. The majority of patients were treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone, or rituximab only. The 90-minute rituximab infusion schedule was well tolerated, with no grade 3 or 4 infusion-related adverse events observed. Conclusion: A rapid infusion rituximab over 90 minutes is well tolerated and safe when administered as the second and subsequent infusions in the course of therapy. PMID:22942806

A decade of experience with a clinical pharmacokinetics service.

PubMed

Ambrose, P J; Smith, W E; Palarea, E R

1988-09-01

The development, operation, and functions of the pharmacokinetics service at Memorial Medical Center of Long Beach (MMCLB) are described, and the data used to determine the quality and cost-effectiveness of the service are presented. Current functions of the pharmacokinetics service at MMCLB include making brief written comments about the interpretations of serum drug concentrations (SDCs) and oral recommendations to physicians on dosage adjustment; provision of written consultations with dosage recommendations; provision of drug information, education, and research; and development of drug dosing guidelines for the pharmacy and medical staff. During the 10-year existence of this service, costs have been justified on the basis of not only revenue generated by the service (in the form of "drug concentration scheduling" and "drug concentration evaluation" fees charged to patients) but also by cost savings resulting from the prevention of inappropriate, misleading, and potentially dangerous SDCs. An audit conducted in 1986 showed that the policy of having pharmacists schedule the sampling times for SDCs saves about $500,000 annually. Quality assurance has been documented by auditing compliance with and therapeutic effectiveness of dosing guidelines and by working with laboratory personnel to identify and prevent spurious SDC results and assay errors. The methods used by the pharmacokinetics service at MMCLB to document the benefits of the service have been vital in proving both its cost-effectiveness and its positive effect on patient care.

Can high-dose fotemustine reverse MGMT resistance in glioblastoma multiforme?

PubMed

Gallo, Chiara; Buonerba, Carlo; Di Lorenzo, Giuseppe; Romeo, Valeria; De Placido, Sabino; Marinelli, Alfredo

2010-11-01

Glioblastoma multiforme (GBM), the highest grade malignant glioma, is associated with a grim prognosis-median overall survival is in the range 12-15 months, despite optimum treatment. Surgery to the maximum possible extent, external beam radiotherapy, and systemic temozolomide chemotherapy are current standard treatments for newly diagnosed GBM, with intracerebral delivery of carmustine wafers (Gliadel). Unfortunately, the effectiveness of chemotherapy can be hampered by the DNA repair enzyme O6-methylguanine methyltransferase (MGMT), which confers resistance both to temozolomide and nitrosoureas, for example fotemustine and carmustine. MGMT activity can be measured by PCR and immunohistochemistry, with the former being the current validated technique. High-dose chemotherapy can deplete MGMT levels in GBM cells and has proved feasible in various trials on temozolomide, in both newly diagnosed and recurrent GBM. We here report the unique case of a GBM patient, with high MGMT expression by immunohistochemistry, who underwent an experimental, high-dose fotemustine schedule after surgery and radiotherapy. Although treatment caused two episodes of grade 3-4 thrombocytopenia, a complete response and survival of more than three years were achieved, with a 30% increase in dose intensity compared with the standard fotemustine schedule.

12 CFR 1005.36 - Transfers scheduled before the date of transfer.

Code of Federal Regulations, 2014 CFR

2014-01-01

... of transfer. (a) Timing. (1) For a one-time transfer scheduled five or more business days before the... the timing requirements of that section. (b) Accuracy. (1) For a one-time transfer scheduled five or... 12 Banks and Banking 8 2014-01-01 2014-01-01 false Transfers scheduled before the date of transfer...

MeNZB vaccine and epidemic control: when do you stop vaccinating?

PubMed

Loring, Belinda J; Turner, Nikki; Petousis-Harris, Helen

2008-11-05

New Zealand developed a strain-specific group B meningococcal vaccine to control an epidemic. Following a mass vaccination campaign of three doses to the population under 20 years of age, commencing in July 2004, the vaccine continued to be offered routinely as a four-dose schedule from 6 weeks of age. There is little international data on when to cease epidemic vaccination campaigns. The decision to stop using this vaccine needed to take into account a range of factors. These included epidemiology, vaccine effectiveness and duration of immunity, vaccine coverage, concomitant use with other vaccinations being added to the infant schedule, vaccine supply and cost-benefit criteria. This paper discusses these issues, along with the potential challenges for communication to both health professionals and the public.

Sci-Thur PM – Colourful Interactions: Highlights 05: Opal–the Oncology Patient Application

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

Joseph, Ackeem; Herrera, David; Kildea, John

We describe Opal (Oncology portal and application), the mobile phone app and patient portal that we have developed and are deploying for Radiation Oncology patients at our cancer centre. Opal is a novel tool to empower patients with their own personal medical data, including appointment schedules, consultation notes, test results, radiotherapy treatment planning information and wait time management. Furthermore, due to its integration with our electronic medical record and treatment planning database, Opal will allow us to collect patient reported outcomes from consenting patients and link them directly with dose volume histograms and other treatment data.

Hypofractionated radiosurgery for intact or resected brain metastases: defining the optimal dose and fractionation.

PubMed

Eaton, Bree R; Gebhardt, Brian; Prabhu, Roshan; Shu, Hui-Kuo; Curran, Walter J; Crocker, Ian

2013-06-07

Hypofractionated Radiosurgery (HR) is a therapeutic option for delivering partial brain radiotherapy (RT) to large brain metastases or resection cavities otherwise not amenable to single fraction radiosurgery (SRS). The use, safety and efficacy of HR for brain metastases is not well characterized and the optimal RT dose-fractionation schedule is undefined. Forty-two patients treated with HR in 3-5 fractions for 20 (48%) intact and 22 (52%) resected brain metastases with a median maximum dimension of 3.9 cm (0.8-6.4 cm) between May 2008 and August 2011 were reviewed. Twenty-two patients (52%) had received prior radiation therapy. Local (LC), intracranial progression free survival (PFS) and overall survival (OS) are reported and analyzed for relationship to multiple RT variables through Cox-regression analysis. The most common dose-fractionation schedules were 21 Gy in 3 fractions (67%), 24 Gy in 4 fractions (14%) and 30 Gy in 5 fractions (12%). After a median follow-up time of 15 months (range 2-41), local failure occurred in 13 patients (29%) and was a first site of failure in 6 patients (14%). Kaplan-Meier estimates of 1 year LC, intracranial PFS, and OS are: 61% (95% CI 0.53 - 0.70), 55% (95% CI 0.47 - 0.63), and 73% (95% CI 0.65 - 0.79), respectively. Local tumor control was negatively associated with PTV volume (p = 0.007) and was a significant predictor of OS (HR 0.57, 95% CI 0.33 - 0.98, p = 0.04). Symptomatic radiation necrosis occurred in 3 patients (7%). HR is well tolerated in both new and recurrent, previously irradiated intact or resected brain metastases. Local control is negatively associated with PTV volume and a significant predictor of overall survival, suggesting a need for dose escalation when using HR for large intracranial lesions.

Optimal dose of rocuronium bromide undergoing adenotonsillectomy under 5% sevoflurane with fentanyl.

PubMed

Huh, Hyub; Park, Jeong Jun; Kim, Ji Yeong; Kim, Tae Hoon; Yoon, Seung Zhoo; Shin, Hye Won; Lee, Hye-Won; Lim, Hye-Ja; Cho, Jang Eun

2017-10-01

Adenotonsillectomy is a short surgical procedure under general anaesthesia in children. An ideal muscle relaxant for adenotonsillectomy would create an intense neuromuscular block while having a quick recovery time without postoperative morbidity. We compared the effect of different doses of rocuronium for the tracheal intubation in children under 5% sevoflurane and fentanyl. 75 children (aged 3-10 years, ASA I) scheduled for adenotonsillectomy were enrolled. Anaesthesia was induced with propofol 2.5 mg/kg, followed by fentanyl 2 μg/kg. After mask ventilation with 5 vol% sevoflurane in 100% oxygen for 2 min, 2 ml of study drug was administered intravenously, i.e., either normal saline (S Group) or one of two doses (0.15 or 0.3 mg/kg) of rocuronium. We assessed conditions during tracheal intubation and also recorded the surgical condition, the time from discontinuation of sevoflurane to extubation and PAED scale, pain scores in PACU. Rocuronium groups (96% and 100%, respectively; P < 0.01) showed statistically superior clinically acceptable intubating conditions than the saline group (72%). The 0.3 mg/kg rocuronium (80%) treatment clearly resulted in excellent intubating conditions compared with the 0.15 mg/kg group (44%; p = 0.028). There was no significant difference in the time to extubation and surgical condition, and in the postoperative measures of emergence delirium, pain, and recovery time among the three groups. A dose of 0.3 mg/kg rocuronium may provide optimal intubating conditions without delayed recovery in 5% sevoflurane anaesthesia with fentanyl in children undergoing adenotonsillectomy. NCT02467595. Copyright © 2017 Elsevier B.V. All rights reserved.

Designing a fuzzy scheduler for hard real-time systems

NASA Technical Reports Server (NTRS)

Yen, John; Lee, Jonathan; Pfluger, Nathan; Natarajan, Swami

1992-01-01

In hard real-time systems, tasks have to be performed not only correctly, but also in a timely fashion. If timing constraints are not met, there might be severe consequences. Task scheduling is the most important problem in designing a hard real-time system, because the scheduling algorithm ensures that tasks meet their deadlines. However, the inherent nature of uncertainty in dynamic hard real-time systems increases the problems inherent in scheduling. In an effort to alleviate these problems, we have developed a fuzzy scheduler to facilitate searching for a feasible schedule. A set of fuzzy rules are proposed to guide the search. The situation we are trying to address is the performance of the system when no feasible solution can be found, and therefore, certain tasks will not be executed. We wish to limit the number of important tasks that are not scheduled.

Ketamine versus alfentanil combined with propofol for sedation in colonoscopy procedures: a randomized prospective study.

PubMed

Türk, Hacer Şebnem; Aydoğmuş, Meltem; Ünsal, Oya; Işıl, Canan Tülay; Citgez, Bülent; Oba, Sibel; Açık, Mehmet Eren

2014-12-01

Different drug combinations are used for sedation in colonoscopy procedures. A ketamine-propofol (ketofol) mixture provides effective sedation and has minimal adverse effects. Alfentanil also provides anesthesia for short surgical procedures by incremental injection as an adjunct. However, no study has investigated the use of ketofol compared with an opioid-propofol combination in colonoscopic procedures. A total of 70 patients, ASA physical status I-II, scheduled to undergo elective colonoscopy, were enrolled in this prospective randomized study and allocated to two groups. After premedication, sedation induction was performed with 0.5 mg/kg ketamine +1 mg/kg propofol in Group KP, and 10 mg/kg alfentanil +1 mg/kg propofol in Group AP. Propofol was added when required. Demographic data, colonoscopy duration, recovery time, discharge time, mean arterial pressure (MAP), heart rate (HR), peripheral oxygen saturation, Ramsey Sedation Scale values, colonoscopy patients' satisfaction scores, and complications were recorded. The need for additional propofol doses was significantly higher in Group AP than in Group KP. MAP at minute 1 and 5, Ramsey Sedation Scale at minute 5, and discharge time were significantly higher in Group KP than in Group AP. Additional propofol doses and total propofol dose were significantly lower in Group KP than in Group AP. Ketofol provided better hemodynamic stability and quality of sedation compared with alfentanil-propofol combination in elective colonoscopy, and required fewer additional propofol; however, it prolonged discharge time. Both combinations can safely be used in colonoscopy sedation.

Corneal targeted nanoparticles for sustained natamycin delivery and their PK/PD indices: an approach to reduce dose and dosing frequency.

PubMed

Chandasana, Hardik; Prasad, Yarra Durga; Chhonker, Yashpal S; Chaitanya, Telaprolu K; Mishra, Nripendra N; Mitra, Kalyan; Shukla, Praveen K; Bhatta, Rabi S

2014-12-30

Natamycin is the only approved medication for the treatment of mycotic keratitis. Current dosage regimen include one drop of natamycin suspension (5% w/v) instilled in the conjunctival sac at hourly or two hourly intervals for several days which has poor patient compliance. The purpose of the present study was to design a corneal targeted nanoformulation in order to reduce dose and dosing frequency of natamycin and evaluate its pharmacokinetic/pharmacodynamic indices in comparison with clinical marketed preparation. The nanoparticles prepared by nanoprecipitation method were in nanometer size range with high entrapment efficiency and positive surface charge. In-vitro release studies indicated prolonged release of natamycin up to 8h. In-vitro antifungal activity was comparable with marketed preparation. The performance of nanoformulations was evaluated in rabbit eyes. The concentration of natamycin in tear fluid was determined by using LC-MS/MS. The pharmacokinetic parameters such as area under the curve, t½ and mean residence time were significantly higher and clearance was significantly lower for nanoformulations with that of marketed preparation. The optimized dosing schedule to maintain natamycin concentration above tenfold of MIC90 was one instillation in every 5h. Moreover, 1/5th dose reduction of nanoformulation was also effective. Copyright © 2014 Elsevier B.V. All rights reserved.

Single dose filgastrim in cytotoxic-induced neutropaenia in children.

PubMed

Abdallah, F K

2008-01-01

To document the impact of fixed dose weight adjusted filgastrim (G-CSF) in cytotoxic-induced neutropaenia. A descriptive cross-sectional study. Paediatric Oncology Unit at Kenyatta National Hospital, Nairobi, Kenya. All paediatric oncology patients who had developed cytotoxic-induced neutropaenia. The following were documented for every tissue proven case of malignancy; age, sex, type of malignancy, treatment regimen and schedule, initial blood count at the time of neutropaenia; subsequent blood counts daily for five days from day one of single dose filgastrim, and the calculated neutrophil incremental count. Initially eight patients with solid tumours previously treated with filgastrim revealed that cytotoxic induced neutropaenia could be ameliorated by a single dose of filgastrim. Subsequently, the study listed thirty patients. This cohort consisted of; 37% rhabdomyosarcoma, 30% Burkitts, 27% acute lymphoblastic leukaemia and 6% Hodgkin's lymphoma. Increased neutrophil count after 48 hours was documented in 26 (87%) patients, with absolute neutrophil counts range of 0.5 to 31.5 x 10(9)/L. This response was significantly influenced by gender (p>0.0001), malignancy type and chemotherapy regimen (p>0.001). The study shows that chemotherapy induced neutropaenia can be alleviated by a single dose of filgastrim without adverse effects on lymphoblastic leukaemia. This study suggests that a single dose of filgastrim should be first tried in cytotoxic induced neutropaenia in the paediatric age group.

Research on Production Scheduling System with Bottleneck Based on Multi-agent

NASA Astrophysics Data System (ADS)

Zhenqiang, Bao; Weiye, Wang; Peng, Wang; Pan, Quanke

Aimed at the imbalance problem of resource capacity in Production Scheduling System, this paper uses Production Scheduling System based on multi-agent which has been constructed, and combines the dynamic and autonomous of Agent; the bottleneck problem in the scheduling is solved dynamically. Firstly, this paper uses Bottleneck Resource Agent to find out the bottleneck resource in the production line, analyses the inherent mechanism of bottleneck, and describes the production scheduling process based on bottleneck resource. Bottleneck Decomposition Agent harmonizes the relationship of job's arrival time and transfer time in Bottleneck Resource Agent and Non-Bottleneck Resource Agents, therefore, the dynamic scheduling problem is simplified as the single machine scheduling of each resource which takes part in the scheduling. Finally, the dynamic real-time scheduling problem is effectively solved in Production Scheduling System.

Immunogenicity and safety evaluation of bivalent types 1 and 3 oral poliovirus vaccine by comparing different poliomyelitis vaccination schedules in China: A randomized controlled non-inferiority clinical trial

PubMed Central

Qiu, Jingjun; Yang, Yunkai; Huang, Lirong; Wang, Ling; Jiang, Zhiwei; Gong, Jian; Wang, Wei; Wang, Hongyan; Guo, Shaohong; Li, Chanjuan; Wei, Shuyuan; Mo, Zhaojun; Xia, Jielai

2017-01-01

ABSTRACT Background: The type 2 component of the oral poliovirus vaccine is targeted for global withdrawal through a switch from the trivalent oral poliovirus vaccine (tOPV) to a bivalent oral poliovirus vaccine (bOPV). The switch is intended to prevent paralytic polio caused by circulating vaccine-derived poliovirus type 2. We aimed to assess the immunogenicity and safety profile of 6 vaccination schedules with different sequential doses of inactivated poliovirus vaccine (IPV), tOPV, or bOPV. Methods: A randomized controlled trial was conducted in China in 2015. Healthy newborn babies randomly received one of the following 6 vaccination schedules: cIPV-bOPV-bOPV(I-B-B), cIPV-tOPV-tOPV(I-T-T), cIPV-cIPV-bOPV(I-I-B), cIPV-cIPV-tOPV(I-I-T), cIPV-cIPV-cIPV(I-I-I), or tOPV-tOPV-tOPV(T-T-T). Doses were administered sequentially at 4–6 week intervals after collecting baseline blood samples. Patients were proactively followed up for observation of adverse events after the first dose and 30 days after all doses. The primary study objective was to investigate the immunogenicity and safety profile of different vaccine schedules, evaluated by seroconversion, seroprotection and antibody titer against poliovirus types 1, 2, and 3 in the per-protocol population. Results: Of 600 newborn babies enrolled, 504 (84.0%) were included in the per-protocol population. For type 1 poliovirus, the differences in the seroconversion were 1.17% (95% CI = −2.74%, 5.08%) between I-B-B and I-T-T and 0.00% (95% CI: −6.99%, 6.99%) between I-I-B and I-I-T; for type 3 poliovirus, differences in the seroconversion were 3.49% (95% CI: −1.50%, 8.48%) between I-B-B and I-T-T and −2.32% (95% CI: −5.51%, 0.86%) between I-I-B and I-I-T. The non-inferiority conclusion was achieved in both poliovirus type 1 and 3 with the margin of −10%. Of 24 serious adverse events reported, no one was vaccine-related. Conclusions: The vaccination schedules with bOPV followed by one or 2 doses of IPV were recommended to substitute for vaccinations involving tOPV without compromising the immunogenicity and safety in the Chinese population. The findings will be essential for policy formulation by national and global authorities to facilitate polio elimination. PMID:28362135

The adequate rocuronium dose required for complete block of the adductor muscles of the thigh.

