Improving safety on rural local and tribal roads site safety analysis - user guide #1.

DOT National Transportation Integrated Search

2014-08-01

This User Guide presents an example of how rural local and Tribal practitioners can study conditions at a preselected site. It demonstrates the step-by-step safety analysis process presented in Improving Safety on Rural Local and Tribal Roads Saf...

29 CFR 5.15 - Limitations, variations, tolerances, and exemptions under the Contract Work Hours and Safety...

Code of Federal Regulations, 2010 CFR

2010-07-01

... the Contract Work Hours and Safety Standards Act. 5.15 Section 5.15 Labor Office of the Secretary of... WORK HOURS AND SAFETY STANDARDS ACT) Davis-Bacon and Related Acts Provisions and Procedures § 5.15 Limitations, variations, tolerances, and exemptions under the Contract Work Hours and Safety Standards Act. (a...

Safety and tolerability of transcranial direct current stimulation to stroke patients - A phase I current escalation study.

PubMed

Chhatbar, Pratik Y; Chen, Rong; Deardorff, Rachael; Dellenbach, Blair; Kautz, Steven A; George, Mark S; Feng, Wuwei

A prior meta-analysis revealed that higher doses of transcranial direct current stimulation (tDCS) have a better post-stroke upper-extremity motor recovery. While this finding suggests that currents greater than the typically used 2 mA may be more efficacious, the safety and tolerability of higher currents have not been assessed in stroke patients. We aim to assess the safety and tolerability of single session of up to 4 mA in stroke patients. We adapted a traditional 3 + 3 study design with a current escalation schedule of 1»2»2.5»3»3.5»4 mA for this tDCS safety study. We administered one 30-min session of bihemispheric montage tDCS and simultaneous customary occupational therapy to patients with first-ever ischemic stroke. We assessed safety with pre-defined stopping rules and investigated tolerability through a questionnaire. Additionally, we monitored body resistance and skin temperature in real-time at the electrode contact site. Eighteen patients completed the study. The current was escalated to 4 mA without meeting the pre-defined stopping rules or causing any major safety concern. 50% of patients experienced transient skin redness without injury. No rise in temperature (range 26°C-35 °C) was noted and skin barrier function remained intact (i.e. body resistance >1 kΩ). Our phase I safety study supports that single session of bihemispheric tDCS with current up to 4 mA is safe and tolerable in stroke patients. A phase II study to further test the safety and preliminary efficacy with multi-session tDCS at 4 mA (as compared with lower current and sham stimulation) is a logical next step. ClinicalTrials.gov Identifier: NCT02763826. Copyright © 2017 Elsevier Inc. All rights reserved.

Fall Protection Characteristics of Safety Belts and Human Impact Tolerance.

PubMed

Hino, Yasumichi; Ohdo, Katsutoshi; Takahashi, Hiroki

2014-08-23

Many fatal accidents due to falls from heights have occurred at construction sites not only in Japan but also in other countries. This study aims to determine the fall prevention performance of two types of safety belts: a body belt 1) , which has been used for more than 40 yr in the Japanese construction industry as a general type of safety equipment for fall accident prevention, and a full harness 2, 3) , which has been used in many other countries. To determine human tolerance for impact trauma, this study discusses features of safety belts with reference 4-9) to relevant studies in the medical science, automobile crash safety, and aircrew safety. For this purpose, simple drop tests were carried out in a virtual workplace to measure impact load, head acceleration, and posture in the experiments, the Hybrid-III pedestrian model 10) was used as a human dummy. Hybrid-III is typically employed in official automobile crash tests (New Car Assessment Program: NCAP) and is currently recognized as a model that faithfully reproduces dynamic responses. Experimental results shows that safety performance strongly depends on both the variety of safety belts used and the shock absorbers attached onto lanyards. These findings indicate that fall prevention equipment, such as safety belts, lanyards, and shock absorbers, must be improved to reduce impact injuries to the human head and body during falls.

Fall protection characteristics of safety belts and human impact tolerance.

PubMed

Hino, Yasumichi; Ohdo, Katsutoshi; Takahashi, Hiroki

2014-01-01

Many fatal accidents due to falls from heights have occurred at construction sites not only in Japan but also in other countries. This study aims to determine the fall prevention performance of two types of safety belts: a body belt, which has been used for more than 40 yr in the Japanese construction industry as a general type of safety equipment for fall accident prevention, and a full harness, which has been used in many other countries. To determine human tolerance for impact trauma, this study discusses features of safety belts with reference to relevant studies in the medical science, automobile crash safety, and aircrew safety. For this purpose, simple drop tests were carried out in a virtual workplace to measure impact load, head acceleration, and posture in the experiments, the Hybrid-III pedestrian model was used as a human dummy. Hybrid-III is typically employed in official automobile crash tests (New Car Assessment Program: NCAP) and is currently recognized as a model that faithfully reproduces dynamic responses. Experimental results shows that safety performance strongly depends on both the variety of safety belts used and the shock absorbers attached onto lanyards. These findings indicate that fall prevention equipment, such as safety belts, lanyards, and shock absorbers, must be improved to reduce impact injuries to the human head and body during falls.

Implementing local agency safety management

DOT National Transportation Integrated Search

2003-12-17

For local agencies to mount a successful effort toward reducing motor vehicle collisions and their costs, an effective systematic approach must be taken. A Safety Management System (SMS) has two basic components: a collaborative information exchange ...

Meta-Analysis on Randomized Controlled Trials of Vaccines with QS-21 or ISCOMATRIX Adjuvant: Safety and Tolerability.

PubMed

Bigaeva, Emilia; Doorn, Eva van; Liu, Heng; Hak, Eelko

2016-01-01

QS-21 shows in vitro hemolytic effect and causes side effects in vivo. New saponin adjuvant formulations with better toxicity profiles are needed. This study aims to evaluate the safety and tolerability of QS-21 and the improved saponin adjuvants (ISCOM, ISCOMATRIX and Matrix-M™) from vaccine trials. A systematic literature search was conducted from MEDLINE, EMBASE, Cochrane library and Clinicaltrials.gov. We selected for the meta-analysis randomized controlled trials (RCTs) of vaccines adjuvanted with QS-21, ISCOM, ISCOMATRIX or Matrix-M™, which included a placebo control group and reported safety outcomes. Pooled risk ratios (RRs) and their 95% confidence intervals (CIs) were calculated using a random-effects model. Jadad scale was used to assess the study quality. Nine RCTs were eligible for the meta-analysis: six trials on QS-21-adjuvanted vaccines and three trials on ISCOMATRIX-adjuvanted, with 907 patients in total. There were no studies on ISCOM or Matrix-M™ adjuvanted vaccines matching the inclusion criteria. Meta-analysis identified an increased risk for diarrhea in patients receiving QS21-adjuvanted vaccines (RR 2.55, 95% CI 1.04-6.24). No increase in the incidence of the reported systemic AEs was observed for ISCOMATRIX-adjuvanted vaccines. QS-21- and ISCOMATRIX-adjuvanted vaccines caused a significantly higher incidence of injection site pain (RR 4.11, 95% CI 1.10-15.35 and RR 2.55, 95% CI 1.41-4.59, respectively). ISCOMATRIX-adjuvanted vaccines also increased the incidence of injection site swelling (RR 3.43, 95% CI 1.08-10.97). Our findings suggest that vaccines adjuvanted with either QS-21 or ISCOMATRIX posed no specific safety concern. Furthermore, our results indicate that the use of ISCOMATRIX enables a better systemic tolerability profile when compared to the use of QS-21. However, no better local tolerance was observed for ISCOMATRIX-adjuvanted vaccines in immunized non-healthy subjects. This meta-analysis is limited by the relatively

Assessing the general safety and tolerability of vildagliptin: value of pooled analyses from a large safety database versus evaluation of individual studies

PubMed Central

Schweizer, Anja; Dejager, Sylvie; Foley, James E; Kothny, Wolfgang

2011-01-01

Aim: Analyzing safety aspects of a drug from individual studies can lead to difficult-to-interpret results. The aim of this paper is therefore to assess the general safety and tolerability, including incidences of the most common adverse events (AEs), of vildagliptin based on a large pooled database of Phase II and III clinical trials. Methods: Safety data were pooled from 38 studies of ≥12 to ≥104 weeks’ duration. AE profiles of vildagliptin (50 mg bid; N = 6116) were evaluated relative to a pool of comparators (placebo and active comparators; N = 6210). Absolute incidence rates were calculated for all AEs, serious AEs (SAEs), discontinuations due to AEs, and deaths. Results: Overall AEs, SAEs, discontinuations due to AEs, and deaths were all reported with a similar frequency in patients receiving vildagliptin (69.1%, 8.9%, 5.7%, and 0.4%, respectively) and patients receiving comparators (69.0%, 9.0%, 6.4%, and 0.4%, respectively), whereas drug-related AEs were seen with a lower frequency in vildagliptin-treated patients (15.7% vs 21.7% with comparators). The incidences of the most commonly reported specific AEs were also similar between vildagliptin and comparators, except for increased incidences of hypoglycemia, tremor, and hyperhidrosis in the comparator group related to the use of sulfonylureas. Conclusions: The present pooled analysis shows that vildagliptin was overall well tolerated in clinical trials of up to >2 years in duration. The data further emphasize the value of a pooled analysis from a large safety database versus assessing safety and tolerability from individual studies. PMID:21415917

Safety and tolerability of 13-valent pneumococcal conjugate vaccine in the elderly

PubMed Central

Durando, Paolo; Rosselli, Roberto; Cremonesi, Ilaria; Orsi, Andrea; Albanese, Erika; Barberis, Ilaria; Paganino, Chiara; Trucchi, Cecilia; Martini, Mariano; Marensi, Lorenzo; Turello, Valter; Study Group, the Ligurian Pneumococcal; Bregante, Alessandro; Cacciani, Roberto; Iudici, Rocco; La Marca, Diego; Pedano, Leonardo; Petrucci, Amadio Franco; Santolini, Maria; Sbisà, Valentina; Zacconi, Monica

2014-01-01

Background In September 2011 the European Medical Agency authorized the use of 13-valent pneumococcal conjugate vaccine (PCV13) in adults aged ≥50 years. The same occurred in the US in December 2011 when the Food and Drug Administration approved the use of PCV13 in the same target age-group with indication for the prevention of invasive pneumococcal diseases and community acquired pneumonia sustained by the serotypes contained in the vaccine. The Liguria Region, in Italy, implemented in 2013 an active and free of charge immunization strategy with PCV13 among adults affected by specific risk conditions and the elderly aged ≥70 years. Methods An observational study was performed in order to assess the safety and tolerability of PCV13 among elderly dwelling in the metropolitan area of Genoa, the capital city of Liguria Region. Eligible subjects, who received PCV13 following the public health immunization campaign at the Local Health Unit 3 of Genoa, provided a written informed consent to take part in the study. Eight-hundred-seventy-one subjects were enrolled between October 2013 and May 2014: all were monitored by qualified healthcare personnel for at least 30 min after vaccination at the outpatient clinics, in order to assess any possible sudden reaction. The occurrence of a series of local and systemic solicited reactions and of any unsolicited Adverse Events (AEs) was monitored using a self-administered clinical diary and by regular phone contacts up to 14 and 21 d following immunization, respectively. Moreover, a 6-months follow-up following vaccination was planned in order to monitor Severe Adverse Events (SAEs). Results No sudden reaction occurred in vaccinees at the outpatient clinics. Pain (27.4%) was the most frequent reaction reported by subjects at the injection site, while new muscle pain (13.6%), fatigue (10.7%), and headache (9.9%) resulted the most common systemic reactions. Rates of the main reactions reported in this on-field study resulted

Randomized phase I trials of the safety/tolerability of anti-LINGO-1 monoclonal antibody BIIB033

PubMed Central

Tran, Jonathan Q.; Rana, Jitesh; Barkhof, Frederik; Melamed, Isaac; Gevorkyan, Hakop; Wattjes, Mike P.; de Jong, Remko; Brosofsky, Kristin; Ray, Soma; Xu, Lei; Zhao, Jim; Parr, Edward

2014-01-01

Objective: To evaluate the safety, tolerability, and pharmacokinetics (PK) of BIIB033 (anti-LINGO-1 monoclonal antibody) in healthy volunteers and participants with multiple sclerosis (MS). Methods: In 2 separate randomized, placebo-controlled studies, single ascending doses (SAD; 0.1–100 mg/kg) of BIIB033 or placebo were administered via IV infusion or subcutaneous injection to 72 healthy volunteers, and multiple ascending doses (MAD; 0.3–100 mg/kg; 2 doses separated by 14 days) of BIIB033 or placebo were administered via IV infusion to 47 participants with relapsing-remitting or secondary progressive MS. Safety assessments included adverse event (AE) monitoring, neurologic examinations, conventional and nonconventional MRI, EEG, optical coherence tomography, retinal examinations, and evoked potentials. Serum and CSF PK as well as the immunogenicity of BIIB033 were also evaluated. Results: All 72 healthy volunteers and 47 participants with MS were included in the safety analyses. BIIB033 infusions were well tolerated. The frequency of AEs was similar between BIIB033 and placebo. There were no serious AEs or deaths. No clinically significant changes in any of the safety measures were observed. BIIB033 PK was similar between healthy volunteers and participants with MS. Doses of ≥10 mg/kg resulted in BIIB033 concentrations similar to or higher than the concentration associated with 90% of the maximum remyelination effect in rat remyelination studies. The incidence of anti-drug antibody production was low. Conclusions: The emerging safety, tolerability, and PK of BIIB033 support advancing BIIB033 into phase II clinical development as a potential treatment for CNS demyelination disorders. Classification of evidence: This study provides Class I evidence that BIIB033 is well tolerated and safe (serious adverse event rate 0%, 95% confidence interval 0–7.6%). PMID:25340070

Fall Protection Characteristics of Safety Belts and Human Impact Tolerance

PubMed Central

HINO, Yasumichi; OHDO, Katsutoshi; TAKAHASHI, Hiroki

2014-01-01

Abstract: Many fatal accidents due to falls from heights have occurred at construction sites not only in Japan but also in other countries. This study aims to determine the fall prevention performance of two types of safety belts: a body belt1), which has been used for more than 40 yr in the Japanese construction industry as a general type of safety equipment for fall accident prevention, and a full harness2, 3), which has been used in many other countries. To determine human tolerance for impact trauma, this study discusses features of safety belts with reference4,5,6,7,8,9) to relevant studies in the medical science, automobile crash safety, and aircrew safety. For this purpose, simple drop tests were carried out in a virtual workplace to measure impact load, head acceleration, and posture in the experiments, the Hybrid-III pedestrian model10) was used as a human dummy. Hybrid-III is typically employed in official automobile crash tests (New Car Assessment Program: NCAP) and is currently recognized as a model that faithfully reproduces dynamic responses. Experimental results shows that safety performance strongly depends on both the variety of safety belts used and the shock absorbers attached onto lanyards. These findings indicate that fall prevention equipment, such as safety belts, lanyards, and shock absorbers, must be improved to reduce impact injuries to the human head and body during falls. PMID:25345426

Hypothermia for preventing chemotherapy-induced neuropathy - a pilot study on safety and tolerability in healthy controls.

PubMed

Bandla, Aishwarya; Sundar, Raghav; Liao, Lun-De; Sze Hui Tan, Stacey; Lee, Soo-Chin; Thakor, Nitish V; Wilder-Smith, Einar P V

2016-01-01

Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting side effect of several chemotherapeutic agents, often leading to treatment discontinuation. Up to 20% of patients treated with weekly paclitaxel experience severe CIPN and no effective treatment has been established so far. The mechanisms of CIPN damage are unclear, but are directly dose-related. We had earlier demonstrated, in rats, the influence of hypothermia in reducing nerve blood flow. Here, we hypothesize that continuous flow limb hypothermia during chemotherapy reduces the incidence and severity of CIPN, by limiting deliverance of the neurotoxic drug to the peripheral nerves. In this study, prior to assessing the effect of hypothermia in preventing CIPN in cancer subjects undergoing paclitaxel chemotherapy, we assess the safety and tolerable temperatures for limb hypothermia in healthy human subjects. In 15 healthy human subjects, hypothermia was administered as continuous flow cooling, unilaterally, via a thermoregulator setup covering the digits up to the elbow/knee, along with continuous skin temperature monitoring. Thermoregulator coolant temperatures between 25 °C and 20 °C were tested for tolerability, based on a carefully designed temperature regulation protocol, and maintained for three hours mimicking the duration of chemotherapy. Tolerability was evaluated using various safety and tolerability scores to monitor the subjects. At the end of the cooling session the healthy subjects presented without significant adverse effects, the main being brief mild skin erythema and transient numbness. Coolant temperatures as low as 22 °C were well tolerated continuously over three hours. Our results confirm the safety and tolerability of continuous flow limb hypothermia in healthy subjects. Further studies will use 22 °C thermoregulator temperature to investigate hypothermia in preventing CIPN in breast cancer patients receiving adjuvant weekly paclitaxel. This pilot study

Workplace Violence and Perceptions of Safety Among Emergency Department Staff Members: Experiences, Expectations, Tolerance, Reporting, and Recommendations.

PubMed

Copeland, Darcy; Henry, Melissa

Workplace violence (WPV) is a widely recognized problem in emergency departments (EDs). The majority of WPV studies do not include nonclinical staff and do not address expectations of violence, tolerance to violence, or perceptions of safety. Among a multidisciplinary sample of ED staff members, specific study aims were to (a) describe exposure to WPV; (b) describe perceptions of safety, tolerance to violence, and expectation of violence; (c) describe reporting behaviors and perceived barriers to reporting violence; (d) examine relationships between demographic variables, experiences of violence, tolerance to violence, perceptions of safety, and reporting behaviors; and (e) identify perceptions of viable interventions to improve workplace safety. A cross-sectional design was used to survey ED staff members in a Level 1 Shock Trauma center. Eleven disciplines were represented in 147 completed surveys; 88% of respondents reported exposure to WPV in the previous 6 months. Members of every discipline reported exposure to WPV; 98% of the sample felt safe at work and 64% felt violence was an expected part of the job. Most violence was not reported, primarily because "nobody was hurt." Emergency department staff members expected and experienced violence; nevertheless, there was a widespread perception of safety. Perceptions of safety and reasons for not reporting did not mirror previous findings. The WPV exposure is not isolated to clinical staff members and occurs even when prevention strategies are in place. The definition of WPV and the individual's interpretation of the event might preclude reporting.

Pilot Study on the Safety and Tolerability of Extended Release Niacin for HIV-infected Patients with Hypertriglyceridemia

PubMed Central

Souza, Scott A; Walsh, Erica J; Shippey, Ford; Shikuma, Cecilia

2010-01-01

Background To determine the safety and tolerability of extended release niacin (ERN) in HIV-infected patients. Methods This was a pilot, open-label, 36 week study evaluating the safety and tolerability of ERN in HIV-infected patients with hypertriglyceridemia. Subjects with cardiovascular disease, diabetes or liver disease were excluded. Subjects with persistent elevation of triglyceride (TG) >200 after 8 weeks on American Heart Association Step One and Two Diets were started on ERN 500mg once daily, with continuation of the diet and exercise recommendations until the end of the study. ERN was increased by 500mg every 4 weeks, to a maximum of 1500mg/day, depending on subject tolerability. Safety and tolerability of ERN were assessed. Results Ten subjects enrolled received ERN. Dose titration and maintenance to 1500mg/day were achieved in all 10 subjects. No subject required dose adjustment. Mild flushing was experienced in 8 subjects. Asymptomatic hypophosphotemia was noted in 4 subjects; all resolved with oral phosphate supplementation. Median TG was reduced by 254 mg/dL (p<0.05). Non-significant changes were noted in liver enzymes, HDL, LDL, and total cholesterol. Fasting insulin and glucose levels did not change with treatment. Conclusion In this pilot study, ERN was well-tolerated and resulted in reduction of TG. Although the results of this study are promising, the study is limited in the small number of subjects. Further investigation is warranted. PMID:20533755

Safety envelope for load tolerance of structural element design based on multi-stage testing

DOE PAGES

Park, Chanyoung; Kim, Nam H.

2016-09-06

Structural elements, such as stiffened panels and lap joints, are basic components of aircraft structures. For aircraft structural design, designers select predesigned elements satisfying the design load requirement based on their load-carrying capabilities. Therefore, estimation of safety envelope of structural elements for load tolerances would be a good investment for design purpose. In this article, a method of estimating safety envelope is presented using probabilistic classification, which can estimate a specific level of failure probability under both aleatory and epistemic uncertainties. An important contribution of this article is that the calculation uncertainty is reflected in building a safety envelope usingmore » Gaussian process, and the effect of element test data on reducing the calculation uncertainty is incorporated by updating the Gaussian process model with the element test data. It is shown that even one element test can significantly reduce the calculation uncertainty due to lacking knowledge of actual physics, so that conservativeness in a safety envelope is significantly reduced. The proposed approach was demonstrated with a cantilever beam example, which represents a structural element. The example shows that calculation uncertainty provides about 93% conservativeness against the uncertainty due to a few element tests. As a result, it is shown that even a single element test can increase the load tolerance modeled with the safety envelope by 20%.« less

Efficacy, safety, tolerability and price of newly approved drugs in solid tumors.

PubMed

Barnes, Tristan A; Amir, Eitan; Templeton, Arnoud J; Gomez-Garcia, Susana; Navarro, Beatriz; Seruga, Bostjan; Ocana, Alberto

2017-05-01

New anti-cancer drugs utilize diverse mechanisms of action. Here we evaluate their differential efficacy, safety, tolerability and price. Drugs approved for solid tumor treatment between 2000 and 2015 were identified and analyzed in subgroups: agents targeting oncogenes (group 1), anti-angiogenics (group 2), immunotherapy (group 3), and chemotherapy (group 4). Hazard ratios (HRs) were extracted from the registration trials and pooled in a meta-analysis. Odds ratios for toxic death, treatment discontinuation and grade 3-4 toxicity were compared to control groups. The Micromedex Red Book was used to calculate the monthly price. Analysis included 74 studies comprising 48,527 patients. Progression-free survival (PFS) was improved to a greater degree with groups 1 and 2 than with groups 3 and 4, (pooled HR: 0.54, 0.56, 0.63, and 0.76 for groups 1-4 respectively, p for difference <0.001). Compared to PFS, there was a lower magnitude of improvement overall survival in all groups and the degree of benefit was less for group 4 than for other groups (pooled HR: 0.77, 0.78, 0.68, and 0.83 for groups 1-4 respectively, p for difference=0.007). Compared to control groups in individual trials, immunotherapy was associated with better safety and tolerability than other groups. Drug prices have increased over time with no significant difference between groups. There was no meaningful correlation between pricing and efficacy. Compared to control groups, immunotherapeutics and drugs targeting oncogenes or angiogenesis improve efficacy to a greater degree than chemotherapy. Immunotherapy appears to have better safety and tolerability profile compared to other cancer therapies. Market price of drugs is not related to efficacy. Copyright © 2017 Elsevier Ltd. All rights reserved.

An escalating dose study to assess the safety, tolerability and immunogenicity of a Herpes Simplex Virus DNA vaccine, COR-1.

PubMed

Dutton, Julie L; Woo, Wai-Ping; Chandra, Janin; Xu, Yan; Li, Bo; Finlayson, Neil; Griffin, Paul; Frazer, Ian H

2016-12-01

This paper describes a single site, open-label Phase I clinical trial evaluating the safety, tolerability and immunogenicity in healthy volunteers of a herpes simplex polynucleotide vaccine that has previously been shown to enhance immunogenicity and protect against lethal herpes simplex virus type 2 (HSV-2) challenge in mice. Five escalating doses of the vaccine, COR-1, were given by intradermal injection to HSV-1 and 2 seronegative healthy individuals. COR-1 was found to be safe and well-tolerated; the only vaccine-related adverse events were mild. While vaccine-induced antibody responses were not detectable, cell-mediated immune responses to HSV-specific peptide groups were identified in 19 of the 20 subjects who completed the study, and local inflammation at the immunisation site was observed. This study indicates COR-1 has potential to be used as a therapeutic vaccine for HSV-2 infection.

Trust index based fault tolerant multiple event localization algorithm for WSNs.

PubMed

Xu, Xianghua; Gao, Xueyong; Wan, Jian; Xiong, Naixue

2011-01-01

This paper investigates the use of wireless sensor networks for multiple event source localization using binary information from the sensor nodes. The events could continually emit signals whose strength is attenuated inversely proportional to the distance from the source. In this context, faults occur due to various reasons and are manifested when a node reports a wrong decision. In order to reduce the impact of node faults on the accuracy of multiple event localization, we introduce a trust index model to evaluate the fidelity of information which the nodes report and use in the event detection process, and propose the Trust Index based Subtract on Negative Add on Positive (TISNAP) localization algorithm, which reduces the impact of faulty nodes on the event localization by decreasing their trust index, to improve the accuracy of event localization and performance of fault tolerance for multiple event source localization. The algorithm includes three phases: first, the sink identifies the cluster nodes to determine the number of events occurred in the entire region by analyzing the binary data reported by all nodes; then, it constructs the likelihood matrix related to the cluster nodes and estimates the location of all events according to the alarmed status and trust index of the nodes around the cluster nodes. Finally, the sink updates the trust index of all nodes according to the fidelity of their information in the previous reporting cycle. The algorithm improves the accuracy of localization and performance of fault tolerance in multiple event source localization. The experiment results show that when the probability of node fault is close to 50%, the algorithm can still accurately determine the number of the events and have better accuracy of localization compared with other algorithms.

Trust Index Based Fault Tolerant Multiple Event Localization Algorithm for WSNs

PubMed Central

Xu, Xianghua; Gao, Xueyong; Wan, Jian; Xiong, Naixue

2011-01-01

This paper investigates the use of wireless sensor networks for multiple event source localization using binary information from the sensor nodes. The events could continually emit signals whose strength is attenuated inversely proportional to the distance from the source. In this context, faults occur due to various reasons and are manifested when a node reports a wrong decision. In order to reduce the impact of node faults on the accuracy of multiple event localization, we introduce a trust index model to evaluate the fidelity of information which the nodes report and use in the event detection process, and propose the Trust Index based Subtract on Negative Add on Positive (TISNAP) localization algorithm, which reduces the impact of faulty nodes on the event localization by decreasing their trust index, to improve the accuracy of event localization and performance of fault tolerance for multiple event source localization. The algorithm includes three phases: first, the sink identifies the cluster nodes to determine the number of events occurred in the entire region by analyzing the binary data reported by all nodes; then, it constructs the likelihood matrix related to the cluster nodes and estimates the location of all events according to the alarmed status and trust index of the nodes around the cluster nodes. Finally, the sink updates the trust index of all nodes according to the fidelity of their information in the previous reporting cycle. The algorithm improves the accuracy of localization and performance of fault tolerance in multiple event source localization. The experiment results show that when the probability of node fault is close to 50%, the algorithm can still accurately determine the number of the events and have better accuracy of localization compared with other algorithms. PMID:22163972

Safety and tolerability of adjunctive rosiglitazone treatment for children with uncomplicated malaria.

PubMed

Varo, Rosauro; Crowley, Valerie M; Sitoe, Antonio; Madrid, Lola; Serghides, Lena; Bila, Rubao; Mucavele, Helio; Mayor, Alfredo; Bassat, Quique; Kain, Kevin C

2017-05-23

Despite the widespread use and availability of rapidly acting anti-malarials, the fatality rate of severe malaria in sub-Saharan Africa remains high. Adjunctive therapies that target the host response to malaria infection may further decrease mortality over that of anti-malarial agents alone. Peroxisome proliferator-activated receptor-gamma agonists (e.g. rosiglitazone) have been shown to act on several pathways implicated in the pathogenesis of severe malaria and may improve clinical outcome as an adjunctive intervention. In this study, the safety and tolerability of adjunctive rosiglitazone in paediatric uncomplicated malaria infection was evaluated in Mozambique, as a prelude to its evaluation in a randomized controlled trial in paediatric severe malaria. The study was a prospective, randomized, double-blind, placebo-controlled, phase IIa trial of rosiglitazone (0.045 mg/kg/dose) twice daily for 4 days versus placebo as adjunctive treatment in addition to Mozambican standard of care (artemisinin combination therapy Coartem ® ) in children with uncomplicated malaria. The primary outcomes were tolerability and safety, including clinical, haematological, biochemical, and electrocardiographic evaluations. Thirty children were enrolled: 20 were assigned to rosiglitazone and 10 to placebo. Rosiglitazone treatment did not induce hypoglycaemia nor significantly alter clinical, biochemical, haematological, or electrocardiographic parameters. Adjunctive rosiglitazone was safe and well-tolerated in children with uncomplicated malaria, permitting the extension of its evaluation as adjunctive therapy for severe malaria. The trial is registered with Clinicaltrials.gov, NCT02694874.

Meta-Analysis on Randomized Controlled Trials of Vaccines with QS-21 or ISCOMATRIX Adjuvant: Safety and Tolerability

PubMed Central

Bigaeva, Emilia; van Doorn, Eva; Liu, Heng; Hak, Eelko

2016-01-01

Background and Objectives QS-21 shows in vitro hemolytic effect and causes side effects in vivo. New saponin adjuvant formulations with better toxicity profiles are needed. This study aims to evaluate the safety and tolerability of QS-21 and the improved saponin adjuvants (ISCOM, ISCOMATRIX and Matrix-M™) from vaccine trials. Methods A systematic literature search was conducted from MEDLINE, EMBASE, Cochrane library and Clinicaltrials.gov. We selected for the meta-analysis randomized controlled trials (RCTs) of vaccines adjuvanted with QS-21, ISCOM, ISCOMATRIX or Matrix-M™, which included a placebo control group and reported safety outcomes. Pooled risk ratios (RRs) and their 95% confidence intervals (CIs) were calculated using a random-effects model. Jadad scale was used to assess the study quality. Results Nine RCTs were eligible for the meta-analysis: six trials on QS-21-adjuvanted vaccines and three trials on ISCOMATRIX-adjuvanted, with 907 patients in total. There were no studies on ISCOM or Matrix-M™ adjuvanted vaccines matching the inclusion criteria. Meta-analysis identified an increased risk for diarrhea in patients receiving QS21-adjuvanted vaccines (RR 2.55, 95% CI 1.04–6.24). No increase in the incidence of the reported systemic AEs was observed for ISCOMATRIX-adjuvanted vaccines. QS-21- and ISCOMATRIX-adjuvanted vaccines caused a significantly higher incidence of injection site pain (RR 4.11, 95% CI 1.10–15.35 and RR 2.55, 95% CI 1.41–4.59, respectively). ISCOMATRIX-adjuvanted vaccines also increased the incidence of injection site swelling (RR 3.43, 95% CI 1.08–10.97). Conclusions Our findings suggest that vaccines adjuvanted with either QS-21 or ISCOMATRIX posed no specific safety concern. Furthermore, our results indicate that the use of ISCOMATRIX enables a better systemic tolerability profile when compared to the use of QS-21. However, no better local tolerance was observed for ISCOMATRIX-adjuvanted vaccines in immunized non

Pharmacokinetics, safety and tolerability of a novel tocopheryl phosphate mixture/oxycodone transdermal patch system: a Phase I study.

PubMed

Gavin, Paul D; Simon, Lee S; Schlagheck, Thomas; Smith, Alisha J; Shakib, Sepehr

2017-07-01

To characterize the pharmacokinetic profile and evaluate the safety and tolerability of a transdermal oxycodone patch containing tocopheryl phosphate mixture (TPM). Eleven healthy subjects received a single application of three TPM/oxycodone patches applied to the torso for 72 h. Oxycodone was detected 8.0 ± 2.7-h postpatch administration, reaching a mean maximum plasma concentration of 3.41 ± 1.34 ng/ml at 49.3 ± 21.2 h. The safety profile was consistent with the application method and known side-effect profile of oxycodone and naltrexone. No treatment-limiting skin irritation was observed. A 3-day application of the TPM/oxycodone patch demonstrated an acceptable safety profile and was well tolerated by healthy subjects, with limited dermal irritation following application.

Efficacy, safety and tolerability of rasagiline as adjunctive therapy in elderly patients with Parkinson's disease.

PubMed

Tolosa, E; Stern, M B

2012-02-01

Rasagiline, an MAO-B inhibitor, is indicated for the treatment of Parkinson's disease (PD). In this post hoc analysis, the efficacy, safety and tolerability of rasagiline as an adjunct to levodopa were compared with placebo in elderly (≥70 years) and younger (<70 years) patients with PD. Data were pooled from the Parkinson's Rasagiline: Efficacy and Safety on the Treatment of 'OFF' and Lasting effect in Adjunct therapy with Rasagiline Given Once daily randomized, double-blind, placebo-controlled trials with the primary efficacy end-point being the reduction from baseline in daily OFF time. Secondary efficacy end-points included scores for Clinical Global Improvement (CGI)-Examiner during ON time, Unified Parkinson's Disease Rating Scale (UPDRS)-ADL during OFF time, UPDRS-Motor during ON time and total daily ON time with and without troublesome dyskinesia. Tolerability was evaluated from adverse events (AEs) in the two age groups. Rasagiline decreased daily OFF time versus placebo (P<0.01) and improved CGI-Examiner score (P=0.001) and UPDRS-Motor ON score (P<0.05). Changes in UPDRS-ADL OFF score and total daily ON time without dyskinesia also favoured rasagiline but were not significant. Between-group comparisons (≥70 vs. <70 years) showed that efficacy was unaffected by age for all end-points (P>0.1), and rasagiline was well tolerated amongst both groups of patients with a comparable incidence of total and dopaminergic AEs (P>0.1). Adjunct rasagiline is efficacious and well tolerated in elderly non-demented patients (≥70 years) with moderate to advanced PD. Confirmation of the efficacy and safety of rasagiline in the elderly patient subgroup is especially relevant because of the increasing number of elderly patients with PD. © 2011 The Author(s). European Journal of Neurology © 2011 EFNS.