PubMed

Fujimoto, M; Kawano, K; Yamamoto, T

2018-03-01

Rocuronium can prevent the obturator jerk during transurethral resection of bladder tumors. We investigated the adequate rocuronium dose required for complete block of the thigh adductor muscles, and its correlation with individual responses of the adductor pollicis muscle to rocuronium. Eleven patients scheduled for transurethral resection of bladder tumors under general anesthesia were investigated. After general anesthesia induction, neuromuscular monitoring of the adductor pollicis muscle and ultrasonography-guided stimulation of the obturator nerve was commenced. Rocuronium, 0.15 mg/kg, was repeatedly administered intravenously. The adequate rocuronium dose required for complete block of the thigh muscles, defined as the cumulative dose of rocuronium administered until that time, and its correlation with the first twitch response of the adductor pollicis muscle on train-of-four stimulation after initial rocuronium administration was analyzed. The rocuronium dose found adequate for complete block of the thigh muscles was 0.30 mg/kg in seven patients and 0.45 mg/kg in the remaining four patients, which did not correlate with the first twitch response. At the time of complete block of the thigh muscles, the neuromuscular blockade level of the adductor pollicis muscle varied greatly, although the level was never more profound than a post-tetanic count of 1. Although the response of the adductor pollicis muscle to rocuronium cannot be used to determine the adequate rocuronium dose required for complete block of the thigh muscles, intense blockade, with maintenance of post-tetanic count at ≤ 1 in the adductor pollicis muscle is essential to prevent the obturator jerk. © 2017 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

Pharmacokinetics, safety, and tolerability of rotigotine transdermal system in healthy Japanese and Caucasian subjects following multiple-dose administration.

PubMed

Cawello, Willi; Kim, Seong Ryul; Braun, Marina; Elshoff, Jan-Peer; Masahiro, Takeuchi; Ikeda, Junji; Funaki, Tomoo

2016-08-01

Rotigotine is a dopamine receptor agonist indicated for the treatment of Parkinson's disease and moderate-to-severe restless legs syndrome. Continuous transdermal delivery of rotigotine via a silicon-based patch maintains stable plasma concentrations over 24 h. The objective of the study was to evaluate the pharmacokinetics, safety, and tolerability of a multiple-dose schedule of rotigotine transdermal patch in Japanese and Caucasian subjects. In this open-label, repeated-dose, parallel-group study (ClinicalTrials.gov: NCT01854216), healthy male and female subjects of Japanese or Caucasian ethnic origin were matched by gender, body mass index, and age. Subjects underwent a 9-day patch application period. 12 Japanese and 12 Caucasian subjects were included in the pharmacokinetic analyses. Mean apparent doses (actual amount of drug delivered) increased proportionally with rotigotine nominal dosages (1, 2, and 4 mg/24 h) and were similar for both ethnic groups, with large inter-individual variability. Mean plasma concentration-time profiles for unconjugated rotigotine were similar in both ethnic groups at day 3 for each dosage. Peak concentrations (C max,ss) and area under the concentration-time curves from pre-dose to the concentration measured 24 h after administration of patch (AUC(0-24,ss)) showed similar exposure in both groups; higher values in Japanese subjects were explained by differences in body weight. For total rotigotine, C max,ss and AUC(0-24,ss) values were higher in Caucasian subjects and could be explained by small differences in apparent dose. Rotigotine was generally well tolerated following multiple applications up to 4 mg/24 h. These findings suggest similar dosage requirements for rotigotine transdermal system in Japanese and Caucasian populations.

Partial breast radiotherapy with simple teletherapy techniques.

PubMed

Fekete, Gábor; Újhidy, Dóra; Együd, Zsófia; Kiscsatári, Laura; Marosi, Gusztáv; Kahán, Zsuzsanna; Varga, Zoltán

2015-01-01

A prospective pilot study of partial breast irradiation (PBI) with conventional vs hypofractionated schedules was set out. The study aimed to determine efficacy, acute and late side effects, and the preference of photon vs electron irradiation based on individual features. Patients were enrolled according to internationally accepted guidelines on PBI. Conformal radiotherapy plans were generated with both photon and electron beams, and the preferred technique based on dose homogeneity and the radiation exposure of healthy tissues was applied. For electron dose verification, a special phantom was constructed. Patients were randomized for fractionation schedules of 25 × 2 vs 13 × 3Gy. Skin and breast changes were registered at the time of and ≥1 year after the completion of radiotherapy. Dose homogeneity was better with photons. If the tumor bed was located in the inner quadrants, electron beam gave superior results regarding conformity and sparing of organ at risk (OAR). If the tumor was situated in the lateral quadrants, conformity was better with photons. A depth of the tumor bed ≥3.0cm predicted the superiority of photon irradiation (odds ratio [OR] = 23.6, 95% CI: 5.2 to 107.5, p < 0.001) with >90% sensitivity and specificity. After a median follow-up of 39 months, among 72 irradiated cases, 1 local relapse out of the tumor bed was detected. Acute radiodermatitis of grade I to II, hyperpigmentation, and telangiectasia developed ≥1 year after radiotherapy, exclusively after electron beam radiotherapy. The choice of electrons or photons for PBI should be based on tumor bed location; the used methods are efficient and feasible. Copyright © 2015 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.

Protective specific immunity induced by doxorubicin plus TNF-alpha combination treatment of EL4 lymphoma-bearing C57BL/6 mice.

PubMed

Ehrke, M J; Verstovsek, S; Maccubbin, D L; Ujházy, P; Zaleskis, G; Berleth, E; Mihich, E

2000-07-01

The therapeutic efficacy of a single (day 8), moderate dose (4 mg/kg, i.v.) of doxorubicin (DOX, Adriamycin) combined with recombinant human TNF-alpha (3 different doses and 5 different schedules, i.v.) was evaluated in C57BL/6 mice bearing an implant (s.c.) of the DOX-sensitive, TNF-alpha-resistant EL4 lymphoma. In parallel to monitoring survival, the levels of several host anti-tumor cytolytic effector functions of splenocytes and thymocytes were evaluated throughout the treatment period and in long-term survivors (LTS). DOX treatment alone resulted in a moderate (approx. 20%) increase in life span but no cures. TNF-alpha alone, at any tested dose or schedule, had little or no positive effect on survival. The combinations of DOX and TNF-alpha were only slightly better than DOX alone with respect to the time to death of mice that died (approx. 29% increase); however, each of the combinations involving 1,000 U TNF-alpha/injection produced a fraction (20% to 80%) of LTS. The host defense activities examined included those of splenic and thymic cytolytic T lymphocytes (CTL) and lymphokine-activated killer cells as well as splenic tumoricidal macrophages. Although most activities were modulated by tumor growth and/or treatment, only CTL responsiveness appeared to correlate with survival. CTL activity in the treated groups with LTS was significantly higher than in control groups late in the treatment period. Finally, ex vivo analyses of splenocytes and thymocytes together with the rejection of implanted tumor at 17 months established that LTS displayed specific long-term immune memory. Copyright 2000 Wiley-Liss, Inc.

[Immunisation schedule of the Spanish Association of Paediatrics: 2014 recommendations].

PubMed

Moreno-Pérez, D; Alvarez García, F J; Arístegui Fernández, J; Cilleruelo Ortega, M J; Corretger Rauet, J M; García Sánchez, N; Hernández Merino, A; Hernández-Sampelayo Matos, T; Merino Moína, M; Ortigosa Del Castillo, L; Ruiz-Contreras, J

2014-01-01

The Advisory Committee on Vaccines of the Spanish Association of Paediatrics (CAV-AEP) updates the immunisation schedule every year, taking into account epidemiological data as well as evidence on safety, effectiveness and efficiency of vaccines. The present schedule includes levels of recommendation. We have graded, as routine vaccinations, those that the CAV-AEP consider all children should receive; as recommended those that fit the profile for universal childhood immunisation and would ideally be given to all children, but that can be prioritised according to the resources available for their public funding; and as risk group vaccinations those that specifically target individuals in special situations. Immunisation schedules tend to be dynamic and adaptable to ongoing epidemiological changes. Based on the latest epidemiological trends, CAV-AEP recommends the administration of the first dose of MMR and varicella vaccines at age 12 months, with the second dose at age 2-3 years; the administration of DTaP or Tdap vaccine at age 4-6 years, always followed by another Tdap dose at 11-12 years; and the three meningococcal C scheme at 2 months, 12 months and 12 years of age. It reasserts its recommendation to include vaccination against pneumococcal disease in the routine immunisation schedule. The CAV-AEP believes that the coverage of vaccination against human papillomavirus in girls aged 11-12 years must be increased. Universal vaccination against varicella in the second year of life is an effective strategy, and the immediate public availability of the vaccine is requested in order to guarantee the right of healthy children to be vaccinated. Vaccination against rotavirus is recommended in all infants due to the morbidity and elevated healthcare burden of the virus. The Committee stresses the need to vaccinate population groups considered at risk against influenza and hepatitis A. The recently authorised meningococcal B vaccine has opened a chapter of hope in the prevention of this disease. In anticipation of upcoming national and international studies, the Committee recommends the vaccine for the control of disease outbreaks, and insists on the need to be available in pharmacies. Finally, it emphasises the need to bring incomplete vaccinations up to date following the catch-up immunisation schedule. Copyright © 2013 Asociación Española de Pediatría. Published by Elsevier Espana. All rights reserved.

An algorithm for a single machine scheduling problem with sequence dependent setup times and scheduling windows

NASA Technical Reports Server (NTRS)

Moore, J. E.

1975-01-01

An enumeration algorithm is presented for solving a scheduling problem similar to the single machine job shop problem with sequence dependent setup times. The scheduling problem differs from the job shop problem in two ways. First, its objective is to select an optimum subset of the available tasks to be performed during a fixed period of time. Secondly, each task scheduled is constrained to occur within its particular scheduling window. The algorithm is currently being used to develop typical observational timelines for a telescope that will be operated in earth orbit. Computational times associated with timeline development are presented.

Dose-Fractionation Sensitivity of Prostate Cancer Deduced From Radiotherapy Outcomes of 5,969 Patients in Seven International Institutional Datasets: {alpha}/{beta} = 1.4 (0.9-2.2) Gy

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

Miralbell, Raymond, E-mail: Raymond.Miralbell@hcuge.ch; Institut Oncologic Teknon, Barcelona; Roberts, Stephen A.

2012-01-01

Purpose: There are reports of a high sensitivity of prostate cancer to radiotherapy dose fractionation, and this has prompted several trials of hypofractionation schedules. It remains unclear whether hypofractionation will provide a significant therapeutic benefit in the treatment of prostate cancer, and whether there are different fractionation sensitivities for different stages of disease. In order to address this, multiple primary datasets have been collected for analysis. Methods and Materials: Seven datasets were assembled from institutions worldwide. A total of 5969 patients were treated using external beams with or without androgen deprivation (AD). Standard fractionation (1.8-2.0 Gy per fraction) was usedmore » for 40% of the patients, and hypofractionation (2.5-6.7 Gy per fraction) for the remainder. The overall treatment time ranged from 1 to 8 weeks. Low-risk patients comprised 23% of the total, intermediate-risk 44%, and high-risk 33%. Direct analysis of the primary data for tumor control at 5 years was undertaken, using the Phoenix criterion of biochemical relapse-free survival, in order to calculate values in the linear-quadratic equation of k (natural log of the effective target cell number), {alpha} (dose-response slope using very low doses per fraction), and the ratio {alpha}/{beta} that characterizes dose-fractionation sensitivity. Results: There was no significant difference between the {alpha}/{beta} value for the three risk groups, and the value of {alpha}/{beta} for the pooled data was 1.4 (95% CI = 0.9-2.2) Gy. Androgen deprivation improved the bNED outcome index by about 5% for all risk groups, but did not affect the {alpha}/{beta} value. Conclusions: The overall {alpha}/{beta} value was consistently low, unaffected by AD deprivation, and lower than the appropriate values for late normal-tissue morbidity. Hence the fractionation sensitivity differential (tumor/normal tissue) favors the use of hypofractionated radiotherapy schedules for all risk groups, which is also very beneficial logistically in limited-resource settings.« less

Inhibiting the Aurora B Kinase Potently Suppresses Repopulation During Fractionated Irradiation of Human Lung Cancer Cell Lines

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

Sak, Ali, E-mail: ali.sak@uni-due.de; Stuschke, Martin; Groneberg, Michael

2012-10-01

Purpose: The use of molecular-targeted agents during radiotherapy of non-small-cell lung cancer (NSCLC) is a promising strategy to inhibit repopulation, thereby improving therapeutic outcome. We assessed the combined effectiveness of inhibiting Aurora B kinase and irradiation on human NSCLC cell lines in vitro. Methods and Materials: NSCLC cell lines were exposed to concentrations of AZD1152-hydroxyquinazoline pyrazol anilide (AZD1152-HQPA) inhibiting colony formation by 50% (IC50{sub clone}) in combination with single dose irradiation or different fractionation schedules using multiple 2-Gy fractions per day up to total doses of 4-40 Gy. The total irradiation dose required to control growth of 50% of themore » plaque monolayers (TCD50) was determined. Apoptosis, G2/M progression, and polyploidization were also analyzed. Results: TCD50 values after single dose irradiation were similar for the H460 and H661 cell lines with 11.4 {+-} 0.2 Gy and 10.7 {+-} 0.3 Gy, respectively. Fractionated irradiation using 3 Multiplication-Sign 2 Gy/day, 2 Multiplication-Sign 2 Gy/day, and 1 Multiplication-Sign 2 Gy/day schedules significantly increased TCD50 values for both cell lines grown as plaque monolayers with increasing radiation treatment time. This could be explained by a repopulation effect per day that counteracts 75 {+-} 8% and 27 {+-} 6% of the effect of a 2-Gy fraction in H460 and H661 cells, respectively. AZD1152-HQPA treatment concomitant to radiotherapy significantly decreased the daily repopulation effect (H460: 28 {+-} 5%, H661: 10 {+-} 4% of a 2-Gy fraction per day). Treatment with IC50{sub clone} AZD1152-HPQA did not induce apoptosis, prolong radiation-induced G2 arrest, or delay cell cycle progression before the spindle check point. However, polyploidization was detected, especially in cell lines without functional p53. Conclusions: Inhibition of Aurora B kinase with low AZD1152-HQPA concentrations during irradiation of NSCLC cell lines affects repopulation during radiotherapy. Thus, concomitant Aurora B kinase inhibition and irradiation may be a promising strategy for fast repopulating tumors, which are difficult to cure by dose escalation based on conventional fractionation.« less

Project Scheduling Based on Risk of Gas Transmission Pipe

NASA Astrophysics Data System (ADS)

Silvianita; Nurbaity, A.; Mulyadi, Y.; Suntoyo; Chamelia, D. M.

2018-03-01

The planning of a project has a time limit on which must be completed before or right at a predetermined time. Thus, in a project planning, it is necessary to have scheduling management that is useful for completing a project to achieve maximum results by considering the constraints that will exists. Scheduling management is undertaken to deal with uncertainties and negative impacts of time and cost in project completion. This paper explains about scheduling management in gas transmission pipeline project Gresik-Semarang to find out which scheduling plan is most effectively used in accordance with its risk value. Scheduling management in this paper is assissted by Microsoft Project software to find the critical path of existing project scheduling planning data. Critical path is the longest scheduling path with the fastest completion time. The result is found a critical path on project scheduling with completion time is 152 days. Furthermore, the calculation of risk is done by using House of Risk (HOR) method and it is found that the critical path has a share of 40.98 percent of all causes of the occurence of risk events that will be experienced.

A rational quantitative approach to determine the best dosing regimen for a target therapeutic effect: a unified formalism for antibiotic evaluation.

PubMed

Li, Jun; Nekka, Fahima

2013-02-21

The determination of an optimal dosing regimen is a critical step to enhance the drug efficacy and avoid toxicity. Rational dosing recommendations based on mathematical considerations are increasingly being adopted in the process of drug development and use. In this paper, we propose a quantitative approach to evaluate the efficacy of antibiotic agents. By integrating both pharmacokinetic (PK) and pharmacodynamic (PD) information, this approach gives rise to a unified formalism able to measure the cause-effect of dosing regimens. This new pharmaco-metric allows to cover a whole range of antibiotics, including the two well known concentration and time dependent classes, through the introduction of the Hill-dependency concept. As a direct fallout, our formalism opens a new path toward the bioequivalence evaluation in terms of PK and PD, which associates the in vivo drug concentration and the in vitro drug effect. Using this new approach, we succeeded to reveal unexpected, but relevant behaviors of drug performance when different drug regimens and drug classes are considered. Of particular notice, we found that the doses required to reach the same therapeutic effect, when scheduled differently, exhibit completely different tendencies for concentration and time dependent drugs. Moreover, we theoretically confirmed the previous experimental results of the superiority of the once daily regimen of aminoglycosides. The proposed methodology is appealing for its computational features and can easily be applicable to design fair clinical protocols or rationalize prescription decisions. Copyright © 2012 Elsevier Ltd. All rights reserved.

[Immunisation schedule of the Spanish Association of Paediatrics: 2017 recommendations].