Safety and tolerability of intracerebroventricular PDGF-BB in Parkinson's disease patients.

PubMed

Paul, Gesine; Zachrisson, Olof; Varrone, Andrea; Almqvist, Per; Jerling, Markus; Lind, Göran; Rehncrona, Stig; Linderoth, Bengt; Bjartmarz, Hjalmar; Shafer, Lisa L; Coffey, Robert; Svensson, Mikael; Mercer, Katarina Jansson; Forsberg, Anton; Halldin, Christer; Svenningsson, Per; Widner, Håkan; Frisén, Jonas; Pålhagen, Sven; Haegerstrand, Anders

2015-03-02

BACKGROUND. Recombinant human PDGF-BB (rhPDGF-BB) reduces Parkinsonian symptoms and increases dopamine transporter (DAT) binding in several animal models of Parkinson's disease (PD). Effects of rhPDGF-BB are the result of proliferation of ventricular wall progenitor cells and reversed by blocking mitosis. Based on these restorative effects, we assessed the safety and tolerability of intracerebroventricular (i.c.v.) rhPDGF-BB administration in individuals with PD. METHODS. We conducted a double-blind, randomized, placebo-controlled phase I/IIa study at two clinical centers in Sweden. Twelve patients with moderate PD received rhPDGF-BB via an implanted drug infusion pump and an investigational i.c.v. catheter. Patients were assigned to a dose cohort (0.2, 1.5, or 5 μg rhPDGF-BB per day) and then randomized to active treatment or placebo (3:1) for a 12-day treatment period. The primary objective was to assess safety and tolerability of i.c.v.-delivered rhPDGF-BB. Secondary outcome assessments included several clinical rating scales and changes in DAT binding. The follow-up period was 85 days. RESULTS. All patients completed the study. There were no unresolved adverse events. Serious adverse events occurred in three patients; however, these were unrelated to rhPDGF-BB administration. Secondary outcome parameters did not show dose-dependent changes in clinical rating scales, but there was a positive effect on DAT binding in the right putamen. CONCLUSION. At all doses tested, i.c.v. administration of rhPDGF-BB was well tolerated. Results support further clinical development of rhPDGF-BB for patients with PD. TRIAL REGISTRATION. Clinical Trials.gov NCT00866502. FUNDING. Newron Sweden AB (former NeuroNova AB) and Swedish Governmental Agency for Innovation Systems (VINNOVA).

Safety, Tolerability & Potential Anti-cancer Activity of Increasing Doses of AZD5363 in Different Treatment Schedules

ClinicalTrials.gov

2018-06-22

Advanced Solid Malignancy; Safety and Tolerability; Pharmacokinetics; Pharmacodynamics; Tumour Response; Advanced or Metastatic Breast Cancer; Ovarian Cancer; Cervical Cancer; Endometrial Cancer; PIK3CA; AKT1; PTEN; ER Positive; HER2 Positive

Safety Verification of a Fault Tolerant Reconfigurable Autonomous Goal-Based Robotic Control System

NASA Technical Reports Server (NTRS)

Braman, Julia M. B.; Murray, Richard M; Wagner, David A.

2007-01-01

Fault tolerance and safety verification of control systems are essential for the success of autonomous robotic systems. A control architecture called Mission Data System (MDS), developed at the Jet Propulsion Laboratory, takes a goal-based control approach. In this paper, a method for converting goal network control programs into linear hybrid systems is developed. The linear hybrid system can then be verified for safety in the presence of failures using existing symbolic model checkers. An example task is simulated in MDS and successfully verified using HyTech, a symbolic model checking software for linear hybrid systems.

Local tolerability and effectiveness of Ketospray® 10% cutaneous spray solution.

PubMed

Fulga, I; Lupescu, O; Spircu, T

2012-12-01

Orally administrated nonsteroidal anti-inflammatory drugs are effective in the treatment of a variety of acute and chronic pain conditions but their use may be associated with serious systemic adverse effects which are correlated with the therapeutic plasma levels of the drug. In order to minimize the incidence of drug related systemic events, topical formulations of the nonsteroidal anti-inflammatory drugs have been developed. A recently performed review of the evidence from randomized, double-blind, placebo controlled trials with topically applied NSAIDs in the treatment of acute pain confirmed the previously described pain relief effectiveness. For all topical nonsteroidal anti-inflammatory drugs combined, in comparison to placebo, the number needed to treat (NNT) to achieve a clinically meaningful pain relief of 50 % was 4.5 (3.9 to 5.3) for treatment periods of 6 to 14 days. Local skin reactions were generally mild and transient, and did not differ from placebo. The present is an observational, multicenter, open-label, non-interventional, post-authorization safety study as it is defined by Article 21 of the European Clinical Trials Directive 2001/20/EC. The main objective of this study was to evaluate the local tolerability and the therapeutic efficacy of static and pain on movement intensity reduction of Ketospray® 10% cutaneous spray solution administered in accordance with the terms of the marketing authorization and last version of summary of product characteristics approved by National Medicines Agency of Romania. In compliance with the Post-marketing study type, the assignment of the patient to a particular therapeutic strategy fell within current practice. The prescription of the medicine was not subject to compliance with predefined patients' characteristics. No specific, out of the daily practice routine diagnostic, monitoring, instrumental or laboratory assessments were foreseen by the study protocol. Patients' data were collected into respective

Langerhans Cells Maintain Local Tissue Tolerance in a Model of Systemic Autoimmune Disease1

PubMed Central

King, Jennifer K.; Philips, Rachael L.; Eriksson, Anna U.; Kim, Peter J.; Halder, Ramesh C.; Lee, Delphine J.; Singh, Ram Raj

2015-01-01

Systemic autoimmune diseases such as lupus affect multiple organs, usually in a diverse fashion where only certain organs are affected in individual patients. It is unclear whether the ‘local’ immune cells play a role in regulating tissue specificity in relation to disease heterogeneity in systemic autoimmune diseases. Here, we used skin as a model to determine the role of tissue-resident dendritic cells in local and systemic involvement within a systemic lupus disease model. Skin-resident dendritic cells, namely Langerhans cells (LC), have been implicated in regulating tolerance or autoimmunity using elegant transgenic models, however, their role in local versus systemic immune regulation is unknown. We demonstrate that while lymphocytes from skin-draining lymph nodes of autoimmune-prone MRL/MpJ-Faslpr/lpr mice react spontaneously to a physiological skin self-Ag desmoglein-3, epicutaneous applications of desmoglein-3 induced tolerance that is dependent on LCs. Inducible ablation of LCs in adult, preclinical MRL/MpJ-Faslpr/lpr and MRL/MpJ-Fas+/+ mice resulted in increased autoantibodies against skin Ags and markedly accelerated lupus dermatitis with increased local macrophage infiltration, but had no effect on systemic autoantibodies such as anti-dsDNA Abs or disease in other organs such as kidneys, lung, and liver. Furthermore, skin-draining lymph nodes of LC-ablated MRL/MpJ-Faslpr/lpr mice had significantly fewer CD4+ T-cells producing anti-inflammatory cytokine IL-10 than LC-intact controls. These results indicate that a skin-resident dendritic cell population regulates local tolerance in systemic lupus and emphasize the importance of the local immune milieu in preventing tissue-specific autoimmunity yet have no effect on systemic autoimmunity. PMID:26071559

Safety, tolerability, and cerebrospinal fluid penetration of ursodeoxycholic Acid in patients with amyotrophic lateral sclerosis.

PubMed

Parry, Gareth J; Rodrigues, Cecilia M P; Aranha, Marcia M; Hilbert, Sarah J; Davey, Cynthia; Kelkar, Praful; Low, Walter C; Steer, Clifford J

2010-01-01

Amyotrophic lateral sclerosis is a progressive degenerative disease, which typically leads to death in 3 to 5 years. Neuronal cell death offers a potential target for therapeutic intervention. Ursodeoxycholic acid is a cytoprotective, endogenous bile acid that has been shown to be neuroprotective in experimental Huntington and Alzheimer diseases, retinal degeneration, and ischemic and hemorrhagic stroke. The objective of this research was to study the safety and the tolerability of ursodeoxycholic acid in amyotrophic lateral sclerosis and document effective and dose-dependent cerebrospinal fluid penetration. Eighteen patients were randomly assigned to receive ursodeoxycholic acid at doses of 15, 30, and 50 mg/kg of body weight per day. Serum and cerebrospinal fluid were obtained for analysis after 4 weeks of treatment. Treatment-emergent clinical and laboratory events were monitored weekly. Our data indicated that ursodeoxycholic acid is well tolerated by all subjects at all doses. We also showed that ursodeoxycholic acid is well absorbed after oral administration and crosses the blood-brain barrier in a dose-dependent manner. These results show excellent safety and tolerability of ursodeoxycholic acid. The drug penetrates the cerebrospinal fluid in a dose-dependent manner. A large, placebo-controlled clinical trial is needed to assess the efficacy of ursodeoxycholic acid in treating amyotrophic lateral sclerosis.

Reactor Safety Gap Evaluation of Accident Tolerant Components and Severe Accident Analysis

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

Farmer, Mitchell T.; Bunt, R.; Corradini, M.

The overall objective of this study was to conduct a technology gap evaluation on accident tolerant components and severe accident analysis methodologies with the goal of identifying any data and/or knowledge gaps that may exist, given the current state of light water reactor (LWR) severe accident research, and additionally augmented by insights obtained from the Fukushima accident. The ultimate benefit of this activity is that the results can be used to refine the Department of Energy’s (DOE) Reactor Safety Technology (RST) research and development (R&D) program plan to address key knowledge gaps in severe accident phenomena and analyses that affectmore » reactor safety and that are not currently being addressed by the industry or the Nuclear Regulatory Commission (NRC).« less

Safety and Tolerability of Atomoxetine over 3 to 4 Years in Children with ADHD

ERIC Educational Resources Information Center

Donnelly, Craig; Bangs, Mark; Trzepacz, Paula; Jin, Ling; Zhang, Shuyu; Witte, Michael M.; Ball, Susan G.; Spencer, Thomas J.

2009-01-01

Data from 13 double-blind, placebo-controlled trials and three open-label extension studies were pooled to examine the safety of atomoxetine for treating attention deficit hyperactivity disorder in children and adolescents for less than or equal to three or four years. Results show that atomoxetine is safe and well tolerated in the subjects.

Safety and tolerability of intracerebroventricular PDGF-BB in Parkinson’s disease patients

PubMed Central

Paul, Gesine; Zachrisson, Olof; Varrone, Andrea; Almqvist, Per; Jerling, Markus; Lind, Göran; Rehncrona, Stig; Linderoth, Bengt; Bjartmarz, Hjalmar; Shafer, Lisa L.; Coffey, Robert; Svensson, Mikael; Mercer, Katarina Jansson; Forsberg, Anton; Halldin, Christer; Svenningsson, Per; Widner, Håkan; Frisén, Jonas; Pålhagen, Sven; Haegerstrand, Anders

2015-01-01

BACKGROUND. Recombinant human PDGF-BB (rhPDGF-BB) reduces Parkinsonian symptoms and increases dopamine transporter (DAT) binding in several animal models of Parkinson’s disease (PD). Effects of rhPDGF-BB are the result of proliferation of ventricular wall progenitor cells and reversed by blocking mitosis. Based on these restorative effects, we assessed the safety and tolerability of intracerebroventricular (i.c.v.) rhPDGF-BB administration in individuals with PD. METHODS. We conducted a double-blind, randomized, placebo-controlled phase I/IIa study at two clinical centers in Sweden. Twelve patients with moderate PD received rhPDGF-BB via an implanted drug infusion pump and an investigational i.c.v. catheter. Patients were assigned to a dose cohort (0.2, 1.5, or 5 μg rhPDGF-BB per day) and then randomized to active treatment or placebo (3:1) for a 12-day treatment period. The primary objective was to assess safety and tolerability of i.c.v.-delivered rhPDGF-BB. Secondary outcome assessments included several clinical rating scales and changes in DAT binding. The follow-up period was 85 days. RESULTS. All patients completed the study. There were no unresolved adverse events. Serious adverse events occurred in three patients; however, these were unrelated to rhPDGF-BB administration. Secondary outcome parameters did not show dose-dependent changes in clinical rating scales, but there was a positive effect on DAT binding in the right putamen. CONCLUSION. At all doses tested, i.c.v. administration of rhPDGF-BB was well tolerated. Results support further clinical development of rhPDGF-BB for patients with PD. TRIAL REGISTRATION. Clinical Trials.gov NCT00866502. FUNDING. Newron Sweden AB (former NeuroNova AB) and Swedish Governmental Agency for Innovation Systems (VINNOVA). PMID:25689258

Local air temperature tolerance: a sensible basis for estimating climate variability

NASA Astrophysics Data System (ADS)

Kärner, Olavi; Post, Piia

2016-11-01

The customary representation of climate using sample moments is generally biased due to the noticeably nonstationary behaviour of many climate series. In this study, we introduce a moment-free climate representation based on a statistical model fitted to a long-term daily air temperature anomaly series. This model allows us to separate the climate and weather scale variability in the series. As a result, the climate scale can be characterized using the mean annual cycle of series and local air temperature tolerance, where the latter is computed using the fitted model. The representation of weather scale variability is specified using the frequency and the range of outliers based on the tolerance. The scheme is illustrated using five long-term air temperature records observed by different European meteorological stations.

Efficacy, Safety, and Tolerability of Armodafinil Therapy for Hypersomnia Associated With Dementia With Lewy Bodies: A Pilot Study

PubMed Central

Lapid, Maria I.; Kuntz, Karen M.; Mason, Sara S.; Aakre, Jeremiah A.; Lundt, Emily S.; Kremers, Walter; Allen, Laura A.; Drubach, Daniel A.; Boeve, Bradley F.

2017-01-01

Background/Aims Hypersomnia is common in dementia with Lewy bodies (DLB). We assessed the efficacy, safety, and tolerability of armodafinil for hypersomnia associated with DLB. Methods We performed a 12-week pilot trial of armodafinil therapy (125–250 mg orally daily) in DLB outpatients with hypersomnia. Patients underwent neurologic examinations, neuropsychological battery, laboratory testing, electrocardiography, and polysomnography. Efficacy was assessed at 2, 4, 8, and 12 weeks. Safety assessment included laboratory examinations, QTc interval, and heart rate. Tolerability was assessed by analysis of adverse events. Data were analyzed using the last-observation-carried-forward method. Results Of 20 participants, 17 completed the protocol. Median age was 72 years, most were men (80%), and most had spouses as caregivers. Epworth Sleepiness Scale (P<.001), Maintenance of Wakefulness Test (P=.003), and Clinical Global Impression of Change (P<.001) scores improved at week 12. Neuropsychiatric Inventory total score (P=.003), visual hallucinations (P=.003), and agitation (P=.02) improved at week 4. Caregiver overall quality of life improved at week 12 (P=.004). No adverse events occurred. Conclusion These pilot data suggest improvements in hypersomnia and wakefulness and reasonable safety and tolerability of armodafinil therapy in hypersomnolent patients with DLB. Our findings inform the use of pharmacologic strategies to manage hypersomnolence in these patients. PMID:28448998

Safety, tolerability and efficacy of intradermal rabies immunization with DebioJect™.

PubMed

Vescovo, Paul; Rettby, Nils; Ramaniraka, Nirinarilala; Liberman, Julie; Hart, Karen; Cachemaille, Astrid; Piveteau, Laurent-Dominique; Zanoni, Reto; Bart, Pierre-Alexandre; Pantaleo, Giuseppe

2017-03-27

In a single-center study, 66 healthy volunteers aged between 18 and 50years were randomized to be immunized against rabies with three different injection routes: intradermal with DebioJect™ (IDJ), standard intradermal with classical needle (IDS), also called Mantoux method, and intramuscular with classical needle (IM). "Vaccin rabique Pasteur®" and saline solution (NaCl 0.9%) were administered at D0, D7 and D28. Antigen doses for both intradermal routes were 1/5 of the dose for IM. Tolerability, safety and induced immunogenicity of IDJ were compared to IDS and IM routes. Pain was evaluated at needle insertion and at product injection for all vaccination visits. Solicited Adverse Event (SolAE) and local reactogenicity symptoms including pain, redness and pruritus were recorded daily following each vaccination visit. Adverse events (AE) were recorded over the whole duration of the study. Humoral immune response was measured by assessing the rabies virus neutralizing antibody (VNA) titers using Rapid Fluorescent Focus Inhibition Test (RFFIT). Results demonstrated that the DebioJect™ is a safe, reliable and efficient device. Significant decreases of pain at needle insertion and at vaccine injection were reported with IDJ compared to IDS and IM. All local reactogenicity symptoms (pain, redness and pruritus) after injection with either vaccine or saline solution, were similar for IDJ and IDS, except that IDJ injection induced more redness 30min after saline solution. No systemic SolAE was deemed related to DebioJect™ and classical needles. No AE was deemed related to DebioJect™. No Serious Adverse Event (SAE) was reported during the study. At the end of the study all participants were considered immunized against rabies and no significant difference in humoral response was observed between the 3 studied routes. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Abuse Tolerance Improvements

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

Orendorff, Christopher J.; Nagasubramanian, Ganesan; Fenton, Kyle R.

As lithium-ion battery technologies mature, the size and energy of these systems continues to increase (> 50 kWh for EVs); making safety and reliability of these high energy systems increasingly important. While most material advances for lithium-ion chemistries are directed toward improving cell performance (capacity, energy, cycle life, etc.), there are a variety of materials advancements that can be made to improve lithium-ion battery safety. Issues including energetic thermal runaway, electrolyte decomposition and flammability, anode SEI stability, and cell-level abuse tolerance continue to be critical safety concerns. This report highlights work with our collaborators to develop advanced materials to improvemore » lithium-ion battery safety and abuse tolerance and to perform cell-level characterization of new materials.« less

Spatial difference in genetic variation for fenitrothion tolerance between local populations of Daphnia galeata in Lake Kasumigaura, Japan.

PubMed

Mano, Hiroyuki; Tanaka, Yoshinari

2017-12-01

This study examines the spatial difference in genetic variation for tolerance to a pesticide, fenitrothion, in Daphnia galeata at field sites in Lake Kasumigaura, Japan. We estimated genetic values of isofemale lines established from dormant eggs of D. galeata collected from field sampling sites with the toxicant threshold model applied using acute toxicity. We compared genetic values and variances and broad-sense heritability across different sites in the lake. Results showed that the mean tolerance values to fenitrothion did not differ spatially. The variance in genetic value and heritability of fenitrothion tolerance significantly differed between sampling sites, revealing that long-term ecological risk of fenitrothion may differ between local populations in the lake. These results have implications for aquatic toxicology research, suggesting that differences in genetic variation of tolerance to a chemical among local populations must be considered for understanding the long-term ecological risks of the chemical over a large geographic area.

Safety and tolerability of bilastine 10 mg administered for 12 weeks in children with allergic diseases.

PubMed

Novák, Zoltán; Yáñez, Anahí; Kiss, Ildikó; Kuna, Piotr; Tortajada-Girbés, Miguel; Valiente, Román

2016-08-01

Regulations on medicinal products for paediatric use require that pharmacokinetics and safety be characterized specifically in the paediatric population. A previous study established that a 10-mg dose of bilastine in children aged 2 to <12 years provided an equivalent systemic exposure as 20 mg in adults. The current study assessed the safety and tolerability of bilastine 10 mg in children with allergic rhinoconjunctivitis and chronic urticaria. In this phase III, multicentre, double-blind study, children were randomized to once-daily treatment with bilastine 10-mg oral dispersible table (n = 260) or placebo (n = 249) for 12 weeks. Safety evaluations included treatment-emergent adverse events (TEAEs), laboratory tests, cardiac safety (ECG recordings) and somnolence/sedation using the Pediatric Sleep Questionnaire (PSQ). The primary hypothesis of non-inferiority between bilastine 10 mg and placebo was demonstrated on the basis of a near-equivalent proportion of children in each treatment arm without TEAEs during 12 weeks' treatment (31.5 vs. 32.5%). No clinically relevant differences between bilastine 10 mg and placebo were observed from baseline to study end for TEAEs or related TEAEs, ECG parameters and PSQ scores. The majority of TEAEs were mild or moderate in intensity. TEAEs led to discontinuation of two patients treated with bilastine 10 mg and one patient treated with placebo. Bilastine 10 mg had a safety and tolerability profile similar to that of placebo in children aged 2 to <12 years with allergic rhinoconjunctivitis or chronic urticaria. © 2016 The Authors. Pediatric Allergy and Immunology Published by John Wiley & Sons Ltd.

Safety and tolerability review of lorcaserin in clinical trials.

PubMed

Greenway, F L; Shanahan, W; Fain, R; Ma, T; Rubino, D

2016-10-01

Lorcaserin is a novel selective serotonin 2C receptor agonist indicated by the US Food and Drug Administration for chronic weight management in adults with obesity or overweight with ≥1 comorbidity. The safety and efficacy of lorcaserin were established during two Phase III clinical trials in patients without diabetes (BLOOM and BLOSSOM) and one Phase III clinical trial in patients with type 2 diabetes (BLOOM-DM). Headache was the most common adverse event experienced by patients during all Phase III trials. Additional adverse events occurring in >5% of patients receiving lorcaserin included dizziness, fatigue, nausea, dry mouth and constipation in patients without diabetes, and hypoglycaemia, back pain, cough and fatigue in patients with diabetes. In a pooled analysis of echocardiographic data collected during the three lorcaserin Phase III trials, the incidence of FDA-defined valvulopathy was similar in patients taking lorcaserin and the placebo. Here, the safety profile of lorcaserin at the FDA-approved dose of 10 mg twice daily is reviewed using data from the lorcaserin Phase III programme, with a focus on theoretical adverse events commonly associated with agonists of the serotonin receptor family. Based on the lorcaserin Phase III clinical trial data, lorcaserin is safe and well tolerated in the indicated patient populations. © 2016 World Obesity.

Safety and tolerability of a cell culture derived trivalent subunit inactivated influenza vaccine administered to healthy children and adolescents: A Phase III, randomized, multicenter, observer-blind study.

PubMed

Nolan, Terry; Chotpitayasunondh, Tawee; Capeding, Maria Rosario; Carson, Simon; Senders, Shelly David; Jaehnig, Peter; de Rooij, Richard; Chandra, Richa

2016-01-04

Cell culture-derived inactivated influenza vaccines (TIVc) are necessary for scale and predictability of production to meet global demand. This study compared the safety and tolerability of TIVc with an egg-derived trivalent influenza vaccine (TIVf) in 4-17 yearolds. A Phase 3 observer blind, multicenter study enrolled 2055 healthy participants randomized 2:1 to receive either TIVc or TIVf, respectively (1372 TIVc and 683 TIVf evaluable subjects). Participants received one dose each on Days 1 and 28 (4-8 year-olds not previously vaccinated [NPV]) or one dose on Day 1 (4-8 and 9-17 yearolds previously vaccinated [PV]). Solicited adverse events (AEs) occurring within 7 days after each vaccination were assessed; participants were followed up for 6 months after their last dose for safety. Most solicited and unsolicited AEs were mild to moderate with <1% in the severe category. No withdrawals due to AEs, deaths or vaccine-related SAEs were reported. TIVc and TIVf were similar in percentages of participants reporting solicited reactions in 4-8 years NPV group after the 1st dose: local reactions, TIVc: 48%, TIVf: 43%; systemic reactions, TIVc: 34%, TIVf: 32%; percentages were lower following the 2nd dose in TIVc; local reactions: TIVc: 40%; TIVf: 43%; systemic reactions: TIVc: 21%; TIVf: 22%. In 4-17 years PV group, solicited reactions were lower following TIVf, local reactions: TIVc: 53%; TIVf: 43%; systemic reactions: TIVc: 37%, TIVf: 30%. Injection-site pain was the most common solicited reaction, and was similar following TIVc and TIVf in 4-8 yearolds (TIVc: 56%; TIVf: 55%), and lower following TIVf in 9-17 years group (TIVc: 52%; TIVf: 42%). Reporting of unsolicited AEs was similar for TIVc and TIVf across the two age groups. TIVc was well tolerated and had a safety and reactogenicity profile similar to that of TIVf in healthy 4-17 yearolds (NCT01857206). Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Tolerance and safety of superficial chemical peeling with salicylic acid in various facial dermatoses.

PubMed

Bari, Arfan Ul; Iqbal, Zafar; Rahman, Simeen Ber

2005-01-01

Chemical peeling is a skin-wounding procedure that may have some potentially undesirable side-effects. The present study is directed towards safety concerns associated with superficial chemical peeling with salicylic acid in various facial dermatoses. The study was a non-comparative and a prospective one. Two hundred and sixty-eight patients of either sex, aged between 10 to 60 years, undergoing superficial chemical peeling for various facial dermatoses (melasma, acne vulgaris, freckles, post-inflammatory scars/pigmentation, actinic keratoses, plane facial warts, etc.) were included in the study. Eight weekly peeling sessions were carried out in each patient. Tolerance to the procedure and any undesirable effects noted during these sessions were recorded. Almost all the patients tolerated the procedure well. Mild discomfort, burning, irritation and erythema were quite common but the incidence of major side-effects was very low and these too, were easily manageable. There was no significant difference in the incidence of side-effects between facial dermatoses (melasma, acne and other pigmentary disorders). Chemical peeling with salicylic acid is a well tolerated and safe treatment modality in many superficial facial dermatoses.

Localization and Quantification of Callose in the Streptophyte Green Algae Zygnema and Klebsormidium: Correlation with Desiccation Tolerance

PubMed Central

Herburger, Klaus; Holzinger, Andreas

2015-01-01

Freshwater green algae started to colonize terrestrial habitats about 460 million years ago, giving rise to the evolution of land plants. Today, several streptophyte green algae occur in aero-terrestrial habitats with unpredictable fluctuations in water availability, serving as ideal models for investigating desiccation tolerance. We tested the hypothesis that callose, a β-d-1,3-glucan, is incorporated specifically in strained areas of the cell wall due to cellular water loss, implicating a contribution to desiccation tolerance. In the early diverging genus Klebsormidium, callose was drastically increased already after 30 min of desiccation stress. Localization studies demonstrated an increase in callose in the undulating cross cell walls during cellular water loss, allowing a regulated shrinkage and expansion after rehydration. This correlates with a high desiccation tolerance demonstrated by a full recovery of the photosynthetic yield visualized at the subcellular level by Imaging-PAM. Furthermore, abundant callose in terminal cell walls might facilitate cell detachment to release dispersal units. In contrast, in the late diverging Zygnema, the callose content did not change upon desiccation for up to 3.5 h and was primarily localized in the corners between individual cells and at terminal cells. While these callose deposits still imply reduction of mechanical damage, the photosynthetic yield did not recover fully in the investigated young cultures of Zygnema upon rehydration. The abundance and specific localization of callose correlates with the higher desiccation tolerance in Klebsormidium when compared with Zygnema. PMID:26412780

Dual specific oral tolerance induction using interferon gamma for IgE-mediated anaphylactic food allergy and the dissociation of local skin allergy and systemic oral allergy: tolerance or desensitization?

PubMed

Noh, G; Jang, E H

2014-01-01

Specific oral tolerance induction (SOTI) for IgE-mediated food allergy (IFA) can be successfully achieved using interfero gamma (classic SOTI). In this study, a tolerable dose was introduced during tolerance induction with interferon gamma (dual SOTI), and its effectiveness was evaluated. The study population comprised 25 IFA patients. Blood samples were taken for analysis, including complete blood count with differential counts of eosinophils, serum total IgE levels, and specific IgE for allergenic foods. Skin prick tests were conducted with the allergens. Oral food challenges were performed to diagnose IFA. Ten patients received dual SOTI, 5 received classic SOTI, 5 received SOTI without interferon gamma (original SOTI), and 5 were not treated (controls). Patients treated with dual SOTI and classic SOTI using interferon gamma became tolerant to the allergenic food. The tolerable dose was introduced successfully in dual SOTI. It was difficult to proceed with the same dosing protocol used for classic SOTI in cases treated with original SOTI. Following dual SOTI, the systemic reaction to oral intake subsided, but the local skin reaction to contact with the allergenic food persisted. Dual SOTI is an improved protocol for SOTI using interferon gamma for IFA.The local skin reaction and systemic reaction to oral intake were dissociated following dual SOTI. In cases of food allergy, tolerance appears to result from desensitization to allergens.

Safety and tolerability of injectable lipid-lowering drugs: a review of available clinical data.

PubMed

Cicero, Arrigo F G; Tartagni, Elisa; Ertek, Sibel

2014-08-01

To answer the need of a better low-density lipoprotein (LDL) cholesterol control in statin-treated patients at high risk for cardiovascular disease, new injectable lipid-lowering drugs with innovative mechanisms of action are in advanced phase of development or have just been approved. Evolocumab and alirocumab are fully human monoclonal antibodies inhibiting the proprotein convertase subtilisin/kexin type 9 (PCSK9) that binds to hepatic LDL receptor and prevents it from normal recycling by targeting it for degradation. Mipomersen specifically binds to a segment of the human apolipoprotein B100 messenger RNA, blocking the translation of the gene product. Phase II (for evolocumab and alirocumab) and III (for evolocumab) trials show that PCSK9 inhibitors are equally well tolerated, with adverse events mainly limited to mild-to-moderate nasopharyngitis, injection-site pain, arthralgia and back pain. Mipomersen use is mainly associated to hepatosteatosis, increased transaminases (> 3 times the upper limit of normal), mild-to-moderate injection-site reactions and flu-like symptoms. PCSK9 inhibitors have demonstrated their good safety and tolerability in a large number of subjects with different clinical conditions, including statin-intolerance, enlarging their potential use in a broader range of patients. Further data on long-term mipomersen safety are required.

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

PubMed

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

2012-11-01

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

Pharmacokinetics and local tolerance of cefovecin sodium after intra-articular administration in horses.

PubMed

Pérez-Nogués, M; Encinas, T; López-SanRoman, J

2017-01-01

Searching for new therapeutic options against septic arthritis in horses, this research was focused on the study of the kinetics and local side effects after the intra-articular treatment of horses with cefovecin sodium. A single dose (240 mg) of the drug (Convenia ® ) was administered into the radiocarpal joint of adult healthy horses (n = 6), and drug concentrations in plasma and synovial fluid were determined by high-performance liquid chromatography (HPLC). Local tolerance was also studied based on the modification of different joint physiopathological parameters (pH, cellular, and protein concentration in synovial fluid). Although no clinically relevant joint damage was noticed, significant increases in the protein concentrations at 5 min and in the cellular concentration at 30 min after cefovecin administration were observed in the treated radiocarpal joints. The duration of the cefovecin above the minimal inhibitory concentration (MIC) ≤1 μg/mL was 28.80 ± 2.58 h in the radiocarpal joint and 16.00 ± 2.86 h in plasma. The results of this study showed that intra-articular administration of cefovecin sodium in horses could be considered in the future to manage septic arthritis in horses, as it offers a good pharmacokinetic behavior and good local tolerance. © 2016 John Wiley & Sons Ltd.

Intentions and knowledge shaping local safety policy: A comparison of two Swedish cities.

PubMed

Hanberger, Anders; Lundström, Ulf; Mårald, Gunilla

2015-12-01

This article explores how intentions and knowledge shape two Swedish cities' local safety policy (LSP). The applied framework is derived from the integration of governance and implementation research and the theory of knowledge and its use. The study shows that LSPs are shaped by a mix of intentions and different kinds of knowledge, and intentions and knowledge interplay and intertwine in many ways. Key-persons construct LSPs when they work out solutions to urgent safety problems and take departure in the local context, its pre-conditions, and their experience-based and professional knowledge. The state governs LSP softly through management by objectives in the background, but more often key-actor intentions and commitments, local safety problems, and events initiated and influenced LSPs. The article contributes to a better understanding of conditions for LSPs in multi-level governance. The article can be used to improve governance, identify implementation problems and knowledge needs that will improve LSPs and the overall safety situation in the community. The study has implications for how LSPs should be evaluated; many different evaluation criteria can be appropriate, such as relevance, legitimacy, achievement of key actors' objectives, sustainability of policy solutions, and creation of a local safety culture. Copyright © 2015 Elsevier Ltd and National Safety Council. All rights reserved.