PubMed

Moreno-Pérez, David; Álvarez García, Francisco José; Arístegui Fernández, Javier; Cilleruelo Ortega, María José; Corretger Rauet, José María; García Sánchez, Nuria; Hernández Merino, Ángel; Hernández-Sampelayo Matos, Teresa; Merino Moína, Manuel; Ortigosa Del Castillo, Luis; Ruiz-Contreras, Jesús

2017-02-01

The Advisory Committee on Vaccines of the Spanish Association of Paediatrics (CAV- AEP) annually publishes the immunisation schedule which, in our opinion, is considered optimal for children resident in Spain, taking into account the evidence available on current vaccines. Pneumococcal and varicella immunisation in early childhood is already included in all funded vaccines present in the regional immunisation programmes. Furthermore, this committee establishes recommendations on vaccines not included in official calendars (non-funded immunisations), such as rotavirus, meningococcal B, and meningococcal ACWY. As regards funded immunisations, 2+1 strategy (2, 4, 11-12 months) with hexavalent (DTaP-IPV-Hib-HB) and 13-valent pneumococcal vaccines is recommended. Administration of the 6-year booster dose with DTaP is recommended, as well as a poliomyelitis dose for children who had received the 2+1 scheme, with the Tdap vaccine for adolescents and pregnant women between 27 and 32 weeks gestation. The two-dose scheme should be used for MMR (12 months and 2-4 years) and varicella (15 months and 2-4 years). Coverage of human papillomavirus vaccination in girls aged 12 with a two-dose scheme (0, 6 months) should be improved. Information and recommendations for male adolescents about potential beneficial effects of the tetravalent HPV vaccine should also be provided. ACWY meningococcal vaccine is the optimal choice in adolescents. For recommended unfunded immunisations, the CAV-AEP recommends the administration of meningococcal B vaccine, due to the current availability in Spanish community pharmacies, with a 3+1 scheme. CAV-AEP requests the incorporation of this vaccine in the funded unified schedule. Vaccination against rotavirus is recommended in all infants. Copyright © 2016 Asociación Española de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.

Pharmacogenetics during standardised initiation of thiopurine treatment in inflammatory bowel disease

PubMed Central

Hindorf, U; Lindqvist, M; Peterson, C; Söderkvist, P; Ström, M; Hjortswang, H; Pousette, A; Almer, S

2006-01-01

Background Firm recommendations about the way thiopurine drugs are introduced and the use of thiopurine methyltransferase (TPMT) and metabolite measurements during treatment in inflammatory bowel disease (IBD) are lacking. Aim To evaluate pharmacokinetics and tolerance after initiation of thiopurine treatment with a fixed dosing schedule in patients with IBD. Patients 60 consecutive patients with Crohn's disease (n = 33) or ulcerative colitis (n = 27) were included in a 20 week open, prospective study. Methods Thiopurine treatment was introduced using a predefined dose escalation schedule, reaching a daily target dose at week 3 of 2.5 mg azathioprine or 1.25 mg 6‐mercaptopurine per kg body weight. TPMT and ITPA genotypes, TPMT activity, TPMT gene expression, and thiopurine metabolites were determined. Clinical outcome and occurrence of adverse events were monitored. Results 27 patients completed the study per protocol, while 33 were withdrawn (early protocol violation (n = 5), TPMT deficiency (n = 1), thiopurine related adverse events (n = 27)); 67% of patients with adverse events tolerated long term treatment on a lower dose (median 1.32 mg azathioprine/kg body weight). TPMT activity did not change during the 20 week course of the study but a significant decrease in TPMT gene expression was found (TPMT/huCYC ratio; p = 0.02). Patients with meTIMP concentrations >11 450 pmol/8×108 red blood cells during steady state at week 5 had an increased risk of developing myelotoxicity (odds ratio = 45.0; p = 0.015). Conclusions After initiation of thiopurine treatment using a fixed dosing schedule, no general induction of TPMT enzyme activity occurred, though TPMT gene expression decreased. The development of different types of toxicity was unpredictable, but we found that measurement of meTIMP early in the steady state phase helped to identify patients at risk of developing myelotoxicity. PMID:16543290

Tisagenlecleucel Injection

MedlinePlus

... that has returned or is unresponsive to other treatment(s). Tisagenlecleucel injection is in a class of medications ... scheduled cell collection appointment(s) or to receive your treatment dose. You should plan to stay within 2 ...

Axicabtagene Injection

MedlinePlus

... that has returned or is unresponsive to other treatment(s) in people who have already been treated with ... scheduled cell collection appointment(s) or to receive your treatment dose. You should plan to stay near where ...

Immunogenicity of a combined schedule of 7-valent pneumococcal conjugate vaccine followed by a 23-valent polysaccharide vaccine in adult recipients of heart or lung transplants.

PubMed

Gattringer, R; Winkler, H; Roedler, S; Jaksch, P; Herkner, H; Burgmann, H

2011-10-01

A combined schedule of 7-valent pneumococcal conjugate vaccine (PCV7) followed by 23-valent pneumococcal polysaccharide vaccine (PPV23) was evaluated retrospectively in 26 adult recipients of heart or lung transplants. PCV7 was immunogenic in these patients but there appeared to be no benefit from the additional PPV23 dose. © 2011 John Wiley & Sons A/S.

VAXELN Experimentation: Programming a Real-Time Periodic Task Dispatcher Using VAXELN Ada 1.1

DTIC Science & Technology

1987-11-01

synchronization to the SQM and VAXELN semaphores. Based on real-time scheduling theory, the optimal rate-monotonic scheduling algorithm [Lui 73...schedulability test based on the rate-monotonic algorithm , namely task-lumping [Sha 871, was necessary to cal- culate the theoretically expected schedulability...8217 Guide Digital Equipment Corporation, Maynard, MA, 1986. [Lui 73] Liu, C.L., Layland, J.W. Scheduling Algorithms for Multi-programming in a Hard-Real-Time

Uracil-ftorafur: an oral fluoropyrimidine active in colorectal cancer.

PubMed

Sulkes, A; Benner, S E; Canetta, R M

1998-10-01

This review describes the early clinical development of uracil-ftorafur (UFT), an oral fluoropyrimidine, designed in 1978 by adding uracil to ftorafur. The review focuses on the treatment of colorectal cancer and summarizes the Japanese experience and the phase I and II trials performed in the United States and Europe. Clinical trials of UFT published in the Western world have included 581 patients with colorectal cancer. UFT has been administered in these trials as a single agent or biomodulated by leucovorin (LV). UFT was administered daily in split doses for periods that ranged from 14 to 28 days. The activity of oral UFT in large-bowel cancer when administered with oral LV (approximately 50 mg/dose) has resulted in objective response rates of approximately 40%. Response rates of approximately 25% (range, 17% to 39%) were reported when UFT was administered as a single agent or with lower doses of LV. The highest dose-intensities of UFT are achieved with 28-day schedules of administration. The maximum-tolerated dose (MTD) of UFT with this schedule, when administered concomitantly with oral LV 150 mg daily, is 300 mg/m2 daily. The dose-limiting toxicity (DLT) of UFT has generally been diarrhea. Other commonly described toxicities include nausea and vomiting, fatigue, and stomatitis. Myelosuppression occurs infrequently. Typically, hand-foot syndrome and neurologic toxicity are lacking. UFT is a fluoropyrimidine active in colorectal cancer. The oral route of administration and improved safety profile represent important advantages over both conventional and infusional fluorouracil (5-FU) regimens.

Lanreotide autogel every 6 weeks compared with Lanreotide microparticles every 3 weeks in patients with well differentiated neuroendocrine tumors: a Phase III Study.

PubMed

Bajetta, Emilio; Procopio, Giuseppe; Catena, Laura; Martinetti, Antonia; De Dosso, Sara; Ricci, Sergio; Lecchi, Alberto S; Boscani, Paolo F; Iacobelli, Stefano; Carteni, Giacomo; De Braud, Filippo; Loli, Paola; Tartaglia, Andreas; Bajetta, Roberto; Ferrari, Leonardo

2006-11-15

The noninferiority of a 6-week dosing schedule of lanreotide Autogel (Lan ATG) at a dose of 120 mg compared with a 3-week dosing schedule of lanreotide microparticles (Lan MP) at a dose of 60 mg was investigated in patients with neuroendocrine tumors (NET). Patients who had sporadic, well differentiated NET with a low grade of malignancy were recruited for this open-label, Phase III, multicenter trial. Patients were randomized to receive either 3 deep subcutaneous injections of Lan ATG (120 mg, every 6 weeks) or 6 intramuscular injections of Lan MP (60 mg, every 3 weeks). Tumor markers, tumor size, and symptoms were assessed between baseline and Week 18. Success was classified as a response that ranged from disappearance to an increase <25% in tumor marker, tumor size, or symptom frequency. Sixty patients were randomized, and 46 patients completed the study. Both for tumor markers and for tumor size, Lan ATG was not inferior to Lan MP (55% and 59% of patients responded on tumor markers, respectively; 68% and 66% of patients responded on tumor size, respectively). There were too few symptomatic patients to compare carcinoid symptoms. Both treatments were tolerated well, and no safety concerns were identified. Lan ATG at a dose of 120 mg every 6 weeks was as effective for controlling NET as Lan MP at a dose of 60 mg every 3 weeks.

Flavopiridol Can Be Safely Administered Using a Pharmacologically Derived Schedule and Demonstrates Activity in Relapsed and Refractory Non-Hodgkin’s Lymphoma

PubMed Central

Jones, Jeffrey A.; Rupert, Amy S.; Poi, Ming; Phelps, Mitch A.; Andritsos, Leslie; Baiocchi, Robert; Benson, Don M.; Blum, Kristie A.; Christian, Beth; Flynn, Joseph; Penza, Sam; Porcu, Pierluigi; Grever, Michael R.; Byrd, John C.

2014-01-01

Flavopiridol is a broad cyclin-dependent kinase inhibitor (CDKI) that induces apoptosis of malignant lymphocytes in vitro and in murine lymphoma models. We conducted a phase I dose-escalation study to determine the maximum tolerated dose (MTD) for single-agent flavopiridol administered on a pharmacokinetically derived hybrid dosing schedule to patients with relapsed and refractory non-Hodgkin’s lymphoma. Dose was escalated independently in one of four cohorts: indolent B-cell (cohort 1), mantle cell (cohort 2), intermediate grade B-cell including transformed lymphoma (cohort 3), and T-/NK-cell excluding primary cutaneous disease (cohort 4). Forty-six patients were accrued. Grade 3 or 4 leukopenia was observed in the majority of patients (60%), but infection was infrequent. Common non-hematologic toxicties included diarrhea and fatigue. Biochemical tumor lysis was observed in only 2 patients, and no patients required hemodialysis for its management. Dose escalation was completed in two cohorts (indolent and aggressive B-cell). Dose-limiting toxicities were not observed, and the MTD was not reached in either cohort at the highest dose tested (50 mg/m2 bolus + 50 mg/m2 continuous infusion weekly for 4 consecutive weeks of a 6 week cycle). Clinical benefit was observed in 26% of 43 patients evaluable for response, including 14% with partial responses (2 mantle cell, 3 indolent B-cell, and 1 diffuse large B-cell). The single-agent activity of this first-generation CDKI suggests that other agents in this class merit further study in lymphoid malignancies, both alone and in combination. PMID:23959599

Comparison of the effect of rocuronium dosing based on corrected or lean body weight on rapid sequence induction and neuromuscular blockade duration in obese female patients

PubMed Central

Sakızcı-Uyar, Bahar; Çelik, Şeref; Postacı, Aysun; Bayraktar, Yeşim; Dikmen, Bayazit; Özkoçak-Turan, Işıl; Saçan, Özlem

2016-01-01

Objectives: To compare onset time, duration of action, and tracheal intubation conditions in obese patients when the intubation dose of rocuronium was based on corrected body weight (CBW) versus lean body weight (LBW) for rapid sequence induction. Methods: This prospective study was carried out at Numune Education and Research Hospital, Ankara, Turkey between August 2013 and May 2014. Forty female obese patients scheduled for laparoscopic surgery under general anesthesia were randomized into 2 groups. Group CBW (n=20) received 1.2 mg/kg rocuronium based on CBW, and group LBW (n=20) received 1.2 mg/kg rocuronium based on LBW. Endotracheal intubation was performed 60 seconds after injection of muscle relaxant, and intubating conditions were evaluated. Neuromuscular transmission was monitored using acceleromyography of the adductor pollicis. Onset time, defined as time to depression of the twitch tension to 95% of its control value, and duration of action, defined as time to achieve one response to train-of-four stimulation (T1) were recorded. Results: No significant differences were observed between the groups in intubation conditions or onset time (50-60 seconds median, 30-30 interquartile range [IQR]). Duration of action was significantly longer in the CBW group (60 minutes median, 12 IQR) than the LBW group (35 minutes median, 16 IQR; p<0.01). Conclusion: In obese patients, dosing of 1.2 mg/kg rocuronium based on LBW provides excellent or good tracheal intubating conditions within 60 seconds after administration and does not lead to prolonged duration of action. PMID:26739976

An intensified dosing schedule of subcutaneous methotrexate in patients with moderate to severe plaque-type psoriasis (METOP): a 52 week, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

PubMed

Warren, Richard B; Mrowietz, Ulrich; von Kiedrowski, Ralph; Niesmann, Johannes; Wilsmann-Theis, Dagmar; Ghoreschi, Kamran; Zschocke, Ina; Falk, Thomas M; Blödorn-Schlicht, Norbert; Reich, Kristian

2017-02-04

Methotrexate is one of the most commonly used systemic drugs for the treatment of moderate to severe psoriasis; however, high-quality evidence for its use is sparse and limited to use of oral dosing. We aimed to assess the effect of an intensified dosing schedule of subcutaneous methotrexate in patients with moderate to severe plaque-type psoriasis. We did this prospective, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial (METOP) at 16 sites in Germany, France, the Netherlands, and the UK. Eligible patients were aged 18 years or older, had a diagnosis of chronic plaque psoriasis for at least 6 months before baseline, had currently moderate to severe disease, and were methotrexate treatment-naive. Participants were randomly assigned (3:1), via a computer-generated random number sequence integrated into an electronic data capture system, to receive either methotrexate at a starting dose of 17·5 mg/week or placebo for the first 16 weeks, followed by methotrexate treatment of all patients up to 52 weeks (methotrexate-methotrexate vs placebo-methotrexate groups). Dose escalation to 22·5 mg/week was allowed after 8 weeks of methotrexate treatment if patients had not achieved at least a 50% reduction in baseline Psoriasis Area and Severity Index score (PASI), with corresponding volume increases in placebo injections. Treatment was combined with folic acid 5 mg/week. Group allocation was concealed from participants and investigators from the time of randomisation until an interim database lock at week 16, and was open label from week 16 onwards, with no masking of participants or investigators. The primary efficacy endpoint was a 75% reduction in PASI score (PASI 75) from baseline to week 16. We did analysis by modified intention to treat, with non-responder imputation. This study is registered with EudraCT, number 2012-002716-10. Between Feb 22, 2013, and May 13, 2015, we randomly assigned 120 patients to receive methotrexate (n=91) or placebo (n=29). At week 16, a PASI 75 response was achieved in 37 (41%) patients in the methotrexate group compared with three (10%) patients in the placebo group (relative risk 3·93, 95% CI 1·31-11·81; p=0·0026). Subcutaneous methotrexate was generally well tolerated; no patients died or had serious infections, malignancies, or major adverse cardiovascular events. Serious adverse events were recorded in three (3%) patients who received methotrexate for the full 52 week treatment period. Our findings show a favourable 52 week risk-benefit profile of subcutaneous methotrexate in patients with psoriasis. The route of administration and the intensified dosing schedule should be considered when methotrexate is used in this patient group. Medac. Copyright © 2017 Elsevier Ltd. All rights reserved.

Instructional versus schedule control of humans' choices in situations of diminishing returns

PubMed Central

Hackenberg, Timothy D.; Joker, Veronica R.

1994-01-01

Four adult humans chose repeatedly between a fixed-time schedule (of points later exchangeable for money) and a progressive-time schedule that began at 0 s and increased by a fixed number of seconds with each point delivered by that schedule. Each point delivered by the fixed-time schedule reset the requirements of the progressive-time schedule to its minimum value. Subjects were provided with instructions that specified a particular sequence of choices. Under the initial conditions, the instructions accurately specified the optimal choice sequence. Thus, control by instructions and optimal control by the programmed contingencies both supported the same performance. To distinguish the effects of instructions from schedule sensitivity, the correspondence between the instructed and optimal choice patterns was gradually altered across conditions by varying the step size of the progressive-time schedule while maintaining the same instructions. Step size was manipulated, typically in 1-s units, first in an ascending and then in a descending sequence of conditions. Instructions quickly established control in all 4 subjects but, by narrowing the range of choice patterns, they reduced subsequent sensitivity to schedule changes. Instructional control was maintained across the ascending sequence of progressive-time values for each subject, but eventually diminished, giving way to more schedule-appropriate patterns. The transition from instruction-appropriate to schedule-appropriate behavior was characterized by an increase in the variability of choice patterns and local increases in point density. On the descending sequence of progressive-time values, behavior appeared to be schedule sensitive, sometimes even optimally sensitive, but it did not always change systematically with the contingencies, suggesting the involvement of other factors. PMID:16812747

Schedule Risk Assessment

NASA Technical Reports Server (NTRS)

Smith, Greg

2003-01-01

Schedule risk assessments determine the likelihood of finishing on time. Each task in a schedule has a varying degree of probability of being finished on time. A schedule risk assessment quantifies these probabilities by assigning values to each task. This viewgraph presentation contains a flow chart for conducting a schedule risk assessment, and profiles applicable several methods of data analysis.

A dose schedule for intraarticular steroids in juvenile arthritis.

PubMed

Eberhard, B Anne; Ilowite, Norman T; Sison, Cristina

2012-02-01

To determine whether the intraarticular (IA) dose of triamcinolone hexacetonide (TH) or triamcinolone acetonide (TA) influences time to relapse among patients with juvenile idiopathic arthritis (JIA). The primary endpoint variable was the time to relapse of arthritis in the affected joint after an intraarticular (IA) injection. A relapse was defined as the reoccurrence of active arthritis in the injected joint. Analysis was carried out including only the first IA joint injection for each patient. Further analysis was conducted including the first knee injection alone. A separate analysis within the IA corticosteroid groups was performed using the Spearman rank coefficient, to determine if dose of IA steroid affected time to relapse. Records from 186 patients with JIA (145 females, 41 males) injected with either TH or TA were collected from January 1995 through December 2003. All subjects were followed for a minimum of 15 months from the time of IA injection. Of the 794 joint injections, 422 (53.1%) were injected with TH and 372 (46.9%) with TA. There were 111 first joint injections (all joints) with TH and 70 with TA. There were 89 first joint injections (knee only) with TH and 56 with TA. TH proved more effective than TA with respect to the time to relapse for first injection into all joints (10.47 ± 0.42 mo vs 8.66 ± 0.59 mo; p < 0.001), and for first injections into knee only (11.04 ± 0.44 vs 8.99 ± 0.65 mo; p < 0.001). IA doses ranged from 0.4 to 4 mg/kg (mean 1.56 ± 0.76) for TH and from 0.5 to 8 mg/kg (mean 2.54 ± 1.74) for TA. There was no correlation between time to relapse and dose of either TH and TA (r = 0.1, p > 0.5). There was no correlation between time to relapse and sex, duration of illness, age of patient, concurrent medications, or subtype of JIA. In a larger dataset (794 injections) we have confirmed our previous findings (227 injections) that TH is a more effective IA corticosteroid than TA. In this much larger data analysis, dose of IA corticosteroid in the range we studied did not significantly influence the duration of response.