Ambient but not local lactate underlies neuronal tolerance to prolonged glucose deprivation

PubMed Central

Sobieski, Courtney; Shu, Hong-Jin

2018-01-01

Neurons require a nearly constant supply of ATP. Glucose is the predominant source of brain ATP, but the direct effects of prolonged glucose deprivation on neuronal viability and function remain unclear. In sparse rat hippocampal microcultures, neurons were surprisingly resilient to 16 h glucose removal in the absence of secondary excitotoxicity. Neuronal survival and synaptic transmission were unaffected by prolonged removal of exogenous glucose. Inhibition of lactate transport decreased microculture neuronal survival during concurrent glucose deprivation, suggesting that endogenously released lactate is important for tolerance to glucose deprivation. Tandem depolarization and glucose deprivation also reduced neuronal survival, and trace glucose concentrations afforded neuroprotection. Mass cultures, in contrast to microcultures, were insensitive to depolarizing glucose deprivation, a difference attributable to increased extracellular lactate levels. Removal of local astrocyte support did not reduce survival in response to glucose deprivation or alter evoked excitatory transmission, suggesting that on-demand, local lactate shuttling is not necessary for neuronal tolerance to prolonged glucose removal. Taken together, these data suggest that endogenously produced lactate available globally in the extracellular milieu sustains neurons in the absence of glucose. A better understanding of resilience mechanisms in reduced preparations could lead to therapeutic strategies aimed to bolster these mechanisms in vulnerable neuronal populations. PMID:29617444

A Randomized, Double-Blind, Placebo-Controlled Study to Investigate the Safety, Tolerability, and Pharmacokinetics of Single Enantiomer (+)-Mefloquine Compared with Racemic Mefloquine in Healthy Persons

PubMed Central

Tansley, Robert; Lotharius, Julie; Priestley, Anthony; Bull, Fiona; Duparc, Stephan; Möhrle, Jörg

2010-01-01

Racemic mefloquine is a highly effective antimalarial whose clinical utility has been compromised by its association with neuropsychiatric and gastrointestinal side effects. It is hypothesized that the cause of the side effects may reside in the (−) enantiomer. We sought to compare the safety, tolerability and pharmacokinetic profile of (+)-mefloquine with racemic mefloquine in a randomized, ascending-dose, double-blind, active and placebo-controlled, parallel cohort study in healthy male and female adult volunteers. Although differing in its manifestations, both study drugs displayed a substantially worse tolerability profile compared with placebo. The systemic clearance was slower for (−)-mefloquine than (+)-mefloquine. Thus, (+)-mefloquine has a different safety and tolerability profile compared with racemic mefloquine but its global safety profile is not superior and replacement of the currently used antimalarial drug with (+)-mefloquine is not warranted. PMID:21118921

Safety, tolerability, and risks associated with first- and second-generation antipsychotics: a state-of-the-art clinical review

PubMed Central

Solmi, Marco; Murru, Andrea; Pacchiarotti, Isabella; Undurraga, Juan; Veronese, Nicola; Fornaro, Michele; Stubbs, Brendon; Monaco, Francesco; Vieta, Eduard; Seeman, Mary V; Correll, Christoph U; Carvalho, André F

2017-01-01

Since the discovery of chlorpromazine (CPZ) in 1952, first-generation antipsychotics (FGAs) have revolutionized psychiatric care in terms of facilitating discharge from hospital and enabling large numbers of patients with severe mental illness (SMI) to be treated in the community. Second-generation antipsychotics (SGAs) ushered in a progressive shift from the paternalistic management of SMI symptoms to a patient-centered approach, which emphasized targets important to patients – psychosocial functioning, quality of life, and recovery. These drugs are no longer limited to specific Diagnostic and Statistical Manual of Mental Disorders (DSM) categories. Evidence indicates that SGAs show an improved safety and tolerability profile compared with FGAs. The incidence of treatment-emergent extrapyramidal side effects is lower, and there is less impairment of cognitive function and treatment-related negative symptoms. However, treatment with SGAs has been associated with a wide range of untoward effects, among which treatment-emergent weight gain and metabolic abnormalities are of notable concern. The present clinical review aims to summarize the safety and tolerability profile of selected FGAs and SGAs and to link treatment-related adverse effects to the pharmacodynamic profile of each drug. Evidence, predominantly derived from systematic reviews, meta-analyses, and clinical trials of the drugs amisulpride, aripiprazole, asenapine, brexpiprazole, cariprazine, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, sertindole, ziprasidone, CPZ, haloperidol, loxapine, and perphenazine, is summarized. In addition, the safety and tolerability profiles of antipsychotics are discussed in the context of the “behavioral toxicity” conceptual framework, which considers the longitudinal course and the clinical and therapeutic consequences of treatment-emergent side effects. In SMI, SGAs with safer metabolic profiles should ideally be prescribed

Tolerability and safety of the intake of bovine milk oligosaccharides extracted from cheese whey in healthy human adults.

PubMed

Smilowitz, Jennifer T; Lemay, Danielle G; Kalanetra, Karen M; Chin, Elizabeth L; Zivkovic, Angela M; Breck, Melissa A; German, J Bruce; Mills, David A; Slupsky, Carolyn; Barile, Daniela

2017-01-01

Mechanistic research suggests a unique evolutionary relationship between complex milk oligosaccharides and cognate bifidobacteria enriched in breast-fed infants. Bovine milk oligosaccharides (BMO) were recently identified as structurally and functionally similar to human milk oligosaccharides. The present single-blind three-way crossover study is the first to determine the safety and tolerability of BMO consumption by healthy human participants ( n 12) and its effects on faecal microbiota and microbial metabolism. Participants consumed each supplement (placebo-control; low- and high-BMO doses) for eleven consecutive days, followed by a 2-week washout period prior to initiating the next supplement arm. Low and high BMO doses were consumed as 25 and 35 % of each individual's daily fibre intake, respectively. Safety and tolerability were measured using standardised questionnaires on gut and stomach discomfort and stool consistency. Faecal extracts were profiled for bacterial populations by next-generation sequencing (NGS) and bifidobacteria presence was confirmed using quantitative PCR. Urine was analysed for changes in microbial metabolism using nuclear magnetic resonance spectroscopy ( 1 H-NMR). Consumption of both the low and high BMO doses was well tolerated and did not change stool consistency from baseline. Multivariate analysis of the NGS results demonstrated no change in faecal microbiota phyla among the placebo-control and BMO supplement groups. In conclusion, BMO supplementation was well tolerated in healthy adults and has the potential to shift faecal microbiota toward beneficial strains as part of a synbiotic treatment with probiotic cultures that selectively metabolise oligosaccharides.

Local Food Systems Food Safety Concerns.

PubMed

Chapman, Benjamin; Gunter, Chris

2018-04-01

Foodborne disease causes an estimated 48 million illnesses and 3,000 deaths annually (Scallan E, et al., Emerg Infect Dis 17:7-15, 2011), with U.S. economic costs estimated at $152 billion to $1.4 trillion annually (Roberts T, Am J Agric Econ 89:1183-1188, 2007; Scharff RL, http://www.pewtrusts.org/en/research-and-analysis/reports/0001/01/01/healthrelated-costs-from-foodborne-illness-in-the-united-states, 2010). An increasing number of these illnesses are associated with fresh fruits and vegetables. An analysis of outbreaks from 1990 to 2003 found that 12% of outbreaks and 20% of outbreak-related illnesses were associated with produce (Klein S, Smith DeWaal CS, Center for Science in the Public Interest, https://cspinet.org/sites/default/files/attachment/ddreport.pdf, June 2008; Lynch M, Tauxe R, Hedberg C, Epidemiol Infect 137:307-315, 2009). These food safety problems have resulted in various stakeholders recommending the shift to a more preventative and risk-based food safety system. A modern risk-based food safety system takes a farm-to-fork preventative approach to food safety and relies on the proactive collection and analysis of data to better understand potential hazards and risk factors, to design and evaluate interventions, and to prioritize prevention efforts. Such a system focuses limited resources at the points in the food system with the likelihood of having greatest benefit to public health. As shared kitchens, food hubs, and local food systems such as community supported agriculture are becoming more prevalent throughout the United States, so are foodborne illness outbreaks at these locations. At these locations, many with limited resources, food safety methods of prevention are rarely the main focus. This lack of focus on food safety knowledge is why a growing number of foodborne illness outbreaks are occurring at these locations.

77 FR 6007 - Quarterly Listings; Safety Zones, Security Zones, Special Local Regulations, Drawbridge Operation...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-07

...] Quarterly Listings; Safety Zones, Security Zones, Special Local Regulations, Drawbridge Operation... they could be published in the Federal Register. This notice lists temporary safety zones, security zones, special local regulations, drawbridge operation regulations and regulated navigation areas, all...

SLSF in-reactor local fault safety experiment P4. Final report

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

Thompson, D. H.; Holland, J. W.; Braid, T. H.

The Sodium Loop Safety Facility (SLSF), a major facility in the US fast-reactor safety program, has been used to simulate a variety of sodium-cooled fast reactor accidents. SLSF experiment P4 was conducted to investigate the behavior of a "worse-than-case" local fault configuration. Objectives of this experiment were to eject molten fuel into a 37-pin bundle of full-length Fast-Test-Reactor-type fuel pins form heat-generating fuel canisters, to characterize the severity of any molten fuel-coolant interaction, and to demonstrate that any resulting blockage could either be tolerated during continued power operation or detected by global monitors to prevent fuel failure propagation. The designmore » goal for molten fuel release was 10 to 30 g. Explusion of molten fuel from fuel canisters caused failure of adjacent pins and a partial flow channel blockage in the fuel bundle during full-power operation. Molten fuel and fuel debris also lodged against the inner surface of the test subassembly hex-can wall. The total fuel disruption of 310 g evaluated from posttest examination data was in excellent agreement with results from the SLSF delayed neutron detection system, but exceeded the target molten fuel release by an order of magnitude. This report contains a summary description of the SLSF in-reactor loop and support systems and the experiment operations. results of the detailed macro- and microexamination of disrupted fuel and metal and results from the analysis of the on-line experimental data are described, as are the interpretations and conclusions drawn from the posttest evaluations. 60 refs., 74 figs.« less

Two MATE Transporters with Different Subcellular Localization are Involved in Al Tolerance in Buckwheat.

PubMed

Lei, Gui Jie; Yokosho, Kengo; Yamaji, Naoki; Ma, Jian Feng

2017-12-01

Buckwheat (Fagopyrum esculentum) shows high tolerance to aluminum (Al) toxicity, but the molecular mechanisms responsible for this high Al tolerance are still poorly understood. Here, we investigated the involvement of two MATE (multi-drug and toxic compound extrusion) genes in Al tolerance. Both FeMATE1 and FeMATE2 showed efflux transport activity for citrate, but not for oxalate when expressed in Xenopus oocytes. A transient assay with buckwheat leaf protoplasts using green fluorescent protein (GFP) fusion showed that FeMATE1 was mainly localized to the plasma membrane, whereas FeMATE2 was localized to the trans-Golgi and Golgi. The expression of FeMATE1 was induced by Al only in the roots, but that of FeMATE2 was up-regulated in both the roots and leaves. Furthermore, the expression of both genes only responded to Al toxicity, but not to other stresses including low pH, cadmium (Cd) and lanthanum (La). Heterologous expression of FeMATE1 or FeMATE2 in the Arabidopsis mutant atmate partially rescued its Al tolerance. Expression of FeMATE1 also partially recovered the Al-induced secretion of citrate in the transgenic lines, whereas expression of FeMATE2 did not complement the citrate secretion. Further physiological analysis showed that buckwheat roots also secreted citrate in addition to oxalate in response to Al in a dose-responsive manner. Taken together, our results indicate that FeMATE1 is involved in the Al-activated citrate secretion in the roots, while FeMATE2 is probably responsible for transporting citrate into the Golgi system for the internal detoxification of Al in the roots and leaves of buckwheat. © The Author 2017. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Radiation Tolerant Interfaces: Influence of Local Stoichiometry at the Misfit Dislocation on Radiation Damage Resistance of Metal/Oxide Interfaces

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

Shutthanandan, Vaithiyalingam; Choudhury, Samrat; Manandhar, Sandeep

The interaction of radiation with materials controls the performance, reliability, and safety of many structures in nuclear power systems. Revolutionary improvements in radiation damage resistance may be attainable if methods can be found to manipulate interface properties to give optimal interface stability and point defect recombination capability. To understand how variations in interface properties such as misfit dislocation density and local chemistry affect radiation-induced defect absorption and recombination, a model system of metallic Cr xV 1-x (0 ≤ x ≤ 1) epitaxial films deposited on MgO(001) single crystal substrates has been explored in this paper. By controlling film composition, themore » lattice mismatch between the film and MgO is adjusted to vary the misfit dislocation density at the metal/oxide interface. The stability of these interfaces under various irradiation conditions is studied experimentally and theoretically. The results indicate that, unlike at metal/metal interfaces, the misfit dislocation density does not dominate radiation damage tolerance at metal/oxide interfaces. Rather, the stoichiometry and the location of the misfit dislocation extra half-plane (in the metal or the oxide) drive radiation-induced defect behavior. Finally, together, these results demonstrate the sensitivity of defect recombination to interfacial chemistry and provide new avenues for engineering radiation-tolerant nanomaterials for next-generation nuclear power plants.« less

Radiation Tolerant Interfaces: Influence of Local Stoichiometry at the Misfit Dislocation on Radiation Damage Resistance of Metal/Oxide Interfaces

DOE PAGES

Shutthanandan, Vaithiyalingam; Choudhury, Samrat; Manandhar, Sandeep; ...

2017-04-24

The interaction of radiation with materials controls the performance, reliability, and safety of many structures in nuclear power systems. Revolutionary improvements in radiation damage resistance may be attainable if methods can be found to manipulate interface properties to give optimal interface stability and point defect recombination capability. To understand how variations in interface properties such as misfit dislocation density and local chemistry affect radiation-induced defect absorption and recombination, a model system of metallic Cr xV 1-x (0 ≤ x ≤ 1) epitaxial films deposited on MgO(001) single crystal substrates has been explored in this paper. By controlling film composition, themore » lattice mismatch between the film and MgO is adjusted to vary the misfit dislocation density at the metal/oxide interface. The stability of these interfaces under various irradiation conditions is studied experimentally and theoretically. The results indicate that, unlike at metal/metal interfaces, the misfit dislocation density does not dominate radiation damage tolerance at metal/oxide interfaces. Rather, the stoichiometry and the location of the misfit dislocation extra half-plane (in the metal or the oxide) drive radiation-induced defect behavior. Finally, together, these results demonstrate the sensitivity of defect recombination to interfacial chemistry and provide new avenues for engineering radiation-tolerant nanomaterials for next-generation nuclear power plants.« less

Data collection and analysis for local roadway safety assessment.

DOT National Transportation Integrated Search

2014-11-01

The project Data Analysis for Local Roadway : Assessment conducted systematic road-safety : assessment and identified major risks that can be el : iminated or reduced by pr : actical road-improvement : measures. Specifically, the primary task o...

76 FR 70342 - Quarterly Listings; Safety Zones, Security Zones, Special Local Regulations, Drawbridge Operation...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-11-14

...] Quarterly Listings; Safety Zones, Security Zones, Special Local Regulations, Drawbridge Operation... published in the Federal Register. This notice lists temporary safety zones, security zones, special local..., telephone (202) 372-3862. For questions on viewing, or on submitting material to the docket, contact Ms...

Safety and tolerability of fexofenadine for the treatment of allergic rhinitis in children 2 to 5 years old.

PubMed

Milgrom, Henry; Kittner, Barbara; Lanier, Robert; Hampel, Frank C

2007-10-01

The safety of fexofenadine has been examined extensively in adults and school-age children. However, the safety of fexofenadine in children younger than 6 years has not been reported to date. To compare the safety and tolerability of twice-daily fexofenadine hydrochloride, 30 mg, and placebo in preschool children aged 2 to 5 years with allergic rhinitis. This was a multicenter, double-blind, randomized, placebo-controlled, parallel-group study, conducted between February 29, 2000, and June 14, 2001. Participants were randomized to either fexofenadine hydrochloride, 30 mg, or placebo twice daily for a 2-week period. To facilitate dosing, capsule content was mixed with applesauce (approximately 10 mL). Safety assessments depended on date of entry into the study because of an amendment to the protocol. Before the amendment, assessments included physical examination, vital signs reporting (oral temperature, heart rate, and respiratory rate), and adverse event (AE) reporting. After the amendment, safety assessments included laboratory testing (blood chemistry and hematology profiles), physical examination, 12-lead electrocardiography, and vital signs (oral temperature, blood pressure, heart rate, and respiratory rate) and AE reporting. Treatment-emergent AEs were observed in 116 of 231 participants receiving placebo and 111 of 222 receiving fexofenadine. These AEs were possibly related to study medication in 19 (8.2%) and 21 (9.5%) of the participants receiving placebo and fexofenadine, respectively, and most frequently involved the digestive system. No clinically relevant differences in laboratory measures, vital signs, and physical examinations were observed. The findings show that fexofenadine hydrochloride, 30 mg, is well tolerated and has a good safety profile in children aged 2 to 5 years with allergic rhinitis.

Safety and tolerability of omecamtiv mecarbil during exercise in patients with ischemic cardiomyopathy and angina.

PubMed

Greenberg, Barry H; Chou, Willis; Saikali, Khalil G; Escandón, Rafael; Lee, Jacqueline H; Chen, Michael M; Treshkur, Tatyana; Megreladze, Irakli; Wasserman, Scott M; Eisenberg, Paul; Malik, Fady I; Wolff, Andrew A; Shaburishvili, Tamaz

2015-01-01

The goal of this study was to assess the safety and tolerability of omecamtiv mecarbil treatment during symptom-limited exercise in patients with ischemic cardiomyopathy and angina. These patients may have increased vulnerability to prolongation of the systolic ejection time. Omecamtiv mecarbil is a selective cardiac myosin activator that augments cardiac contractility in patients with systolic heart failure through a dose-dependent increase in systolic ejection time. In this double-blind, placebo-controlled study, patients with chronic heart failure were randomized 2:1 to receive omecamtiv mecarbil or placebo in 2 sequential cohorts of escalating doses designed to achieve plasma concentrations previously shown to increase systolic function. Patients underwent 2 symptom-limited exercise treadmill tests (ETTs) at baseline (ETT1 and ETT2) and again before the end of a 20-h infusion of omecamtiv mecarbil (ETT3). The primary pre-defined safety endpoint (i.e., the proportion of patients who stopped ETT3 because of angina at a stage earlier than baseline) was observed in 1 patient receiving placebo and none receiving omecamtiv mecarbil. No dose-dependent differences emerged in the proportion of patients stopping ETT3 for any reason or in the pattern of adverse events. Doses of omecamtiv mecarbil producing plasma concentrations previously shown to increase systolic function were well tolerated during exercise in these study patients with ischemic cardiomyopathy and angina. There was no indication that treatment increased the likelihood of myocardial ischemia in this high-risk population. (Pharmacokinetics [PK] and Tolerability of Intravenous [IV] and Oral CK-1827452 in Patients With Ischemic Cardiomyopathy and Angina; NCT00682565). Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Safety and tolerability of cell culture-derived and egg-derived trivalent influenza vaccines in 3 to <18-year-old children and adolescents at risk of influenza-related complications.

PubMed

Diez-Domingo, Javier; de Martino, Maurizio; Lopez, Jose Garcia-Sicilia; Zuccotti, Gian Vincenzo; Icardi, Giancarlo; Villani, Alberto; Moreno-Perez, David; Hernández, María Méndez; Aldeán, Javier Álvarez; Mateen, Ahmed Abdul; Enweonye, Igwebuike; de Rooij, Richard; Chandra, Richa

2016-08-01

This descriptive, non-comparative, phase III study evaluated the safety and tolerability of cell culture-derived (TIVc) and egg-derived (TIV) seasonal influenza vaccines in children at risk of influenza-related complications. Four hundred and thirty subjects were randomized 2:1 to TIVc or TIV. Subjects aged 3 to <9 years received one dose (if previously vaccinated, n=89) or two doses (if not previously vaccinated, n=124) of the study vaccines; the 9 to <18-year-olds (n=213) received one dose. Reactogenicity was assessed for 7 days after vaccination; safety was monitored for 6 months. After any vaccination, the most frequently reported solicited local adverse event (AE) was tenderness/pain (TIVc 44%, 66%, 53% and TIV 56%, 51%, 65% in the age groups 3 to <6 years, 6 to <9 years, and 9 to <18 years, respectively) and the systemic AE was irritability (22% TIVc, 24% TIV) in 3 to <6-year-olds and headache in 6 to <9-year-olds (20% TIVc, 13% TIV) and 9 to <18-year-olds (21% TIVc, 26% TIV). There were no cases of severe fever (≥40°C). No vaccine-related serious AEs were noted. New onset of chronic disease was reported in ≤1% of subjects. TIVc and TIV had acceptable tolerability and similar safety profiles in at-risk children (NCT01998477). Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

A COMPARATIVE ANALYSIS BETWEEN FRANCE AND JAPAN ON LOCAL GOVERNMENTS' INVOLVEMENT IN NUCLEAR SAFETY GOVERNANCE

NASA Astrophysics Data System (ADS)

Sugawara, Shin-Etsu; Shiroyama, Hideaki

This paper shows a comparative analysis between France and Japan on the way of the local governments' involvement in nuclear safety governance through some interviews. In France, a law came into force that requires related local governments to establish "Commision Locale d'Information" (CLI), which means the local governments officially involve in nuclear regulatory activity. Meanwhile, in Japan, related local governments substantially involve in the operation of nuclear facilities through the "safety agreements" in spite of the lack of legal authority. As a result of comparative analysis, we can point out some institutional input from French cases as follows: to clarify the local governments' roles in the nuclear regulation system, to establish the official channels of communication among nuclear utilities, national regulatory authorities and local governments, and to stipulate explicitly the transparency as a purpose of safety regulation.

Computationally optimized ECoG stimulation with local safety constraints.

PubMed

Guler, Seyhmus; Dannhauer, Moritz; Roig-Solvas, Biel; Gkogkidis, Alexis; Macleod, Rob; Ball, Tonio; Ojemann, Jeffrey G; Brooks, Dana H

2018-06-01

Direct stimulation of the cortical surface is used clinically for cortical mapping and modulation of local activity. Future applications of cortical modulation and brain-computer interfaces may also use cortical stimulation methods. One common method to deliver current is through electrocorticography (ECoG) stimulation in which a dense array of electrodes are placed subdurally or epidurally to stimulate the cortex. However, proximity to cortical tissue limits the amount of current that can be delivered safely. It may be desirable to deliver higher current to a specific local region of interest (ROI) while limiting current to other local areas more stringently than is guaranteed by global safety limits. Two commonly used global safety constraints bound the total injected current and individual electrode currents. However, these two sets of constraints may not be sufficient to prevent high current density locally (hot-spots). In this work, we propose an efficient approach that prevents current density hot-spots in the entire brain while optimizing ECoG stimulus patterns for targeted stimulation. Specifically, we maximize the current along a particular desired directional field in the ROI while respecting three safety constraints: one on the total injected current, one on individual electrode currents, and the third on the local current density magnitude in the brain. This third set of constraints creates a computational barrier due to the huge number of constraints needed to bound the current density at every point in the entire brain. We overcome this barrier by adopting an efficient two-step approach. In the first step, the proposed method identifies the safe brain region, which cannot contain any hot-spots solely based on the global bounds on total injected current and individual electrode currents. In the second step, the proposed algorithm iteratively adjusts the stimulus pattern to arrive at a solution that exhibits no hot-spots in the remaining brain. We

Variation in soil aluminium tolerance genes is associated with local adaptation to soils at the Park Grass Experiment.

PubMed

Gould, Billie; McCouch, Susan; Geber, Monica

2014-12-01

Studies of the wild grass Anthoxanthum odoratum at the long-term Park Grass Experiment (PGE, Harpenden, UK) document a well-known example of rapid plant evolution in response to environmental change. Repeated fertilizer applications have acidified the soil in some experimental plots over the past 150+ years, and Anthoxanthum subpopulations have quickly become locally adapted. Early reciprocal transplants showed subpopulation differentiation specifically in response to soil aluminium (Al) toxicity across the experiment, even at small (30 m) spatial scales. Almost 40 years after its original measurement, we reassessed the degree of local adaptation to soil Al at the PGE using updated phenotyping methods and identified genes with variation linked to the tolerance trait. Root growth assays show that plants are locally adapted to soil Al at both the seedling and adult growth stages, but to a smaller extent than previously inferred. Among a large suite of candidate loci that were previously shown to have Al-sensitive expression differences between sensitive and tolerant plants, three loci contained SNPs that are associated with both Al tolerance and soil acidity: an Al-sensitive malate transporter (ALMT), a tonoplast intrinsic protein (TIP) and the putative homolog of the rice cell-wall modification gene STAR1. Natural genetic variation at these loci is likely to have contributed to the recent rapid evolution at PGE. Continued study of Al tolerance variants in Anthoxanthum will allow us to test hypotheses about the nature and source of genetic variation that enables some species to adapt to soil acidification and other types of rapid environmental change. © 2014 John Wiley & Sons Ltd.

[Cannabinoids in palliative care: Systematic review and meta-analysis of efficacy, tolerability and safety].

PubMed

Mücke, M; Carter, C; Cuhls, H; Prüß, M; Radbruch, L; Häuser, W

2016-02-01

Cannabinoids have multiple medical indications in palliative care, such as relief of pain or nausea or increase of appetite and weight stabilisation. The value of cannabinoids for these indications is not resolved sufficiently for palliative patients. A systematic review with meta-analysis of the efficacy, tolerability and safety on the basis of randomised controlled studies (RCT) or randomised open label or crossover studies has not yet been conducted. An extensive search for RCTs, randomised open label or crossover studies dealing with the underlying question was performed in the databases of Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PsycINFO, PubMed, Scopus and Clinicaltrials.gov up to April 2015. Studies with a duration of ≥ 2 weeks and ≥ 10 participants per treatment group were included into analysis. Using a random effects model, pooled estimates of event rates for categorical data and standardized mean differences (SMD) for continuous variables and risk differences (RD) for dichotomous variables were calculated. Out of initially 108 studies 9, with a total of 1561 participants suffering from advanced or end stage diseases, were included. The median study duration of the cancer research was 8 weeks (16 days-11 weeks), of the HIV research 6 weeks (3-12 weeks) and of the study concentrating on Alzheimer's 2 × 6 weeks. The outcome results for cannabis/cannabinoids vs. placebo in patients with cancer were not significant for the 30 % decrease in pain (RD: 0.07; 95 % confidence interval (CI): - 0.01 to 0.16; p = 0.07), caloric intake (SMD: 0.2; 95 % CI: - 0.66 to 1.06; p = 0.65) or sleep problems (SMD: - 0.09; 95 % CI: - 0.62 to 0.43; p = 0.72). In the treatment of HIV cannabinoids were superior to placebo for the outcome of weight change (SMD: 0.57; 95 % CI: 0.22-0.92; p = 0.001). Change in appetite was significant for the treatment of HIV (SMD: 0.57; 95 % CI: 0.11-1.03; p = 0.02), but

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

PubMed

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

2015-01-01

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

Immunogenicity, safety and tolerability of inactivated trivalent influenza vaccine in overweight and obese children.

PubMed

Esposito, Susanna; Giavoli, Claudia; Trombetta, Claudia; Bianchini, Sonia; Montinaro, Valentina; Spada, Anna; Montomoli, Emanuele; Principi, Nicola

2016-01-02

Obesity may be a risk factor for increased hospitalization and deaths from infections due to respiratory pathogens. Additionally, obese patients appear to have impaired immunity after some vaccinations. To evaluate the immunogenicity, safety and tolerability of an inactivated trivalent influenza vaccine (TIV) in overweight and obese children, 28 overweight/obese pediatric patients and 23 healthy normal weight controls aged 3-14 years received a dose of TIV. Four weeks after vaccine administration, significantly higher seroprotection rates against the A/H1N1 strain were observed among overweight/obese children compared with normal weight controls (p<0.05). Four months after vaccination, similar or slightly higher seroconversion and seroprotection rates against the A/H1N1 and A/H3N2 strains were detected in overweight/obese than in normal weight children, whereas significantly higher rates of seroconversion and seroprotection against the B strain were found in overweight/obese patients than in normal weight controls (p<0.05 for seroconversion and seroprotection). Geometric mean titers (GMTs) and fold increase against B strains were significantly higher in overweight/obese patients than in normal weight controls 4 months after vaccine administration (p<0.01 for GMT values and p<0.05 for fold increase). The frequency of local and systemic reactions was similar between the groups, and there were no serious adverse events. The results of this study indicate that in overweight and obese children, antibody response to TIV administration is similar or slightly higher than that evidenced in normal weight subjects of similar age and this situation persists for at least 4 months after vaccine administration in the presence of a favorable safety profile. Copyright © 2015 Elsevier Ltd. All rights reserved.

Safety and tolerability of the Easy Vax™ clinical epidermal electroporation system in healthy adults.

PubMed

El-Kamary, Samer S; Billington, Melissa; Deitz, Stephen; Colby, Elaina; Rhinehart, Howard; Wu, Yukun; Blackwelder, William; Edelman, Robert; Lee, Albert; King, Alan

2012-01-01

DNA vaccines are cost-effective and versatile, though intracellular delivery has been challenging in humans. Alternative delivery modalities such as electroporation have demonstrated improved immune responses, but are painful. In this single-center, double-blind, medical device trial, we evaluated the safety and tolerability of Easy Vax™ dermal electroporation system, alone (without DNA) in healthy adults. Three randomized protocol doses were administered to 10 subjects (80% white, 60% female, mean age: 32.1 years) in each of two areas (total of six doses). Two subjects complained of shooting pain, burning and/or tingling when doses were administered to the forearm region, but not the lateral deltoid regions. Subsequent doses for the remaining eight subjects were restricted to the deltoid regions only. Tolerability pain scores never exceeded 3 of 10 in the 11-Point Pain Rating scale, and 12 of 100 in the Visual Analog Scale (VAS), and lower in follow-up evaluations (P < 0.0001), with no significant difference between the three dosing protocols. Electrical properties of the skin, measured automatically by the device, showed no correlation between pain intensity and skin conductance. In conclusion, the Easy Vax™ electroporation device is safe and well tolerated when administered over the lateral deltoid skin regions in healthy volunteers.

Local Road Safety Peer Exchange – Region 9 : An RSPCB Peer Exchange

DOT National Transportation Integrated Search

2013-09-01

This report provides a summary of the proceedings of the Region 9 Local Road Safety Peer Exchange held in Sacramento, California on September 17 and 18, 2013. The Federal Highway Administration (FHWA) Office of Safety (HSA) sponsored the peer exchang...

Safety, tolerability, and systemic absorption of dapivirine vaginal microbicide gel in healthy, HIV-negative women.

PubMed

Nel, Annalene M; Coplan, Paul; van de Wijgert, Janneke H; Kapiga, Saidi H; von Mollendorf, Claire; Geubbels, Eveline; Vyankandondera, Joseph; Rees, Helen V; Masenga, Gileard; Kiwelu, Ireen; Moyes, Jocelyn; Smythe, Shanique C

2009-07-31

To assess the local and systemic safety of dapivirine vaginal gel vs. placebo gel as well as the systemic absorption of dapivirine in healthy, HIV-negative women. Two prospective, randomized, double-blind, placebo-controlled phase I/II studies were conducted at five research centers, four in Africa and one in Belgium. A total of 119 women used dapivirine gel (concentrations of 0.001, 0.002, 0.005, or 0.02%), and 28 used placebo gel twice daily for 42 days. The primary endpoints were colposcopic findings, adverse events, Division of AIDS grade 3 or grade 4 laboratory values, and plasma levels of dapivirine. Safety data were similar for the dapivirine and placebo gels. None of the adverse events with incidence more than 5% occurred with greater frequency in the dapivirine than placebo groups. Similar percentages of placebo and dapivirine gel users had adverse events that were considered by the investigator to be related to study gel. A total of five serious adverse events occurred in the two studies, and none was assessed as related to study gel. Mean plasma concentrations of dapivirine were approximately dose proportional, and, within each dose group, mean concentrations were similar on days 7, 28, and 42. The maximum observed mean concentration was 474 pg/ml in the 0.02% gel group on day 28. Two weeks after the final application of study gel, mean concentrations decreased to 5 pg/ml or less. Twice daily administration of dapivirine vaginal gel for 42 days was safe and well tolerated with low systemic absorption in healthy, HIV-negative women suggesting that continued development is warranted.

Local tolerance and stability up to 24 months of a new 20% proline-stabilized polyclonal immunoglobulin for subcutaneous administration.

PubMed

Maeder, Werner; Lieby, Patricia; Sebald, Andrea; Spycher, Martin; Pedrussio, Renzo; Bolli, Reinhard

2011-01-01

Subcutaneous administration of human IgG is an alternative to intravenous replacement therapy that is associated with more stable serum IgG levels and fewer systemic adverse events. Highly concentrated IgG solutions are most convenient to minimize infusion volume, but their preparation and stability presents substantial technical difficulties. We report on the stability and local tolerance of IgPro20, an l-proline-stabilized, 20% polyvalent human IgG developed for subcutaneous administration. Stability was tested according to ICH guidelines. Local tolerance and vasoactivity were examined in rabbit and rat models, respectively. The presence of l-proline in IgPro20 reduced viscosity and addition of Polysorbate 80 and inert gassing improved the appearance of the solution. After storage at 25 °C for 24 months, monomer + dimer content, aggregates, and fragments were within specification (≥ 90.0%, ≤ 4.0%, and ≤ 10.0%, respectively), and Fc function and antibody activities were maintained. In rats, intravenous injection of IgPro20 produced mild and transient hypotension comparable to that seen with intravenous IgG products. Local tolerance of IgPro20 in rabbits was comparable to that of a marketed subcutaneous IgG, Beriglobin P. Functionality and quality of IgPro20 are maintained during storage at 25 °C for at least 24 months. The product is well tolerated as assessed in animal models. Copyright © 2010 The International Association for Biologicals. Published by Elsevier Ltd. All rights reserved.

An Obstacle-Tolerant Path Planning Algorithm for Mobile-Anchor-Node-Assisted Localization

PubMed Central

Tsai, Rong-Guei

2018-01-01

The location information obtained using a sensor is a critical requirement in wireless sensor networks. Numerous localization schemes have been proposed, among which mobile-anchor-node-assisted localization (MANAL) can reduce costs and overcome environmental constraints. A mobile anchor node (MAN) provides its own location information to assist the localization of sensor nodes. Numerous path planning schemes have been proposed for MANAL, but most scenarios assume the absence of obstacles in the environment. However, in a realistic environment, sensor nodes cannot be located because the obstacles block the path traversed by the MAN, thereby rendering the sensor incapable of receiving sufficient three location information from the MAN. This study proposes the obstacle-tolerant path planning (OTPP) approach to solve the sensor location problem owing to obstacle blockage. OTPP can approximate the optimum beacon point number and path planning, thereby ensuring that all the unknown nodes can receive the three location information from the MAN and reduce the number of MAN broadcast packet times. Experimental results demonstrate that OTPP performs better than Z-curves because it reduces the total number of beacon points utilized and is thus more suitable in an obstacle-present environment. Compared to the Z-curve, OTPP can reduce localization error and improve localization coverage. PMID:29547582

Safety and tolerability of BufferGel, a novel vaginal microbicide, in women in the United States.

PubMed

Mayer, K H; Peipert, J; Fleming, T; Fullem, A; Moench, T; Cu-Uvin, S; Bentley, M; Chesney, M; Rosenberg, Z

2001-02-01

BufferGel (ReProtect, LLC) is a vaginal gel with an acidic buffering action that was designed to prevent vaginal neutralization by semen. The purpose of this study was to evaluate the safety and tolerability of BufferGel (ReProtect, Limited Liability Company) applied vaginally either once or twice daily by 27 women who were at low risk for acquisition of human immunodeficiency virus (HIV). Participants initially used the product once daily for 14 days and then twice daily for 14 days; they underwent colposcopy before and after product exposure. BufferGel was well tolerated, although two-thirds of the participants reported at least 1 mild or moderate adverse experience. The most common adverse events were irritative genitourinary symptoms. Product use was discontinued after 3 adverse events. BufferGel was well tolerated in women at low risk for acquisition of HIV; toxicity was limited and occurred at frequencies similar to those in women who did not use any vaginal product and at levels lower than in women who used detergent-based microbicides.

Safety and Tolerability of Hyperbaric Oxygen Therapy in Cats and Dogs.

PubMed

Birnie, Gemma L; Fry, Darren R; Best, Matthew P

2018-05-14

This prospective clinical trial was designed to evaluate the safety of hyperbaric oxygen therapy (HBOT) in a population of cats and dogs with a variety of naturally occurring diseases. Seventy-eight dogs and twelve cats with various naturally occurring disease conditions, who had the potential to benefit from HBOT, were enrolled in the study. These patients were treated with HBOT in a monoplace hyperbaric oxygen chamber at 2 air pressure absolute for a treatment length of either 45 min or 60 min. There were 230 hyperbaric oxygen treatments performed during the study period. No major adverse effects were observed. There were 76 minor adverse effects recorded, which were not considered to be of clinical significance. Hyperbaric oxygen therapy was well tolerated and there were no major adverse effects recorded during treatment.

Safety and tolerability of ibrutinib monotherapy in Japanese patients with relapsed/refractory B cell malignancies.

PubMed

Tobinai, Kensei; Ogura, Michinori; Ishizawa, Kenichi; Suzuki, Tatsuya; Munakata, Wataru; Uchida, Toshiki; Aoki, Tomohiro; Morishita, Takanobu; Ushijima, Yoko; Takahara, Satoko

2016-01-01

In this phase I dose-escalation study we evaluated the safety, tolerability, pharmacokinetics, and antitumor activity of ibrutinib, an oral covalent inhibitor of Bruton's tyrosine kinase (BTK, in Japanese patients with relapsed/refractory B cell malignancies (RRBCM). Fifteen patients aged 42-78 years were enrolled to one of three cohorts. Cohort 1 (n = 3) consisted of two phases, a single-dose (140 and 280 mg) phase and a multiple-dose (420 mg) phase of ibrutinib; cohort 2 (n = 6) included multiple doses of ibrutinib 560 mg; and cohort 3 (n = 6) included only patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) dosed at ibrutinib 420 mg. One patient (CLL/SLL cohort) experienced grade 3 pneumonia and sepsis, which were considered dose-limiting toxicities. No deaths were reported. The most common (≥ 20% patients) adverse events were neutropenia, anemia, nasopharyngitis, increased bilirubin, and rash. Dose-dependent increase in maximum plasma concentration and area under the concentration from 0 to the last quantifiable time was observed, while time to reach maximum plasma concentration and elimination half-life was similar between doses. The overall response rate was 73.3% (11/15) for all cohorts combined. Overall, ibrutinib (420 and 560 mg) was tolerable with acceptable safety profiles and effective for Japanese patients with RRBCM including CLL/SLL. NCT01704963.

Ganciclovir ophthalmic gel 0.15% for the treatment of acute herpetic keratitis: background, effectiveness, tolerability, safety, and future applications

PubMed Central

Chou, Timothy Y; Hong, Bennett Y

2014-01-01

Eye disease due to herpes simplex virus (HSV) is a leading cause of ocular morbidity and the number one infectious cause of unilateral corneal blindness in the developed parts of the globe. Recurrent keratitis can result in progressive corneal scarring, thinning, and vascularization. Antiviral agents employed against HSV have primarily been nucleoside analogs. Early generation drugs included idoxuridine, iododesoxycytidine, vidarabine, and trifluridine. While effective, they tended to have low bioavailability and measurable local cellular toxicity due to their nonselective mode of action. Acyclovir 0.3% ointment is a more selective agent, and had become a first-line topical drug for acute HSV keratitis in Europe and other places outside of the US. Ganciclovir 0.15% gel is the most recently approved topical treatment for herpes keratitis. Compared to acyclovir 0.3% ointment, ganciclovir 0.15% gel has been shown to be better tolerated and no less effective in several Phase II and III trials. Additionally, topical ganciclovir does not cause adverse systemic side effects and is therapeutic at lower concentrations. Based on safety, efficacy, and tolerability, ganciclovir 0.15% gel should now be considered a front-line topical drug in the treatment of dendritic herpes simplex epithelial keratitis. Topics of future investigation regarding other potential uses for ganciclovir gel may include the prophylaxis of recurrent HSV epithelial keratitis, treatment of other forms of ocular disease caused by herpesviruses and adenovirus, and ganciclovir gel as an adjunct to antitumor therapy. PMID:25187721

Tolerability and safety of Souvenaid in patients with mild Alzheimer's disease: results of multi-center, 24-week, open-label extension study.

PubMed

Olde Rikkert, Marcel G M; Verhey, Frans R; Blesa, Rafael; von Arnim, Christine A F; Bongers, Anke; Harrison, John; Sijben, John; Scarpini, Elio; Vandewoude, Maurits F J; Vellas, Bruno; Witkamp, Renger; Kamphuis, Patrick J G H; Scheltens, Philip

2015-01-01

The medical food Souvenaid, containing the specific nutrient combination Fortasyn Connect, is designed to improve synapse formation and function in patients with Alzheimer's disease (AD). Two double-blind randomized controlled trials (RCT) with Souvenaid of 12 and 24 week duration (Souvenir I and Souvenir II) showed that memory performance was improved in drug-naïve mild AD patients, whereas no effects on cognition were observed in a 24-week RCT (S-Connect) in mild to moderate AD patients using AD medication. Souvenaid was well-tolerated in all RCTs. In this 24-week open-label extension (OLE) study to the 24-week Souvenir II RCT, long-term safety and intake adherence of the medical food Souvenaid was evaluated. Patients with mild AD (n = 201) received Souvenaid once-daily during the OLE. Main outcome parameters were safety and product intake adherence. The memory domain z-score from a revised neuropsychological test battery was continued as exploratory parameter. Compared to the RCT, a similar (low) incidence and type of adverse events was observed, being mainly (68.3%) of mild intensity. Pooled data (RCT and OLE) showed that 48-week use of Souvenaid was well tolerated with high intake adherence (96.1%). Furthermore, a significant increase in the exploratory memory outcome was observed in both the active-active and control-active groups during Souvenaid intervention. Souvenaid use for up to 48-weeks was well tolerated with a favorable safety profile and high intake adherence. The findings in this OLE study warrant further investigation toward the long-term safety and efficacy of Souvenaid in a well-controlled, double-blind RCT.

Pharmacokinetics, Safety, and Tolerability of Lamotrigine Chewable/Dispersible Tablet Following Repeat-Dose Administration in Healthy Chinese Volunteers.

PubMed

Li, Yan; Zhang, Fan; Xu, Yanmei; Hu, Joice; Li, Huafang

2018-03-26

In this open-label, single-center study, the pharmacokinetics, safety, and tolerability of lamotrigine chewable/dispersible tablets were assessed in healthy Chinese volunteers. Each volunteer (N = 16) received repeat doses of oral lamotrigine titrated from 25 mg to 50 mg to 100 mg over 42 days and was followed up for 10-17 days. Safety and tolerability were assessed throughout the study. Lamotrigine pharmacokinetic parameters were estimated using noncompartmental analysis. Overall, 15 (94%) volunteers completed the study. Lamotrigine serum concentrations peaked 2.5 hours postdose, with a mean terminal half-life of 36.8 hours. The apparent lamotrigine oral clearance was 1577.88 mL/h. The accumulation ratios (day 14 vs day 1) were 2.53 and 2.58 for area under the curve and peak concentration, respectively. Lamotrigine 25 to 100 mg once daily exhibited dose-proportional pharmacokinetics (based on area under the curve and peak concentration), following repeat dosing. Nine volunteers reported adverse events, 2 experienced oropharyngeal pain, each receiving 25 mg and 50 mg. One volunteer withdrew due to an increase in liver enzymes. No deaths, serious adverse effects, or skin rashes were reported during the study. No new safety concerns were observed. Overall, the pharmacokinetic profiles after repeat doses of lamotrigine chewable/dispersible tablets once daily in a Chinese population were similar to those observed in Western populations. © 2018, The American College of Clinical Pharmacology.

Local Road Safety Peer Exchange - Regions 3 & 5 : An RSPCB Peer Exchange

DOT National Transportation Integrated Search

2013-06-01

This report provides a summary of the proceedings of the Local Road Safety Peer Exchange held in Columbus, Ohio on June 12 and 13, 2013. The Federal Highway Administration (FHWA) sponsored the Peer Exchange in coordination with the Region 3 & 5 Local...

Local Road Safety Peer Exchange – Region 4 : An RSPCB Peer Exchange

DOT National Transportation Integrated Search

2013-03-01

This report provides a summary of the proceedings of the Local Road Safety Peer Exchange held in Atlanta, Georgia on March 6th and 7th, 2013. The Federal Highway Administration (FHWA) sponsored the Peer Exchange in coordination with Region 4 Local Te...

Local Road Safety Peer Exchange – Region 7 : An RSPCB Peer Exchange

DOT National Transportation Integrated Search

2012-05-01

This report provides a summary of the proceedings of the Local Road Safety Peer Exchange held in Denver, Colorado from May 31 to June 1, 2012. The Federal Highway Administration (FHWA) sponsored the Peer Exchange in coordination with Region 7 Local a...

Safety and tolerability of adjunctive lacosamide intravenous loading dose in lacosamide-naive patients with partial-onset seizures.

PubMed

Fountain, Nathan B; Krauss, Gregory; Isojarvi, Jouko; Dilley, Deanne; Doty, Pamela; Rudd, G David

2013-01-01

To examine the safety and tolerability of rapidly initiating adjunctive lacosamide via a single intravenous loading dose followed by twice-daily oral lacosamide in lacosamide-naive adults with partial-onset seizures. This open-label, multicenter trial, enrolled patients with epilepsy who were taking 1-2 antiepileptic drugs (AEDs) in one of four sequential cohorts containing 25 subjects each. An intravenous lacosamide loading dose (200, 300, or 400 mg) was administered over 15 min followed 12 h later by initiation of oral dosing consisting of one-half of the loading dose administered twice daily for 6.5 days. The first cohort was administered lacosamide 200 mg/day, followed by a cohort at 300 mg/day, and then a cohort at 400 mg/day. The results from each cohort were evaluated before enrolling the next highest dose level. The fourth cohort enrolled patients at the highest dose with clinically acceptable safety and tolerability results. Safety evaluations included treatment-emergent adverse events (TEAEs), patient withdrawals due to TEAEs, and changes in vital signs, 12-lead electrocardiography (ECG) studies, laboratory parameters, and clinical examinations. Postinfusion lacosamide plasma concentrations were also evaluated. A total of 100 patients were enrolled, 25 in each cohort. The loading dose for the repeat cohort was 300 mg; therefore, 25 patients were enrolled at 200 mg/day, 50 at 300 mg/day, and 25 at 400 mg/day. Most TEAEs occurred within the first 4 h following infusion; dose-related TEAEs (incidence ≥10%) during this timeframe included dizziness, somnolence, and nausea. Seven patients withdrew, all due to TEAEs: three (6%) from the combined 300 mg group and four (16%) from the 400 mg group; four of these patients discontinued within 4 h following infusion. The most common TEAEs leading to discontinuation (overall incidence >1%) were dizziness (6%), nausea (5%), and vomiting (3%). No clinically relevant pattern of changes from baseline ECG, clinical

Feasibility, tolerability and safety of pediatric hyperpolarized 129Xe magnetic resonance imaging in healthy volunteers and children with cystic fibrosis.

PubMed

Walkup, Laura L; Thomen, Robert P; Akinyi, Teckla G; Watters, Erin; Ruppert, Kai; Clancy, John P; Woods, Jason C; Cleveland, Zackary I

2016-11-01

Hyperpolarized 129 Xe is a promising contrast agent for MRI of pediatric lung function, but its safety and tolerability in children have not been rigorously assessed. To assess the feasibility, safety and tolerability of hyperpolarized 129 Xe gas as an inhaled contrast agent for pediatric pulmonary MRI in healthy control subjects and in children with cystic fibrosis. Seventeen healthy control subjects (ages 6-15 years, 11 boys) and 11 children with cystic fibrosis (ages 8-16 years, 4 boys) underwent 129 Xe MRI, receiving up to three doses of 129 Xe gas prepared by either a commercially available or a homebuilt 129 Xe polarizer. Subject heart rate and SpO 2 were monitored for 2 min post inhalation and compared to resting baseline values. Adverse events were reported via follow-up phone call at days 1 and 30 (range ±7 days) post-MRI. All children tolerated multiple doses of 129 Xe, and no children withdrew from the study. Relative to baseline, most children who received a full dose of gas for imaging (10 of 12 controls and 8 of 11 children with cystic fibrosis) experienced a nadir in SpO 2 (mean -6.0 ± standard deviation 7.2%, P≤0.001); however within 2 min post inhalation SpO 2 values showed no significant difference from baseline (P=0.11). There was a slight elevation in heart rate (mean +6.6 ± 13.9 beats per minute [bpm], P=0.021), which returned from baseline within 2 min post inhalation (P=0.35). Brief side effects related to the anesthetic properties of xenon were mild and quickly resolved without intervention. No serious or severe adverse events were observed; in total, four minor adverse events (14.3%) were reported following 129 Xe MRI, but all were deemed unrelated to the study. The feasibility, safety and tolerability of 129 Xe MRI has been assessed in a small group of children as young as 6 years. SpO 2 changes were consistent with the expected physiological effects of a short anoxic breath-hold, and other mild side effects were

Safety and pharmacokinetics of ramucirumab in combination with docetaxel in Japanese patients with locally advanced or metastatic breast cancer: a Phase Ib study.

PubMed

Masuda, Norikazu; Iwata, Hiroji; Aogi, Kenjiro; Xu, Yihuan; Ibrahim, Ayman; Gao, Ling; Dalal, Rita; Yoshikawa, Reigetsu; Sasaki, Yasutsuna

2016-12-01

The primary objective of this study was to investigate the safety and tolerability and to confirm the recommended dose of the anti-vascular endothelial growth factor receptor 2 monoclonal antibody ramucirumab in combination with docetaxel in Japanese patients with metastatic/locally advanced breast cancer. In this multicenter, single-arm, Phase Ib trial, eligibility criteria included: 20 years or older, Eastern Cooperative Oncology Group performance status of 0/1 and confirmed diagnosis of human epidermal growth factor receptor 2-negative metastatic/locally recurrent inoperable breast adenocarcinoma. Patients received docetaxel (75 mg/m 2 ) followed by ramucirumab (10 mg/kg) on Day 1 of 21-day cycles. Recommended dose was defined as <33% dose-limiting toxicities in dose-limiting toxicity-evaluable patients in Cycle 1. The safety, pharmacokinetics, immunogenicity and antitumor activity were examined. Seven patients were treated. Most adverse events were mild to moderate. Two patients during Cycle 1 experienced a dose-limiting toxicity; one patient each experienced Grade 3 febrile neutropenia and Grade 3 gingivitis. Both dose-limiting toxicities subsequently resolved. No patients discontinued study therapies during Cycle 1. Four serious adverse events were possibly related to ramucirumab in combination with docetaxel. Anti-ramucirumab antibodies were not detected. Pharmacokinetic analysis revealed low total body clearance and long apparent terminal elimination half-life (~7-12 days). Partial response was reported in four patients. The combination of ramucirumab and docetaxel was tolerable in female Japanese patients with breast cancer. Ramucirumab 10 mg/kg in combination with docetaxel (75 mg/m 2 ) was confirmed as the recommended dose among Japanese patients, supporting its use in future studies. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Delivery of a national home safety equipment scheme in England: a survey of local scheme leaders.

PubMed

Mulvaney, C A; Watson, M C; Hamilton, T; Errington, G

2013-11-01

Unintentional home injuries sustained by preschool children are a major cause of morbidity in the UK. Home safety equipment schemes may reduce home injury rates. In 2009, the Royal Society for the Prevention of Accidents was appointed as central coordinator of a two-year, £18m national home safety equipment scheme in England. This paper reports the findings from a national survey of all scheme leaders responsible for local scheme delivery. A questionnaire mailed to all local scheme leaders sought details of how the schemes were operated locally; barriers and facilitators to scheme implementation; evaluation of the local scheme and its sustainability. A response rate of 73% was achieved. Health visitors and family support workers played a key role in both the identification of eligible families and performing home safety checks. The majority of local scheme leaders (94.6%) reported that they thought their local scheme had been successful in including those families considered 'harder to engage'. Many scheme leaders (72.4%) reported that they had evaluated the provision of safety equipment in their scheme and over half (56.6%) stated that they would not be able to continue the scheme once funding ceased. Local schemes need support to effectively evaluate their scheme and to seek sustainability funding to ensure the future of the scheme. There remains a lack of evidence of whether the provision of home safety equipment reduces injuries in preschool children.

Safety, tolerability, and immunogenicity of zoster vaccine in subjects on chronic/maintenance corticosteroids.

PubMed

Russell, Amy F; Parrino, Janie; Fisher, Chester L; Spieler, Wolfgang; Stek, Jon E; Coll, Kathleen E; Su, Shu-Chih; Xu, Jin; Li, Xiaoming; Schlienger, Katia; Silber, Jeffrey L

2015-06-17

This randomized, placebo-controlled study assessed the safety, tolerability, and immunogenicity of live virus zoster vaccine (ZV) in individuals receiving chronic/maintenance systemic corticosteroid therapy (daily dose equivalent of 5-20mg prednisone) for ≥2 weeks prior to vaccination and ≥6 weeks postvaccination. Subjects were followed for adverse experiences (AEs), exposure to varicella or herpes zoster (HZ), or development of varicella/varicella-like or HZ/HZ-like rashes for 42 days postvaccination (primary safety follow-up period) and for serious AEs (SAEs) through Day 182 postvaccination (secondary follow-up period). Varicella-zoster virus (VZV) antibody titers by glycoprotein enzyme-linked immunosorbent assay (gpELISA) were measured at baseline and at Week 6 postvaccination. The proportions of subjects reporting systemic AEs and SAEs were similar in both groups. A higher percentage of subjects reported injection-site AEs in the ZV group (21.5%) than in the placebo group (12.1%). One SAE of ophthalmic HZ (onset Day 16 postvaccination) was reported in the ZV group and deemed vaccine-related by the study investigator; however, PCR testing confirmed the presence of wild-type (not vaccine strain) VZV. Geometric mean titer (GMT) at 6 weeks postvaccination was higher for ZV recipients than placebo recipients, with estimated geometric mean fold rises (GMFR) of 2.3 (CI: 2.0, 2.7) and 1.1 (CI: 1.0, 1.2) respectfully. In adults ≥60 years old on chronic/maintenance corticosteroids, ZV was generally well tolerated and immunogenic. The VZV-specific gpELISA antibody GMT at 6 weeks postvaccination and the GMFR from baseline to 6 weeks postvaccination were higher in the ZV group than in the placebo group. Copyright © 2015 Elsevier Ltd. All rights reserved.

Influence of domperidone on pharmacokinetics, safety and tolerability of the dopamine agonist rotigotine

PubMed Central

Braun, Marina; Cawello, Willi; Boekens, Hilmar; Horstmann, Rolf

2009-01-01

AIMS To evaluate the influence of the antiemetic agent domperidone on steady-state pharmacokinetics, safety and tolerability of multiple-dose treatment of the transdermally applied non-ergolinic dopamine agonist rotigotine. METHODS Sixteen healthy male subjects (mean age 30.3 years) participated in a randomized, two-way crossover clinical trial. Treatment A consisted of transdermal rotigotine patch (2 mg (24 h)−1, 10 cm2, total drug content 4.5 mg) applied daily for 4 days, and concomitant oral domperidone (10 mg t.i.d.) for 5 days. For treatment B, subjects received only transdermal rotigotine treatment (daily for 4 days). Pharmacokinetic variables describing systemic exposure and renal elimination of rotigotine and metabolites, and safety and tolerability of the treatment were assessed. RESULTS The primary steady-state pharmacokinetic parameters (Cmax,ss and AUC(0–24),ss) were similar with or without co-administration of domperidone. Geometric mean ratios were close to 1 and respective 90% confidence intervals were within the acceptance range of bioequivalence (0.8, 1.25): Cmax,ss 0.96 (0.86, 1.08) and AUC(0–24),ss 0.97 (0.87, 1.08). tmax,ss, t1/2, secondary parameters calculated on days 4/5 after repeated patch application (Cmin,ss, Cave,ss, AUC(0–tz)) and renal elimination for unconjugated rotigotine and its metabolites were also similar with and without comedication of domperidone. A reduction in the dopaminergic side-effect nausea was seen with domperidone comedication. CONCLUSIONS No changes of pharmacokinetic parameters describing systemic exposure and renal elimination of rotigotine were observed when domperidone was administered concomitantly with rotigotine. The lack of pharmacokinetic interactions indicates that a dose adjustment of rotigotine transdermal patch is not necessary with concomitant use of domperidone. PMID:19094160

Evaluation of the Safety, Tolerability, and Pharmacokinetics of Gammaplex® 10% Versus Gammaplex® 5% in Subjects with Primary Immunodeficiency.

PubMed

Wasserman, Richard L; Melamed, Isaac R; Stein, Mark R; Jolles, Stephen; Norton, Miranda; Moy, James N

2017-04-01

This phase 3, multicenter, open-label, randomized, two-period, crossover bioequivalence trial evaluated the safety, tolerability, and pharmacokinetics of intravenous immunoglobulins (IVIGs) Gammaplex 5% and Gammaplex 10% in 33 adults and 15 children with primary immunodeficiency diseases (PIDs). Eligible adults received five Gammaplex 5% infusions followed by five Gammaplex 10% infusions, or vice versa, stratified by a 21- or 28-day dosing regimen. Pediatric subjects received five Gammaplex 10% infusions only. The primary objective, to demonstrate the bioequivalence of Gammaplex 10% and Gammaplex 5% at the 28-day dosing interval, was met based on the Gammaplex 10%/Gammaplex 5% ratio of area under the concentration versus time curve (AUC 0-28 ) values. Throughout the study, total immunoglobulin G trough levels were well maintained, with total values generally ≥600 mg/dL (minimum level for study inclusion). At the dosing schedules and infusion rates used in this study, safety and tolerability were comparable and acceptable in adult and pediatric PID subjects treated with Gammaplex 10% and 5%. In this study, the first direct comparison of 5% IVIG and 10% IVIG products in PID subjects, the pharmacokinetic analysis demonstrated bioequivalence of Gammaplex 10% and Gammaplex 5% at the 28-day dosing interval. The Gammaplex 10% formulation was safe and well tolerated in pediatric and adult PID subjects. Based on the results from this bridging study in PID subjects, Gammaplex 10% could be expected to have a therapeutic effect similar to the licensed Gammaplex 5%, which has demonstrated efficacy and tolerability in patients with PID and idiopathic thrombocytopenic purpura.

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

PubMed

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

2011-04-01

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

Nuclear-localized AtHSPR links abscisic acid-dependent salt tolerance and antioxidant defense in Arabidopsis.

PubMed

Yang, Tao; Zhang, Liang; Hao, Hongyan; Zhang, Peng; Zhu, Haowei; Cheng, Wei; Wang, Yongli; Wang, Xinyu; Wang, Chongying

2015-12-01

Salt stress from soil or irrigation water limits plant growth. A T-DNA insertion mutant in C24, named athspr (Arabidopsis thaliana heat shock protein-related), showed several phenotypes, including reduced organ size and enhanced sensitivity to environmental cues. The athspr mutant is severely impaired under salinity levels at which wild-type (WT) plants grow normally. AtHSPR encodes a nuclear-localized protein with ATPase activity, and its expression was enhanced by high salinity and abscisic acid (ABA). Overexpression (OE) of AtHSPR significantly enhanced tolerance to salt stress by increasing the activities of the antioxidant system and by maintaining K(+) /Na(+) homeostasis. Quantitative RT-PCR analyses showed that OE of AtHSPR increased the expression of ABA/stress-responsive, salt overly sensitive (SOS)-related and antioxidant-related genes. In addition, ABA content was reduced in athspr plants with or without salt stress, and exogenous ABA restored WT-like salt tolerance to athspr plants. athspr exhibited increased leaf stomatal density and stomatal index, slower ABA-induced stomatal closure and reduced drought tolerance relative to the WT. AtHSPR OE enhanced drought tolerance by reducing leaf water loss and stomatal aperture. Transcript profiling in athspr showed a differential salt-stress response for genes involved in accumulation of reactive oxygen species (ROS), ABA signaling, cell death, stress response and photosynthesis. Taken together, our results suggested that AtHSPR is involved in salt tolerance in Arabidopsis through modulation of ROS levels, ABA-dependent stomatal closure, photosynthesis and K(+) /Na(+) homeostasis. © 2015 The Authors The Plant Journal © 2015 John Wiley & Sons Ltd.

Efficacy and safety of a new topical keratolytic treatment for localized hyperkeratosis in adults.

PubMed

Sadick, Neil S; Coutanceau, Christine; Sibaud, Vincent; Merial-Kieny, Christelle

2010-12-01

Palmoplantar keratoderma (PPK) is a heterogeneous group of skin disorders characterized by symmetrical diffuse or patchy areas of hyperkeratosis on the palms and soles. This study aimed to evaluate the efficacy and safety of a topical keratolytic treatment for localized hyperkeratosis. International, randomized, vehicle-controlled, double-blind, intra-individual comparative study. Clinical signs assessed by the investigator significantly improved in both group from baseline to day 10 and day 21 (P<0.001). Mean improvement was significantly more marked on the treated side than the control side (except pruritus) at day 10 for hyperkeratosis (-0.58 ± 0.59 versus -0.41 ± 0.51, P=0.009), desquamation (-0.62 ± 0.69 versus -0.47 ± 0.67, P=0.042) and dryness (-0.75 ± 0.67 versus -0.57 ± 0.67, P=0.014). At day 21, dryness (-1.16 ± 0.80 versus -1.00 ± 0.79, P=0.036) was significantly improved but only a trend for hyperkeratosis (-0.86 ± 0.76 versus -0.72 ± 0.72, P=0.158) and desquamation (-0.83 ± 0.85 versus -0.65 ± 0.85, P=0.057) was observed. Tolerance was considered to be good or very good in more than 92 percent patients. Both patients and investigators were satisfied in more than 84 percent of cases with the topical keratolytic treatment efficacy. Safety profile was highly satisfactory. This topical keratolytic treatment represents a valuable first-line option for mild to moderate hyperkeratosis.

Road safety perspectives among employees of a multinational corporation in urban India: local context for global injury prevention.

PubMed

Jacoby, Sara F; Winston, Flaura K; Richmond, Therese S

2017-12-01

In rapidly developing economies, like urban India, where road traffic injury rates are among the world's highest, the corporate workplace offers a non-traditional venue for road safety interventions. In partnership with a major multinational corporation (MNC) with a large Indian workforce, this study aimed to elicit local employee perspectives on road safety to inform a global corporate health platform. The safety attitudes and behaviours of 75 employees were collected through self-report survey and focus groups in the MNC offices in Bangalore and Pune. Analysis of these data uncovered incongruity between employee knowledge of safety strategies and their enacted safety behaviours and identified local preference for interventions and policy-level actions. The methods modelled by this study offer a straightforward approach for eliciting employee perspective for local road safety interventions that fit within a global strategy to improve employee health. Study findings suggest that MNCs can employ a range of strategies to improve the road traffic safety of their employees in settings like urban India including: implementing corporate traffic safety policy, making local infrastructure changes to improve road and traffic conditions, advocating for road safety with government partners and providing employees with education and access to safety equipment and safe transportation options.

Clinical Safety and Tolerability of Vildagliptin - Insights from Randomised Trials, Observational Studies and Post-marketing Surveillance.

PubMed

Mathieu, Chantal; Kozlovski, Plamen; Paldánius, Päivi M; Foley, James E; Modgill, Vikas; Evans, Marc; Serban, Carmen

2017-08-01

Vildagliptin is one of the most extensively studied dipeptidyl peptidase-4 (DPP-4) inhibitors in terms of its clinical utility. Over the last decade, a vast panorama of evidence on the benefit-risk profile of vildagliptin has been generated in patients with type 2 diabetes mellitus (T2DM). In this article, we review the cumulative evidence on the safety of vildagliptin from the clinical development programme, as well as reports of rare adverse drug reactions detected during the post-marketing surveillance of the drug. Across clinical studies, the overall safety and tolerability profile of vildagliptin was similar to placebo, and it was supported by real-world data in a broad population of patients with T2DM, making DPP-4 inhibitors, like vildagliptin, a safe option for managing patients with T2DM.

[Tolerance, safety and efficacy of the one-day preparation of PEG3350 + bisacodyl compared to 2 days of PEG3350 + bisacodyl in pediatric patients].

PubMed

Portillo Canizalez, Ligia Marcela; Blanco Rodriguez, Gerardo; Teyssier Morales, Gustavo; Penchyna Grub, Jaime; Trauernicht Mendieta, Sean; Zurita-Cruz, Jessie Nallely

Multiple intestinal preparations have been used in children undergoing colonoscopy, with variable limitation due to acceptance, tolerance, and proper cleaning. The objective of this study was to compare the tolerability, safety and efficacy of the colonoscopy preparation with 1 day with PEG 3350 (poliethylenglycol) (4g/kg/day) + bisacodyl compared to 2 days of preparation with PEG 3350 (2g/kg/day) + bisacodyl in pediatric patients. A clinical, randomized, and blind trial was performed. Patients aged 2 to 18 years scheduled for colonoscopy were included. Patients were randomized into two groups: 1 day of preparation with PEG 3350 4g/kg/day + bisacodyl and 2 days of preparation with PEG 3350 2g/kg/day + bisacodyl. Through a questionnaire, physical examination and endoscopic evaluation (Boston scale), the tolerance, safety and efficacy of the 2 preparations to be evaluated were determined. Student's t test was performed for quantitative variables and χ 2 for qualitative variables. There were no significant differences in compliance rates, adverse effects, and extent of colonoscopic evaluation. Tolerance and safety between the intestinal preparation for 1-day colonoscopy with PEG 3350 (4g/kg/day) + bisacodyl and the 2-day preparation with PEG 3350 (2g/kg/day) + bisacodyl were similar. The quality of cleanliness was good in both groups, being partially more effective in the 1-day group with PEG 3350 (4g/kg/day). Copyright © 2017 Hospital Infantil de México Federico Gómez. Publicado por Masson Doyma México S.A. All rights reserved.