Dedicated heterogeneous node scheduling including backfill scheduling

DOEpatents

Wood, Robert R [Livermore, CA; Eckert, Philip D [Livermore, CA; Hommes, Gregg [Pleasanton, CA

2006-07-25

A method and system for job backfill scheduling dedicated heterogeneous nodes in a multi-node computing environment. Heterogeneous nodes are grouped into homogeneous node sub-pools. For each sub-pool, a free node schedule (FNS) is created so that the number of to chart the free nodes over time. For each prioritized job, using the FNS of sub-pools having nodes useable by a particular job, to determine the earliest time range (ETR) capable of running the job. Once determined for a particular job, scheduling the job to run in that ETR. If the ETR determined for a lower priority job (LPJ) has a start time earlier than a higher priority job (HPJ), then the LPJ is scheduled in that ETR if it would not disturb the anticipated start times of any HPJ previously scheduled for a future time. Thus, efficient utilization and throughput of such computing environments may be increased by utilizing resources otherwise remaining idle.

Compilation time analysis to minimize run-time overhead in preemptive scheduling on multiprocessors

NASA Astrophysics Data System (ADS)

Wauters, Piet; Lauwereins, Rudy; Peperstraete, J.

1994-10-01

This paper describes a scheduling method for hard real-time Digital Signal Processing (DSP) applications, implemented on a multi-processor. Due to the very high operating frequencies of DSP applications (typically hundreds of kHz) runtime overhead should be kept as small as possible. Because static scheduling introduces very little run-time overhead it is used as much as possible. Dynamic pre-emption of tasks is allowed if and only if it leads to better performance in spite of the extra run-time overhead. We essentially combine static scheduling with dynamic pre-emption using static priorities. Since we are dealing with hard real-time applications we must be able to guarantee at compile-time that all timing requirements will be satisfied at run-time. We will show that our method performs at least as good as any static scheduling method. It also reduces the total amount of dynamic pre-emptions compared with run time methods like deadline monotonic scheduling.

Timeliness and risk factors associated with delay for pneumococcal conjugate 10-valent routine immunization in Brazilian children.

PubMed

Sartori, Ana Lucia; Minamisava, Ruth; Afonso, Eliane Terezinha; Policena, Gabriela Moreira; Pessoni, Grécia Carolina; Bierrenbach, Ana Luiza; Andrade, Ana Lucia

2017-02-15

Vaccination coverage is the usual metrics to evaluate the immunization programs performance. For the 10-valent pneumococcal conjugate (PCV10) vaccine, measuring the delay of vaccination is also important, particularly as younger children are at increased risk of disease. Routinely collected administrative data was used to assess the timeliness of PCV10 vaccination, and the factors associated with delay to receive the first and second doses, and the completion of the PCV10 3+1 schedule. A population-based retrospective cohort study was conducted with children born in 2012 in Central Brazil. Children who received the PCV10 first dose in public health services were followed-up until 23months of age. Timeliness of receiving each PCV10 dose at any given age was defined as receiving the dose within 28days grace period from the recommended age by the National Immunization Program. Log-binomial regression models were used to examine risk factors for delays of the first dose and the completion PCV10 3+1 schedule. In total, 14,282 children were included in the cohort of study. Delayed vaccination occurred in 9.4%, 23.8%, 36.8% and 39.9% children for the first, second, third and the booster doses, respectively. A total of 1912 children (12.8% of the cohort) were not adequately vaccinated at the 6months of life; 1,071 (7%) received the second dose after 6months of age, 784 (5.4%) did not receive the second dose, and 57 (0.4%) received the first dose after six months of life. A considerable delay was found in PCV10 third and booster doses. Almost 2 thousand children had not received the recommended PCV10 doses at 6months of age. Timeliness of vaccination is an issue in Brazil although high vaccination coverages. Copyright © 2017 Elsevier Ltd. All rights reserved.

Dose-Response Effects of Long-Acting Liquid Methylphenidate in Children with Attention Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD): A Pilot Study

ERIC Educational Resources Information Center

Kim, Soo-Jeong; Shonka, Sophia; French, William P.; Strickland, Jennifer; Miller, Lindsey; Stein, Mark A.

2017-01-01

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…

Appointment standardization evaluation in a primary care facility.

PubMed

Huang, Yu-Li

2016-07-11

Purpose - The purpose of this paper is to evaluate the performance on standardizing appointment slot length in a primary care clinic to understand the impact of providers' preferences and practice differences. Design/methodology/approach - The treatment time data were collected for each provider. There were six patient types: emergency/urgent care (ER/UC), follow-up patient (FU), new patient, office visit (OV), physical exam, and well-child care. Simulation model was developed to capture patient flow and measure patient wait time, provider idle time, cost, overtime, finish time, and the number of patients scheduled. Four scheduling scenarios were compared: scheduled all patients at 20 minutes; scheduled ER/UC, FU, OV at 20 minutes and others at 40 minutes; scheduled patient types on individual provider preference; and scheduled patient types on combined provider preference. Findings - Standardized scheduling among providers increase cost by 57 per cent, patient wait time by 83 per cent, provider idle time by five minutes per patient, overtime by 22 minutes, finish time by 30 minutes, and decrease patient access to care by approximately 11 per cent. An individualized scheduling approach could save as much as 14 per cent on cost and schedule 1.5 more patients. The combined preference method could save about 8 per cent while the number of patients scheduled remained the same. Research limitations/implications - The challenge is to actually disseminate the findings to medical providers and adjust scheduling systems accordingly. Originality/value - This paper concluded standardization of providers' clinic preference and practice negatively impact clinic service quality and access to care.

Time-critical multirate scheduling using contemporary real-time operating system services

NASA Technical Reports Server (NTRS)

Eckhardt, D. E., Jr.

1983-01-01

Although real-time operating systems provide many of the task control services necessary to process time-critical applications (i.e., applications with fixed, invariant deadlines), it may still be necessary to provide a scheduling algorithm at a level above the operating system in order to coordinate a set of synchronized, time-critical tasks executing at different cyclic rates. The scheduling requirements for such applications and develops scheduling algorithms using services provided by contemporary real-time operating systems.

External beam radiotherapy for palliation of painful bone metastases: pooled data bioeffect dose response analysis of dose fractionation

NASA Astrophysics Data System (ADS)

Naveen, T.; Supe, Sanjay S.; Ganesh, K. M.; Samuel, Jacob

2009-01-01

Bone metastases develop in up to 70% of newly diagnosed cancer patients and result in immobility, anxiety, and depression, severely diminishing the patients quality of life. Radiotherapy is a frequently used modality for bone metastasis and has been shown to be effective in reducing metastatic bone pain and in some instances, causing tumor shrinkage or growth inhibition. There is controversy surrounding the optimal fractionation schedule and total dose of external beam radiotherapy, despite many randomized trials and overviews addressing the issue. This study was undertaken to apply BED to clinical fractionation data of radiotherapeutic management of bone metastases in order to arrive at optimum BED values for acceptable level of response rate. A computerised literature search was conducted to identify all prospective clinical studies that addressed the issue of fractionation for the treatment of bone metastasis. The results of these studies were pooled together to form the database for the analysis. A total of 4111 number of patients received radiation dose ranging from 4 to 40.5 Gy in 1 to 15 fractions with dose per fraction ranging from 2 to 10 Gy. Single fraction treatments were delivered in 2013 patients and the dose varied from 4 to 10 Gy. Multifraction treatments were delivered in 2098 patients and the dose varied from 15 to 40.5 Gy. The biological effective dose (BED) was evaluated for each fractionation schedule using the linear quadratic model and an α/β value of 10 Gy. Response rate increased significantly beyond a BED value of 14.4 Gy (p < 0.01). Based on our analysis and indications from the literature about higher retreatment and fracture rate of single fraction treatments, minimum BED value of 14.4 Gy is recommended.

Phase I study of single-agent ribociclib in Japanese patients with advanced solid tumors.

PubMed

Doi, Toshihiko; Hewes, Becker; Kakizume, Tomoyuki; Tajima, Takeshi; Ishikawa, Norifumi; Yamada, Yasuhide

2018-01-01

The cyclin D-CDK4/6-INK4-Rb pathway is frequently dysregulated in cancers. Ribociclib, an orally available, selective CDK4/6 inhibitor, showed preliminary clinical activity in a phase I study in the USA and Europe for patients with solid tumors and lymphomas. The present study aimed to determine the single-agent maximum tolerated dose (MTD) and recommended dose for expansion (RDE) in Japanese patients with advanced solid tumors. Ribociclib safety, tolerability, pharmacokinetic profile, and preliminary antitumor activity were also assessed. Japanese patients with solid tumors that had progressed on prior therapies received escalating doses of single-agent ribociclib on a 3-weeks-on/1-week-off schedule. Treatment continued until the development of toxicity or disease progression. A dose escalation was planned for patients with esophageal cancer. In the dose-escalation phase, 4 patients received 400 mg ribociclib and 13 patients received 600 mg ribociclib. Four patients experienced dose-limiting toxicities, 3 of whom were in the 600 mg group. The RDE was declared to be 600 mg, and the MTD was not determined. The most frequent adverse events were hematologic and gastrointestinal. Four patients achieved stable disease at the 600 mg dose; no patients achieved complete or partial response. All patients discontinued the study, the majority due to disease progression. No patients discontinued due to adverse events. Dose escalation was not pursued due to lack of observed efficacy in esophageal cancer. At the RDE of 600 mg/d on a 3-weeks-on/1-week-off schedule, ribociclib showed acceptable safety and tolerability profiles in Japanese patients with advanced solid tumors. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Low or High Fractionation Dose {beta}-Radiotherapy for Pterygium? A Randomized Clinical Trial

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

Viani, Gustavo Arruda, E-mail: gusviani@gmail.com; De Fendi, Ligia Issa; Fonseca, Ellen Carrara

2012-02-01

Purpose: Postoperative adjuvant treatment using {beta}-radiotherapy (RT) is a proven technique for reducing the recurrence of pterygium. A randomized trial was conducted to determine whether a low fractionation dose of 2 Gy within 10 fractions would provide local control similar to that after a high fractionation dose of 5 Gy within 7 fractions for surgically resected pterygium. Methods: A randomized trial was conducted in 200 patients (216 pterygia) between February 2006 and July 2007. Only patients with fresh pterygium resected using a bare sclera method and given RT within 3 days were included. Postoperative RT was delivered using a strontium-90more » eye applicator. The pterygia were randomly treated using either 5 Gy within 7 fractions (Group 1) or 2 Gy within 10 fractions (Group 2). The local control rate was calculated from the date of surgery. Results: Of the 216 pterygia included, 112 were allocated to Group 1 and 104 to Group 2. The 3-year local control rate for Groups 1 and 2 was 93.8% and 92.3%, respectively (p = .616). A statistically significant difference for cosmetic effect (p = .034), photophobia (p = .02), irritation (p = .001), and scleromalacia (p = .017) was noted in favor of Group 2. Conclusions: No better local control rate for postoperative pterygium was obtained using high-dose fractionation vs. low-dose fractionation. However, a low-dose fractionation schedule produced better cosmetic effects and resulted in fewer symptoms than high-dose fractionation. Moreover, pterygia can be safely treated in terms of local recurrence using RT schedules with a biologic effective dose of 24-52.5 Gy{sub 10.}.« less

Scheduling and Delivering Aircraft to Departure Fixes in the NY Metroplex with Controller-Managed Spacing Tools

NASA Technical Reports Server (NTRS)

Chevalley, Eric; Parke, Bonny; Kraut, Josh M.; Bienert, Nancy; Omar, Faisal; Palmer, Everett A.

2015-01-01

In this paper, successful Time-Based Flow Management (TBFM) scheduling systems for arrivals are considered and adapted to apply to departures. We present a concept of operations that integrates Controller-Managed Spacing tools for departures (CMS-D) with existing tactical departure scheduling tools to coordinate demand at departure fixes in a metroplex environment. We tested our concept in a Human-in-the-Loop simulation and compared the effect of two scheduling conditions: 1) "Departure Scheduling" consisting of an emulation of the Integrated Departure and Arrival Capability (IDAC) where Towers and a Planner (Traffic Management Coordinator at the appropriate facility) coordinate aircraft scheduled takeoff times to departure fixes; and 2) "Arrival Sensitive Departure Scheduling" where, in addition, the Tower and Planner also consider arrival Scheduled Time of Arrivals (STAs) at the airport's dependent runway. Results indicate little difference between the two scheduling conditions, but a large difference between the No Tools and the two scheduling conditions with CMS-D tools. The scheduling/CMS-D tools conditions markedly reduced heading, speed clearances, and workload for controllers who were merging flows at the departure fixes. In the tool conditions, departure controllers conditioned departures earlier rather than later when aircraft were tied near the departure fixes. In the scheduling/CMS-D tools conditions, departures crossed the departure fixes 50 seconds earlier and with an 8% error rate (consisting of time ahead or behind desired time of arrival) compared to a 19% error rate in the No Tool condition. Two exploratory runs showed that similar beneficial effects can be obtained only with the CMS-D tools without scheduling takeoff times, but at the cost of a somewhat higher workload for controllers, indicating the benefits of pre-departure scheduling of aircraft with minimal delays. Hence, we found that CMS-D tools were very beneficial in the metroplex environment we tested but that further research is needed to clarify the benefits of the various scheduling approaches.

Departure Queue Prediction for Strategic and Tactical Surface Scheduler Integration

NASA Technical Reports Server (NTRS)

Zelinski, Shannon; Windhorst, Robert

2016-01-01

A departure metering concept to be demonstrated at Charlotte Douglas International Airport (CLT) will integrate strategic and tactical surface scheduling components to enable the respective collaborative decision making and improved efficiency benefits these two methods of scheduling provide. This study analyzes the effect of tactical scheduling on strategic scheduler predictability. Strategic queue predictions and target gate pushback times to achieve a desired queue length are compared between fast time simulations of CLT surface operations with and without tactical scheduling. The use of variable departure rates as a strategic scheduler input was shown to substantially improve queue predictions over static departure rates. With target queue length calibration, the strategic scheduler can be tuned to produce average delays within one minute of the tactical scheduler. However, root mean square differences between strategic and tactical delays were between 12 and 15 minutes due to the different methods the strategic and tactical schedulers use to predict takeoff times and generate gate pushback clearances. This demonstrates how difficult it is for the strategic scheduler to predict tactical scheduler assigned gate delays on an individual flight basis as the tactical scheduler adjusts departure sequence to accommodate arrival interactions. Strategic/tactical scheduler compatibility may be improved by providing more arrival information to the strategic scheduler and stabilizing tactical scheduler changes to runway sequence in response to arrivals.

Impact of vaccination against Haemophilus influenzae type b with and without a booster dose on meningitis in four South American countries.

PubMed

Garcia, Salvador; Lagos, Rosanna; Muñoz, Alma; Picón, Teresa; Rosa, Raquel; Alfonso, Adriana; Abriata, Graciela; Gentile, Angela; Romanin, Viviana; Regueira, Mabel; Chiavetta, Laura; Agudelo, Clara Inés; Castañeda, Elizabeth; De la Hoz, Fernando; Higuera, Ana Betty; Arce, Patricia; Cohen, Adam L; Verani, Jennifer; Zuber, Patrick; Gabastou, Jean-Marc; Pastor, Desiree; Flannery, Brendan; Andrus, Jon

2012-01-05

To inform World Health Organization recommendations regarding use of Haemophilus influenzae type b (Hib) vaccines in national immunization programs, a multi-country evaluation of trends in Hib meningitis incidence and prevalence of nasopharyngeal Hib carriage was conducted in four South American countries using either a primary, three-dose immunization schedule without a booster dose or with a booster dose in the second year of life. Surveillance data suggest that high coverage of Hib conjugate vaccine sustained low incidence of Hib meningitis and low prevalence of Hib carriage whether or not a booster dose was used. Copyright © 2011 Elsevier Ltd. All rights reserved.

Combined hepatitis A and B vaccines: a review of their immunogenicity and tolerability.

PubMed

Murdoch, David L; Goa, Karen; Figgitt, David P

2003-01-01

Three combined hepatitis A and B vaccine preparations are commercially available in various countries: a two-dose paediatric formulation (Ambirix) [administered at months 0 and 6-12]; and a three-dose adult (Twinrix Adult) or paediatric (Twinrix Paediatric) formulation (administered at months 0, 1 and 6). The adult vaccine provides consistent, marked immunogenicity which is at least similar to that of its constituent vaccines used together and with a tolerability profile that is possibly improved. An accelerated, day-0, -7 and -21 regimen has also shown immunogenicity similar to that of the monovalent vaccines given concurrently, and now has an emerging role in adults likely to travel to hepatitis A virus (HAV) and/or hepatitis B virus (HBV) endemic regions within 1 month. The adult vaccine appears effective and generally well tolerated when given concurrently with monovalent typhoid vaccine (Typherix). Immunogenicity of the two-dose paediatric vaccine is high and appears to be similar whether administered as a month-0, -6 or month-0, -12 schedule and when compared to that of the three-dose paediatric vaccine (months 0, 1, 6), both of which provide a similar degree of protection to the adult vaccine. Although both preparations also provide high end-of-schedule seroprotection against hepatitis B surface antigen, protection between the first and second doses of the two-dose regimen appears lower than with the three-dose schedule. Therefore, the three-dose paediatric vaccine is a practical option in individuals at risk of immediate exposure to HBV, while the two-dose regimen may have an important function in immunisation programmes in regions where such risk is low. Combined hepatitis A and B vaccines are generally well tolerated. The most frequently reported adverse events in clinical trials were injection-site pain and redness, and general fatigue and headache; most events were mild and transient. Pharmacoeconomic models suggest the combined vaccine is cost effective compared with no vaccine (in children/adolescents) or monovalent hepatitis B vaccine (in children/adolescents and prison inmates). The three commercially available combined hepatitis A and B adult and paediatric vaccines are highly immunogenic and generally well tolerated; the adult vaccine demonstrates immunogenicity at least as marked as that of monovalent hepatitis A and B vaccines. While further research is required to confirm potential advantages such as improved cost effectiveness, the combined vaccines have established a key role in the prevention of hepatitis A and B in defined risk groups, and have an expanding role in population-based vaccination programmes with younger age groups.