Strengthening patient safety in transitions of care: an emerging role for local medical centres in Norway.

PubMed

Kongsvik, Trond; Halvorsen, Kristin; Osmundsen, Tonje; Gjøsund, Gudveig

2016-08-30

Patient safety has gained less attention in primary care in comparison to specialised care. We explore how local medical centres (LMCs) can play a role in strengthening patient safety, both locally and in transitions between care levels. LMCs represent a form of intermediate care organisation in Norway that is increasingly used as a strategy for integrated care policies. The analysis is based on institutional theory and general safety theories. A qualitative design was applied, involving 20 interviews of nursing home managers, managers at local medical centres and administrative personnel. The LMCs mediate important information between care levels, partly by means of workarounds, but also as a result of having access to the different information and communications technology (ICT) systems in use. Their knowledge of local conditions is found to be a key asset. LMCs are providers of competence and training for the local level, as well as serving as quality assurers. As a growing organisational form in Norway, LMCs have to legitimise their role in the health care system. They represent an asset to the local level in terms of information, competence and quality assurance. As they have overlapping competencies, tasks and responsibilities with other parts of the health care system, they add to organisational redundancy and strengthen patient safety.

Evaluation of the safety and tolerability profile of Sativex: is it reassuring enough?

PubMed

Wade, Derick

2012-04-01

The adoption of new drug therapies involves an assessment of risk:benefit based upon the best clinical evidence, including clinical trials but also everyday clinical practice data collection. However, in the case of Sativex, a cannabinoid medicine containing the two main active ingredients of cannabis, δ-9-tetrahydrocannabinol and cannabidiol, the picture is somewhat clouded by preconceived views regarding the world's most widely used illicit drug, herbal cannabis. In this review, I aim to look beyond these preconceptions and evaluate the body of published data concerning this medicine currently approved in different countries for the management of one of the most frequent and disabling symptoms associated with multiple sclerosis, spasticity. In particular, data relevant to areas of concern such as tolerability, safety, psychoactivity, effects on withdrawal (including possible drug tolerance) and finally the potential for abuse/dependence are evaluated. Balancing these risk factors, the main positive clinical data published over the years by the Oxford Centre for Enablement, following on from the first pilot study in 2004, are presented. Based upon our experience, the benefits that are seen initially with Sativex when treating multiple sclerosis spasticity patients are generally maintained during long-term treatment. Furthermore, following withdrawal of Sativex, symptoms often return, but, beyond this, sudden cessation is generally safe with no evidence of physiological or psychological dependence. Dose escalation has not usually been observed in clinical trials or clinical practice after the first titration weeks. Adverse effects occur relatively frequently, but they are usually mild to moderate in intensity and rarely require drug discontinuation. Overall, Sativex appears to be well-tolerated and a useful addition for patients who have failed treatment with traditional antispastic agents.

49 CFR 350.339 - What are tolerance guidelines?

Code of Federal Regulations, 2010 CFR

2010-10-01

... 49 Transportation 5 2010-10-01 2010-10-01 false What are tolerance guidelines? 350.339 Section 350... MOTOR CARRIER SAFETY ASSISTANCE PROGRAM Funding § 350.339 What are tolerance guidelines? Tolerance guidelines set forth the limited deviations from the FMCSRs allowed in your State's laws and regulations...

Recent Updates on the Systemic and Local Safety of Intranasal Steroids.

PubMed

Jang, Tae Young; Kim, Young Hyo

2016-01-01

Allergic rhinitis is a global health problem, and its prevalence rate and socioeconomic burden continue to increase. Intranasal steroid (INS) is the first treatment choice in the majority of patients, because of its ability to effectively control allergic symptoms. However, patients and clinicians are concerned about the potential adverse effects of prolonged INS use. We performed to review for evaluating systemic and local safety of INS use, by searching MEDLINE, EMBASE, and Cochrane Library database for identification of relevant articles. In the present study, the systemic bioavailabilities of several commercially available INSs were researched, and then systemic safeties were reviewed with focus on suppression of the hypothalamus-pituitary-adrenal axis and their effects on pediatric growth. In addition, local adverse effects, such as, epistaxis and nasal septal perforation, were investigated. Finally, the authors proposed some techniques in order to avoid these complications. INSs offer a safe, effective means of treating allergic rhinitis in the short- and long-term with no or minimal adverse systemic and local effects. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Evaluation of the Safety and Tolerability of Conjunctival Ring for Posterior Segment of the Eye.

PubMed

Kinoshita, Satoshi; Ohguchi, Takeshi; Noda, Kousuke; Murata, Miyuki; Yasueda, Shin-Ichi; Obata, Haruka; Matsunaga, Toru; Fukushima, Tsutomu; Kanda, Atsuhiro; Ishida, Susumu

2017-08-01

To evaluate the safety and tolerability of conjunctival rings (CRs), a novel device for drug delivery to the posterior segment of the eye. In animal studies, CRs containing 5% dexamethasone sodium phosphate (DSP) or vehicle solution were placed on the right and left eyes of C57BL/6J mice, respectively. Contact lenses (CLs) containing vehicle solution were used as a control. Twenty-four hours after placement of the CRs, corneal fluorescein staining was graded based on the McDonald-Shadduck scoring system, ranging from 0 to 4. In humans, CRs containing vehicle solution were placed on the right eye of healthy volunteers for 9 hours. The corneal curvature, corneal thickness, intraocular pressure, visual acuity, tear production (Schirmer I test), tear film break-up time and fluorescein staining scores of the cornea (scores ranging from 0 to 3) and conjunctiva (scores ranging from 0 to 6) were assessed before and after wearing the CRs. The release characteristics of DSP from CRs were also evaluated. In animal experiments, corneal fluorescein staining scores were 1 or less in all the groups, and there was no significant difference between the CR group and the CL group. In the preclinical safety evaluation of CR for humans, ophthalmic examination revealed that CR caused no significant changes in all the parameters investigated including corneal curvature (p = 0.77), corneal thickness (p = 0.96), intraocular pressure (p = 0.59), visual acuity (p = 0.14), Schirmer I test results (p = 0.76), tear film break-up time (p = 0.68), corneal fluorescein staining scores (p = 0.64), and conjunctival fluorescein staining scores (p = 0.52). The DSP release from CRs occurs within a few hours, which is similar to the drug-release property of medicated CL, as reported previously. The current data showed the safety and tolerability of CR as a drug delivery device for the treatment of posterior segment diseases.

A qualitative study of Southern U.S. consumers' top of the mind beliefs about the safety of local beef.

PubMed

Telligman, Amy L; Worosz, Michelle R; Bratcher, Christy L

2017-02-01

Following the Reasoned Action Approach, the aim of this study was to explore consumers' top-of-mind food safety beliefs about local beef. Beef consumers recruited from farmers' markets (N = 101) and grocery stores (N = 174) across the state of Alabama participated in face-to-face intercept surveys. The survey included closed- and open-ended questions designed to elicit consumers' food safety beliefs about local beef. Results indicate that beef safety was not a top-of-mind concern for a majority of participants, however of the total number of participants familiar with the term "local beef" (n = 168, 61%), a majority (n = 105, 63%) associated local beef with improved food safety. Content analysis of verbatim text revealed that consumers believed local beef was safer because they possess greater knowledge about the product and less shipping was involved. Respondents also believe that locally processed meat is derived from small-scale operations which provided the assurance that local beef is more likely to meet U.S. regulatory standards and therefore be safer. Consumers believe they have more oversight of local beef due to both their relationships with supply chain actors and proximity which also provided food safety assurances. Copyright © 2016 Elsevier Ltd. All rights reserved.

A 12-Month Open-Label Extension Study of the Safety and Tolerability of Lisdexamfetamine Dimesylate for Major Depressive Disorder in Adults.

PubMed

Richards, Cynthia; Iosifescu, Dan V; Mago, Rajnish; Sarkis, Elias; Geibel, Brooke; Dauphin, Matthew; McIntyre, Roger S; Weisler, Richard; Brawman-Mintzer, Olga; Gu, Joan; Madhoo, Manisha

2018-06-16

Psychostimulant augmentation is considered a potential treatment strategy for individuals with major depressive disorder who do not adequately respond to antidepressant monotherapy. The primary objective of this 12-month open-label extension study was to evaluate the safety and tolerability of lisdexamfetamine dimesylate (LDX) as augmentation therapy to an antidepressant in adults with major depressive disorder. Eligible adults who completed 1 of 3 short-term antecedent LDX augmentation of antidepressant monotherapy studies were treated with dose-optimized LDX (20-70 mg) for up to 52 weeks while continuing on the index antidepressant (escitalopram, sertraline, venlafaxine extended-release, or duloxetine) assigned during the antecedent short-term studies. Safety and tolerability assessments included the occurrence of treatment-emergent adverse events and vital sign changes. All 3 antecedent studies failed to meet the prespecified primary efficacy endpoint, so this open-label study was terminated early. Headache (15.5% [241/1559]), dry mouth (13.6% [212/1559]), insomnia (13.1% [204/1559]), and decreased appetite (12.1% [189/1559]) were the most frequently reported treatment-emergent adverse events. The greatest mean ± SD increases observed for systolic and diastolic blood pressure and for pulse were 2.6 ± 10.85 and 1.7 ± 7.94 mm Hg and 6.9 ± 10.27 bpm, respectively. Monitoring determined that less than 1% of participants experienced potentially clinically important changes in systolic blood pressure (10 [0.6%]), diastolic blood pressure (8 [0.5%]), or pulse (6 [0.4%]). The overall safety and tolerability of long-term LDX augmentation of antidepressant monotherapy was consistent with the profiles of the short-term antecedent studies, with no evidence of new safety signals.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and

Structured versus long-chain triglycerides: a safety, tolerance, and efficacy randomized study in colorectal surgical patients.

PubMed

Bellantone, R; Bossola, M; Carriero, C; Malerba, M; Nucera, P; Ratto, C; Crucitti, P; Pacelli, F; Doglietto, G B; Crucitti, F

1999-01-01

After trauma or surgery, researchers have suggested that medium-chain triglycerides have metabolic advantages, although they are toxic in large doses. To try to reduce this potential toxicity, structured lipids, which provide a higher oxidation rate, faster clearance from blood, improved nitrogen balance, and less accumulation in the reticuloendothelial system, could be used. Therefore, we evaluated, through a blind randomized study, the safety, tolerance, and efficacy of structured triglycerides, compared with long-chain triglycerides (LCT), in patients undergoing colorectal surgery. Nineteen patients were randomized to receive long-chain or structured triglycerides as a lipid source. They received the same amount of calories (27.2/kg/d), glucose (4 g/kg/d), protein (0.2 g/kg/d), and lipids (11.2 kcal/kg/d). Patients were evaluated during and after the treatment for clinical and laboratory variables, daily and cumulative nitrogen balance, urinary excretion of 3-methyl-histidine, and urinary 3-methylhistidine/creatinine ratio. No adverse effect that required the interruption of the treatment was observed. Triglyceride levels and clinical and laboratory variables were similar in the two groups. A predominantly positive nitrogen balance was observed from day 2 until day 5 in the LCT group and from day 1 until day 4 in the structured triglycerides group. The cumulative nitrogen balance (in grams) for days 1 to 3 was 9.7+/-5.2 in the experimental group and 4.4+/-11.8 in the control group (p = .2). For days 1 to 5 it was 10.7+/-10.5 and 6.5+/-17.9 (p = .05), respectively. The excretion of 3-methylhistidine was higher in the control group but decreased in the following days and was similar to the experimental group on day 5. This study represents the first report in which structured triglycerides are administered in postoperative patients to evaluate safety, tolerance, and efficacy. It suggests that Fe73403 is safe, well tolerated, and efficacious in terms of nitrogen

Safety, tolerability, and immunogenicity of two Zika virus DNA vaccine candidates in healthy adults: randomised, open-label, phase 1 clinical trials.

PubMed

Gaudinski, Martin R; Houser, Katherine V; Morabito, Kaitlyn M; Hu, Zonghui; Yamshchikov, Galina; Rothwell, Ro Shauna; Berkowitz, Nina; Mendoza, Floreliz; Saunders, Jamie G; Novik, Laura; Hendel, Cynthia S; Holman, LaSonji A; Gordon, Ingelise J; Cox, Josephine H; Edupuganti, Srilatha; McArthur, Monica A; Rouphael, Nadine G; Lyke, Kirsten E; Cummings, Ginny E; Sitar, Sandra; Bailer, Robert T; Foreman, Bryant M; Burgomaster, Katherine; Pelc, Rebecca S; Gordon, David N; DeMaso, Christina R; Dowd, Kimberly A; Laurencot, Carolyn; Schwartz, Richard M; Mascola, John R; Graham, Barney S; Pierson, Theodore C; Ledgerwood, Julie E; Chen, Grace L

2018-02-10

The Zika virus epidemic and associated congenital infections have prompted rapid vaccine development. We assessed two new DNA vaccines expressing premembrane and envelope Zika virus structural proteins. We did two phase 1, randomised, open-label trials involving healthy adult volunteers. The VRC 319 trial, done in three centres, assessed plasmid VRC5288 (Zika virus and Japanese encephalitis virus chimera), and the VRC 320, done in one centre, assessed plasmid VRC5283 (wild-type Zika virus). Eligible participants were aged 18-35 years in VRC19 and 18-50 years in VRC 320. Participants were randomly assigned 1:1 by a computer-generated randomisation schedule prepared by the study statistician. All participants received intramuscular injection of 4 mg vaccine. In VRC 319 participants were assigned to receive vaccinations via needle and syringe at 0 and 8 weeks, 0 and 12 weeks, 0, 4, and 8 weeks, or 0, 4, and 20 weeks. In VRC 320 participants were assigned to receive vaccinations at 0, 4, and 8 weeks via single-dose needle and syringe injection in one deltoid or split-dose needle and syringe or needle-free injection with the Stratis device (Pharmajet, Golden, CO, USA) in each deltoid. Both trials followed up volunteers for 24 months for the primary endpoint of safety, assessed as local and systemic reactogenicity in the 7 days after each vaccination and all adverse events in the 28 days after each vaccination. The secondary endpoint in both trials was immunogenicity 4 weeks after last vaccination. These trials are registered with ClinicalTrials.gov, numbers NCT02840487 and NCT02996461. VRC 319 enrolled 80 participants (20 in each group), and VRC 320 enrolled 45 participants (15 in each group). One participant in VRC 319 and two in VRC 320 withdrew after one dose of vaccine, but were included in the safety analyses. Both vaccines were safe and well tolerated. All local and systemic symptoms were mild to moderate. In both studies, pain and tenderness at the injection site

Safety profile of levetiracetam.

PubMed

Arroyo, Santiago; Crawford, Pamela

2003-05-01

A good balance between safety and tolerability is necessary for an antiepileptic drug (AED) to be successful in the management of patients with epilepsy. Levetiracetam is one of the new generation of AEDs licensed as an add-on therapy for the treatment of patients with partial-onset seizures. Leveti-racetam's mechanisms of action are not fully understood. Controlled clinical trials, open-label studies, and postmarketing surveillance indicate that leveti-racetam has a favorable safety profile characterized by little effect on vital signs or clinical laboratory values, reported adverse events that are mild to moderate, and no known drug-drug interactions. The tolerability of levetiracetam may extend to both pediatric and elderly patients based on analyses of small numbers of patients. Tolerability is maintained over the long term. Levetirac-etam does not appear to have a different safety profile in learning-disabled patients. Levetiracetam appears to have a good balance between tolerability and efficacy in the treatment of a wide variety of patients with partial epilepsy.

Safety and feasibility of breast lesion localization using magnetic seeds (Magseed): a multi-centre, open-label cohort study.

PubMed

Harvey, James R; Lim, Yit; Murphy, John; Howe, Miles; Morris, Julie; Goyal, Amit; Maxwell, Anthony J

2018-06-01

Wire localization has several disadvantages, notably wire migration and difficulty scheduling the procedure close to surgery. Radioactive seed localization overcomes these disadvantages, but implementation is limited due to radiation safety requirements. Magnetic seeds potentially offer the logistical benefits and transcutaneous detection equivalence of a radioactive seed, with easier implementation. This study was designed to evaluate the feasibility and safety of using magnetic seeds for breast lesion localization. A two-centre open-label cohort study to assess the feasibility and safety of magnetic seed (Magseed) localization of breast lesions. Magseeds were placed under radiological guidance into women having total mastectomy surgery. The primary outcome measure was seed migration distance. Secondary outcome measures included accuracy of placement, ease of transcutaneous detection, seed integrity and safety. Twenty-nine Magseeds were placed into the breasts of 28 patients under ultrasound guidance. There was no migration of the seeds between placement and surgery. Twenty-seven seeds were placed directly in the target lesion with the other seeds being 2 and 3 mm away. All seeds were detectable transcutaneously in all breast sizes and at all depths. There were no complications or safety issues. Magnetic seeds are a feasible and safe method of breast lesion localization. They can be accurately placed, demonstrate no migration in this feasibility study and are detectable in all sizes and depths of breast tissue. Now that safety and feasibility have been demonstrated, further clinical studies are required to evaluate the seed's effectiveness in wide local excision surgery.

Pharmacokinetics, pharmacodynamics, tolerability, and safety of exenatide in Japanese patients with type 2 diabetes mellitus.

PubMed

Kothare, Prajakti A; Linnebjerg, Helle; Isaka, Yoshitaka; Uenaka, Kazunori; Yamamura, Ayuko; Yeo, Kwee Poo; de la Peña, Amparo; Teng, Choo Hua; Mace, Kenneth; Fineman, Mark; Shigeta, Hirofumi; Sakata, Yukikuni; Irie, Shin

2008-12-01

In this single-blind, parallel, placebo-controlled study, the pharmacokinetics, pharmacodynamics, tolerability, and safety of subcutaneous exenatide were evaluated in 40 Japanese patients with type 2 diabetes. Patients were allocated to 4 groups and randomized to receive exenatide (n = 8/group) or placebo (n = 2/group), with all receiving placebo on day 1. On day 2, patients received single-dose exenatide (2.5 microg [group A] or 5 microg [groups B, C, and D]) or placebo and then bid on days 3 to 5. On days 6 to 10, groups A and B continued on 2.5 and 5 microg bid; groups C and D received 10 and 15 microg bid, respectively. The last dose was given on the morning of day 10. All adverse events were mild or moderate in severity. Exenatide was generally well tolerated up to 10 microg. Exenatide was well absorbed with a median t(max) of 1.5 hours and mean t((1/2)) of 1.6 hours; exposure increased with dose. Up to 10 microg, exenatide reduced postprandial glucose concentrations in a dose-dependent fashion compared with placebo; decreases were similar for 10 and 15 microg. An E(max) model demonstrated that doses higher than 2.5 microg were necessary for adequate glycemic response. Based on tolerability and pharmacokinetic/pharmacodynamic relationships, 5 and 10 microg exenatide may be considered for further clinical development in Japanese patients with type 2 diabetes.

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

PubMed

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

2014-04-01

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

[Evidences of safety and tolerability of the zoledronic acid 5 mg yearly in the post-menopausal osteoporosis: the HORIZON project].

PubMed

Dalle Carbonare, L; Bertoldo, F; Lo Cascio, V

2009-01-01

Bisphosphonates are the most commonly prescribed medications for the treatment of osteoporosis. Despite evidence supporting the anti-fracture efficacy of aminobisphosphonates approximately 50% of patients do not follow their prescribed treatment regimen and/or discontinue treatment within the first year. Poor compliance is associated with negative outcomes, including increased fracture risk. Tolerability and safety are among the causes of poor compliance. Intravenous bisphosphonates avoids the gastrointestial intolerance and the complex dosing instruction of the oral route ensuring full compliance which may provide improved efficacy. However, there are some concerns regarding potent intravenous bisphosphonates as zoledronic acid with respect to tolerability, mainly the acute phase response and to safety, mainly a theoretical risk of over suppression of bone turnover, renal toxicity and osteonecrosis of the jaw. In the HORIZON study, 152 patients on active treatment (82) or placebo (70) underwent to a bone biopsy after double tetracycline labeling. Bone biopsies (iliac crest) were obtained at the final visit at month 36, 1 year after the last infusion. The biopsies were analyzed by histomorphometry on bone sections and by micro-CT (microCT) analysis. One hundred forthy-three biopsies (76 zoledronic acid, 67 placebo) had at least one microCT parameter measured and 111 were available for quantitative histomorphometry (59 zoledronic acid, 52 placebo). Micro-CT analysis of bone structure revealed higher trabecular bone volume (BV/TV), decreased trabecular separation (Tb.Sp), and a strong trend towards improvement in connectivity density in biopsies obtained from patients treated with zoledronic acid, indicating preservation of trabecular bone structure with respect to placebo. Histomorphometric analysis obtained from patients treated with zoledronic acid exhibited reduction of bone turnover, as suggested by decreased activation frequency (Ac.F) by 63%, mineralizing

Overexpression of a Plasma Membrane-Localized SbSRP-Like Protein Enhances Salinity and Osmotic Stress Tolerance in Transgenic Tobacco

PubMed Central

Udawat, Pushpika; Jha, Rajesh K.; Mishra, Avinash; Jha, Bhavanath

2017-01-01

An obligate halophyte, Salicornia brachiata grows in salt marshes and is considered to be a potential resource of salt- and drought-responsive genes. It is important to develop an understanding of the mechanisms behind enhanced salt tolerance. To increase this understanding, a novel SbSRP gene was cloned, characterized, over-expressed, and functionally validated in the model plant Nicotiana tabacum. The genome of the halophyte S. brachiata contains two homologs of an intronless SbSRP gene of 1,262 bp in length that encodes for a stress-related protein. An in vivo localization study confirmed that SbSRP is localized on the plasma membrane. Transgenic tobacco plants (T1) that constitutively over-express the SbSRP gene showed improved salinity and osmotic stress tolerance. In comparison to Wild Type (WT) and Vector Control (VC) plants, transgenic lines showed elevated relative water and chlorophyll content, lower malondialdehyde content, lower electrolyte leakage and higher accumulation of proline, free amino acids, sugars, polyphenols, and starch under abiotic stress treatments. Furthermore, a lower build-up of H2O2 content and superoxide-radicals was found in transgenic lines compared to WT and VC plants under stress conditions. Transcript expression of Nt-APX (ascorbate peroxidase), Nt-CAT (catalase), Nt-SOD (superoxide dismutase), Nt-DREB (dehydration responsive element binding factor), and Nt-AP2 (apetala2) genes was higher in transgenic lines under stress compared to WT and VC plants. The results suggested that overexpression of membrane-localized SbSRP mitigates salt and osmotic stress in the transgenic tobacco plant. It was hypothesized that SbSRP can be a transporter protein to transmit the environmental stimuli downward through the plasma membrane. However, a detailed study is required to ascertain its exact role in the abiotic stress tolerance mechanism. Overall, SbSRP is a potential candidate to be used for engineering salt and osmotic tolerance in crops

76 FR 22620 - Triflusulfuron-Methyl; Pesticide Tolerances

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-22

... under the Federal Food, Drug, and Cosmetic Act (FFDCA). DATES: This regulation is effective April 22... Determination of Safety Section 408(b)(2)(A)(i) of FFDCA allows EPA to establish a tolerance (the legal limit... determination on aggregate exposure for triflusulfuron-methyl, including exposure resulting from the tolerances...

Safety of concurrent adjuvant radiotherapy and chemotherapy for locally advanced soft tissue sarcoma.

PubMed

Greto, Daniela; Loi, Mauro; Saieva, Calogero; Muntoni, Cristina; Delli Paoli, Camilla; Becherini, Carlotta; Ciabatti, Cinzia; Perna, Marco; Campanacci, Domenico; Terziani, Francesca; Beltrami, Giovanni; Scoccianti, Guido; Bonomo, Pierluigi; Meattini, Icro; Desideri, Isacco; Simontacchi, Gabriele; Mangoni, Monica; Livi, Lorenzo

2018-04-01

This retrospective study analyzes the safety and feasibility of concurrent chemoradiotherapy (CRT) in adjuvant treatment of soft tissue sarcoma (STS). A total of 158 patients with STS were retrospectively analyzed. Anthracycline-based computed tomography was performed in high-risk patients. Acute radiotherapy toxicity and chemotherapy-related toxicity were assessed according to the Common Terminology Criteria for Adverse Events 4.0; late radiotherapy toxicity was recorded according to Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria. Fifty-four (34.2%) patients received CRT. Mean follow up was 5.4 years (range .2-21.1 years). Local DFS-recurrence-free survival, distant DFS-relapse-free survival, and overall survival were 79.1%, 76.4%, and 64.6%, respectively, at last follow-up. Leukopenia occurred in 11.4% of patients. Skin acute toxicity developed in 60.1% of patients and determined interruption of radiotherapy treatment in 19 (12%) patients. Nineteen patients (12%) experienced moderate fibrosis (grade 2). Mild and moderate joint stiffness was recorded in 16 (10.1%) patients. Size ≥5 cm was the only predictor of local recurrence at multivariate analysis (hazard ratio [HR] 9.65, 95% confidence interval [CI] 1.28-72.83, p = .028). Age and stage resulted as independent distant relapse predictors (HR 4.77, 95% CI 1.81-12.58, p = .002 and HR 4.83, CI 1.41-16.57, p = .012, respectively). At Cox regression univariate analysis, Karnofsky Performance Status, size, and stage were significant survival predictors (HR 2.23, 95% CI 1.02-4.87, p = .045; HR 2.88, 95% CI 1.10-7.52, p = .031; HR 2.59, 95% CI 1.11-6.04, p = .028). Concurrent CRT is a well-tolerated treatment option with no additional toxicity compared to exclusive radiotherapy or sequential CRT.

Accuracy, safety, and tolerability of tissue collection by Cytosponge vs endoscopy for evaluation of eosinophilic esophagitis.

PubMed

Katzka, David A; Geno, Debra M; Ravi, Anupama; Smyrk, Thomas C; Lao-Sirieix, Pierre; Miremadi, Ahmed; Miramedi, Ahmed; Debiram, Irene; O'Donovan, Maria; Kita, Hirohito; Kephart, Gail M; Kryzer, Lori A; Camilleri, Michael; Alexander, Jeffrey A; Fitzgerald, Rebecca C

2015-01-01

Management of eosinophilic esophagitis (EoE) requires repeated endoscopic collection of mucosal samples to assess disease activity and response to therapy. An easier and less expensive means of monitoring of EoE is required. We compared the accuracy, safety, and tolerability of sample collection via Cytosponge (an ingestible gelatin capsule comprising compressed mesh attached to a string) with those of endoscopy for assessment of EoE. Esophageal tissues were collected from 20 patients with EoE (all with dysphagia, 15 with stricture, 13 with active EoE) via Cytosponge and then by endoscopy. Number of eosinophils/high-power field and levels of eosinophil-derived neurotoxin were determined; hematoxylin-eosin staining was performed. We compared the adequacy, diagnostic accuracy, safety, and patient preference for sample collection via Cytosponge vs endoscopy procedures. All 20 samples collected by Cytosponge were adequate for analysis. By using a cutoff value of 15 eosinophils/high power field, analysis of samples collected by Cytosponge identified 11 of the 13 individuals with active EoE (83%); additional features such as abscesses were also identified. Numbers of eosinophils in samples collected by Cytosponge correlated with those in samples collected by endoscopy (r = 0.50, P = .025). Analysis of tissues collected by Cytosponge identified 4 of the 7 patients without active EoE (57% specificity), as well as 3 cases of active EoE not identified by analysis of endoscopy samples. Including information on level of eosinophil-derived neurotoxin did not increase the accuracy of diagnosis. No complications occurred during the Cytosponge procedure, which was preferred by all patients, compared with endoscopy. In a feasibility study, the Cytosponge is a safe and well-tolerated method for collecting near mucosal specimens. Analysis of numbers of eosinophils/high-power field identified patients with active EoE with 83% sensitivity. Larger studies are needed to establish the

Dams and Levees: Safety Risks

NASA Astrophysics Data System (ADS)

Carter, N. T.

2017-12-01

development of state levee safety programs. As of 2017, federal funding for work pursuant to these provisions has been limited. Key policy considerations include (1) whether the status quo regarding investment and responsibilities in dam and levee safety results in a tolerable level of risk nationally and locally, and (2) who bears those risks.

Safety and Tolerance Evaluation of Milk Fat Globule Membrane-Enriched Infant Formulas: A Randomized Controlled Multicenter Non-Inferiority Trial in Healthy Term Infants

PubMed Central

Billeaud, Claude; Puccio, Giuseppe; Saliba, Elie; Guillois, Bernard; Vaysse, Carole; Pecquet, Sophie; Steenhout, Philippe

2014-01-01

OBJECTIVE This multicenter non-inferiority study evaluated the safety of infant formulas enriched with bovine milk fat globule membrane (MFGM) fractions. METHODS Healthy, full-term infants (n = 119) age ≤14 days were randomized to standard infant formula (control), standard formula enriched with a lipid-rich MFGM fraction (MFGM-L), or standard formula enriched with a protein-rich MFGM fraction (MFGM-P). Primary outcome was mean weight gain per day from enrollment to age 4 months (non-inferiority margin: −3.0 g/day). Secondary (length, head circumference, tolerability, morbidity, adverse events) and exploratory (phospholipids, metabolic markers, immune markers) outcomes were also evaluated. RESULTS Weight gain was non-inferior in the MFGM-L and MFGM-P groups compared with the control group. Among secondary and exploratory outcomes, few between-group differences were observed. Formula tolerance rates were high (>94%) in all groups. Adverse event and morbidity rates were similar across groups except for a higher rate of eczema in the MFGM-P group (13.9% vs control [3.5%], MFGM-L [1.4%]). CONCLUSION Both MFGM-enriched formulas met the primary safety endpoint of non-inferiority in weight gain and were generally well tolerated, although a higher rate of eczema was observed in the MFGM-P group. PMID:25452707

Comparison of safety, efficacy and tolerability of dexibuprofen and ibuprofen in the treatment of osteoarthritis of the hip or knee.

PubMed

Zamani, Omid; Böttcher, Elke; Rieger, Jörg D; Mitterhuber, Johann; Hawel, Reinhold; Stallinger, Sylvia; Eller, Norbert

2014-06-01

In this observer-blinded, multicenter, non-inferiority study, 489 patients suffering from painful osteoarthritis of the hip or knee were included to investigate safety and tolerability of Dexibuprofen vs. Ibuprofen powder for oral suspension. Only patients who had everyday joint pain for the past 3 months and "moderate" to "severe" global pain intensity in the involved hip/knee of within the last 48 h were enrolled. The treatment period was up to 14 days with a control visit after 3 days. The test product was Dexibuprofen 400 mg powder for oral suspension (daily dose 800 mg) compared to Ibuprofen 400 mg powder for oral suspension (daily dose 1,600 mg). Gastrointestinal adverse drug reactions were reported in 8 patients (3.3 %) in the Dexibuprofen group and in 19 patients (7.8 %) in the Ibuprofen group. Statistically significant non-inferiority was shown for Dexibuprofen. Comparing both groups by a Chi square test showed a statistical significant lower proportion of related gastrointestinal events in the Dexibuprofen group. All analyses of secondary tolerability parameters showed the same result of a significantly better safety profile in this therapy setting for Dexibuprofen compared to Ibuprofen. The sum of pain intensity, pain relief and global assessments showed no significant difference between treatment groups. In summary, analyses revealed at least non-inferiority in terms of efficacy and a statistically significant better safety profile for the Dexibuprofen treatment.

Safety and tolerability of combination therapy vs. standard treatment alone for patients with previously treated non-small cell lung cancer | Center for Cancer Research

Cancer.gov

Dr. James Gulley is leading a team to test the safety and tolerability of the combination of nivolumab and CV301 to see if it can improve the survival for patientis with metastatic non-small cell lung cancer.  Learn more...

Local food protection and safety infrastructure and capacity: a Maryland case study.

PubMed

Kufel, Joanna Zablotsky; Resnick, Beth A; Fox, Mary; Frattaroli, Shannon; Gielen, Andrea; Burke, Thomas A

2011-01-01

In Maryland, county Food Protection Programs (FPP), housed within Environmental Public Health (EPH) Divisions, maintain responsibility for regular inspection of all food service facilities (FSF). With growing concerns about how our food supply is protected, it is important to determine the state and effectiveness of our food safety systems. This research elucidates the roles, responsibilities, strengths, and weaknesses of Food Safety and Protection Programs in Maryland. A 16-question survey tool, which addressed facets of the local food protection infrastructure, including FSF inspections, staffing, budget, and foodborne illness surveillance, was distributed to all 24 county FPP. The number of FSF in Maryland increased 97% from 2001 to 2006 and counties had an average inspection completion rate of 73%, with a 4% increase over the time period. Statewide, there were 4.1 EPH full-time employees (FTE) per 10 000 population and 1.6 FPP FTE per 10 000 population. EPH Division budgets increased 63% statewide, from $19.5 million in 2000 to $31.9 million in 2007. FPP budgets also increased 59% over the period, from $6.2 million in 2000 to $9.8 million in 2007. This study offers new quantitative measures of the demands, capacities, and performance of Food Protection and Safety Programs in Maryland. This assessment of local EPH and FPP capacity also offers insight into the strengths and weaknesses of the local food protection and safety infrastructure. Importantly, it reveals an infrastructure and dedicated food protection workforce that inspects the food supply and responds to foodborne illness outbreaks. Yet, resources vary substantially from county to county, impacting which services can be provided and how well they can be performed. This can, in turn, impact the potential risk of foodborne illness and the public's overall health.

A phase 2 study of the safety, tolerability, and pharmacodynamics of FBS0701, a novel oral iron chelator, in transfusional iron overload

PubMed Central

Neufeld, Ellis J.; Galanello, Renzo; Viprakasit, Vip; Aydinok, Yesim; Piga, Antonio; Harmatz, Paul; Forni, Gian Luca; Shah, Farrukh T.; Grace, Rachael F.; Porter, John B.; Wood, John C.; Peppe, Jennifer; Jones, Amber

2012-01-01

This was a 24-week, multicenter phase- 2 study designed to assess safety, tolerability, and pharmacodynamics of FBS0701, a novel oral chelator, in adults with transfusional iron overload. Fifty-one patients, stratified by transfusional iron intake, were randomized to FBS0701 at either 14.5 or 29 mg/kg/d (16 and 32 mg/kg/d salt form). FBS0701 was generally well tolerated at both doses. Forty-nine patients (96%) completed the study. There were no drug-related serious adverse events. No adverse events (AEs) showed dose-dependency in frequency or severity. Treatment-related nausea, vomiting, abdominal pain, and diarrhea were each noted in < 5% of patients. Mean serum creatinine did not change significantly from Baseline or between dose groups. Transaminases wer increased in 8 (16%), three of whom acquired HCV on-study from a single blood bank while five had an abnormal baseline ALT. The 24 week mean change in liver iron concentration (ΔLIC) at 14.5 mg/kg/d was +3.1 mg/g (dw); 29% achieved a decrease in LIC. Mean ΔLIC at 29 mg/kg/d was −0.3 mg/g (dw); 44% achieved a decrease in LIC (P < .03 for ΔLIC between doses). The safety and tolerability profile at therapeutic doses compare favorably to other oral chelators. This trial was registered at www.clinicaltrials.gov as NCT01186419. PMID:22251482

A phase 2 study of the safety, tolerability, and pharmacodynamics of FBS0701, a novel oral iron chelator, in transfusional iron overload.

PubMed

Neufeld, Ellis J; Galanello, Renzo; Viprakasit, Vip; Aydinok, Yesim; Piga, Antonio; Harmatz, Paul; Forni, Gian Luca; Shah, Farrukh T; Grace, Rachael F; Porter, John B; Wood, John C; Peppe, Jennifer; Jones, Amber; Rienhoff, Hugh Young

2012-04-05

This was a 24-week, multicenter phase-2 study designed to assess safety, tolerability, and pharmacodynamics of FBS0701, a novel oral chelator, in adults with transfusional iron overload. Fifty-one patients, stratified by transfusional iron intake, were randomized to FBS0701 at either 14.5 or 29 mg/kg/d (16 and 32 mg/kg/d salt form). FBS0701 was generally well tolerated at both doses. Forty-nine patients (96%) completed the study. There were no drug-related serious adverse events. No adverse events (AEs) showed dose-dependency in frequency or severity. Treatment-related nausea, vomiting, abdominal pain, and diarrhea were each noted in < 5% of patients. Mean serum creatinine did not change significantly from Baseline or between dose groups. Transaminases wer increased in 8 (16%), three of whom acquired HCV on-study from a single blood bank while five had an abnormal baseline ALT. The 24 week mean change in liver iron concentration (ΔLIC) at 14.5 mg/kg/d was +3.1 mg/g (dw); 29% achieved a decrease in LIC. Mean ΔLIC at 29 mg/kg/d was -0.3 mg/g (dw); 44% achieved a decrease in LIC (P < .03 for ΔLIC between doses). The safety and tolerability profile at therapeutic doses compare favorably to other oral chelators.

Safety and tolerability of rifaximin for the treatment of irritable bowel syndrome without constipation: a pooled analysis of randomised, double-blind, placebo-controlled trials.

PubMed

Schoenfeld, P; Pimentel, M; Chang, L; Lembo, A; Chey, W D; Yu, J; Paterson, C; Bortey, E; Forbes, W P

2014-05-01

The efficacy of rifaximin, a nonsystemic, gut-targeted antibiotic for reducing non-constipation-predominant irritable bowel syndrome (non-C IBS) symptoms, has been demonstrated in one phase 2b and two phase 3 randomised, double-blind, placebo-controlled trials, but detailed data about rifaximin safety and tolerability during treatment and subsequent follow-up periods are lacking. To assess and determine the frequency of rifaximin and placebo adverse events (AEs) in phase 2b and phase 3 non-C IBS trials. A post hoc pooled safety analysis of the phase 2b (rifaximin 275, 550, and 1100 mg twice daily for 2 weeks; 550 mg twice daily for 4 weeks) and phase 3 (rifaximin 550 mg three times daily for 2 weeks) studies was performed. Data on treatment and post-treatment AEs were collected. Patients were followed up for 12 weeks and 10 weeks post-treatment in the phase 2b and phase 3 trials, respectively. Patients receiving rifaximin (n = 1103) and placebo (n = 829) had a similar incidence of drug-related AEs (12.1% vs. 10.7%), serious AEs (1.5% vs. 2.2%), drug-related AEs resulting in study discontinuation (0.8% vs. 0.8%), gastrointestinal-associated AEs (12.2% vs. 12.2%) and infection-associated AEs (8.5% vs. 9.5%). There were no cases of Clostridium difficile colitis or deaths. The safety and tolerability profile of rifaximin during treatment and post-treatment was comparable to placebo. Future research should define the safety and tolerability profile, including risk of C. difficile colitis and microbial antibiotic resistance, with repeated courses of rifaximin in patients with non-constipation-predominant irritable bowel syndrome (ClinicalTrials.gov: NCT00269412, NCT00731679, and NCT00724126). © 2014 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.

Tolerability, safety, and efficacy of PEG 3350 as a 1-day bowel preparation in children.

PubMed

Walia, Ritu; Steffen, Rita; Feinberg, Lisa; Worley, Sarah; Mahajan, Lori

2013-02-01

The aim of the study was to evaluate the tolerability, safety, and efficacy of polyethylene glycol (PEG) 3350 without electrolytes as a 1-day bowel preparation for colonoscopy in children. A prospective study of 45 children undergoing colonoscopy prescribed PEG 3350 without electrolytes mixed with a commercial electrolyte beverage was performed. Patients <45 kg received 136 g of PEG 3350 without electrolytes mixed in 32 ounces of Gatorade. Patients ≥ 45 kg were given 255 g of PEG 3350 without electrolytes in 64 ounces of Gatorade A basic metabolic panel was performed at the time of the clinic visit and just before colonoscopy. Patients completed a survey related to bowel preparation. Endoscopists graded bowel preparation and noted the proximal extent of the examination. A total of 44 patients (14 ± 3 years) completed the study. One patient was excluded due to protocol breach. All subjects reported the preparation was easy (61%) or tolerable (39%). Adverse events included nausea (34%), abdominal pain (23%), vomiting (16%), abdominal distension (20%), bloating (23%), and dizziness (7%). Although significant changes in serum glucose and CO2 were noted, no therapeutic interventions were indicated. Significant changes in sodium, potassium chloride, blood urea nitrogen, or creatinine did not occur. Colonic preparation was rated as excellent in 23%, good in 52%, fair in 23%, and poor in 2% of patients. Intubation of the ileum was successful in 100%. One-day bowel preparation with high dose PEG 3350 mixed with commercial electrolyte solution is tolerable, safe, and effective in children before colonoscopy.

Randomised clinical trial: the safety and tolerability of Trichuris suis ova in patients with Crohn's disease.

PubMed

Sandborn, W J; Elliott, D E; Weinstock, J; Summers, R W; Landry-Wheeler, A; Silver, N; Harnett, M D; Hanauer, S B

2013-08-01

Recent evidence suggests that embryonated eggs of the porcine whipworm Trichuris suis ova (TSO) may be an effective treatment for inflammatory bowel disease (IBD). To assess the safety and tolerability of TSO following a single dose in patients with Crohn's disease. This was a sequential dose-escalation (500, 2500 and 7500 viable embryonated TSO), randomised, double-blind, placebo-controlled study to evaluate the safety of a single dose of oral suspension TSO in patients with Crohn's disease. Twelve patients were randomised into each of three cohorts. Patients were assessed 1, 3, 5, 7, 9, 11 and 14 days following dosing (via a telephone call and diary symptom collection through 14 days postdose) for adverse events, changes to concomitant medications and gastrointestinal (GI) signs and symptoms. Patients were again assessed at Months 1, 2 and 6. Eighteen males and 18 females were enrolled, ages 20 to 54 years. All patients were dosed and completed the initial 2-month follow-up period (five patients did not attend their 6-month study visit). GI disorders were reported with the highest frequency; 7 (25.9%) TSO-treated patients and 3 (33.3%) placebo-treated patients. No dose-dependent relationship was observed, with 3 (33.3%) placebo, 4 (44.4%) TSO 500, 0 (0.0%) TSO 2500 and 3 (33.3%) TSO 7500 patients experiencing at least one GI event, and no clinically meaningful changes in GI signs and symptoms. A single dose of Trichuris suis ova up to 7500 ova was well tolerated and did not result in short- or long-term treatment-related side effects. Clinicaltrials.gov NCT01576461. © 2013 John Wiley & Sons Ltd.

Analysis of the safety and pharmacodynamics of human fibrinogen concentrate in animals

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

Beyerle, Andrea, E-mail: andrea.beyerle@cslbehring.com; Nolte, Marc W.; Solomon, Cristina

Fibrinogen, a soluble 340 kDa plasma glycoprotein, is critical in achieving and maintaining hemostasis. Reduced fibrinogen levels are associated with an increased risk of bleeding and recent research has investigated the efficacy of fibrinogen concentrate for controlling perioperative bleeding. European guidelines on the management of perioperative bleeding recommend the use of fibrinogen concentrate if significant bleeding is accompanied by plasma fibrinogen levels less than 1.5–2.0 g/l. Plasma-derived human fibrinogen concentrate has been available for therapeutic use since 1956. The overall aim of the comprehensive series of non-clinical investigations presented was to evaluate i) the pharmacodynamic and pharmacokinetic characteristics and ii)more » the safety and tolerability profile of human fibrinogen concentrate Haemocomplettan P® (RiaSTAP®). Pharmacodynamic characteristics were assessed in rabbits, pharmacokinetic parameters were determined in rabbits and rats and a safety pharmacology study was performed in beagle dogs. Additional toxicology tests included: single-dose toxicity tests in mice and rats; local tolerance tests in rabbits; and neoantigenicity tests in rabbits and guinea pigs following the introduction of pasteurization in the manufacturing process. Human fibrinogen concentrate was shown to be pharmacodynamically active in rabbits and dogs and well tolerated, with no adverse events and no influence on circulation, respiration or hematological parameters in rabbits, mice, rats and dogs. In these non-clinical investigations, human fibrinogen concentrate showed a good safety profile. This data adds to the safety information available to date, strengthening the current body of knowledge regarding this hemostatic agent. - Highlights: • A comprehensive series of pre-clinical investigations of human fibrinogen concentrate. • Human fibrinogen concentrate was shown to be pharmacodynamically active. • Human fibrinogen concentrate was well

Local Road Safety Peer Exchange – Region 1 : An RSPCB Peer Exchange

DOT National Transportation Integrated Search

2012-10-01

This report provides a summary of the proceedings of the Local Road Safety Peer Exchange held in Piscataway, New Jersey October 10th and 11th, 2012. The Federal Highway Administration (FHWA) sponsored the Peer Exchange in coordination with Region 1 L...

The challenge of compiling data profiles to stimulate local preventive health action: a European case study from child safety.

PubMed

Alexander, Denise; Rigby, Michael; Gissler, Mika; Köhler, Lennart; MacKay, Morag

2015-05-01

Positive recent experience of presenting comparative child safety data at national level has instigated policy action in Europe. It was hoped a Child Safety Index could quantify how safe a community, region or locality is for its children in comparison with similar areas within Europe, as a focus for local targeted action. Validated indicators proposed by previous European projects identified from areas of child injury prevention, such as road safety, burns or poisoning, were selected to give a balanced profile, and populated from available published data. An index using a sub-score for each specific injury topic was proposed. The indicators' presentation, sensitivity and appropriateness were considered, as well as data availability. Satisfactory indicators were not identified for all areas and very few local area data were available. This forced the researchers to conclude that at present, constructing a reliable Child Safety Index for use at the local level is not feasible. There is a worrying lack of data available at the sub-national level to support injury prevention, evaluate interventions, and enable informed local decision making.

Tolerance Signatures in Transplant Recipients

PubMed Central

Newell, Kenneth A.; Turka, Laurence A.

2015-01-01

Purpose of review The intent of this review is to describe biomarkers that predict or identify individuals who exhibit tolerance to a transplanted organ. The identification of tolerance biomarkers would spare some individuals the toxicity of immunosuppressive agents, enhance the safety of studies to induce tolerance, and provide insights into mechanisms of tolerance that may aid in designing new regimens. Recent findings Studies of tolerant kidney transplant recipients have revealed an association with B cells. More recent studies have suggested that these B cells may be less mature than from those in nontolerant recipients, and specially suited to suppress alloimmune responses. Biomarkers in tolerant liver transplant patients appear to be distinct from those associated renal tolerance. Most reports have identified an association with NK and/or γδ T cells rather than B cells. Recent data indicate biomarkers associated with iron homeostasis within the transplanted liver more accurately predict the tolerant state than do biomarkers expressed in the blood, suggesting that the renal allograft itself, which is infrequently sampled, would be informative. Summary Given the encouraging progress in identifying tolerance biomarkers, it will be important to validate these markers in larger studies of transplant recipients undergoing prospective minimization or withdrawal of immunosuppression. PMID:26107969

Oncological safety of skin sparing mastectomy followed by immediate reconstruction for locally advanced breast cancer.

PubMed

Lim, Woosung; Ko, Beom-Seok; Kim, Hee-Jung; Lee, Jong Won; Eom, Jin Sup; Son, Byung Ho; Lee, Taik Jong; Ahn, Sei-Hyun

2010-07-01

Skin sparing mastectomy (SSM) has been demonstrated as an oncologically safe procedure for early breast cancer in several studies. But few studies concerned the safety of SSM for patients with locally advanced breast cancer; therefore, its safety for these patients is less clear. The purpose of this study is to examine the oncological safety of SSM followed by immediate reconstruction for locally advanced breast cancer. We retrospectively analyzed 897 breast cancer patients who underwent mastectomy for stage IIB (T3N0)-III between 1996 and 2005. Of 897, 87 underwent SSM (n = 73) or nipple sparing mastectomy (NSM, n = 14). We compared the local recurrence (LR) rate, disease-free survival (DFS) and overall survival (OS) for SSM group with conventional mastectomy group. The 5-year DFS and OS of SSM group were not worse than those of CM group for all stages. LR rate was 3.0% (2/67) for IIB, 2.8% (1/36) for IIIA, 4.5% (1/22) for IIIC, and 5.0% (1/20) for T3 in SSM group. There was no difference in LR rates between SSM group and CM group for all stages. Our study demonstrates that SSM followed by immediate reconstruction is oncologically safe for locally advanced breast cancer. (c) 2010 Wiley-Liss, Inc.

Single dose pharmacokinetics, pharmacodynamics, tolerability and safety of BAY 60-5521, a potent inhibitor of cholesteryl ester transfer protein.

PubMed

Boettcher, Michael-Friedrich; Heinig, Roland; Schmeck, Carsten; Kohlsdorfer, Christian; Ludwig, Matthias; Schaefer, Anja; Gelfert-Peukert, Sabine; Wensing, Georg; Weber, Olaf

2012-02-01

To determine pharmacokinetics (PK), pharmacodynamics (PD), tolerability and safety of BAY 60-5521, a potent inhibitor of cholesteryl ester transfer protein (CETP). The first in man (FIM) study investigated the safety, tolerability, pharmacodynamics and pharmacokinetics in healthy male subjects following administration of single oral doses. The study was performed using a randomized, single-blind, placebo-controlled, single dose-escalation design. Thirty-eight young healthy male subjects (aged 20-45 years) received an oral dose of 5, 12.5, 25 or 50 mg BAY 60-5521 (n= 28) or were treated with a placebo (n= 10). In all four dose steps, only one adverse event (25 mg; mild skin rash) was considered drug related. Clinical laboratory parameters showed no clinically relevant changes. A clear dose-dependent CETP inhibition could be demonstrated starting at a dose of 5 mg. At a dose of 25 mg, a CETP inhibition >50% over 18 h was observed. After 50 mg, CETP inhibition >50% lasted more than 50 h. Twenty-four h after administration mean HDL-C-values showed a nearly dose-proportional increase. Following administration of 50 mg, a significant HDL-C increase of about 30% relative to baseline values was found. BAY 60-5521 was slowly absorbed reaching maximum concentrations in plasma after 4 to 6 h. The disposition in plasma was multi-exponential with an estimated mean terminal half-life of 76 to 144 h. BAY 60-5521 was clinically safe and well tolerated. No effects on heart rate, blood pressure and ECG recordings were observed during the study. A clear pharmacodynamic effect on CETP inhibition and HDL could be demonstrated. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

Tolerability and safety of the intravenous immunoglobulin octagam® 10% in patients with immune thrombocytopenia: a post-authorisation safety analysis of two non-interventional phase IV trials.

PubMed

Wietek, Stefan; Svorc, Daniel; Debes, Anette; Svae, Tor-Einar

2018-05-01

To provide detailed data on the tolerability and safety of octagam ® 10%, a ready-to-use intravenous immunoglobulin, in a subgroup of patients with immune thrombocytopenia (ITP) involved in an integrated analysis of post-authorisation safety surveillance (PASS) studies. A subgroup analysis was conducted using data collected from two non-interventional studies that included patients with ITP treated with octagam ® 10%. Patients were observed and monitored for possible adverse drug reactions (ADRs) during or after administration of octagam ® 10%, with a particular focus on thromboembolic events (TEEs). ADRs were analysed at the case and event level. In this analysis of 112 patients receiving octagam ® 10% (mean dose 0.4 g/kg/infusion), there were five cases with at least one adverse drug reaction (ADR) associated with 626 infusions of octagam ® 10% (case incidence of 0.8% per infusion). ADRs were of mild or moderate severity. There were a total of 10 events, most commonly back pain (n = 3) and headache (n = 2). Nausea, dizziness and a sensation of heaviness were also reported. The remaining two events involved drug exposure during pregnancy. There were no TEEs or other serious ADRs. In this subgroup analysis of patients who received octagam ® 10% (manufactured using an amended process) in two PASS studies, the overall ADR rate was low, with ADRs occurring in only 0.8% of all infusions. No TEEs or other serious ADRs were reported. Routine clinical use of octagam ® 10% was safe and well tolerated, with no unexpected safety issues, in patients with ITP. The two studies from which data were taken are registered with the International Standard Randomised Controlled Trial Number Registry, numbers ISRCTN58800347 and ISRCTN02245668.

Safety, tolerability and pharmacokinetics of a novel phosphodiesterase inhibitor, E6005 ointment, in healthy volunteers and in patients with atopic dermatitis.

PubMed

Ohba, Fuminori; Nomoto, Maiko; Hojo, Seiichiro; Akama, Hideto

2016-01-01

The purpose of the present studies was to assess the safety, tolerability and pharmacokinetics of topical application of a novel phosphodiesterase inhibitor, E6005, in healthy volunteers and in patients with atopic dermatitis (AD). In two randomized, investigator-blind, vehicle-controlled studies, we evaluated the topical application of E6005 ointment at concentrations ranging from 0.01% to 0.2% in healthy volunteers (Study 001) and in patients with AD (Study 101). Thirty-six subjects were enrolled in Study 001 and 40 in Study 101. Neither skin irritation nor photosensitization was observed with application of E6005 in Study 001. Four subjects receiving E6005 in Study 001 experienced a treatment-emergent adverse event (application site edema, increased alanine aminotransferase or erythema); three of these subjects discontinued the study. Two subjects receiving E6005 in Study 101 experienced an adverse event (gout or enterocolitis); one discontinued the study. Plasma concentrations of E6005 were below the limit of quantification (1 ng/ml) in both studies. E6005 ointment exhibited acceptable safety and tolerability. Topical application of E6005 ointment resulted in very low systemic exposure to E6005 in healthy volunteers and in patients with AD.

Plasticity and stress tolerance override local adaptation in the responses of Mediterranean holm oak seedlings to drought and cold.

PubMed

Gimeno, Teresa E; Pías, Beatriz; Lemos-Filho, José P; Valladares, Fernando

2009-01-01

Plant populations of widely distributed species experience a broad range of environmental conditions that can be faced by phenotypic plasticity or ecotypic differentiation and local adaptation. The strategy chosen will determine a population's ability to respond to climate change. To explore this, we grew Quercus ilex (L.) seedlings from acorns collected at six selected populations from climatically contrasting localities and evaluated their response to drought and late season cold events. Maximum photosynthetic rate (A(max)), instantaneous water use efficiency (iWUE), and thermal tolerance to freeze and heat (estimated from chlorophyll fluorescence versus temperature curves) were measured in 5-month-old seedlings in control (no stress), drought (water-stressed), and cold (low suboptimal temperature) conditions. The observed responses were similar for the six populations: drought decreased A(max) and increased iWUE, and cold reduced A(max) and iWUE. All the seedlings maintained photosynthetic activity under adverse conditions (drought and cold), and rapidly increased their iWUE by closing stomata when exposed to drought. Heat and freeze tolerances were similarly high for seedlings from all the populations, and they were significantly increased by drought and cold, respectively; and were positively related to each other. Differences in seedling performance across populations were primarily induced by maternal effects mediated by seed size and to a lesser extent by idiosyncratic physiologic responses to drought and low temperatures. Tolerance to multiple stresses together with the capacity to physiologically acclimate to heat waves and cold snaps may allow Q. ilex to cope with the increasingly stressful conditions imposed by climate change. Lack of evidence of physiologic seedling adaptation to local climate may reflect opposing selection pressures to complex, multidimensional environmental conditions operating within the distribution range of this species.

Efficacy and local tolerability of povidone iodine and octenidine hydrochloride solution for the antiseptic preparation of the orificium urethrae.

PubMed

Rudolph, P; Fritze, F; Reimer, K; Klebingat, K J; Kramer, A

1999-01-01

In a randomized clinical study, 61 hospitalized men were examined to test the local tolerability and antimicrobial efficacy of antiseptic treatment of the genitals with povidone iodine versus octenidine hydrochloride solution. Antibacterial efficacy was established by comparing the total aerobic bacterial colony count from standardized swabs from the orificium urethrae externum before, immediately after, and 30 and 60 min after antisepsis. Tolerability was assessed by dermatoscopy, applying a scale to rate the criteria of reddening, erosions and microbleeding. pH-value was taken and the nitracin yellow test carried out at several intervals. Patients assessed sensations (itching, burning, warmth, cold tension) in visual analogue scales. The test for equivalence in efficacy of both antiseptic agents produced no significant result (P = 0.3). The sum score of tolerability produced a better result for povidone iodine. In addition, the drop in the pH value after observed antisepsis with povidone iodine provides an additional protective mechanism against bacterial colonization.

77 FR 27621 - Special Local Regulations and Safety Zone; War of 1812 Bicentennial Commemorations, Chesapeake...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-05-11

...] RIN 1625-AA08, 1625-AA00 Special Local Regulations and Safety Zone; War of 1812 Bicentennial... Chesapeake Bay and Port of Baltimore, Maryland for War of 1812 Bicentennial Commemorations activities. These actions are necessary to provide for the safety of life on navigable waters before, during, and after War...

77 FR 15323 - Special Local Regulations and Safety Zone; War of 1812 Bicentennial Commemorations, Chesapeake...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-15

...] RIN 1625-AA08, AA00 Special Local Regulations and Safety Zone; War of 1812 Bicentennial Commemorations... Chesapeake Bay and Port of Baltimore, Maryland for War of 1812 Bicentennial Commemorations activities. This action is necessary to provide for the safety of life on navigable waters before, during, and after War...

Safety of tumescent liposuction under local anesthesia in a series of 4,380 patients.

PubMed

Boeni, Roland

2011-01-01

Liposuction is increasingly performed under local anesthesia and in an outpatient setting. The term 'tumescent liposuction' has been used in the literature in patients receiving other forms of anesthesia as well, hence the confusion regarding the safety profile of liposuction performed under local anesthesia alone. To analyze the safety of tumescent liposuction performed under local anesthesia in a larger group of patients. Between 2003 and 2010, 4,380 consecutive patients underwent tumescent liposuction by the same surgeon. The occurrence of complications was recorded in detail. There were no serious complications requiring hospitalization. There were no injuries, no nerve damage or permanent lymphedema, no deep venous thrombosis or seroma. Seven patients needed closer follow-up due to large hematoma (n = 3; no drainage needed), allergic drug reaction to doxycycline (n = 2), erysipelas (n = 1) and generalized edema (n = 1). Tumescent liposuction under local anesthesia is a safe method, providing it is performed by an experienced surgeon and the guidelines of care for liposuction are strictly followed. Copyright © 2011 S. Karger AG, Basel.

Hysterosalpingo-foam sonography (HyFoSy): Tolerability, safety and the occurrence of pregnancy post-procedure.

PubMed

Tanaka, Keisuke; Chua, Jackie; Cincotta, Robert; Ballard, Emma L; Duncombe, Gregory

2018-02-01

Fallopian tube patency testing is an essential part of infertility evaluation. Hysterosalpingo-contrast sonography (HyCoSy) has been described as reliable, well tolerated and safe compared to other modalities such as laparoscopy and a dye test or hysterosalpingography. Limited availability of the previously used contrast has led to the introduction of a foam contrast agent as an alternative. To assess the tolerability, safety and occurrence of pregnancy post-procedure of hysterosalpingo-foam sonography (HyFoSy). A retrospective cohort study of women who had a HyFoSy at Queensland Ultrasound for Women from March 2013 to February 2015. A questionnaire was sent to their referring doctor to identify any complications or subsequent pregnancies with or without artificial reproductive technology (ART) within six months of the HyFoSy. Of 200 women, four cases were abandoned due to difficulty introducing the intracervical catheter, severe discomfort or a vasovagal episode. Response from referring doctors for 155 women reported no post-procedural complication. One hundred and eleven women were followed up for at least six months. Twenty-four out of 59 women (40.7%) who had ART and 24 out of 52 women (46.2%) who did not have ART conceived. Fifty percent of women who were nulligravida at the time of investigation, found to have at least one patent fallopian tube, whose partner had a normal semen analysis, spontaneously conceived within the time of follow up. HyFoSy is well tolerated and safe. A preponderance of pregnancies in the first month after HyFoSy suggests that a therapeutic effect may exist. © 2017 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.

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

PubMed Central

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

2013-01-01

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

Safety and tolerance of a probiotic formula in early infancy comparing two probiotic agents: a pilot study.

PubMed

Weizman, Zvi; Alsheikh, Ahmed

2006-10-01

To compare the safety and tolerance of two formulas, supplemented with different probiotic agents, in early infancy. Prospective randomized placebo-controlled trial. Clinics of a University Medical Center. Full-term healthy infants aged less than 4 months. Infants were randomly assigned for 4 weeks to a standard milk-based formula supplemented with either Bifidobacterium lactis (BB-12), Lactobacillus reuteri (ATCC 55730) or a probiotics-free formula. Growth parameters, daily characteristics of feeding, stooling and behavior, and side effects. Fifty-nine infants, aged 3-65 days, were included. Subjects in all three groups were similar at entry in terms of gestational age, birth weight, sex, growth parameters and breast feeding rate prior to the study. The supplemented formulas were well accepted and did not reveal any adverse effects. A comparison of growth parameters, and variables of feeding, stooling and crying and irritability did not reveal any significant differences between groups. The use of formula supplemented with either Lactobacillus reuteri or Bifidobacterium lactis in early infancy, was safe, well tolerated and did not adversely affect growth, stooling habits or infant behavior.

[Efficacy, tolerability and safety of paliperidone extended-release in the treatment of schizophrenia and schizoaffective disorder].

PubMed

Bellantuono, Cesario; Santone, Giovanni

2012-01-01

The paper represents a systematic review on the efficacy, tolerability and safety of paliperidone, an antipsychotic drug recently approved in Italy for the treatment of schizophrenia and of schizoaffective disorder. A comprehensive PubMed search using the term "paliperidone" was performed from January 1980 to February 2011. Papers reporting data on efficacy in the treatment of schizophrenia and of schizoaffective disorder were included, also if published as abstracts and all retrieved articles were manually searched for other references of interest. Paliperidone was found to be effective in short and long-term treatment of schizophrenia, as well as in the treatment of schizoaffective disorder. For both disorders, paliperidone showed to be effective in improving psychotic and affective symptoms. In the studies analyzed it was well tolerated and the most frequent reported adverse events were mild extrapyramidal symptoms and an increase in serum prolactin levels. Paliperidone has been shown to be an effective and safe medication for the treatment of schizophrenia and schizoaffective disorder. Further controlled clinical trials are needed to confirm this clinical profile in the long-term treatment, as well as for specific conditions such as schizophrenic patients with medical comorbidities.

Efficacy, safety, and tolerance of the non-ergoline dopamine agonist pramipexole in the treatment of advanced Parkinson's disease: a double blind, placebo controlled, randomised, multicentre study.

PubMed

Pinter, M M; Pogarell, O; Oertel, W H

1999-04-01

Pramipexole, a non-ergot dopamine D2/D3 receptor agonist, was investigated as an add on drug in advanced parkinsonian patients with motor fluctuations to assess efficacy, safety, and tolerance. Seventy eight patients of either sex with advanced Parkinson's disease and treatment complications such as motor fluctuations were enrolled into a double blind, placebo controlled, randomised, multicentre study (phase II) and assigned to add on treatment with pramipexole (n=34) versus placebo (n=44) to a previously stabilised antiparkinsonian medication (7 week dose titration interval, 4 week maintenance period). The primary end point of efficacy was the change from baseline in the total score of the unified Parkinson's disease rating scale (UPDRS) in the on "period" (2 hours after intake of study medication). Safety and tolerability were assessed on the basis of adverse events, vital signs, laboratory measurements, and ECG recordings. There was a significant improvement of the pramipexole group in UPDRS total scores, subscores part II, III (activities of daily living and motor examination), and IV (complications of therapy). Mean UPDRS total score decreased by 37.3% under pramipexole compared with 12.2% under placebo (p<0.001). Patients under pramipexole reported an overall reduction in "off" periods of 12%--resulting in 1.7 more hours "on" time a day--compared with an increase in "off" periods of 2% under placebo. There were no unexpected safety results. The adverse event profile disclosed a high tolerability. The most important adverse events under pramipexole were fatigue, dyskinesia, and vivid dreams. Pramipexole administration is an efficacious and well tolerated add on therapy in patients with advanced Parkinson's disease with an improvement in activities of daily living, motor function, and treatment associated complications.

Safety, Tolerability, and Efficacy of Quetiapine in Youth with Schizophrenia or Bipolar I Disorder: A 26-Week, Open-Label, Continuation Study

PubMed Central

Pathak, Sanjeev; Earley, Willie R.; Liu, Sherry; DelBello, Melissa

2013-01-01

Abstract Objective The purpose of this study was to describe the safety, tolerability, and efficacy of quetiapine monotherapy continued for up to 26-weeks in youth with schizophrenia or bipolar I disorder. Methods Medically healthy boys and girls with a baseline Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV-TR) diagnosis of schizophrenia (ages 13–17 years) or a manic episode of bipolar I disorder (ages 10–17 years) who participated in one of two acute, double-blind, placebo-controlled studies of immediate-release quetiapine were potentially eligible to enroll in a 26-week, open-label study. During the open-label study, quetiapine was flexibly dosed at 400–800 mg/day, with options to reduce dosing to 200 mg/day based on tolerability. Safety and tolerability outcomes assessed from open-label baseline to week 26 included adverse events (AEs), metabolic/laboratory parameters, extrapyramidal symptoms, suicidality, and vital signs. Results Of 381 patients enrolled in the open-label study (n=176, schizophrenia; n=205, bipolar disorder diagnosis), 237 patients (62.2%) completed the 26-week study period (71.0%, schizophrenia; 54.6%, bipolar disorder). The most common AEs reported during the study included somnolence, headache, sedation, weight increase, and vomiting. A total of 14.9% of patients experienced a shift to potentially clinically significant low levels of high-density lipoprotein cholesterol and 10.2% of patients experienced a shift to potentially clinically significant high triglyceride levels. Weight gain ≥7% was reported in 35.6% of patients between open-label baseline and final visit. After adjustment for normal growth, 18.3% of study participants experienced clinically significant weight gain (i.e., increase in body mass index ≥0.5 standard deviations from baseline). Conclusions In this 26-week study, quetiapine flexibly dosed at 400–800 mg/day, with options to reduce dosing based on tolerability, was generally safe

Safety and tolerability of Bifidobacterium longum subspecies infantis EVC001 supplementation in healthy term breastfed infants: a phase I clinical trial.