Switching from an oral dopamine receptor agonist to rotigotine transdermal patch: a review of clinical data with a focus on patient perspective.

PubMed

Chung, Sun Ju; Asgharnejad, Mahnaz; Bauer, Lars; Benitez, Arturo; Boroojerdi, Babak; Heidbrede, Tanja; Little, Allison; Kim, Han Joon

2017-07-01

Dopamine receptor agonists (DAs) are commonly used to treat Parkinson's disease (PD) and restless legs syndrome (RLS). In certain situations, switching from oral DAs to rotigotine transdermal patch may be beneficial for the patient (e.g., optimal symptom control/side effects/perioperative management, preference for once-daily/non-oral administration, RLS augmentation treatment). Areas covered: This narrative review summarizes available data on DA dose equivalency, dose conversions, switching schedules, safety, tolerability, efficacy and patient treatment preferences of switching from oral DAs to rotigotine (and vice versa) in patients with PD/RLS. The studies were identified in a PubMed search (up to 8 November 2016) using terms ('dopamine receptor agonist' OR 'rotigotine') AND 'switch'. Expert commentary: Randomized controlled studies often do not address the challenges clinicians face in practice, e.g., switching medications within the same class when dosing is not a one-to-one ratio. The authors describe three open-label studies in PD where oral DAs were successfully switched to rotigotine, and review three studies in RLS where oral DAs/levodopa were switched to rotigotine. Finally, the authors provide a suggested tool for switching from oral DAs to rotigotine, which includes dose conversion factors and switching schedules. The authors' view is that low-dose oral DAs (equivalent to ≤8 mg/24 h rotigotine) may be switched overnight.

Development and pilot testing of daily Interactive Voice Response (IVR) calls to support antiretroviral adherence in India: A mixed-methods pilot study

PubMed Central

Swendeman, Dallas; Jana, Smarajit; Ray, Protim; Mindry, Deborah; Das, Madhushree; Bhakta, Bhumi

2015-01-01

This two-phase pilot study aimed to design, pilot, and refine an automated Interactive Voice Response (IVR) intervention to support antiretroviral adherence for people living with HIV (PLH), in Kolkata, India. Mixed-methods formative research included a community advisory board (CAB) for IVR message development, one-month pre-post pilot, post-pilot focus groups, and further message development. Two IVR calls are made daily, timed to patients’ dosing schedules, with brief messages (<1-minute) on strategies for self-management of three domains: medical (adherence, symptoms, co-infections), mental health (social support, stress, positive cognitions), and nutrition and hygiene (per PLH preferences). Three ART appointment reminders are also sent each month. One-month pilot results (n=46, 80% women, 60% sex workers) found significant increases in self-reported ART adherence, both within past three days (p=0.05) and time since missed last dose (p=0.015). Depression was common. Messaging content and assessment domains were expanded for testing in a randomized trial is currently underway. PMID:25638037

Development and Pilot Testing of Daily Interactive Voice Response (IVR) Calls to Support Antiretroviral Adherence in India: A Mixed-Methods Pilot Study.

PubMed

Swendeman, Dallas; Jana, Smarajit; Ray, Protim; Mindry, Deborah; Das, Madhushree; Bhakta, Bhumi

2015-06-01

This two-phase pilot study aimed to design, pilot, and refine an automated interactive voice response (IVR) intervention to support antiretroviral adherence for people living with HIV (PLH), in Kolkata, India. Mixed-methods formative research included a community advisory board for IVR message development, 1-month pre-post pilot, post-pilot focus groups, and further message development. Two IVR calls are made daily, timed to patients' dosing schedules, with brief messages (<1-min) on strategies for self-management of three domains: medical (adherence, symptoms, co-infections), mental health (social support, stress, positive cognitions), and nutrition and hygiene (per PLH preferences). Three ART appointment reminders are also sent each month. One-month pilot results (n = 46, 80 % women, 60 % sex workers) found significant increases in self-reported ART adherence, both within past three days (p = 0.05) and time since missed last dose (p = 0.015). Depression was common. Messaging content and assessment domains were expanded for testing in a randomized trial currently underway.

45 CFR 2552.52 - What factors are considered in determining a Foster Grandparent's service schedule?

Code of Federal Regulations, 2011 CFR

2011-10-01

... Grandparent's service schedule? (a) Travel time between the Foster Grandparent's home and place of assignment is not part of the service schedule and is not stipended. (b) Travel time between individual assignments is a part of the service schedule and is stipended. (c) Meal time may be part of the service...

45 CFR 2552.52 - What factors are considered in determining a Foster Grandparent's service schedule?

Code of Federal Regulations, 2010 CFR

2010-10-01

... Grandparent's service schedule? (a) Travel time between the Foster Grandparent's home and place of assignment is not part of the service schedule and is not stipended. (b) Travel time between individual assignments is a part of the service schedule and is stipended. (c) Meal time may be part of the service...

12 CFR 1005.36 - Transfers scheduled in advance.

Code of Federal Regulations, 2013 CFR

2013-01-01

...: § 1005.36 Transfers scheduled before the date of transfer. (a) Timing. (1) For a one-time transfer...) For a one-time transfer scheduled five or more business days in advance or for the first in a series... 12 Banks and Banking 8 2013-01-01 2013-01-01 false Transfers scheduled in advance. 1005.36 Section...

Magnesium sulfate accelerates the onset of low-dose rocuronium in patients undergoing laryngeal microsurgery.

PubMed

Choi, Eun-Su; Jeong, Woo-Jin; Ahn, Soon-Hyun; Oh, Ah-Young; Jeon, Young-Tae; Do, Sang-Hwan

2017-02-01

We evaluated the effect of magnesium sulfate-an enhancer of neuromuscular blockade-on onset and duration of low dose of rocuronium, and on operating conditions during laryngeal microsurgery. Randomized, prospective, double-blinded study. Eighty-four patients scheduled for elective laryngeal microsurgery. Patients were randomly allocated to receive different doses of rocuronium: 0.6 mg/kg (group C, n=28), 0.45 mg/kg (group LR, n=28), or 0.45 mg/kg plus magnesium sulfate 30 mg/kg (group LM, n=28). We measured the onset time and duration of action of rocuronium, and evaluated the surgeon's satisfaction with the operating conditions. Group LR showed significantly delayed onset time (group C: 87±22 seconds, group LR: 127±47 seconds, and group LM: 89±32 seconds; P=.001) and maximal suppression than did other groups (group C: 102±30 seconds, group LR: 155±66 seconds, and group LM: 105±36 seconds; P=.002). Duration of action of rocuronium was significantly longer in group C than in other groups (group C: 39±7 minutes, group LR: 28±8 minutes, group LRM: 31±8 minutes; P<.001). Laryngoscope placement score (P=.002), surgeon's satisfaction (P=.005), and sore throat (P=.035) were significantly worse in group LR. Magnesium sulfate 30 mg/kg accelerated the onset and improved operating conditions of low-dose rocuronium without prolongation of action. Copyright © 2016 Elsevier Inc. All rights reserved.

Balancing antagonistic time and resource utilization constraints in over-subscribed scheduling problems

NASA Technical Reports Server (NTRS)

Smith, Stephen F.; Pathak, Dhiraj K.

1991-01-01

In this paper, we report work aimed at applying concepts of constraint-based problem structuring and multi-perspective scheduling to an over-subscribed scheduling problem. Previous research has demonstrated the utility of these concepts as a means for effectively balancing conflicting objectives in constraint-relaxable scheduling problems, and our goal here is to provide evidence of their similar potential in the context of HST observation scheduling. To this end, we define and experimentally assess the performance of two time-bounded heuristic scheduling strategies in balancing the tradeoff between resource setup time minimization and satisfaction of absolute time constraints. The first strategy considered is motivated by dispatch-based manufacturing scheduling research, and employs a problem decomposition that concentrates local search on minimizing resource idle time due to setup activities. The second is motivated by research in opportunistic scheduling and advocates a problem decomposition that focuses attention on the goal activities that have the tightest temporal constraints. Analysis of experimental results gives evidence of differential superiority on the part of each strategy in different problem solving circumstances. A composite strategy based on recognition of characteristics of the current problem solving state is then defined and tested to illustrate the potential benefits of constraint-based problem structuring and multi-perspective scheduling in over-subscribe scheduling problems.

Interference Cognizant Network Scheduling

NASA Technical Reports Server (NTRS)

Hall, Brendan (Inventor); Bonk, Ted (Inventor); DeLay, Benjamin F. (Inventor); Varadarajan, Srivatsan (Inventor); Smithgall, William Todd (Inventor)

2017-01-01

Systems and methods for interference cognizant network scheduling are provided. In certain embodiments, a method of scheduling communications in a network comprises identifying a bin of a global timeline for scheduling an unscheduled virtual link, wherein a bin is a segment of the timeline; identifying a pre-scheduled virtual link in the bin; and determining if the pre-scheduled and unscheduled virtual links share a port. In certain embodiments, if the unscheduled and pre-scheduled virtual links don't share a port, scheduling transmission of the unscheduled virtual link to overlap with the scheduled transmission of the pre-scheduled virtual link; and if the unscheduled and pre-scheduled virtual links share a port: determining a start time delay for the unscheduled virtual link based on the port; and scheduling transmission of the unscheduled virtual link in the bin based on the start time delay to overlap part of the scheduled transmission of the pre-scheduled virtual link.

Methods to model and predict the ViewRay treatment deliveries to aid patient scheduling and treatment planning

PubMed Central

Liu, Shi; Wu, Yu; Wooten, H. Omar; Green, Olga; Archer, Brent; Li, Harold

2016-01-01

A software tool is developed, given a new treatment plan, to predict treatment delivery time for radiation therapy (RT) treatments of patients on ViewRay magnetic resonance image‐guided radiation therapy (MR‐IGRT) delivery system. This tool is necessary for managing patient treatment scheduling in our clinic. The predicted treatment delivery time and the assessment of plan complexities could also be useful to aid treatment planning. A patient's total treatment delivery time, not including time required for localization, is modeled as the sum of four components: 1) the treatment initialization time; 2) the total beam‐on time; 3) the gantry rotation time; and 4) the multileaf collimator (MLC) motion time. Each of the four components is predicted separately. The total beam‐on time can be calculated using both the planned beam‐on time and the decay‐corrected dose rate. To predict the remain‐ing components, we retrospectively analyzed the patient treatment delivery record files. The initialization time is demonstrated to be random since it depends on the final gantry angle of the previous treatment. Based on modeling the relationships between the gantry rotation angles and the corresponding rotation time, linear regression is applied to predict the gantry rotation time. The MLC motion time is calculated using the leaves delay modeling method and the leaf motion speed. A quantitative analysis was performed to understand the correlation between the total treatment time and the plan complexity. The proposed algorithm is able to predict the ViewRay treatment delivery time with the average prediction error 0.22 min or 1.82%, and the maximal prediction error 0.89 min or 7.88%. The analysis has shown the correlation between the plan modulation (PM) factor and the total treatment delivery time, as well as the treatment delivery duty cycle. A possibility has been identified to significantly reduce MLC motion time by optimizing the positions of closed MLC pairs. The accuracy of the proposed prediction algorithm is sufficient to support patient treatment appointment scheduling. This developed software tool is currently applied in use on a daily basis in our clinic, and could also be used as an important indicator for treatment plan complexity. PACS number(s): 87.55.N PMID:27074472

Working Notes from the 1992 AAAI Spring Symposium on Practical Approaches to Scheduling and Planning

NASA Technical Reports Server (NTRS)

Drummond, Mark; Fox, Mark; Tate, Austin; Zweben, Monte

1992-01-01

The symposium presented issues involved in the development of scheduling systems that can deal with resource and time limitations. To qualify, a system must be implemented and tested to some degree on non-trivial problems (ideally, on real-world problems). However, a system need not be fully deployed to qualify. Systems that schedule actions in terms of metric time constraints typically represent and reason about an external numeric clock or calendar and can be contrasted with those systems that represent time purely symbolically. The following topics are discussed: integrating planning and scheduling; integrating symbolic goals and numerical utilities; managing uncertainty; incremental rescheduling; managing limited computation time; anytime scheduling and planning algorithms, systems; dependency analysis and schedule reuse; management of schedule and plan execution; and incorporation of discrete event techniques.

Advertisement scheduling on commercial radio station using genetics algorithm

NASA Astrophysics Data System (ADS)

Purnamawati, S.; Nababan, E. B.; Tsani, B.; Taqyuddin, R.; Rahmat, R. F.

2018-03-01

On the commercial radio station, the advertising schedule is done manually, which resulted in ineffectiveness of ads schedule. Playback time consists of two types such as prime time and regular time. Radio Ads scheduling will be discussed in this research is based on ad playback schedule between 5am until 12am which rules every 15 minutes. It provides 3 slots ads with playback duration per ads maximum is 1 minute. If the radio broadcast time per day is 12 hours, then the maximum number of ads per day which can be aired is 76 ads. The other is the enactment of rules of prime time, namely the hours where the common people (listeners) have the greatest opportunity to listen to the radio, namely between the hours and hours of 4 am - 8 am, 6 pm - 10 pm. The number of screenings of the same ads on one day are limited to prime time ie 5 times, while for regular time is 8 times. Radio scheduling process is done using genetic algorithms which are composed of processes initialization chromosomes, selection, crossover and mutation. Study on chromosome 3 genes, each chromosome will be evaluated based on the value of fitness calculated based on the number of infractions that occurred on each individual chromosome. Where rule 1 is the number of screenings per ads must not be more than 5 times per day and rule 2 is there should never be two or more scheduling ads delivered on the same day and time. After fitness value of each chromosome is acquired, then the do the selection, crossover and mutation. From this research result, the optimal advertising schedule with schedule a whole day and ads data playback time ads with this level of accuracy: the average percentage was 83.79%.

Anti-tumour activity in RAS-driven tumours by blocking AKT and MEK

PubMed Central

Tolcher, Anthony W.; Khan, Khurum; Ong, Michael; Banerji, Udai; Papadimitrakopoulou, Vassiliki; Gandara, David R.; Patnaik, Amita; Baird, Richard D.; Olmos, David; Garrett, Christopher R.; Skolnik, Jeffrey M.; Rubin, Eric H.; Smith, Paul D.; Huang, Pearl; Learoyd, Maria; Shannon, Keith A.; Morosky, Anne; Tetteh, Ernestina; Jou, Ying-Ming; Papadopoulos, Kyriakos P.; Moreno, Victor; Kaiser, Brianne; Yap, Timothy A.; Yan, Li; de Bono, Johann S.

2014-01-01

Purpose KRAS is the most commonly mutated oncogene in human tumours. KRAS-mutant cells may exhibit resistance to the allosteric MEK1/2 inhibitor selumetinib (AZD6244; ARRY-142886) and allosteric AKT inhibitors (such as MK-2206), the combination of which may overcome resistance to both monotherapies. Experimental Design We conducted a dose/schedule-finding study evaluating MK-2206 and selumetinib in patients with advanced treatment-refractory solid tumours. Recommended dosing schedules were defined as MK-2206 135 mg weekly and selumetinib 100 mg once-daily. Results Grade 3 rash was the most common dose-limiting toxicity (DLT); other DLTs included grade 4 lipase increase, grade 3 stomatitis, diarrhoea, and fatigue, and grade 3 and grade 2 retinal pigment epithelium detachment. There were no meaningful pharmacokinetic drug-drug interactions. Clinical anti-tumour activity included RECIST 1.0-confirmed partial responses in non-small cell lung cancer and low-grade ovarian carcinoma. Conclusion Responses in KRAS-mutant cancers were generally durable. Clinical co-targeting of MEK and AKT signalling may be an important therapeutic strategy in KRAS-driven human malignancies (Trial NCT number NCT01021748). PMID:25516890

Antitumor activity in RAS-driven tumors by blocking AKT and MEK.

PubMed

Tolcher, Anthony W; Khan, Khurum; Ong, Michael; Banerji, Udai; Papadimitrakopoulou, Vassiliki; Gandara, David R; Patnaik, Amita; Baird, Richard D; Olmos, David; Garrett, Christopher R; Skolnik, Jeffrey M; Rubin, Eric H; Smith, Paul D; Huang, Pearl; Learoyd, Maria; Shannon, Keith A; Morosky, Anne; Tetteh, Ernestina; Jou, Ying-Ming; Papadopoulos, Kyriakos P; Moreno, Victor; Kaiser, Brianne; Yap, Timothy A; Yan, Li; de Bono, Johann S

2015-02-15

KRAS is the most commonly mutated oncogene in human tumors. KRAS-mutant cells may exhibit resistance to the allosteric MEK1/2 inhibitor selumetinib (AZD6244; ARRY-142886) and allosteric AKT inhibitors (such as MK-2206), the combination of which may overcome resistance to both monotherapies. We conducted a dose/schedule-finding study evaluating MK-2206 and selumetinib in patients with advanced treatment-refractory solid tumors. Recommended dosing schedules were defined as MK-2206 at 135 mg weekly and selumetinib at 100 mg once daily. Grade 3 rash was the most common dose-limiting toxicity (DLT); other DLTs included grade 4 lipase increase, grade 3 stomatitis, diarrhea, and fatigue, and grade 3 and grade 2 retinal pigment epithelium detachment. There were no meaningful pharmacokinetic drug-drug interactions. Clinical antitumor activity included RECIST 1.0-confirmed partial responses in non-small cell lung cancer and low-grade ovarian carcinoma. Responses in KRAS-mutant cancers were generally durable. Clinical cotargeting of MEK and AKT signaling may be an important therapeutic strategy in KRAS-driven human malignancies (Trial NCT number NCT01021748). ©2014 American Association for Cancer Research.

Phase I study of 6-diazo-5-oxo-L-norleucine (DON).

PubMed

Sklaroff, R B; Casper, E S; Magill, G B; Young, C W

1980-01-01

We conducted a phase I study of 6-diazo-5-oxo-L-norleucine given iv on a twice weekly schedule. Twenty-six evaluable patients received 31 courses of the drug. Doses ranged from 100 to 500 mg/m2. Nausea with vomiting was the dose-limiting toxic effect, transient thrombocytopenia was seen frequently, and mucositis occurred in 39% of the patients. No definite therapeutic responses were observed in 18 patients with measurable lesions. The recommended dose for phase II studies is 200-300 mg/m2 iv twice weekly.

Cash transportation vehicle routing and scheduling under stochastic travel times

NASA Astrophysics Data System (ADS)

Yan, Shangyao; Wang, Sin-Siang; Chang, Yu-Hsuan

2014-03-01

Stochastic disturbances occurring in real-world operations could have a significant influence on the planned routing and scheduling results of cash transportation vehicles. In this study, a time-space network flow technique is utilized to construct a cash transportation vehicle routing and scheduling model incorporating stochastic travel times. In addition, to help security carriers to formulate more flexible routes and schedules, a concept of the similarity of time and space for vehicle routing and scheduling is incorporated into the model. The test results show that the model could be useful for security carriers in actual practice.

Scheduling Dependent Real-Time Activities

DTIC Science & Technology

1990-08-01

dependency relationships in a way that is suitable for all real - time systems . This thesis provides an algorithm, called DASA, that is effective for...scheduling the class of real - time systems known as supervisory control systems. Simulation experiments that account for the time required to make scheduling

5 CFR 610.406 - Holiday for employees on compressed work schedules.

Code of Federal Regulations, 2010 CFR

2010-01-01

... number of hours of the compressed work schedule on that day. (b) If a part-time employee is relieved or... of the compressed work schedule on that day. When a holiday falls on a nonworkday of a part-time... work schedules. (a) If a full-time employee is relieved or prevented from working on a day designated...

Adaptive control of theophylline therapy: importance of blood sampling times.

PubMed

D'Argenio, D Z; Khakmahd, K

1983-10-01

A two-observation protocol for estimating theophylline clearance during a constant-rate intravenous infusion is used to examine the importance of blood sampling schedules with regard to the information content of resulting concentration data. Guided by a theory for calculating maximally informative sample times, population simulations are used to assess the effect of specific sampling times on the precision of resulting clearance estimates and subsequent predictions of theophylline plasma concentrations. The simulations incorporated noise terms for intersubject variability, dosing errors, sample collection errors, and assay error. Clearance was estimated using Chiou's method, least squares, and a Bayesian estimation procedure. The results of these simulations suggest that clinically significant estimation and prediction errors may result when using the above two-point protocol for estimating theophylline clearance if the time separating the two blood samples is less than one population mean elimination half-life.

Coordination of appointments for anesthesia care outside of operating rooms using an enterprise-wide scheduling system.

PubMed

Dexter, Franklin; Xiao, Yan; Dow, Angella J; Strader, Melissa M; Ho, Danny; Wachtel, Ruth E

2007-12-01

An anesthesia department implemented scheduling of anesthetics outside of operating rooms (non-OR) by clerks and nurses from other departments using its hospital's enterprise-wide scheduling system. Observational studies chronicled the change over 2 yr as non-OR time was allocated by specialty, and nonanesthesia clerks and nurses scheduled anesthesia teams. Experimental studies investigated how tabular and graphical displays affected the scheduling of milestones (e.g., NPO times) and appointments before anesthetics. Anesthetics performed in allocated time increased progressively from 0% to 75%. Scheduling of anesthetics by nonanesthesia clerks and nurses increased progressively from 0% to 77%. Consistency of patient instructions was improved. The quality of resulting schedules was good. Implementation was not associated with worsening of multiple operational measures of performance such as cancellation rates, turnover times, or complaints. However, schedulers struggled to understand fasting and arrival times of patients, despite using a web site with statistically generated values in tabular formats. Experiments revealed that people ignored their knowledge that anesthetics can start earlier than scheduled. Participants made good decisions with both tabular and graphical displays when scheduling appointments preceding anesthesia. Enterprise-wide scheduling can coordinate anesthetics with other appointments on the same date and improve consistency and accuracy of patient instructions customized to the probability of an anesthetic starting early. The usefulness of implementation depends on the value in having more patient-centered care and/or in having patients arrive just in time for non-OR anesthesia, surgery, or regional block placement (e.g., at facilities with limited physical space).

Utilization Bound of Non-preemptive Fixed Priority Schedulers

NASA Astrophysics Data System (ADS)

Park, Moonju; Chae, Jinseok

It is known that the schedulability of a non-preemptive task set with fixed priority can be determined in pseudo-polynomial time. However, since Rate Monotonic scheduling is not optimal for non-preemptive scheduling, the applicability of existing polynomial time tests that provide sufficient schedulability conditions, such as Liu and Layland's bound, is limited. This letter proposes a new sufficient condition for non-preemptive fixed priority scheduling that can be used for any fixed priority assignment scheme. It is also shown that the proposed schedulability test has a tighter utilization bound than existing test methods.

Pneumococcal conjugate vaccine 13 delivered as one primary and one booster dose (1 + 1) compared with two primary doses and a booster (2 + 1) in UK infants: a multicentre, parallel group randomised controlled trial.

PubMed

Goldblatt, David; Southern, Jo; Andrews, Nick J; Burbidge, Polly; Partington, Jo; Roalfe, Lucy; Valente Pinto, Marta; Thalasselis, Vasilli; Plested, Emma; Richardson, Hayley; Snape, Matthew D; Miller, Elizabeth

2018-02-01

Infants in the UK were first offered a pneumococcal conjugate vaccine (PCV7) in 2006, given at 2 and 4 months of age and a booster dose at 13 months (2 + 1 schedule). A 13-valent vaccine (PCV13) replaced PCV7 in 2010. We aimed to compare the post-booster antibody response in UK infants given a reduced priming schedule of PCV13 (ie, a 1 + 1 schedule) versus the current 2 + 1 schedule and to assess the potential effect on population protection. In this multicentre, parallel group, randomised controlled trial, we recuited infants due to receive their primary immunisations aged up to 13 weeks on first vaccinations by information booklets mailed out via the NHS Child Health Information Service and the UK National Health Application and Infrastructure Services. Eligible infants were randomly assigned (1:1) to receive PCV13 at 2, 4, and 12 months (2 + 1 schedule) or 3 and 12 months of age (1 + 1 schedule) delivered with other routine vaccinations. Randomisation was done by computer-generated permuted block randomisation, with a block size of six. Participants and clinical trial staff were not masked to treatment allocation. The primary endpoint was serotype-specific immunoglobulin G concentrations values (geometric mean concentrations [GMC] in μg/mL) measured in blood samples collected at 13 months of age. Analysis was by modified intention to treat with all individuals included by randomised group if they had a laboratory result. This trial is registered on the EudraCT clinical trial database, number 2015-000817-32, and ClinicalTrials.gov, number NCT02482636. Between September, 2015, and June, 2016, 376 infants were assessed for eligibility. 81 infants were excluded for not meeting the inclusion criteria (n=50) or for other reasons (n=31). 213 eligible infants were enrolled and randomly allocated to group 1 (n=106; 2 + 1 schedule) or to group 2 (n=107; 1 + 1 schedule). In group 1, 91 serum samples were available for analysis 1 month after booster immunisation versus 86 in group 2. At month 13, post-booster, GMCs were equivalent between schedules for serotypes 3 (0·61 μg/mL in group 1 vs 0·62 μg/mL in group 2), 5 (1·74 μg/mL vs 2·11 μg/mL), 7F (3·98 μg/mL vs 3·36 μg/mL), 9V (2·34 μg/mL vs 2·50 μg/mL), and 19A (8·38 μg/mL vs 8·83 μg/mL). Infants given the 1 + 1 schedule had significantly greater immunogenicity post-booster than those given the 2 + 1 schedule for serotypes 1 (8·92 μg/mL vs 3·07 μg/mL), 4 (3·43 μg/mL vs 2·55 μg/mL), 14 (16·9 μg/mL vs 10·49 μg/mL), and 19F (14·76 μg/mL vs 11·12 μg/mL; adjusted p value range <0·001 to 0·047). The 2 + 1 schedule was superior for serotypes 6A, 6B, 18C and 23F (adjusted p value range <0·0001 to 0·017). In a predefined numerical subset of all of the infants recruited to the study (n=40 [20%]), functional serotype-specific antibody was similar between schedules. 26 serious adverse events were recorded in 21 (10%) infants across the study period; 18 (n=13) were in the 2 + 1 group and eight (n=8) in the 1 + 1 group. Only one serious adverse event, a high temperature and refusal to feed after the first vaccination visit in a child on the 2+1 schedule was considered related to vaccine. Our findings show that for nine of the 13 serotypes in PCV13, post-booster responses in infants primed with a single dose are equivalent or superior to those seen following the standard UK 2 + 1 schedule. Introducing a 1 + 1 schedule in countries with a mature PCV programme and established herd immunity is likely to maintain population control of vaccine-type pneumococcal disease. NIHR and the Bill & Melinda Gates Foundation. Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Scheduler software for tracking and data relay satellite system loading analysis: User manual and programmer guide

NASA Technical Reports Server (NTRS)

Craft, R.; Dunn, C.; Mccord, J.; Simeone, L.

1980-01-01

A user guide and programmer documentation is provided for a system of PRIME 400 minicomputer programs. The system was designed to support loading analyses on the Tracking Data Relay Satellite System (TDRSS). The system is a scheduler for various types of data relays (including tape recorder dumps and real time relays) from orbiting payloads to the TDRSS. Several model options are available to statistically generate data relay requirements. TDRSS time lines (representing resources available for scheduling) and payload/TDRSS acquisition and loss of sight time lines are input to the scheduler from disk. Tabulated output from the interactive system includes a summary of the scheduler activities over time intervals specified by the user and overall summary of scheduler input and output information. A history file, which records every event generated by the scheduler, is written to disk to allow further scheduling on remaining resources and to provide data for graphic displays or additional statistical analysis.

Lessons Learned From the Introduction of Inactivated Poliovirus Vaccine in Bangladesh.

PubMed

Estivariz, Concepcion F; Snider, Cynthia J; Anand, Abhijeet; Hampton, Lee M; Bari, Tajul I; Billah, Mallick M; Chai, Shua J; Wassilak, Steven G; Heffelfinger, James D; Zaman, K

2017-07-01

We assessed programmatic adaptations and infants' uptake of inactivated poliovirus vaccine (IPV) after its introduction into the routine immunization schedule in Bangladesh. Using convenience and probability sampling, we selected 23 health facilities, 36 vaccinators, and 336 caregivers, within 5 districts and 3 city corporations. We collected data during August-October 2015 by conducting interviews, reviewing vaccination records, and observing activities. Knowledge about IPV was high among vaccinators (94%). No problems with IPV storage, transport, or waste disposal were detected, but shortages were reported in 20 health facilities (87%). Wastage per 5-dose vaccine vial was above the recommended 30% in 20 health facilities (87%); all were related to providing <5 doses per open vial. Among eligible infants, 87% and 86% received the third dose of pentavalent and oral poliovirus vaccine, respectively, but only 65% received IPV at the same visit. Among 73 infants not vaccinated with IPV, 58% of caregivers reported that vaccine was unavailable. Bangladesh successfully introduced IPV, but shortages related to insufficient global supply and high vaccine wastage in small outreach immunization sessions might reduce its impact on population immunity. Minimizing wastage and use of a 2-dose fractional-IPV schedule could extend IPV immunization to more children. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.

Novel reinforcement learning paradigm based on response patterning under interval schedules of reinforcement.

PubMed

Schifani, Christin; Sukhanov, Ilya; Dorofeikova, Mariia; Bespalov, Anton

2017-07-28

There is a need to develop cognitive tasks that address valid neuropsychological constructs implicated in disease mechanisms and can be used in animals and humans to guide novel drug discovery. Present experiments aimed to characterize a novel reinforcement learning task based on a classical operant behavioral phenomenon observed in multiple species - differences in response patterning under variable (VI) vs fixed interval (FI) schedules of reinforcement. Wistar rats were trained to press a lever for food under VI30s and later weekly test sessions were introduced with reinforcement schedule switched to FI30s. During the FI30s test session, post-reinforcement pauses (PRPs) gradually grew towards the end of the session reaching 22-43% of the initial values. Animals could be retrained under VI30s conditions, and FI30s test sessions were repeated over a period of several months without appreciable signs of a practice effect. Administration of the non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 ((5S,10R)-(+)-5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate) prior to FI30s sessions prevented adjustment of PRPs associated with the change from VI to FI schedule. This effect was most pronounced at the highest tested dose of MK-801 and appeared to be independent of the effects of this dose on response rates. These results provide initial evidence for the possibility to use different response patterning under VI and FI schedules with equivalent reinforcement density for studying effects of drug treatment on reinforcement learning. Copyright © 2017 Elsevier B.V. All rights reserved.

Bridging non-human primate correlates of protection to reassess the Anthrax Vaccine Adsorbed booster schedule in humans.

PubMed

Schiffer, Jarad M; Chen, Ligong; Dalton, Shannon; Niemuth, Nancy A; Sabourin, Carol L; Quinn, Conrad P

2015-07-17

Anthrax Vaccine Adsorbed (AVA, BioThrax) is approved for use in humans as a priming series of 3 intramuscular (i.m.) injections (0, 1, 6 months; 3-IM) with boosters at 12 and 18 months, and annually thereafter for those at continued risk of infection. A reduction in AVA booster frequency would lessen the burden of vaccination, reduce the cumulative frequency of vaccine associated adverse events and potentially expand vaccine coverage by requiring fewer doses per schedule. Because human inhalation anthrax studies are neither feasible nor ethical, AVA efficacy estimates are determined using cross-species bridging of immune correlates of protection (COP) identified in animal models. We have previously reported that the AVA 3-IM priming series provided high levels of protection in non-human primates (NHP) against inhalation anthrax for up to 4 years after the first vaccination. Penalized logistic regressions of those NHP immunological data identified that anti-protective antigen (anti-PA) IgG concentration measured just prior to infectious challenge was the most accurate single COP. In the present analysis, cross-species logistic regression models of this COP were used to predict probability of survival during a 43 month study in humans receiving the current 3-dose priming and 4 boosters (12, 18, 30 and 42 months; 7-IM) and reduced schedules with boosters at months 18 and 42 only (5-IM), or at month 42 only (4-IM). All models predicted high survival probabilities for the reduced schedules from 7 to 43 months. The predicted survival probabilities for the reduced schedules were 86.8% (4-IM) and 95.8% (5-IM) at month 42 when antibody levels were lowest. The data indicated that 4-IM and 5-IM are both viable alternatives to the current AVA pre-exposure prophylaxis schedule. Published by Elsevier Ltd.

Cell cycle-tailored targeting of metastatic melanoma: Challenges and opportunities.

PubMed

Haass, Nikolas K; Gabrielli, Brian

2017-07-01

The advent of targeted therapies of metastatic melanoma, such as MAPK pathway inhibitors and immune checkpoint antagonists, has turned dermato-oncology from the "bad guy" to the "poster child" in oncology. Current targeted therapies are effective, although here is a clear need to develop combination therapies to delay the onset of resistance. Many antimelanoma drugs impact on the cell cycle but are also dependent on certain cell cycle phases resulting in cell cycle phase-specific drug insensitivity. Here, we raise the question: Have combination trials been abandoned prematurely as ineffective possibly only because drug scheduling was not optimized? Firstly, if both drugs of a combination hit targets in the same melanoma cell, cell cycle-mediated drug insensitivity should be taken into account when planning combination therapies, timing of dosing schedules and choice of drug therapies in solid tumors. Secondly, if the combination is designed to target different tumor cell subpopulations of a heterogeneous tumor, one drug effective in a particular subpopulation should not negatively impact on the other drug targeting another subpopulation. In addition to the role of cell cycle stage and progression on standard chemotherapeutics and targeted drugs, we discuss the utilization of cell cycle checkpoint control defects to enhance chemotherapeutic responses or as targets themselves. We propose that cell cycle-tailored targeting of metastatic melanoma could further improve therapy outcomes and that our real-time cell cycle imaging 3D melanoma spheroid model could be utilized as a tool to measure and design drug scheduling approaches. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

A pharmacokinetic model of filgrastim and pegfilgrastim application in normal mice and those with cyclophosphamide-induced granulocytopaenia.

PubMed

Scholz, M; Ackermann, M; Engel, C; Emmrich, F; Loeffler, M; Kamprad, M

2009-12-01

Recombinant human granulocyte colony-stimulating factor (rhG-CSF) is widely used as treatment for granulocytopaenia during cytotoxic chemotherapy; however, optimal scheduling of this pharmaceutical is unknown. Biomathematical models can help to pre-select optimal application schedules but precise pharmacokinetic properties of the pharmaceuticals are required at first. In this study, we have aimed to construct a pharmacokinetic model of G-CSF derivatives filgrastim and pegfilgrastim in mice. Healthy CD-1 mice and those with cyclophosphamide-induced granulocytopaenia were studied after administration of filgrastim and pegfilgrastim in different dosing and timing schedules. Close meshed time series of granulocytes and G-CSF plasma concentrations were determined. An ordinary differential equations model of pharmacokinetics was constructed on the basis of known mechanisms of drug distribution and degradation. Predictions of the model fit well with all experimental data for both filgrastim and pegfilgrastim. We obtained a unique parameter setting for all experimental scenarios. Differences in pharmacokinetics between filgrastim and pegfilgrastim can be explained by different estimates of model parameters rather than by different model mechanisms. Parameter estimates with respect to distribution and clearance of the drug derivatives are in agreement with qualitative experimental results. Dynamics of filgrastim and pegfilgrastim plasma levels can be explained by the same pharmacokinetic model but different model parameters. Beause of a strong clearance mechanism mediated by granulocytes, granulocytotic and granulocytopaenic conditions must be studied simultaneously to construct a reliable model. The pharmacokinetic model will be extended to a murine model of granulopoiesis under chemotherapy and G-CSF application.