PubMed

Smilowitz, Jennifer T; Moya, Jackelyn; Breck, Melissa A; Cook, Chelsea; Fineberg, Annette; Angkustsiri, Kathleen; Underwood, Mark A

2017-05-30

Historically, bifidobacteria were the dominant intestinal bacteria in breastfed infants. Still abundant in infants in developing nations, levels of intestinal bifidobacteria are low among infants in developed nations. Recent studies have described an intimate relationship between human milk and a specific subspecies of Bifidobacterium, B. longum subsp. infantis (B. infantis), yet supplementation of breastfed, healthy, term infants with this organism, has not been reported. The IMPRINT Study, a Phase I clinical trial, was initiated to determine the safety and tolerability of supplementing breastfed infants with B. infantis (EVC001). Eighty mother-infant dyads were enrolled in either lactation support plus B. infantis supplementation (BiLS) or lactation support alone (LS). Starting with Day 7 postnatal, BiLS infants were fed 1.8-2.8 × 10 10  CFU B. infantis EVC001 daily in breast milk for 21 days. Mothers collected fecal samples, filled out health questionnaires, and kept daily logs about their infants' feeding and gastrointestinal symptoms from birth until Day 61 postnatal. Safety and tolerability were determined from maternal reports. There were no differences in the mean gestational age at birth, weight 1 and 2 months postnatal, and breast milk intake between groups. The mean Log 10 change in fecal Bifidobacterium from Day 6 to Day 28 was higher (p = 0.0002) for BiLS (6.6 ± 2.8 SD) than for LS infants (3.5 ± 3.5 SD). Daily stool number was higher (p < 0.005) for LS and lower (p < 0.05) for BiLS infants during supplementation than at Baseline. During supplementation, watery stools decreased and soft stools increased by 36% over baseline in BiLS infants (p < 0.05) with no significant changes in stool consistency for the LS infants. None of the safety and tolerability endpoints, including flatulence, bloody stool, body temperature, ratings of gastrointestinal symptoms, use of antibiotics or gas-relieving medications, infant colic, jaundice, number

Safety, Tolerability and Immunogenicity of Pentavalent Rotavirus Vaccine Manufactured by a Modified Process.

PubMed

Martinón-Torres, Federico; Greenberg, David; Varman, Meera; Killar, John A; Hille, Darcy; Strable, Erica L; Stek, Jon E; Kaplan, Susan S

2017-04-01

Rotavirus is the leading cause of severe diarrhea in infants and young children. The current formulation of pentavalent rotavirus vaccine (RV5) must be stored refrigerated at 2-8°C. A modified formulation of RV5 (RV5mp) has been developed with stability at 37°C for 7 days and an expiry extended to 36 months when stored at 2-8°C. This study (ClinicalTrials.gov identifier: NCT01600092; EudraCT number: 2012-001611-23) evaluated the safety, tolerability and immunogenicity of RV5mp versus the currently marketed RV5 in infants. To maintain blinding, both vaccine formulations were stored refrigerated at 2-8°C for the duration of the study. Immunogenicity endpoints were (1) serum neutralizing antibody titers to human rotavirus serotypes G1, G2, G3, G4 and P1A[8] and (2) proportion of subjects with a ≥3-fold rise from baseline for serum neutralizing antibody to human rotavirus serotypes G1, G2, G3, G4 and P1A[8] and serum antirotavirus immunoglobulin A. The RV5mp group (n = 505) and RV5 group (n = 509) had comparable safety profiles. There were no deaths and no vaccine-related serious adverse events in this study. With respect to immunogenicity, RV5mp was noninferior compared with RV5. Serum neutralizing antibody responses by country and breast-feeding status were generally consistent with the overall results. RV5mp enhances storage requirements while maintaining the immunogenicity and safety profile of the currently licensed RV5. A vaccine that is stable at room temperature may be more convenient for vaccinators, particularly in places where the cold chain is unreliable, and ultimately will permit more widespread use.

77 FR 22706 - Special Local Regulation and Safety Zone; America's Cup Sailing Events, San Francisco, CA

Federal Register 2010, 2011, 2012, 2013, 2014

2012-04-17

...] Special Local Regulation and Safety Zone; America's Cup Sailing Events, San Francisco, CA AGENCY: Coast... regulation and temporary safety zone proposed for those portions of the ``America's Cup World Series,'' the ``Louis Vuitton Cup'' challenger selection series, and the ``America's Cup Finals Match'' sailing regattas...

Infrastructural requirements for local implementation of safety policies: the discordance between top-down and bottom-up systems of action.

PubMed

Timpka, Toomas; Nordqvist, Cecilia; Lindqvist, Kent

2009-03-09

Safety promotion is planned and practised not only by public health organizations, but also by other welfare state agencies, private companies and non-governmental organizations. The term 'infrastructure' originally denoted the underlying resources needed for warfare, e.g. roads, industries, and an industrial workforce. Today, 'infrastructure' refers to the physical elements, organizations and people needed to run projects in different societal arenas. The aim of this study was to examine associations between infrastructure and local implementation of safety policies in injury prevention and safety promotion programs. Qualitative data on municipalities in Sweden designated as Safe Communities were collected from focus group interviews with municipal politicians and administrators, as well as from policy documents, and materials published on the Internet. Actor network theory was used to identify weaknesses in the present infrastructure and determine strategies that can be used to resolve these. The weakness identification analysis revealed that the factual infrastructure available for effectuating national strategies varied between safety areas and approaches, basically reflecting differences between bureaucratic and network-based organizational models. At the local level, a contradiction between safety promotion and the existence of quasi-markets for local public service providers was found to predispose for a poor local infrastructure diminishing the interest in integrated inter-agency activities. The weakness resolution analysis showed that development of an adequate infrastructure for safety promotion would require adjustment of the legal framework regulating injury data exchange, and would also require rational financial models for multi-party investments in local infrastructures. We found that the "silo" structure of government organization and assignment of resources was a barrier to collaborative action for safety at a community level. It may therefore be

High-Temperature Tolerance of Photosynthesis Can Be Linked to Local Electrical Responses in Leaves of Pea

PubMed Central

Sukhov, Vladimir; Gaspirovich, Vladimir; Mysyagin, Sergey; Vodeneev, Vladimir

2017-01-01

It is known that numerous stimuli induce electrical signals which can increase a plant's tolerance to stressors, including high temperature. However, the physiological role of local electrical responses (LERs), i.e., responses in the zone of stimulus action, in the plant's tolerance has not been sufficiently investigated. The aim of a current work is to analyze the connection between parameters of LERs with the thermal tolerance of photosynthetic processes in pea. Electrical activity and photosynthetic parameters in pea leaves were registered during transitions of air temperature in a measurement head (from 23 to 30°C, from 30 to 40°C, from 40 to 45°C, and from 45 to 23°C). This stepped heating decreased a photosynthetic assimilation of CO2 and induced generation of LERs in the heated leaf. Amplitudes of LERs, quantity of responses during the heating and the number of temperature transition, which induced the first generation of LERs, varied among different pea plants. Parameters of LERs were weakly connected with the photosynthetic assimilation of CO2 during the heating; however, a residual photosynthetic activity after a treatment by high temperatures increased with the growth of amplitudes and quantity of LERs and with lowering of the number of the heating transition, inducing the first electrical response. The effect was not connected with a photosynthetic activity before heating; similar dependences were also observed for effective and maximal quantum yields of photosystem II after heating. We believe that the observed effect can reflect a positive influence of LERs on the thermal tolerance of photosynthesis. It is possible that the process can participate in a plant's adaptation to stressors. PMID:29033854

Long-term efficacy, safety and tolerability of Remoxy for the management of chronic pain.

PubMed

Pergolizzi, Joseph V; Zampogna, Gianpietro; Taylor, Robert; Raffa, Robert B

2015-03-01

Historically, chronic pain generally went under-treated for a variety of objective and subjective reasons, including difficulty to objectively diagnose and manage over a long period of time, potential serious adverse effects of commonly available medications, and patient, healthcare and societal concerns over opioid medications. More recently, in an effort to redress the under-treatment of pain, the number of prescriptions of opioid analgesics has risen dramatically. However, paralleling the increased legitimate use has been a concomitant increase in opioid abuse, misuse and diversion. Pharmaceutical companies have responded by developing a variety of opioid formulations designed to deter abuse by making the products more difficult to tamper with. One such product is Remoxy(®), an extended-release formulation of the strong opioid oxycodone. We review the efficacy, safety and tolerability of this formulation based on the available published literature.

NIP1;2 is a plasma membrane-localized transporter mediating aluminum uptake, translocation, and tolerance in Arabidopsis

PubMed Central

Wang, Yuqi; Li, Ruihong; Li, Demou; Jia, Xiaomin; Zhou, Dangwei; Li, Jianyong; Lyi, Sangbom M.; Hou, Siyu; Huang, Yulan

2017-01-01

Members of the aquaporin (AQP) family have been suggested to transport aluminum (Al) in plants; however, the Al form transported by AQPs and the roles of AQPs in Al tolerance remain elusive. Here we report that NIP1;2, a plasma membrane-localized member of the Arabidopsis nodulin 26-like intrinsic protein (NIP) subfamily of the AQP family, facilitates Al-malate transport from the root cell wall into the root symplasm, with subsequent Al xylem loading and root-to-shoot translocation, which are critical steps in an internal Al tolerance mechanism in Arabidopsis. We found that NIP1;2 transcripts are expressed mainly in the root tips, and that this expression is enhanced by Al but not by other metal stresses. Mutations in NIP1;2 lead to hyperaccumulation of toxic Al3+ in the root cell wall, inhibition of root-to-shoot Al translocation, and a significant reduction in Al tolerance. NIP1;2 facilitates the transport of Al-malate, but not Al3+ ions, in both yeast and Arabidopsis. We demonstrate that the formation of the Al-malate complex in the root tip apoplast is a prerequisite for NIP1;2-mediated Al removal from the root cell wall, and that this requires a functional root malate exudation system mediated by the Al-activated malate transporter, ALMT1. Taken together, these findings reveal a critical linkage between the previously identified Al exclusion mechanism based on root malate release and an internal Al tolerance mechanism identified here through the coordinated function of NIP1;2 and ALMT1, which is required for Al removal from the root cell wall, root-to-shoot Al translocation, and overall Al tolerance in Arabidopsis. PMID:28439024

29 CFR 1905.6 - Public notice of a granted variance, limitation, variation, tolerance, or exemption.

Code of Federal Regulations, 2010 CFR

2010-07-01

..., tolerance, or exemption. 1905.6 Section 1905.6 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR RULES OF PRACTICE FOR VARIANCES, LIMITATIONS, VARIATIONS, TOLERANCES, AND EXEMPTIONS UNDER THE WILLIAMS-STEIGER OCCUPATIONAL SAFETY AND HEALTH ACT OF 1970...

[Piezosurgery for surgically assisted rapid maxillary expansion under local anesthesia].

PubMed

Sun, Hao; Li, Biao; Sun, Hao; Liu, Zhixu; Wang, Xudong

2014-08-01

This study evaluates piezosurgery for surgically assisted rapid maxillary expansion (SARME) under local anesthesia. SARME was performed on adults with maxillary transverse deficiency under local anesthesia with a piezosurgical device. Fourteen patients (six males and eight females) underwent lateral maxillary osteotomies, midpalatal osteotomies, and bilateral pterygomaxillary disjunction. The feelings of patients during the operation were determined through questionnaires. All patients underwent SARME in the out-patient operating room. The surgical procedures were completed under local anesthesia. All patients exhibited satisfactory tolerance. Ultrasonic bone-cutting surgery was recently introduced as a feasible alternative to the conventional tools of cranio-maxillofacial surgery for its technical characteristics of precision and safety. The device used was unique in that cutting action occurred when the tool was employed on mineralized tissues, but stoped on soft tissues. The results of the questionnaires showed that eight (57.14%) patients felt a mild sensation of ultrasonic vibration, tweleve (85.7 1%) felt mild tolerable pain and tooth soreness during surgery, and eleven (78.57%) felt little fear and hardly heard the ultrasonic sound. Preoperative and postoperative six months later measurements showed an evident effect of expansion. Piezosurgery enabled patients to undergo all the steps of SARME under local anesthesia, but more cases and longer follow-up are needed to verif ' the results.

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

PubMed Central

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

2005-01-01

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

Safety and tolerability of azilsartan medoxomil in subjects with essential hypertension: a one-year, phase 3, open-label study.

PubMed

Handley, Alison; Lloyd, Eric; Roberts, Andrew; Barger, Bruce

2016-01-01

This 56-week phase 3, open-label, treat-to-target study, involving 2 consecutive, non-randomized cohorts, evaluated the safety and tolerability of azilsartan medoxomil (AZL-M) in essential hypertension (mean baseline blood pressure [BP] 152/100 mmHg). All subjects (n = 669) initiated AZL-M 40 mg QD, force-titrated to 80 mg QD at week 4, if tolerated. From week 8, subjects could receive additional medications, starting with chlorthalidone (CLD) 25 mg QD (Cohort 1) or hydrochlorothiazide (HCTZ) 12.5-25 mg QD (Cohort 2), if required, to reach BP targets. Adverse events (AEs) were reported in 75.9% of subjects overall in the two cohorts (73.8% Cohort 1, 78.5% Cohort 2). The most common AEs were dizziness (14.3%), headache (9.9%) and fatigue (7.2%). Transient serum creatinine elevations were more frequent with add-on CLD. Clinic systolic/diastolic BP (observed cases at week 56) decreased by 25.2/18.4 mmHg (Cohort 1) and 24.2/17.9 mmHg (Cohort 2). These results demonstrate that AZL-M is well tolerated over the long term and provides stable BP improvements when used in a treat-to-target BP approach with thiazide-type diuretics.

Safety and tolerability of azilsartan medoxomil in subjects with essential hypertension: a one-year, phase 3, open-label study

PubMed Central

Handley, Alison; Lloyd, Eric; Roberts, Andrew; Barger, Bruce

2016-01-01

Abstract This 56-week phase 3, open-label, treat-to-target study, involving 2 consecutive, non-randomized cohorts, evaluated the safety and tolerability of azilsartan medoxomil (AZL-M) in essential hypertension (mean baseline blood pressure [BP] 152/100 mmHg). All subjects (n = 669) initiated AZL-M 40 mg QD, force-titrated to 80 mg QD at week 4, if tolerated. From week 8, subjects could receive additional medications, starting with chlorthalidone (CLD) 25 mg QD (Cohort 1) or hydrochlorothiazide (HCTZ) 12.5–25 mg QD (Cohort 2), if required, to reach BP targets. Adverse events (AEs) were reported in 75.9% of subjects overall in the two cohorts (73.8% Cohort 1, 78.5% Cohort 2). The most common AEs were dizziness (14.3%), headache (9.9%) and fatigue (7.2%). Transient serum creatinine elevations were more frequent with add-on CLD. Clinic systolic/diastolic BP (observed cases at week 56) decreased by 25.2/18.4 mmHg (Cohort 1) and 24.2/17.9 mmHg (Cohort 2). These results demonstrate that AZL-M is well tolerated over the long term and provides stable BP improvements when used in a treat-to-target BP approach with thiazide-type diuretics. PMID:26817604

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

PubMed

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

2013-05-01

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

High thermal tolerance of a rainbow trout population near its southern range limit suggests local thermal adjustment

PubMed Central

Verhille, Christine E.; English, Karl K.; Cocherell, Dennis E.; Farrell, Anthony P.; Fangue, Nann A.

2016-01-01

Transformation of earth's ecosystems by anthropogenic climate change is predicted for the 21st century. In many regions, the associated increase in environmental temperatures and reduced precipitation will have direct effects on the physiological performance of terrestrial and aquatic ectotherms and have already threatened fish biodiversity and important fisheries. The threat of elevated environmental temperatures is particularly salient for members of the Oncorhynchus genus living in California, which is the southern limit of their range. Here, we report the first assessments of the aerobic capacity of a Californian population of wild Oncorhynchus mykiss Walbaum in relationship to water temperature. Our field measurements revealed that wild O. mykiss from the lower Tuolumne River, California maintained 95% of their peak aerobic scope across an impressive temperature range (17.8–24.6°C). The thermal range for peak performance corresponds to local high river temperatures, but represents an unusually high temperature tolerance compared with conspecifics and congeneric species from northern latitudes. This high thermal tolerance suggests that O. mykiss at the southern limit of their indigenous distribution may be locally adjusted relative to more northern populations. From fisheries management and conservation perspectives, these findings challenge the use of a single thermal criterion to regulate the habitat of the O. mykiss species along the entirety of its distribution range. PMID:27957333

A Phase II, Randomized, Double-Blind Clinical Study Evaluating the Safety, Tolerability, and Efficacy of a Topical Minocycline Foam, FMX103, for the Treatment of Facial Papulopustular Rosacea.

PubMed

Mrowietz, Ulrich; Kedem, Tal Hetzroni; Keynan, Rita; Eini, Meir; Tamarkin, Dov; Rom, Dror; Shirvan, Mitchell

2018-06-01

Our objective was to demonstrate the safety, tolerability, and efficacy of a minocycline foam, FMX103, in the treatment of moderate-to-severe facial papulopustular rosacea. This was a phase II, randomized, double-blind, multicenter study. Healthy subjects aged ≥ 18 years with moderate-to-severe rosacea that had been diagnosed ≥ 6 months previously and with ≥ 12 inflammatory facial lesions were randomized (1:1:1) to receive once-daily 1.5% FMX103, 3% FMX103, or vehicle for 12 weeks. The primary endpoint was the absolute change in inflammatory lesion count at week 12. Other assessments included grade 2 or higher Investigator's Global Assessment (IGA) improvement, IGA "clear" or "almost clear" (IGA 0/1), clinical erythema, and safety/tolerability. Safety and efficacy were evaluated at weeks 2, 4, 8, and 12, with a safety follow-up at week 16. A total of 232 subjects were randomized; 213 completed the study. At week 12, inflammatory lesion count reduction was significantly greater for the 1.5 and 3% FMX103 doses than for vehicle (21.1 and 19.1 vs. 7.8, respectively; both p < 0.001). Both doses were significantly better than vehicle for achieving grade 2 or higher IGA improvement and assessment of "clear" or "almost clear." Both doses appeared generally safe and well tolerated. In total, 11 (4.7%) subjects reported treatment-related treatment-emergent adverse events (TEAEs); all but one (eye discharge) were dermal related, and all resolved by study end. No treatment-related systemic TEAEs were reported. Four subjects discontinued the study because of TEAEs (3% FMX103, n = 3; vehicle, n = 1). Topical minocycline foam, FMX103, appeared to be an effective, safe, and well tolerated treatment for moderate-to-severe papulopustular rosacea. These results support further investigation in larger clinical trials. CLINICALTRIALS. NCT02601963.

Management of health and safety in the organization of worktime at the local level.

PubMed

Jeppesen, H J; Bøggild, H

1998-01-01

This study examined the consideration of health and safety issues in the local process of organizing worktime within the framework of regulations. The study encompassed all 7 hospitals in one region of Denmark. Twenty-three semi-structured interviews were carried out with 2 representatives from the different parties involved (management, cooperation committees, health and safety committees from each hospital, and 2 local unions). Furthermore, a questionnaire was sent to all 114 wards with day and night duty. The response rate was 84%. Data were collected on alterations in worktime schedules, responsibilities, reasons for the present design of schedules, and use of inspection reports. The organization of worktime takes place in single wards without external interference and without guidelines other than the minimum standards set in regulations. At the ward level, management and employees were united in a mutual desire for flexibility, despite the fact that regulations were not always followed. No interaction was found in the management of health and safety factors between the parties concerned at different levels. The demands for flexibility in combination with the absence of guidelines and the missing dynamics between the parties involved imply that the handling of health and safety issues in the organization of worktime may be accidental and unsystematic. In order to consider the health and safety of night and shift workers within the framework of regulations, a clarification of responsibilities, operational levels, and cooperation is required between the parties concerned.

Randomized tolerability analysis of clindamycin phosphate 1.2%-tretinoin 0.025% gel used with benzoyl peroxide wash 4% for acne vulgaris.

PubMed

Draelos, Zoe Diana; Potts, Aaron; Alió Saenz, Alessandra B

2010-12-01

The multiple etiologic factors involved in acne vulgaris make the use of several medications necessary to treat the condition. Use of a fixed combination of clindamycin phosphate 1.2% and tretinoin 0.025% in conjunction with a benzoyl peroxide (BPO) wash 4% targets several pathologic factors simultaneously and mitigates the potential for clindamycin-induced Propionibacterium acnes-resistant strains. New formulations may allow such regimens to be effectively used without overly reduced tolerability resulting from the irritation potential of tretinoin and BPO. This randomized, single-blind study investigated the local tolerability, irritation potential, and safety of an aqueous-based gel (clindamycin phosphate 7.2%-tretinoin 0.025% [CT gel]) when used in conjunction with a BPO wash 4% in participants with mild to moderate acne vulgaris. Participants applied the CT gel once daily in the evening for 4 weeks in conjunction with once-daily morning use of either BPO wash 4% or nonmedicated soap-free cleanser lotion (SFC). Local tolerability and irritation potential were assessed by participants and investigators using separate 6-point scales. The frequency and severity of dryness, scaling, erythema, burning/stinging, and itching increased during the first week of treatment in both treatment arms but decreased thereafter. Local tolerability reactions were slightly more frequent in the CT gel + BPO wash group versus the CT gel + SFC group at week 1 but were generally mild and improved within 1 to 2 weeks. In conclusion, therapy with CT gel + BPO wash appears safe and well-tolerated in participants with mild to moderate acne vulgaris.

Safety, tolerability, and pharmacokinetics of sumatriptan suppositories following single and multiple doses in healthy volunteers.

PubMed

Kunka, R L; Hussey, E K; Shaw, S; Warner, P; Aubert, B; Richard, I; Fowler, P A; Pakes, G E

1997-06-01

A suppository formulation of the 5HT1 agonist sumatriptan could prove an important therapeutic option in migraine patients who dislike or poorly tolerate injectable therapy and where oral tablet administration is unsuitable because of severe migraine-related vomiting. Two independent double-blind, randomized clinical studies were conducted to evaluate the safety, tolerability and pharmacokinetics of sumatriptan suppositories following ascending single doses (four different dose levels) and multiple doses. In the four-period, crossover, single-dose study, 24 healthy male subjects were randomized to receive a suppository containing 12.5, 25, 50, or 100 mg on separate occasions 3-14 days apart. The suppositories were generally well tolerated; transient asthenia, drowsiness, and headache were the most frequently reported adverse events, and these were not dose-related. Peak plasma concentrations (Cmax) of sumatriptan were proportional to dose from 25 to 100 mg; area under the plasma concentration-time curve (AUC infinity) values were proportional to dose except at the highest doses, when they were greater than those predicted from lower doses. For all doses, the tmax of sumatriptan occurred within 2.5 h, and the t1/2 was approximately 2 h. In the two-period, placebo-controlled, crossover, repeat-dose study, 12 healthy adult male subjects were randomized to receive either a 50-mg sumatriptan suppository or placebo suppository, administered rectally twice a day, for 11 doses (5 1/2 days). Adverse events were no more frequent with sumatriptan than with placebo, and stool guaiac, rectal examinations, and physical examinations remained normal. No significant differences were noted between Day 1 and Day 6 values in the AUC, Cmax, time of peak serum concentration (tmax), elimination half-life (t 1/2), fraction of the dose excreted in the urine (fe), or renal clearance (Clr) of sumatriptan or its pharmacologically inactive indole acetic acid metabolite. Serum metabolite

Thermal-safety margins and the necessity of thermoregulatory behavior across latitude and elevation

PubMed Central

Sunday, Jennifer M.; Bates, Amanda E.; Kearney, Michael R.; Colwell, Robert K.; Dulvy, Nicholas K.; Longino, John T.; Huey, Raymond B.

2014-01-01

Physiological thermal-tolerance limits of terrestrial ectotherms often exceed local air temperatures, implying a high degree of thermal safety (an excess of warm or cold thermal tolerance). However, air temperatures can be very different from the equilibrium body temperature of an individual ectotherm. Here, we compile thermal-tolerance limits of ectotherms across a wide range of latitudes and elevations and compare these thermal limits both to air and to operative body temperatures (theoretically equilibrated body temperatures) of small ectothermic animals during the warmest and coldest times of the year. We show that extreme operative body temperatures in exposed habitats match or exceed the physiological thermal limits of most ectotherms. Therefore, contrary to previous findings using air temperatures, most ectotherms do not have a physiological thermal-safety margin. They must therefore rely on behavior to avoid overheating during the warmest times, especially in the lowland tropics. Likewise, species living at temperate latitudes and in alpine habitats must retreat to avoid lethal cold exposure. Behavioral plasticity of habitat use and the energetic consequences of thermal retreats are therefore critical aspects of species’ vulnerability to climate warming and extreme events. PMID:24616528

Thermal-safety margins and the necessity of thermoregulatory behavior across latitude and elevation.

PubMed

Sunday, Jennifer M; Bates, Amanda E; Kearney, Michael R; Colwell, Robert K; Dulvy, Nicholas K; Longino, John T; Huey, Raymond B

2014-04-15

Physiological thermal-tolerance limits of terrestrial ectotherms often exceed local air temperatures, implying a high degree of thermal safety (an excess of warm or cold thermal tolerance). However, air temperatures can be very different from the equilibrium body temperature of an individual ectotherm. Here, we compile thermal-tolerance limits of ectotherms across a wide range of latitudes and elevations and compare these thermal limits both to air and to operative body temperatures (theoretically equilibrated body temperatures) of small ectothermic animals during the warmest and coldest times of the year. We show that extreme operative body temperatures in exposed habitats match or exceed the physiological thermal limits of most ectotherms. Therefore, contrary to previous findings using air temperatures, most ectotherms do not have a physiological thermal-safety margin. They must therefore rely on behavior to avoid overheating during the warmest times, especially in the lowland tropics. Likewise, species living at temperate latitudes and in alpine habitats must retreat to avoid lethal cold exposure. Behavioral plasticity of habitat use and the energetic consequences of thermal retreats are therefore critical aspects of species' vulnerability to climate warming and extreme events.

48 CFR 822.304 - Variations, tolerances, and exemptions.

Code of Federal Regulations, 2010 CFR

2010-10-01

... and Safety Standards Act 822.304 Variations, tolerances, and exemptions. When issuing a contract for nursing home care, a contracting officer may exempt a contractor from certain requirements of the Contract Work Hours and Safety Standards Act (40 U.S.C. 3701-3708) regarding the payment of overtime (see 29 CFR...

48 CFR 822.304 - Variations, tolerances, and exemptions.

Code of Federal Regulations, 2011 CFR

2011-10-01

... and Safety Standards Act 822.304 Variations, tolerances, and exemptions. When issuing a contract for nursing home care, a contracting officer may exempt a contractor from certain requirements of the Contract Work Hours and Safety Standards Act (40 U.S.C. 3701-3708) regarding the payment of overtime (see 29 CFR...

Safety and tolerability of MRI-guided infusion of AAV2-hAADC into the mid-brain of nonhuman primate

PubMed Central

Sebastian, Waldy San; Kells, Adrian P; Bringas, John; Samaranch, Lluis; Hadaczek, Piotr; Ciesielska, Agnieszka; Macayan, Michael J; Pivirotto, Phillip J; Forsayeth, John; Osborne, Sheryl; Wright, J Fraser; Green, Foad; Heller, Gregory; Bankiewicz, Krystof S

2014-01-01

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare, autosomal-recessive neurological disorder caused by mutations in the DDC gene that leads to an inability to synthesize catecholamines and serotonin. As a result, patients suffer compromised development, particularly in motor function. A recent gene replacement clinical trial explored putaminal delivery of recombinant adeno-associated virus serotype 2 vector encoding human AADC (AAV2-hAADC) in AADC-deficient children. Unfortunately, patients presented only modest amelioration of motor symptoms, which authors acknowledged could be due to insufficient transduction of putamen. We hypothesize that, with the development of a highly accurate MRI-guided cannula placement technology, a more effective approach might be to target the affected mid-brain neurons directly. Transduction of AADC-deficient dopaminergic neurons in the substantia nigra and ventral tegmental area with locally infused AAV2-hAADC would be expected to lead to restoration of normal dopamine levels in affected children. The objective of this study was to assess the long-term safety and tolerability of bilateral AAV2-hAADC MRI-guided pressurized infusion into the mid-brain of nonhuman primates. Animals received either vehicle, low or high AAV2-hAADC vector dose and were euthanized 1, 3, or 9 months after surgery. Our data indicate that effective mid-brain transduction was achieved without untoward effects. PMID:25541617

Efficacy and tolerability of preservative-free eye drops containing a fixed combination of dorzolamide and timolol in glaucoma patients.

PubMed

Renieri, Giulia; Führer, Katrin; Scheithe, Karl; Lorenz, Katrin; Pfeiffer, Norbert; Thieme, Hagen

2010-12-01

To evaluate the efficacy and tolerability of preservative-free eye drops (dorzolamide/timolol) in routine management of preservative-sensitive glaucoma patients. Data from 2,298 glaucoma patients requiring intraocular pressure (IOP) reduction and suffering from intolerance to benzalkonium chloride or active agents of previously used eye drops were valid for baseline and safety analysis in this prospective, open, noncomparative, multicenter, noninterventional study. Patients were treated with preservative-free dorzolamide/timolol eye drops for 12 weeks. Main efficacy endpoint was IOP reduction after 12 weeks of treatment. Two thousand forty-nine patients were considered for efficacy analysis. Tolerability was assessed by evaluating adverse drug reactions. Mean baseline IOP was 20.8 mmHg. Baseline IOP was reduced to 16.7 mmHg after 12 weeks of treatment corresponding to a mean absolute (percent) change of -4.1 mmHg (-17.3%). The proportion of patients with IOP ≤21 mmHg increased from 59.9% at baseline to 94.6% after 12 weeks. The most frequently reported ocular adverse drug reactions were burning eyes (2.4%) and hyperemia (0.9%). Local tolerability improved in 79.3% of patients compared to their previous glaucoma therapy. This observational study confirms the IOP lowering effect of preservative-free eye drops containing the fixed combination of dorzolamide/timolol in a large patient's population. The drug was well tolerated and improved the local tolerability in the vast majority of patients.

A randomized, phase 1/2 trial of the safety, tolerability, and immunogenicity of bivalent rLP2086 meningococcal B vaccine in healthy infants.

PubMed

Martinon-Torres, Federico; Gimenez-Sanchez, Francisco; Bernaola-Iturbe, Enrique; Diez-Domingo, Javier; Jiang, Qin; Perez, John L

2014-09-08

Neisseria meningitidis serogroup B (MnB) is a major cause of invasive meningococcal disease in infants. A conserved, surface-exposed lipoprotein, LP2086 (a factor H-binding protein [fHBP]), is a promising MnB vaccine target. A bivalent, recombinant vaccine targeting the fHBP (rLP2086) of MnB was developed. This phase 1/2 clinical study was designed to assess the immunogenicity, safety, and tolerability of a 4-dose series of the rLP2086 vaccine at 20-, 60-, 120-, or 200-μg dose levels in vaccine-naive infants when given with routine childhood vaccines. The study was to consist of two phases: a single-blind sentinel phase and an open-label full enrollment phase. During the sentinel phase, randomization of subjects to the next higher dose was delayed pending a 14-day safety review of dose 1 of the preceding dose cohort. The full enrollment phase was to occur after completion of the sentinel phase. Local reactions were generally mild and adverse events infrequent; however, after only 46 infants were randomized into the study, fever rates were 64% and 90% in subjects receiving one 20- or 60-μg rLP2086 dose, respectively. Most fevers were <39.0°C. Only 2 subjects in the 20-μg group and 1 subject in the 60-μg group experienced fevers >39.0°C; no fevers were >40.0°C. Due to these high fever rates, the study was terminated early. No immunogenicity data were collected. This report discusses the safety and acceptability of rLP2086 in infants after one 20- or 60-μg dose. Due to the high fever rate experienced in the 20- and 60-μg groups, rLP2086 in the current formulation may not be acceptable for infants. Copyright © 2014. Published by Elsevier Ltd.

Short-term safety, tolerability and efficacy of a very low-calorie-ketogenic diet interventional weight loss program versus hypocaloric diet in patients with type 2 diabetes mellitus.

PubMed

Goday, A; Bellido, D; Sajoux, I; Crujeiras, A B; Burguera, B; García-Luna, P P; Oleaga, A; Moreno, B; Casanueva, F F

2016-09-19

Brackground:The safety and tolerability of very low-calorie-ketogenic (VLCK) diets are a current concern in the treatment of obese type 2 diabetes mellitus (T2DM) patients. Evaluating the short-term safety and tolerability of a VLCK diet (<50 g of carbohydrate daily) in an interventional weight loss program including lifestyle and behavioral modification support (Diaprokal Method) in subjects with T2DM. Eighty-nine men and women, aged between 30 and 65 years, with T2DM and body mass index between 30 and 35 kg m(-)(2) participated in this prospective, open-label, multi-centric randomized clinical trial with a duration of 4 months. Forty-five subjects were randomly assigned to the interventional weight loss (VLCK diet), and 44 to the standard low-calorie diet. No significant differences in the laboratory safety parameters were found between the two study groups. Changes in the urine albumin-to-creatinine ratio in VLCK diet were not significant and were comparable to control group. Creatinine and blood urea nitrogen did not change significantly relative to baseline nor between groups. Weight loss and reduction in waist circumference in the VLCK diet group were significantly larger than in control subjects (both P<0.001). The decline in HbA1c and glycemic control was larger in the VLCK diet group (P<0.05). No serious adverse events were reported and mild AE in the VLCK diet group declined at last follow-up. The interventional weight loss program based on a VLCK diet is most effective in reducing body weight and improvement of glycemic control than a standard hypocaloric diet with safety and good tolerance for T2DM patients.