Late effect of multiple daily fraction palliation schedule for advanced pelvic malignancies (RTOG 8502)

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

Spanos, W.J. Jr.; Clery, M.; Perez, C.A.

1994-07-30

The purpose was to determine late complication incidence for pelvic palliation using accelerated multiple daily fraction radiation [Radiation Therapy Oncology Group (RTOG) 8502]. None of the patients with < 30 Gy (less than three courses) developed late toxicity. A total of 11/193 (6%) developed Grade 3+ late toxicity (nine Grade 3, on Grade 4, one Grade 5). Actuarial analysis of complication rate by survival time for Grades 3, 4, and 5 shows a cumulative incidence for complications after 6 months that plateaus at 6.9% by 18 months. The cumulative incidence for Grades 4 and 5 is 2.0% by 12 months.more » The difference in late effect for the 2-week rest vs. 4-week rest was not statistically different (p = .47). Patient factors evaluated for increased risk of late complications included prior surgeries, age, sex, KPS and primary. None were found to have significant statistical correlations with late effects. The crude late complications rate is 6%. Actuarial analysis using cumulative incidence shows 6.9% by 18 months. This represents a significant decrease in late complications from 49% seen with higher dose per fraction (10 Gy {times} 3) piloted by Radiation Therapy Oncology Group (7905) for a similar group of patients. Long-term analysis of late complication indicates this schedule can be used in the pelvis with relatively low incidence of complication. This schedule has significant logistic benefits and has been shown to produce good tumor regression and excellent palliation of symptoms. 14 refs., 4 figs., 4 tabs.« less

EP3/FP dual receptor agonist ONO-9054 administered morning or evening to patients with open-angle glaucoma or ocular hypertension: results of a randomised crossover study

PubMed Central

Berlin, Michael S; Rowe-Rendleman, Cheryl; Ahmed, Ike; Ross, Douglas T; Fujii, Akifumi; Ouchi, Takafumi; Quach, Christine; Wood, Andrew; Ward, Caroline L

2016-01-01

Background/aims The novel prostaglandin E (EP) 3 and prostaglandin F (FP) receptor agonist ONO-9054 is effective in lowering intraocular pressure (IOP) in patients with ocular hypertension and open-angle glaucoma when administered once daily. This study compares the effects of morning (AM) versus evening (PM) dosing of ONO-9054 on tolerability and IOP lowering. Methods This was a single-centre, randomised, double-masked, two-sequence, placebo-controlled crossover study in 12 subjects with bilateral primary open-angle glaucoma or ocular hypertension. Two 14-day crossover regimens were separated by a 2-week washout: ONO-9054 (1 drop to each eye) in the morning (07:00) and vehicle in the evening (19:00) and vice versa. IOP was measured multiple times during select days. Ocular examinations also evaluated safety and tolerability. Results Mild ocular hyperaemia, reported by six subjects with PM dosing, was the most frequent adverse event. Mild to moderate dryness was also slightly more frequent after PM dosing. Maximum IOP reduction from baseline occurred on day 2 with decreases from baseline of −7.4 mm Hg (−30.8%) for AM dosing and −9.1 mm Hg, (−38.0%) for PM dosing; after 14 days, mean reduction in IOP was −6.8 mm Hg (−28.6%) for AM dosing and −7.5 mm Hg (−31.0%) for PM dosing. Conclusions PM dosing of ONO-0954 was associated with a slightly increased frequency of mild hyperaemia and mild to moderate dryness. Both dosing schedules provided sustained reduction in IOP. Trial registration number NCT01670266. PMID:26453641

Clinical radiobiology of stage T2-T3 bladder cancer.

PubMed

Majewski, Wojciech; Maciejewski, Boguslaw; Majewski, Stanislaw; Suwinski, Rafal; Miszczyk, Leszek; Tarnawski, Rafal

2004-09-01

To evaluate the relationship between total radiation dose and overall treatment time (OTT) with the treatment outcome, with adjustment for selected clinical factors, in patients with Stage T2-T3 bladder cancer treated with curative radiotherapy (RT). The analysis was based on 480 patients with Stage T2-T3 bladder cancer who were treated at the Center of Oncology in Gliwice between 1975 and 1995. The mean total radiation dose was 65.5 Gy, and the mean OTT was 51 days. In 261 patients (54%), planned and unplanned gaps occurred during RT. Four fractionation schedules were used: (1) conventional fractionation (once daily, 1.8-2.5 Gy/fraction); (2) protracted fractionation (pelvic RT, once daily, 1.6-1.7 Gy/fraction, boost RT, once daily, 2.0 Gy/fraction); (3) accelerated hyperfractionated boost (pelvic RT, once daily, 2.0 Gy/fraction; boost RT, twice daily, 1.3-1.4 Gy/fraction); and (4) accelerated hyperfractionation (pelvic and boost RT, twice daily, 1.2-1.5 Gy/fraction). In all fractionation schedules, the total radiation dose was similar (average 65.5 Gy), but the OTT was different (mean 53 days for conventional fractionation, 62 days for protracted fractionation, 45 days for accelerated hyperfractionated boost, and 41 days for accelerated hyperfractionation). A Cox proportional hazard model and maximum likelihood logistic model were used to evaluate the relationship between the treatment-related parameters (total radiation dose, dose per fraction, and OTT) and clinical factors (clinical T stage, hemoglobin level and bladder capacity before RT) and treatment outcome. With a median follow-up of 76 months, the actuarial 5-year local control rate was 47%, and the overall survival rate was 40%. The logistic analysis, which included the total dose, OTT, and T stage, revealed that all of these factors were significantly related to tumor control probability (p = 0.021 for total radiation dose, p = 0.038 for OTT, and p = 0.00068 for T stage). A multivariate Cox model, which included the treatment-related parameters and other clinical factors, revealed that the hemoglobin level and bladder capacity before RT and T-stage were statistically significant factors determining local control and overall survival. The total radiation dose was of borderline statistical significance for overall survival (p = 0.087), and OTT did not reach statistical significance. The results of our study showed that the treatment outcome after RT for bladder cancer depends mainly on clinical factors: hemoglobin level and bladder capacity before RT, and clinical T stage. An increase in the total radiation dose seemed to be associated with a better treatment outcome. The effect of the OTT was difficult to define, because it was influenced by other prognostic factors.

Computing the Expected Cost of an Appointment Schedule for Statistically Identical Customers with Probabilistic Service Times

PubMed Central

Dietz, Dennis C.

2014-01-01

A cogent method is presented for computing the expected cost of an appointment schedule where customers are statistically identical, the service time distribution has known mean and variance, and customer no-shows occur with time-dependent probability. The approach is computationally efficient and can be easily implemented to evaluate candidate schedules within a schedule optimization algorithm. PMID:24605070

10 CFR 51.15 - Time schedules.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 10 Energy 2 2010-01-01 2010-01-01 false Time schedules. 51.15 Section 51.15 Energy NUCLEAR... REGULATORY FUNCTIONS National Environmental Policy Act-Regulations Implementing Section 102(2) § 51.15 Time... proposed action or a petitioner for rulemaking shall, establish a time schedule for all or any constituent...

10 CFR 51.15 - Time schedules.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 10 Energy 2 2014-01-01 2014-01-01 false Time schedules. 51.15 Section 51.15 Energy NUCLEAR... REGULATORY FUNCTIONS National Environmental Policy Act-Regulations Implementing Section 102(2) § 51.15 Time... proposed action or a petitioner for rulemaking shall, establish a time schedule for all or any constituent...

10 CFR 51.15 - Time schedules.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 10 Energy 2 2011-01-01 2011-01-01 false Time schedules. 51.15 Section 51.15 Energy NUCLEAR... REGULATORY FUNCTIONS National Environmental Policy Act-Regulations Implementing Section 102(2) § 51.15 Time... proposed action or a petitioner for rulemaking shall, establish a time schedule for all or any constituent...

10 CFR 51.15 - Time schedules.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 10 Energy 2 2013-01-01 2013-01-01 false Time schedules. 51.15 Section 51.15 Energy NUCLEAR... REGULATORY FUNCTIONS National Environmental Policy Act-Regulations Implementing Section 102(2) § 51.15 Time... proposed action or a petitioner for rulemaking shall, establish a time schedule for all or any constituent...

Dose-response relationship between light exposure and cycling performance.

PubMed

Knaier, R; Meister, S; Aeschbacher, T; Gemperle, D; Rossmeissl, A; Cajochen, C; Schmidt-Trucksäss, A

2016-07-01

Light has a stimulating effect on physical performance if scheduled according to the chronotype, but dose-dependent effects on performance have not yet been examined. Three groups of healthy men (25.1 ± 3.1 years) were exposed to light for different durations in a parallel group design before a 40-min time-trial. In each group, subjects were exposed to either bright light (BL, 4420 lx) or moderate light (ML, 230 lx) in a randomized order in a crossover design. The durations of light exposure were 120 min prior to and during exercise (2HEX; n = 16), 60 min prior to and during exercise (1HEX; n = 10), or only for 60 min prior to exercise (1H; n = 15). Total work performed during the time-trial in kJ in the 2HEX group was significantly higher in the BL setting (527 kJ) than in ML (512 kJ) (P = 0.002), but not in 1HEX (BL: 485 kJ; ML: 498 kJ) or 1H (BL: 519 kJ; ML: 514 kJ) (P = 0.770; P = 0.485). There was a significant (P = 0.006) positive dose-response relationship between the duration of light exposure and the work performed over the three doses of light exposure. A long duration light exposure is an effective tool to increase total work in a medium length time-trial in subjects normalized for their individual chronotype. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

A nonhuman primate model of the hematopoietic acute radiation syndrome plus medical management.

PubMed

Farese, Ann M; Cohen, Melanie V; Katz, Barry P; Smith, Cassandra P; Jackson, William; Cohen, Daniel M; MacVittie, Thomas J

2012-10-01

The development of medical countermeasures against the hematopoietic subsyndrome of the acute radiation syndrome requires well characterized and validated animal models. The model must define the radiation dose- and time-dependent relationships for mortality and major signs of morbidity to include other organ damage that may contribute to morbidity and mortality. Herein, the authors define these parameters for a nonhuman primate exposed to total body radiation and administered medical management. A blinded, randomized study (n = 48 rhesus macaques) determined the lethal dose-response relationship using bilateral 6 MV linear accelerator photon radiation to doses in the range of 7.20 to 8.90 Gy at 0.80 Gy min(-1). Following irradiation, animals were monitored for complete bloodcounts, body weight, temperature, diarrhea, and hydration status for 60 d. Animals were administered medical management consisting of intravenous fluids, prophylactic antibiotics, blood transfusions, anti-diarrheals, analgesics, and nutrition. The primary endpoint was survival at 60 d post-irradiation; secondary endpoints included hematopoietic-related parameters, number of transfusions, incidence of documented infection, febrile neutropenia, severity of diarrhea, mean survival time of decedents, and tissue histology. The study defined an LD30/60 of 7.06 Gy, LD50/60 of 7.52 Gy, and an LD70/60 of 7.99 Gy with a relatively steep slope of 1.13 probits per linear dose. This study establishes a rhesus macaque model of the hematopoietic acute radiation syndrome and shows the marked effect of medical management on increased survival and overall mean survival time for decedents. Furthermore, following a nuclear terrorist event, medical management may be the only treatment administered at its optimal schedule.

Lorcaserin, a 5-HT2C Agonist, Decreases Nicotine Self-Administration in Female Rats

PubMed Central

Johnson, Joshua E.; Slade, Susan; Wells, Corinne; Cauley, Marty; Petro, Ann; Rose, Jed E.

2011-01-01

Lorcaserin, a selective 5-hydroxytryptamine2C (5-HT2C) agonist, has been shown to facilitate weight loss in obese populations. It was assessed for its efficacy in reducing nicotine self-administration in young adult female Sprague-Dawley rats. The effect of short-term doses (subcutaneous) on nicotine self-administration (0.03 mg/kg per infusion) with a fixed ratio 1 schedule was assessed in 3-h sessions. Short-term lorcaserin doses (0.3125–20 mg/kg) were administered in a counterbalanced order. Significant reduction of nicotine self-administration was achieved with all of the short-term doses in this range. Tests of lorcaserin on locomotor activity detected prominent sedative effects at doses greater than 1.25 mg/kg with more modest transient effects seen at 0.625 to 1.25 mg/kg. Long-term effects of lorcaserin on locomotor activity were tested with repeated injections with 0.625 mg/kg lorcaserin 10 times over 2 weeks. This low lorcaserin dose did not cause an overall change in locomotor activity relative to that of saline-injected controls. Long-term lorcaserin (0.625 mg/kg) significantly reduced nicotine self-administration over a 2-week period of repeated injections. Long-term lorcaserin at this same dose had no significant effects on food self-administration over the same 2-week period of repeated injections. These studies support development of the 5-HT2C agonist lorcaserin to aid tobacco smoking cessation. PMID:21636655

Lorcaserin, a 5-HT2C agonist, decreases nicotine self-administration in female rats.

PubMed

Levin, Edward D; Johnson, Joshua E; Slade, Susan; Wells, Corinne; Cauley, Marty; Petro, Ann; Rose, Jed E

2011-09-01

Lorcaserin, a selective 5-hydroxytryptamine(2C) (5-HT(2C)) agonist, has been shown to facilitate weight loss in obese populations. It was assessed for its efficacy in reducing nicotine self-administration in young adult female Sprague-Dawley rats. The effect of short-term doses (subcutaneous) on nicotine self-administration (0.03 mg/kg per infusion) with a fixed ratio 1 schedule was assessed in 3-h sessions. Short-term lorcaserin doses (0.3125-20 mg/kg) were administered in a counterbalanced order. Significant reduction of nicotine self-administration was achieved with all of the short-term doses in this range. Tests of lorcaserin on locomotor activity detected prominent sedative effects at doses greater than 1.25 mg/kg with more modest transient effects seen at 0.625 to 1.25 mg/kg. Long-term effects of lorcaserin on locomotor activity were tested with repeated injections with 0.625 mg/kg lorcaserin 10 times over 2 weeks. This low lorcaserin dose did not cause an overall change in locomotor activity relative to that of saline-injected controls. Long-term lorcaserin (0.625 mg/kg) significantly reduced nicotine self-administration over a 2-week period of repeated injections. Long-term lorcaserin at this same dose had no significant effects on food self-administration over the same 2-week period of repeated injections. These studies support development of the 5-HT(2C) agonist lorcaserin to aid tobacco smoking cessation.

Effects of 7-day repeated treatment with the 5-HT2A inverse agonist/antagonist pimavanserin on methamphetamine vs. food choice in male rhesus monkeys.

PubMed

Banks, Matthew L

2016-08-01

Preclinical drug vs. food choice is an emerging group of drug self-administration procedures that have shown predictive validity to clinical drug addiction. Emerging data suggest that serotonin (5-HT)2A receptors modulate mesolimbic dopamine function, such that 5-HT2A antagonists blunt the abuse-related neurochemical effects of monoamine transporter substrates, such as amphetamine or methamphetamine. Whether subchronic 5-HT2A antagonist treatment attenuates methamphetamine reinforcement in any preclinical drug self-administration procedure is unknown. The study aim was therefore to determine 7-day treatment effects with the 5-HT2A inverse agonist/antagonist pimavanserin on methamphetamine vs. food choice in monkeys. Behavior was maintained under a concurrent schedule of food delivery (1g pellets, fixed-ratio 100 schedule) and intravenous methamphetamine injections (0-0.32 mg/kg/injection, fixed-ratio 10 schedule) in male rhesus monkeys (n=3). Methamphetamine choice dose-effect functions were determined daily before and during 7-day repeated pimavanserin (1.0-10mg/kg/day, intramuscular) treatment periods. Under control conditions, increasing methamphetamine doses resulted in a corresponding increase in methamphetamine vs. food choice. Repeated pimavanserin administration failed to attenuate methamphetamine choice and produce a reciprocal increase in food choice in any monkey up to doses (3.2-10mg/kg) that suppressed rates of operant responding primarily during components where behavior was maintained by food pellets. Repeated 5-HT2A receptor inverse agonist/antagonist treatment did not attenuate methamphetamine reinforcement under a concurrent schedule of intravenous methamphetamine and food presentation in nonhuman primates. Overall, these results do not support the therapeutic potential of 5-HT2A inverse agonists/antagonists as candidate medications for methamphetamine addiction. Copyright © 2016 The Author(s). Published by Elsevier Ireland Ltd.. All rights reserved.

The challenge of changing the inactivated poliomyelitis vaccine in Latin America: declaration of the Latin American Society of Pediatric Infectious Diseases (SLIPE).

PubMed

Falleiros-Arlant, Luiza Helena; Avila-Agüero, María Luisa; Brea del Castillo, José; Mariño, Cristina

2014-10-01

Even though we have already covered 99% of the path to eradicate poliomyelitis from the world, this disease is still causing paralysis in children. Its eradication means not only the end of wild poliovirus circulation, but vaccine-derived poliovirus circulation as well. Taking into account different factors such as: current epidemiological data, adverse events of the attenuated oral poliomyelitis vaccine (OPV), the availability of an injectable inactivated vaccine (IPV) without the potential of causing the severe adverse events of the oral vaccine (OPV), the efficacy and effectiveness of the IPV in several countries of the world where it has been used for several years, the rationale of changing the vaccination schedule in different Latin American countries; the Latin American Society of Pediatric Infectious Diseases (SLIPE) announces its recommendation of switching to IPV in Latin America, by this Declaration, with an Action Plan for 2014-2015 period as regards vaccination against polio policies in Latin America. 1. The optimal proposed schedule consists of four IPV doses (three doses in the primary schedule plus a booster dose), whether IPV is combined or not with other indicated vaccines in the immunization program of the country. During the OPV to IPV transition phase, an alternative schedule is acceptable; 2. Countries should set optimal strategies in order to maintain and improve vaccination coverage, and implement a nominal immunization registry; 3. Improving the Epidemiological Surveillance of Acute Flaccid Paralysis (AFP) and setting up an environmental surveillance program; 4. Setting up strategies for introducing IPV in National Immunization Programs, such as communicating properly with the population, among others; 5. Bringing scientific societies closer to decision makers; 6. Ensuring optimal supply and prices for IPV introduction; 7. Training vaccination teams; 8. Enhancing the distribution and storing logistics of vaccines. In addition to the scientific evidence, the countries that have not yet decided to switch to IPV should consider the implications of equity and social justice.

Flexible meal-related dosing with repaglinide facilitates glycemic control in therapy-naive type 2 diabetes.

PubMed

Moses, R G; Gomis, R; Frandsen, K B; Schlienger, J L; Dedov, I

2001-01-01

This double-blind randomized placebo-controlled parallel group study assessed the efficacy and safety (with particular regard to body weight and hypoglycemia) of repaglinide when used in a flexible mealtime dosing regimen in a situation close to everyday clinical practice. A total of 408 patients with type 2 diabetes considered poorly controlled by diet, but without a history of previous antidiabetic medication, were randomized to receive 0.5 mg repaglinide at mealtimes (increased to 1 mg after 4 weeks depending on blood glucose response) or placebo for 16 weeks. Patients were free to choose a flexible meal pattern, adjusting the dosing schedule from two to four preprandial doses per day in accordance with a "one meal, one dose; no meal, no dose" principle. Additional snacks were not a requirement of the treatment schedule. Treatment with repaglinide significantly improved glycemic control with respect to baseline and placebo, reducing HbA1c by 1.14% from baseline and fasting plasma glucose by 1.8 mmol/l. Improvement in glycemic control was independent of the meal pattern adopted by patients, including those most commonly taking two or four meals daily, with no correlation between meal pattern and risk of hypoglycemia. The improvement in glycemic control was also independent of degree of obesity and age < or =65 or >65 years. There was no significant body weight increase in the repaglinide group. Mealtime dosing with repaglinide is effective in improving overall glycemic control in type 2 diabetic patients for which control is suboptimal using diet alone. Patients are able to vary their meal pattern from a conventional regimen of three meals daily without compromising control or increasing the risk of adverse events.

Scheduling time-critical graphics on multiple processors

NASA Technical Reports Server (NTRS)

Meyer, Tom W.; Hughes, John F.

1995-01-01

This paper describes an algorithm for the scheduling of time-critical rendering and computation tasks on single- and multiple-processor architectures, with minimal pipelining. It was developed to manage scientific visualization scenes consisting of hundreds of objects, each of which can be computed and displayed at thousands of possible resolution levels. The algorithm generates the time-critical schedule using progressive-refinement techniques; it always returns a feasible schedule and, when allowed to run to completion, produces a near-optimal schedule which takes advantage of almost the entire multiple-processor system.

Radiation dose to the global flying population.

PubMed

Alvarez, Luis E; Eastham, Sebastian D; Barrett, Steven R H

2016-03-01

Civil airliner passengers and crew are exposed to elevated levels of radiation relative to being at sea level. Previous studies have assessed the radiation dose received in particular cases or for cohort studies. Here we present the first estimate of the total radiation dose received by the worldwide civilian flying population. We simulated flights globally from 2000 to 2013 using schedule data, applying a radiation propagation code to estimate the dose associated with each flight. Passengers flying in Europe and North America exceed the International Commission on Radiological Protection annual dose limits at an annual average of 510 or 420 flight hours per year, respectively. However, this falls to 160 or 120 h on specific routes under maximum exposure conditions.

The effect of immunization schedule with the malaria vaccine candidate RTS,S/AS01E on protective efficacy and anti-circumsporozoite protein antibody avidity in African infants.

PubMed

Ajua, Anthony; Lell, Bertrand; Agnandji, Selidji Todagbe; Asante, Kwaku Poku; Owusu-Agyei, Seth; Mwangoka, Grace; Mpina, Maxmilliam; Salim, Nahya; Tanner, Marcel; Abdulla, Salim; Vekemans, Johan; Jongert, Erik; Lievens, Marc; Cambron, Pierre; Ockenhouse, Chris F; Kremsner, Peter G; Mordmüller, Benjamin

2015-02-13

The malaria vaccine RTS,S induces antibodies against the Plasmodium falciparum circumsporozoite protein (CSP) and the concentration of Immunoglobulin G (IgG) against the repeat region of CSP following vaccination is associated with protection from P. falciparum malaria. So far, only the quantity of anti-CSP IgG has been measured and used to predict vaccination success, although quality (measured as avidity) of the antigen-antibody interaction shall be important since only a few sporozoites circulate for a short time after an infectious mosquito bite, likely requiring fast and strong binding. Quantity and avidity of anti-CSP IgG in African infants who received RTS,S/AS01E in a 0-1-2-month or a 0-1-7-month schedule in a phase 2 clinical trial were measured by enzyme-linked immunosorbent assay. Antibody avidity was defined as the proportion of IgG able to bind in the presence of a chaotropic agent (avidity index). The effect of CSP-specific IgG concentration and avidity on protective efficacy was modelled using Cox proportional hazards. After the third dose, quantity and avidity were similar between the two vaccination schedules. IgG avidity after the last vaccine injection was not associated with protection, whereas the change in avidity following second and third RTS,S/AS01E injection was associated with a 54% risk reduction of getting malaria (hazard ratio: 0.46; 95% confidence interval (CI): 0.22-0.99) in those participants with a change in avidity above the median. The change in anti-CSP IgG concentration following second and third injection was associated with a 77% risk reduction of getting malaria (hazard ratio: 0.23, 95% CI: 0.11-0.51). Change in IgG response between vaccine doses merits further evaluation as a surrogate marker for RTS,S efficacy. ClinicalTrials.gov Identifier NCT00436007 .

Rectal cancer delivery of radiotherapy in adequate time and with adequate dose is influenced by treatment center, treatment schedule, and gender and is prognostic parameter for local control: Results of study CAO/ARO/AIO-94

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

Fietkau, Rainer; Roedel, Claus; Hohenberger, Werner

2007-03-15

Purpose: The impact of the delivery of radiotherapy (RT) on treatment results in rectal cancer patients is unknown. Methods and Materials: The data from 788 patients with rectal cancer treated within the German CAO/AIO/ARO-94 phase III trial were analyzed concerning the impact of the delivery of RT (adequate RT: minimal radiation RT dose delivered, 4300 cGy for neoadjuvant RT or 4700 cGy for adjuvant RT; completion of RT in <44 days for neoadjuvant RT or <49 days for adjuvant RT) in different centers on the locoregional recurrence rate (LRR) and disease-free survival (DFS) at 5 years. The LRR, DFS, andmore » delivery of RT were analyzed as endpoints in multivariate analysis. Results: A significant difference was found between the centers and the delivery of RT. The overall delivery of RT was a prognostic factor for the LRR (no RT, 29.6% {+-} 7.8%; inadequate RT, 21.2% {+-} 5.6%; adequate RT, 6.8% {+-} 1.4%; p = 0.0001) and DFS (no RT, 55.1% {+-} 9.1%; inadequate RT, 57.4% {+-} 6.3%; adequate RT, 69.1% {+-} 2.3%; p = 0.02). Postoperatively, delivery of RT was a prognostic factor for LRR on multivariate analysis (together with pathologic stage) but not for DFS (independent parameters, pathologic stage and age). Preoperatively, on multivariate analysis, pathologic stage, but not delivery of RT, was an independent prognostic parameter for LRR and DFS (together with adequate chemotherapy). On multivariate analysis, the treatment center, treatment schedule (neoadjuvant vs. adjuvant RT), and gender were prognostic parameters for adequate RT. Conclusion: Delivery of RT should be regarded as a prognostic factor for LRR in rectal cancer and is influenced by the treatment center, treatment schedule, and patient gender.« less

Outcomes with two different schedules of bortezomib, melphalan, and prednisone (VMP) for previously untreated multiple myeloma: matched pair analysis using long-term follow-up data from the phase 3 VISTA and PETHEMA/GEM05 trials.

PubMed

Mateos, Maria-Victoria; Oriol, Albert; Martínez-López, Joaquín; Teruel, Ana-Isabel; Bengoechea, Enrique; Palomera, Luis; de Arriba, Felipe; Esseltine, Dixie-Lee; Cakana, Andrew; Pei, Lixia; van de Velde, Helgi; Miguel, Jesus San

2016-12-01

Bortezomib-melphalan-prednisone (VMP) is a standard-of-care for previously untreated, transplant-ineligible multiple myeloma (MM). Here, we compared outcomes between VMP regimens in the VISTA trial (9-cycle VMP schedule, including 4 cycles of twice weekly bortezomib) and the PETHEMA/GEM05 trial (less intensive 6-cycle VMP schedule with 1 cycle of twice weekly and 5 cycles of weekly bortezomib, then bortezomib-based maintenance). A total of 113 patient pairs matched by propensity score (estimated using logistic regression and incorporating eight exposure/outcome-related parameters) were included in this retrospective analysis. Median cumulative bortezomib dose was higher in PETHEMA/GEM05 than VISTA (49.6 vs 37.0 mg/m 2 ); median dose intensity was lower (2.0 vs 5.1 mg/m 2 /month). Median progression-free survival (PFS) and time-to-progression (TTP) were significantly longer in PETHEMA/GEM05 than VISTA (PFS, 30.5 vs 20.0 months, p = 0.0265; TTP, 33.8 vs 24.2 months, p = 0.0049) after a median follow-up of 77.2 and 26.0 months, respectively. Median overall survival (OS) was similar (61.3 vs 61.0 months, p = 0.6528; median follow-up, 77.6 vs 60.1 months). Post-induction complete response rate was lower in PETHEMA/GEM05 than VISTA (19 vs 31 %; p = 0.03318); on-study (including maintenance) rate was similar (30 vs 31 %; p = 0.89437). This analysis suggests that the less-intensive PETHEMA/GEM05 VMP regimen plus maintenance may improve PFS and TTP, but not OS, compared with the VISTA VMP regimen. NCT00111319, NCT00443235.

A stimulus-control account of regulated drug intake in rats.

PubMed

Panlilio, Leigh V; Thorndike, Eric B; Schindler, Charles W

2008-02-01

Patterns of drug self-administration are often highly regular, with a consistent pause after each self-injection. This pausing might occur because the animal has learned that additional injections are not reinforcing once the drug effect has reached a certain level, possibly due to the reinforcement system reaching full capacity. Thus, interoceptive effects of the drug might function as a discriminative stimulus, signaling when additional drug will be reinforcing and when it will not. This hypothetical stimulus control aspect of drug self-administration was emulated using a schedule of food reinforcement. Rats' nose-poke responses produced food only when a cue light was present. No drug was administered at any time. However, the state of the light stimulus was determined by calculating what the whole-body drug level would have been if each response in the session had produced a drug injection. The light was only presented while this virtual drug level was below a specific threshold. A range of doses of cocaine and remifentanil were emulated using parameters based on previous self-administration experiments. Response patterns were highly regular, dose-dependent, and remarkably similar to actual drug self-administration. This similarity suggests that the emulation schedule may provide a reasonable model of the contingencies inherent in drug reinforcement. Thus, these results support a stimulus control account of regulated drug intake in which rats learn to discriminate when the level of drug effect has fallen to a point where another self-injection will be reinforcing.

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

PubMed

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

2005-05-01

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

Potential epidemiological and economical impact of two rotavirus vaccines in Colombia.

PubMed

De la Hoz, Fernando; Alvis, Nelson; Narváez, Javier; Cediel, Natalia; Gamboa, Oscar; Velandia, Martha

2010-05-14

A complete economic study was carried out to assess the economical impact of two rotavirus vaccine in Colombia. A Markov decision model was built to assess the health outcomes from birth to 24 months of age for three hypothetical cohorts: one unvaccinated, one vaccinated with 2 doses of Rotarix and the third, with 3 doses of Rotateq. Without vaccination, the annual number of medical visits by diarrhea in children under 2 years would be 1,293,159 cases, with 105,378 medical visits and 470 deaths (IC95% 295-560) related to rotavirus. Without vaccination, rotavirus disease would cost around USD$8 millions including direct and indirect costs. Assuming a cost per dose of USD$7.5, average cost-effectiveness ratio would be USD$663/DALY with Rotarix and USD$1391 with Rotateq. When price per dose falls below USD$7 both vaccines yield a similar average cost-effectiveness ratio (USD$1063/DALY). Incremental cost-effectiveness ratio of Rotateq versus Rotarix was USD$7787/DALY. Cost-effectiveness ratio was influenced mainly by vaccine cost and cost per case hospitalized. Other programmatic aspects such as number of doses to be applied, likelihood of completing vaccination schedule with shorter versus longer schedules, and storage space within the chain cold should be considered to make decisions on which vaccine should be introduced. In conclusion, vaccinating against rotavirus in Colombia with either vaccine would be very cost effective. If cost per vaccinated children falls below USD$3 per dose vaccination would be cost saving. Copyright 2010 Elsevier Ltd. All rights reserved.

A phase I dose-finding study of 5-azacytidine in combination with sodium phenylbutyrate in patients with refractory solid tumors.

PubMed

Lin, Jianqing; Gilbert, Jill; Rudek, Michelle A; Zwiebel, James A; Gore, Steve; Jiemjit, Anchalee; Zhao, Ming; Baker, Sharyn D; Ambinder, Richard F; Herman, James G; Donehower, Ross C; Carducci, Michael A

2009-10-01

This was a phase I trial to determine the minimal effective dose and optimal dose schedule for 5-azacytidine (5-AC) in combination with sodium phenylbutyrate in patients with refractory solid tumors. The pharmacokinetics, pharmacodynamics, and antineoplastic effects were also studied. Three dosing regimens were studied in 27 patients with advanced solid tumors, and toxicity was recorded. The pharmacokinetics of the combination of drugs was evaluated. Repeat tumor biopsies and peripheral blood mononuclear cells (PBMC) were analyzed to evaluate epigenetic changes in response to therapy. EBV titers were evaluated as a surrogate measure for gene re-expression of epigenetic modulation in PBMC. The three dose regimens of 5-AC and phenylbutyrate were generally well tolerated and safe. A total of 48 cycles was administrated to 27 patients. The most common toxicities were bone marrow suppression-related neutropenia and anemia, which were minor. The clinical response rate was disappointing for the combination of agents. One patient showed stable disease for 5 months whereas 26 patients showed progressive disease as the best tumor response. The administration of phenylbutyrate and 5-AC did not seem to alter the pharmacokinetics of either drug. Although there were individual cases of targeted DNA methyltransferase activity and histone H3/4 acetylation changes from paired biopsy or PBMC, no conclusive statement can be made based on these limited correlative studies. The combination of 5-AC and phenylbutyrate across three dose schedules was generally well tolerated and safe, yet lacked any real evidence for clinical benefit.

Phase I dose escalation clinical trial of phenylbutyrate sodium administered twice daily to patients with advanced solid tumors.

PubMed

Camacho, Luis H; Olson, Jon; Tong, William P; Young, Charles W; Spriggs, David R; Malkin, Mark G

2007-04-01

Phenylbutyrate (PBA), and its metabolite phenylacetate (PAA), induce growth inhibition and cellular differentiation in multiple tumor models. However, despite their potential anti-cancer properties, several pharmacodynamic aspects remain unknown. We conducted a dose escalating trial to evaluate twice-daily intravenous PBA infusions for two consecutive weeks (Monday through Friday) every month at five dose levels (60-360 mg/kg/day). Twenty-one patients with the following malignancies were treated: colon carcinoma 4, non-small cell lung carcinoma 4; anaplastic astrocytoma 3, glioblastoma multiforme 3, bladder carcinoma 2, sarcoma 2, and ovarian carcinoma, rectal hemangiopericytoma, and pancreatic carcinoma 1 each. Conversion of PBA to PAA and phenylacetylglutamine (PAG) was documented without catabolic saturation. Plasma content of PBA > or =1 mM was documented for only 3 h following each dose at the top two dosages. The therapy was well tolerated overall. Common adverse effects included grade 1 nausea/vomiting, fatigue, and lightheadedness. Dose limiting toxicities were short-term memory loss, sedation, confusion, nausea, and vomiting. Two patients with anaplastic astrocytoma and a patient with glioblastoma remained stable without tumor progression for 5, 7, and 4 months respectively. Administration of PBA in a twice-daily infusion schedule is safe. The maximum tolerated dose is 300 mg/kg/day. Study designs with more convenient treatment schedules and specific molecular correlates may help to further delineate the mechanism of action of this compound. Future studies evaluating PBA's ability to induce histone acetylation and cell differentiation alone or in combination with other anti-neoplastics are recommended.

Phase 2 trial of bortezomib in combination with rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with bortezomib, rituximab, methotrexate, and cytarabine for untreated mantle cell lymphoma.

PubMed

Romaguera, Jorge E; Wang, Michael; Feng, Lei; Fayad, Luis E; Hagemeister, Frederick; McLaughlin, Peter; Rodriguez, M Alma; Fanale, Michelle; Orlowski, Robert; Kwak, Larry W; Neelapu, Sattva; Oki, Yasuhiro; Pro, Barbara; Younes, Anas; Samaniego, Felipe; Fowler, Nathan; Hartig, Kimberly; Valentinetti, Marisa; Smith, Judy; Ford, Peggy; Naig, Adam; Medeiros, L Jeffrey; Kantarjian, Hagop M; Goy, Andre

2018-05-03

Although the outcomes of patients with mantle cell lymphoma (MCL) have improved, there is still no cure. Bortezomib has a 33% response rate in relapsed/refractory MCL and has shown additive and/or synergistic effects in preclinical trials with known effective agents. This is a report of a prospective phase 2 trial of bortezomib added to rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (BzR-hyperCVAD)/rituximab, high-dose methotrexate, and high-dose cytarabine (BzR-MA) for 95 patients with newly diagnosed MCL. The overall and complete response rates were 100% and 82%, respectively. Hematologic toxicity was high but expected and did not lead to an increased incidence of neutropenic fever or dose reductions in comparison with a similar reported regimen without bortezomib. After a median follow-up of 44 months, the median overall survival had not been reached, and the time to treatment failure (TTF) was 55 months, which is not different from that of historical controls. BzR-hyperCVAD/BzR-MA at the dose and schedule studied produced high rates of response and a TTF similar to that of historical reports without bortezomib. Cancer 2018. © 2018 American Cancer Society. © 2018 American Cancer Society.