Short-term safety, tolerability and efficacy of a very low-calorie-ketogenic diet interventional weight loss program versus hypocaloric diet in patients with type 2 diabetes mellitus

PubMed Central

Goday, A; Bellido, D; Sajoux, I; Crujeiras, A B; Burguera, B; García-Luna, P P; Oleaga, A; Moreno, B; Casanueva, F F

2016-01-01

Brackground: The safety and tolerability of very low-calorie-ketogenic (VLCK) diets are a current concern in the treatment of obese type 2 diabetes mellitus (T2DM) patients. Objective: Evaluating the short-term safety and tolerability of a VLCK diet (<50 g of carbohydrate daily) in an interventional weight loss program including lifestyle and behavioral modification support (Diaprokal Method) in subjects with T2DM. Methods: Eighty-nine men and women, aged between 30 and 65 years, with T2DM and body mass index between 30 and 35 kg m−2 participated in this prospective, open-label, multi-centric randomized clinical trial with a duration of 4 months. Forty-five subjects were randomly assigned to the interventional weight loss (VLCK diet), and 44 to the standard low-calorie diet. Results: No significant differences in the laboratory safety parameters were found between the two study groups. Changes in the urine albumin-to-creatinine ratio in VLCK diet were not significant and were comparable to control group. Creatinine and blood urea nitrogen did not change significantly relative to baseline nor between groups. Weight loss and reduction in waist circumference in the VLCK diet group were significantly larger than in control subjects (both P<0.001). The decline in HbA1c and glycemic control was larger in the VLCK diet group (P<0.05). No serious adverse events were reported and mild AE in the VLCK diet group declined at last follow-up. Conclusions: The interventional weight loss program based on a VLCK diet is most effective in reducing body weight and improvement of glycemic control than a standard hypocaloric diet with safety and good tolerance for T2DM patients. PMID:27643725

Assessing the Impact of Local Agency Traffic Safety Training Using Ethnographic Techniques

ERIC Educational Resources Information Center

Colling, Timothy K.

2010-01-01

Traffic crashes are a significant source of loss of life, personal injury and financial expense in the United States. In 2008 there were 37,261 people killed and an estimated 2,346,000 people injured nationwide in motor vehicle traffic crashes. State and federal agencies are beginning to focus traffic safety improvement effort on local agency…

Safety and tolerability of prescription omega-3 fatty acids: A systematic review and meta-analysis of randomized controlled trials.

PubMed

Chang, Cheng-Ho; Tseng, Ping-Tao; Chen, Nai-Yu; Lin, Pei-Chin; Lin, Pao-Yen; Chang, Jane Pei-Chen; Kuo, Feng-Yu; Lin, Jenshinn; Wu, Ming-Chang; Su, Kuan-Pin

2018-02-01

Omega-3 fatty acids [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] are widely recommended for health promotion. Over the last decade, prescription omega-3 fatty acid products (RxOME3FAs) have been approved for medical indications. Nonetheless, there is no comprehensive analysis of safety and tolerability of RxOME3FAs so far. A systematic review of randomized controlled trials (RCTs) was carried out based on searches in six electronic databases. The studies involving marketed RxOME3FA products were included, and adverse-effect data were extracted for meta-analysis. Subgroup analysis and meta-regression were conducted to explore the sources of potential heterogeneity. Among the 21 included RCTs (total 24,460 participants; 12,750 from RxOME3FA treatment cohort and 11,710 from control cohort), there was no definite evidence of any RxOME3FA-emerging serious adverse event. Compared with the control group, RxOME3FAs were associated with more treatment-related dysgeusia (fishy taste; p = 0.011) and skin abnormalities (eruption, itching, exanthema, or eczema; p < 0.001). Besides, RxOME3FAs had mild adverse effects upon some non-lipid laboratory measurements [elevated fasting blood sugar (p = 0.005); elevated alanine transaminase (p = 0.022); elevated blood urea nitrogen (p = 0.047); decreased hemoglobin (p = 0.002); decreased hematocrit (p = 0.009)]. Subgroup analysis revealed that EPA/DHA combination products were associated with more treatment-related gastrointestinal adverse events [eructation (belching; p = 0.010); nausea (p = 0.044)] and low-density lipoprotein cholesterol elevation (p = 0.009; difference in means = 4.106mg/dL). RxOME3FAs are generally safe and well tolerated but not free of adverse effects. Post-marketing surveillance and observational studies are still necessary to identify long-term adverse effects and to confirm the safety and tolerability profiles of RxOME3FAs. Copyright © 2018 Elsevier Ltd. All rights reserved.

A phase 1 study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of TAK-063, a selective PDE10A inhibitor.

PubMed

Tsai, Max; Chrones, Lambros; Xie, Jinhui; Gevorkyan, Hakop; Macek, Thomas A

2016-10-01

Schizophrenia is a complex neuropsychiatric disorder characterized, in part, by impaired dopamine signaling. TAK-063 is a selective inhibitor of phosphodiesterase 10A, a key regulator of intracellular signaling pathways that is highly expressed in the striatum. Safety, tolerability, and pharmacokinetics of TAK-063 were evaluated in a phase 1 study. Healthy Japanese and non-Japanese volunteers were randomized into dose cohorts of 3, 10, 30, 100, 300, and 1000 mg. Each fasting volunteer randomly received a single dose of TAK-063 or placebo. Individuals from the 100-mg cohort also received a post-washout, 100-mg dose under fed conditions. A total of 84 volunteers enrolled (14 per cohort). The most common drug-related adverse events (AEs) were somnolence (33.3 %), orthostatic tachycardia (19.7 %), and orthostatic hypotension (9.1 %). The three severe AEs recorded occurred at the highest doses: orthostatic hypotension (n = 1; 300 mg) and somnolence (n = 2; 1000 mg). There were no deaths, serious AEs, or discontinuations due to AEs. TAK-063 exposure increased in a dose-dependent manner. Median T max was reached 3 to 4 h postdose. Fed conditions slowed absorption (T max =  6 h) and increased oral bioavailability. Renal elimination was negligible. Safety and pharmacokinetic parameters were similar between Japanese and non-Japanese subjects. Impairments in cognitive function consistent with the effects of other sedative or hypnotic agents were detected using a validated, computerized cognition battery, CNS Vital Signs. TAK-063 was safe and well tolerated at doses up to 1000 mg and demonstrated a pharmacokinetic profile supporting once-daily dosing. Further evaluation of the clinical safety and efficacy of TAK-063 is warranted.

Ergonomics support for local initiative in improving safety and health at work: International Labour Organization experiences in industrially developing countries.

PubMed

Kawakami, T; Kogi, K

2005-04-15

Ergonomics has played essential roles in the technical cooperation activities of the International Labour Organization (ILO) in occupational safety and health in industrially developing countries. Ergonomics support focusing on practical day-to-day needs at the grass-root workplace has strengthened the local initiative in improving safety and health. Practical action-tools such as ergonomics checklists, local good example photos and group discussions have assisted workers and employers in identifying feasible solutions using locally available resources. Direct participation of workers and employers has been promoted in ergonomics training aimed at immediate solutions. ILO Guidelines on Occupational Safety and Health Management Systems have played increasingly important roles in the systematic planning of local improvement actions. Policy-level programmes to develop network support mechanisms to the grass-root workplace were essential for following up and sustaining local achievements. Practical ergonomics support tools, such as action checklists and low-cost improvement guides, should be developed and widely applied so as to reach grass-root levels and help local people create safer and healthier workplaces.

Safety, tolerability, efficacy and pharmacodynamics of the selective JAK1 inhibitor GSK2586184 in patients with systemic lupus erythematosus.

PubMed

Kahl, L; Patel, J; Layton, M; Binks, M; Hicks, K; Leon, G; Hachulla, E; Machado, D; Staumont-Sallé, D; Dickson, M; Condreay, L; Schifano, L; Zamuner, S; van Vollenhoven, R F

2016-11-01

We aimed to evaluate the pharmacodynamics, efficacy, safety and tolerability of the JAK1 inhibitor GSK2586184 in adults with systemic lupus erythematosus (SLE). In this adaptive, randomized, double-blind, placebo-controlled study, patients received oral GSK2586184 50-400 mg, or placebo twice daily for 12 weeks. Primary endpoints included interferon-mediated messenger RNA transcription over time, changes in Safety of Estrogen in Lupus National Assessment-SLE Disease Activity Index score, and number/severity of adverse events. A pre-specified interim analysis was performed when ≥ 5 patients per group completed 2 weeks of treatment. In total, 84-92% of patients were high baseline expressors of the interferon transcriptional biomarkers evaluated. At interim analysis, GSK2586184 showed no significant effect on mean interferon transcriptional biomarker expression (all panels). The study was declared futile and recruitment was halted at 50 patients. Shortly thereafter, significant safety data were identified, including elevated liver enzymes in six patients (one confirmed and one suspected case of Drug Reaction with Eosinophilia and Systemic Symptoms), leading to immediate dosing cessation. Safety of Estrogen in Lupus National Assessment-SLE Disease Activity Index scores were not analysed due to the small number of patients completing the study. The study futility and safety data described for GSK2586184 do not support further evaluation in patients with SLE. Study identifiers: GSK Study JAK115919; ClinicalTrials.gov identifier: NCT01777256.

Pharmacokinetic Profile and Tolerability of Liposomal Bupivacaine Following a Repeated Dose via Local Subcutaneous Infiltration in Healthy Volunteers.

PubMed

Rice, David; Heil, Justin W; Biernat, Lukasz

2017-03-01

Liposomal bupivacaine is indicated for administration into the surgical site to produce post-surgical analgesia. The objectives of this study were to characterize the pharmacokinetic and safety profiles of liposomal bupivacaine following a repeated dose in healthy volunteers. Healthy adults were assigned to receive liposomal bupivacaine via subcutaneous infiltration in a single 266 mg dose (cohort 1) or in two 266 mg doses, with the second dose given immediately, 24, 48, or 72 h after the first dose (cohorts 2-5). Pharmacokinetic parameters were estimated from blood samples collected up to day 14. Subjects were monitored for adverse events and assessed for neurologic function, cardiac function, and infiltration area abnormalities. Twelve subjects were assigned to each cohort. The mean ± standard deviation maximum observed plasma concentration (C max ) of bupivacaine after a single dose was 129 ± 47 ng/mL. The mean C max after the second dose was higher, but always less than double the C max for cohort 1. The highest individual C max (589 ng/mL) was observed in a subject who received the second dose 24 h after the first dose (cohort 4), but was well below the reported thresholds for neurotoxicity and cardiac toxicity (2000 and 4000 ng/mL, respectively). A single and repeated dose were well-tolerated, and there were no clinically meaningful findings regarding neurologic examinations and electrocardiography. The mean C max following a repeated dose of liposomal bupivacaine remained well below accepted values for central nervous system and cardiac toxicity. Liposomal bupivacaine was well-tolerated and revealed no clinically important safety signals. CLINICALTRIALS. NCT02210247.

Efficacy and safety of local steroids for urethra strictures: a systematic review and meta-analysis.

PubMed

Zhang, Kaile; Qi, Er; Zhang, Yumeng; Sa, Yinglong; Fu, Qiang

2014-08-01

Local steroids have been used as an adjuvant therapy to patients undergoing internal urethrotomy (IU) in treating urethral strictures. Whether this technique is effective and safe is still controversial. The aim of this study is to determine the efficacy and safety of local steroids as applied with the IU procedure. A systematic review of the literature was performed by searching Medline, Embase, Cochrane Library Databases, and the Web of Science. We included only prospective randomized, controlled trials that compared the efficacy and safety between IU procedures with applied local steroids and those without. Eight studies were found eligible for further analysis. In total, 203 patients undergoing IU were treated with steroid injection or catheter lubrication. Time to recurrence is statistically significant (mean: 10.14 and 5.07 months, P<0.00001).The number of patients with recurrent stricture formation significantly decreased at different follow-up time points (P=0.05).No statistically significant differences were found between the recurrence rates, adverse effects, and success rates of second IUs in patients with applied local steroids and those without. The use of local steroids with IU seems to prolong time to stricture recurrence but does not seem to affect the high stricture recurrence rate following IU. When local steroids are applied with complementary intention, the disease control outcomes are encouraging. Further robust comparative effectiveness studies are now required.

The development of local calibration factors for implementing the highway safety manual in Maryland.

DOT National Transportation Integrated Search

2014-03-01

The goal of the study was to determine local calibration factors (LCFs) to adjust predicted motor : vehicle traffic crashes for the Maryland-specific application of the Highway Safety Manual : (HSM). Since HSM predictive models were developed using d...

Software safety

NASA Technical Reports Server (NTRS)

Leveson, Nancy

1987-01-01

Software safety and its relationship to other qualities are discussed. It is shown that standard reliability and fault tolerance techniques will not solve the safety problem for the present. A new attitude requires: looking at what you do NOT want software to do along with what you want it to do; and assuming things will go wrong. New procedures and changes to entire software development process are necessary: special software safety analysis techniques are needed; and design techniques, especially eliminating complexity, can be very helpful.

Safety, tolerability, pharmacokinetics and pharmacodynamics of single doses of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in healthy Japanese subjects.

PubMed

Sarashina, Akiko; Koiwai, Kazuki; Seman, Leo J; Yamamura, Norio; Taniguchi, Atsushi; Negishi, Takahiro; Sesoko, Shogo; Woerle, Hans J; Dugi, Klaus A

2013-01-01

This randomized, placebo-controlled within dose groups, double-blind, single rising dose study investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of 1 mg to 100 mg doses of empagliflozin in 48 healthy Japanese male subjects. Empagliflozin was rapidly absorbed, reaching peak levels in 1.25 to 2.50 h; thereafter, plasma concentrations declined in a biphasic fashion, with mean terminal elimination half-life ranging from 7.76 to 11.7 h. Increase in empagliflozin exposure was proportional to dose. Oral clearance was dose independent and ranged from 140 to 172 mL/min. In the 24 h following 100 mg empagliflozin administration, the mean (%CV) amount of glucose excreted in urine was 74.3 (17.1) g. The amount and the maximum rate of glucose excreted via urine increased with dose of empagliflozin. Nine adverse events, all of mild intensity, were reported by 8 subjects (7 with empagliflozin and 1 with the placebo). No hypoglycemia was reported. In conclusion, 1 mg to 100 mg doses of empagliflozin had a good safety and tolerability profile in healthy Japanese male subjects. Exposure to empagliflozin was dose proportional. The amount and rate of urinary glucose excretion were higher with empagliflozin than with the placebo, and increased with empagliflozin dose.

Politicas de tolerancia cero (Zero Tolerance Policies). ERIC Digest.

ERIC Educational Resources Information Center

McAndrews, Tobin

State legislatures and school boards are adopting a growing number of zero-tolerance polices toward weapons, guns, and violence. Zero-tolerance polices are rules intended to address specific school-safety issues. They have arisen in part as a response to the threat of the withdrawal of federal funds under the 1994 Gun-Free Schools Act, and…

46 CFR 162.018-5 - Blow-down adjustment and popping tolerance.

Code of Federal Regulations, 2014 CFR

2014-10-01

..., CONSTRUCTION, AND MATERIALS: SPECIFICATIONS AND APPROVAL ENGINEERING EQUIPMENT Safety Relief Valves, Liquefied Compressed Gas § 162.018-5 Blow-down adjustment and popping tolerance. (a) Safety relief valves shall be so.... Safety relief valves shall be designed to open sharply and reach full lift and capacity at the maximum...

46 CFR 162.018-5 - Blow-down adjustment and popping tolerance.

Code of Federal Regulations, 2011 CFR

2011-10-01

..., CONSTRUCTION, AND MATERIALS: SPECIFICATIONS AND APPROVAL ENGINEERING EQUIPMENT Safety Relief Valves, Liquefied Compressed Gas § 162.018-5 Blow-down adjustment and popping tolerance. (a) Safety relief valves shall be so.... Safety relief valves shall be designed to open sharply and reach full lift and capacity at the maximum...

46 CFR 162.018-5 - Blow-down adjustment and popping tolerance.

Code of Federal Regulations, 2010 CFR

2010-10-01

..., CONSTRUCTION, AND MATERIALS: SPECIFICATIONS AND APPROVAL ENGINEERING EQUIPMENT Safety Relief Valves, Liquefied Compressed Gas § 162.018-5 Blow-down adjustment and popping tolerance. (a) Safety relief valves shall be so.... Safety relief valves shall be designed to open sharply and reach full lift and capacity at the maximum...

46 CFR 162.018-5 - Blow-down adjustment and popping tolerance.

Code of Federal Regulations, 2013 CFR

2013-10-01

..., CONSTRUCTION, AND MATERIALS: SPECIFICATIONS AND APPROVAL ENGINEERING EQUIPMENT Safety Relief Valves, Liquefied Compressed Gas § 162.018-5 Blow-down adjustment and popping tolerance. (a) Safety relief valves shall be so.... Safety relief valves shall be designed to open sharply and reach full lift and capacity at the maximum...

46 CFR 162.018-5 - Blow-down adjustment and popping tolerance.

Code of Federal Regulations, 2012 CFR

2012-10-01

..., CONSTRUCTION, AND MATERIALS: SPECIFICATIONS AND APPROVAL ENGINEERING EQUIPMENT Safety Relief Valves, Liquefied Compressed Gas § 162.018-5 Blow-down adjustment and popping tolerance. (a) Safety relief valves shall be so.... Safety relief valves shall be designed to open sharply and reach full lift and capacity at the maximum...

Long-term safety and tolerability of once-daily mesalamine granules in the maintenance of remission of ulcerative colitis.

PubMed

Lichtenstein, Gary R; Barrett, Andrew C; Bortey, Enoch; Paterson, Craig; Forbes, William P

2014-08-01

Ulcerative colitis (UC), a chronic, relapsing, and remitting inflammatory bowel disease, requires long-term treatment to maintain remission. In this study, the long-term safety and tolerability of mesalamine granules (MG) therapy was evaluated in the maintenance of UC remission. Previous prospective studies evaluating different oral mesalamine formulations have not exceeded a duration of 14 months. A phase 3, multicenter, 24-month, open-label extension study evaluating MG 1.5 g once daily in patients who achieved previous remission from mild to moderate UC was performed. Eligible patients had successfully participated in 1 of 2 previous 6-month double-blind, placebo-controlled trials or were new patients in remission. Safety assessments included monitoring of adverse events (AEs) and clinical laboratory tests. Risk of UC recurrence was assessed by the occurrence of UC-related AEs. Of the 393 patients enrolled (280 from the double-blind studies; 113 new patients), 388 were included in the safety population. The most common AEs included nasopharyngitis (13.9%), headache (11.6%), and diarrhea (10.8%), and the incidence of these events was generally lower in the MG group versus historical placebo group from the double-blind studies. Pancreatic, renal, and hepatic AEs occurred in 23 patients (5.9%). The risk of UC-related AEs was low and was maintained for 24 months during the open-label study. Once-daily MG has a favorable safety profile for the maintenance of remission for up to 2 years in patients with UC.

Safety and tolerability of low-dose naltrexone therapy in children with moderate to severe Crohn's disease: a pilot study.

PubMed

Smith, Jill P; Field, Douglas; Bingaman, Sandra I; Evans, Robert; Mauger, David T

2013-04-01

There is an unmet need for safe and effective medicines to treat children with Crohn's disease. Recently, investigations have shown an association between endogenous opioid peptides and inflammatory cells. The aims of this study were to evaluate the safety and tolerability of an opioid antagonist, naltrexone, in children with moderate to severe Crohn's disease. A pilot clinical trial was conducted in children with moderate to severe Crohn's disease. Fourteen subjects with a mean age of 12.3 years (range, 8 to 17 y) were enrolled. Children were randomized to placebo or naltrexone (0.1 mg/kg) orally for 8 weeks followed by open-labeled treatment with 8 additional weeks of naltrexone. Safety and toxicity were monitored by physical examinations and blood chemistries. Clinical activity was assessed by the Pediatric Crohn's Disease Activity Index (PCDAI) and Quality of life was monitored by the Impact III survey. Oral naltrexone was well tolerated without any serious adverse events in children with moderate to severe Crohn's disease. PCDAI scores significantly decreased from pretreatment values (34.2±3.3) with an 8-week course of naltrexone therapy (21.7±3.9) (P=0.005). Twenty-five percent of those treated with naltrexone were considered in remission (score ≤10) and 67% had improved with mild disease activity (decrease in PCDAI score by at least 10 points) at the end of the study. Systemic and social quality of life improved with naltrexone treatment (P=0.035). Naltrexone therapy seems safe with limited toxicity when given to children with Crohn's disease and may reduce disease activity.

Damage Tolerance Assessment Branch

NASA Technical Reports Server (NTRS)

Walker, James L.

2013-01-01

The Damage Tolerance Assessment Branch evaluates the ability of a structure to perform reliably throughout its service life in the presence of a defect, crack, or other form of damage. Such assessment is fundamental to the use of structural materials and requires an integral blend of materials engineering, fracture testing and analysis, and nondestructive evaluation. The vision of the Branch is to increase the safety of manned space flight by improving the fracture control and the associated nondestructive evaluation processes through development and application of standards, guidelines, advanced test and analytical methods. The Branch also strives to assist and solve non-aerospace related NDE and damage tolerance problems, providing consultation, prototyping and inspection services.

Evaluation of efficacy, pharmacokinetics and tolerability of peptidomimetic aspartic proteinase inhibitors as cream formulation in experimental vaginal candidiasis.

PubMed

De Bernardis, Flavia; Arancia, Silvia; Tringali, Giuseppe; Greco, Maria Cristina; Ragazzoni, Enzo; Calugi, Chiara; Trabocchi, Andrea; Sandini, Silvia; Graziani, Sofia; Cauda, Roberto; Cassone, Antonio; Guarna, Antonio; Navarra, Pierluigi

2014-08-01

It has been previously shown that the treatment with the two protease inhibitors APG12 and APG19 confers protection in a rat model of mucosal candidiasis; in this study, we examined whether these peptidomimetic inhibitors are also effective as a cream formulation in reducing Candida albicans vaginal infection. These efficacy studies were performed in a rat model of estrogen-dependent rat vaginitis by C. albicans on both azole-susceptible and azole-resistant C. albicans, and on both caspofungin-susceptible and caspofungin-resistant C. albicans strains. In vivo studies were also conducted in female albino rats and rabbits to obtain information about the safety, local tolerability and principal pharmacokinetics parameters of the two compounds. Both hit compounds showed remarkable results within the 48-h range as effective inhibitors of the infection, particularly causing rapid decay of vaginal C. albicans burden. Importantly, the two compounds showed marked acceleration of fungus clearance in the rats challenged with the fluconazole-resistant as well as with the capsofungin-resistant strain of C. albicans. Both compounds showed fast elimination rates when given by the intravenous route, and poor systemic absorption after intravaginal cream administration. Test drugs were also well tolerated in 7-day local tolerability experiments in the rabbit. © 2014 Royal Pharmaceutical Society.

78 FR 20277 - Safety Zones & Special Local Regulations; Recurring Marine Events in Captain of the Port Long...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-04-04

...The Coast Guard proposes to add, delete, and modify safety zones and special local regulations and add language to clarify time frames and notification requirements for annual marine events in the Sector Long Island Sound Captain of the Port (COTP) Zone. When these regulated areas are activated and subject to enforcement, this rule would restrict vessels from portions of water areas during these recurring events. The safety zones and special local regulations will facilitate public notification of events and provide protective measures for the maritime public and event participants from the hazards associated with these recurring events.

Efficacy, safety, and improved tolerability of travoprost BAK-free ophthalmic solution compared with prior prostaglandin therapy

PubMed Central

Henry, J Charles; Peace, James H; Stewart, Jeanette A; Stewart, William C

2008-01-01

Purpose To evaluate the efficacy, safety and tolerability of changing to travoprost BAK-free from prior prostaglandin therapy in patients with primary open-angle glaucoma or ocular hypertension. Design Prospective, multi-center, historical control study. Methods Patients treated with latanoprost or bimatoprost who needed alternative therapy due to tolerability issues were enrolled. Patients were surveyed using the Ocular Surface Disease Index (OSDI) to evaluate OSD symptoms prior to changing to travoprost BAK-free dosed once every evening. Patients were re-evaluated 3 months later. Results In 691 patients, travoprost BAK-free demonstrated improved mean OSDI scores compared to either latanoprost or bimatoprost (p < 0.0001). Patients having any baseline OSD symptoms (n = 235) demonstrated significant improvement after switching to travoprost BAK-free (p < 0.0001). In 70.2% of these patients, symptoms were reduced in severity by at least 1 level. After changing medications to travoprost BAK-free, mean intraocular pressure (IOP) was significantly decreased (p < 0.0001). Overall, 72.4% preferred travoprost BAK-free (p < 0.0001, travoprost BAK-free vs prior therapy). Travoprost BAK-free demonstrated less conjunctival hyperemia than either prior therapy (p < 0.0001). Conclusions Patients previously treated with a BAK-preserved prostaglandin analog who are changed to travoprost BAK-free have clinically and statistically significant improvement in their OSD symptoms, decreased hyperemia, and equal or better IOP control. PMID:19668762

49 CFR 325.9 - Measurement tolerances.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 49 Transportation 5 2010-10-01 2010-10-01 false Measurement tolerances. 325.9 Section 325.9 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL MOTOR CARRIER SAFETY... allowed to take into account the effects of the following factors: (1) The consensus standard practice of...

Safety and Tolerability of Transitioning from Cangrelor to Ticagrelor in Patients Who Underwent Percutaneous Coronary Intervention.

PubMed

Badreldin, Hisham A; Carter, Danielle; Cook, Bryan M; Qamar, Arman; Vaduganathan, Muthiah; Bhatt, Deepak L

2017-08-01

The 3 phase 3 CHAMPION (Cangrelor vs Standard Therapy to Achieve Optimal Management of Platelet Inhibition) trials collectively demonstrated the safety of transitioning from cangrelor, a potent, parenteral rapidly-acting P2Y 12 inhibitor, to clopidogrel in patients who underwent percutaneous coronary intervention (PCI). However, variation in timing of therapy, site-specific binding, and drug half-lives may theoretically complicate switching to other oral P2Y 12 inhibitors. Since regulatory approval, limited data are available regarding the "real-world" safety and tolerability of transitioning to these more potent oral P2Y 12 antagonists. From November 2015 to January 2017, we evaluated the clinical profiles and efficacy and safety outcomes in cangrelor-treated patients who underwent PCI transitioned to clopidogrel (n = 42) or ticagrelor (n = 82) at a large, tertiary care center. Most patients receiving cangrelor underwent PCI with a drug-eluting stent for acute coronary syndrome via a radial approach in the background of unfractionated heparin. Stent thrombosis within 48 hours was rare and occurred in 1 patient treated with ticagrelor. Global Use of Strategies to Open Occluded Coronary Arteries-defined bleeding occurred in 20% of patients switched to ticagrelor and 29% of patients switched to clopidogrel, but none were severe or life-threatening. In conclusion, rates of stent thrombosis and severe/life-threatening bleeding were low and comparable with those identified in the CHAMPION program, despite use of more potent oral P2Y 12 inhibition. Copyright © 2017 Elsevier Inc. All rights reserved.

Efficacy, safety, and tolerability of herpes zoster vaccine in persons aged 50-59 years.

PubMed

Schmader, Kenneth E; Levin, Myron J; Gnann, John W; McNeil, Shelly A; Vesikari, Timo; Betts, Robert F; Keay, Susan; Stek, Jon E; Bundick, Nickoya D; Su, Shu-Chih; Zhao, Yanli; Li, Xiaoming; Chan, Ivan S F; Annunziato, Paula W; Parrino, Janie

2012-04-01

Herpes zoster (HZ) adversely affects individuals aged 50-59, but vaccine efficacy has not been assessed in this population. This study was designed to determine the efficacy, safety, and tolerability of zoster vaccine for preventing HZ in persons aged 50-59 years. This was a randomized, double-blind, placebo-controlled study of 22 439 subjects aged 50-59 years conducted in North America and Europe. Subjects were given 1 dose of licensed zoster vaccine (ZV) (Zostavax; Merck) and followed for occurrence of HZ for ≥1 year (mean, 1.3 years) postvaccination until accrual of ≥96 confirmed HZ cases (as determined by testing lesions swabs for varicella zoster virus DNA by polymerase chain reaction). Subjects were followed for all adverse events (AEs) from day 1 to day 42 postvaccination and for serious AEs (SAEs) through day 182 postvaccination. The ZV reduced the incidence of HZ (30 cases in vaccine group, 1.99/1000 person-years vs 99 cases in placebo group, 6.57/1000 person-years). Vaccine efficacy for preventing HZ was 69.8% (95% confidence interval, 54.1-80.6). AEs were reported by 72.8% of subjects in the ZV group and 41.5% in the placebo group, with the difference primarily due to higher rates of injection-site AEs and headache. The proportion of subjects reporting SAEs occurring within 42 days postvaccination (ZV, 0.6%; placebo, 0.5%) and 182 days postvaccination (ZV, 2.1%; placebo, 1.9%) was similar between groups. In subjects aged 50-59 years, the ZV significantly reduced the incidence of HZ and was well tolerated. NCT00534248.

Bowel cleansing before colonoscopy: Balancing efficacy, safety, cost and patient tolerance

PubMed Central

Harrison, Nicole M; Hjelkrem, Michael C

2016-01-01

Effective colorectal cancer screening relies on reliable colonoscopy findings which are themselves dependent on adequate bowel cleansing. Research has consistently demonstrated that inadequate bowel preparation adversely affects the adenoma detection rate and leads gastroenterologists to recommend earlier follow up than is consistent with published guidelines. Poor preparation affects as many as 30% of colonoscopies and contributes to an increased cost of colonoscopies. Patient tolerability is strongly affected by the preparation chosen and manner in which it is administered. Poor tolerability is, in turn, associated with lower quality bowel preparations. Recently, several new developments in both agents being used for bowel preparation and in the timing of administration have brought endoscopists closer to achieving the goal of effective, reliable, safe, and tolerable regimens. Historically, large volume preparations given in a single dose were administered to patients in order to achieve adequate bowel cleansing. These were poorly tolerated, and the unpleasant taste of and significant side effects produced by these large volume regimens contributed significantly to patients’ inability to reliably complete the preparation and to a reluctance to repeat the procedure. Smaller volumes, including preparations that are administered as tablets to be consumed with water, given as split doses have significantly improved both the patient experience and efficacy, and an appreciation of the importance of the preparation to colonoscopy interval have produced additional cleansing. PMID:26788258

Efficacy, tolerance and safety of new intragastric air-filled balloon (Heliosphere BAG) for obesity: the experience of 17 cases.

PubMed

Trande, Paolo; Mussetto, Alessandro; Mirante, Vincenzo G; De Martinis, Elvira; Olivetti, Giampiero; Conigliaro, Rita L; De Micheli, Enrico A

2010-09-01

Overweight and obesity lead to serious health consequences, so that many strategies were recommended for preventing or curing this emerging problem. Treatments are various: diet, physical activity, psychotherapy, drugs, and bariatric surgery. Moreover, during these years, the use of intragastric balloon (BIB) to treat obesity increased rapidly, aimed to (1) reduce bariatric surgical risks; (2) reduce general surgical risks; (3) lead to a significant reduction in the prevalence of cardiovascular diseases, diabetes, musculoskeletal disorders and some cancers. Recently, a new device inflated with air to reduce weight has been developed since 2004 (Heliosphere BAG). Between March 2006 and September 2006, in our unit, intragastric air-filled balloon insertion was performed under general anesthesia and endoscopic control. The balloons were removed after 6 months. We evaluated efficacy, tolerance, and safety of this technique. Seventeen patients (eight men, nine women), with a mean age of 43 +/- 10 years (range 18-65), mean basal BMI of 46 +/- 8 (range 35-58) were included, after providing informed consent. Weight and BMI loss were evaluated in all patients. BMI decreased 4 +/- 3 (range +0.33/-11), weight loss was 11 +/- 9 kg (range +1/-29.5; 8.5%). 14/17 patients maintain a BMI > 35 at the time of balloon removal. The difference between initial weight and BMI was statistically significant (p = 0.02 for weight and p < 0.01 for BMI, T Student test). Tolerance was very good, limited only to some dyspeptic symptoms during the first 3 days after insertion. One asymptomatic gastric ulcer was seen at the removal of balloon. Only one severe adverse effect was registered at the time of insertion (acute coronary syndrome in patient with chronic coronary disease). No serious technical problems were noted at balloon insertion. Balloon removal was more difficult and successful in 15/17 cases (one distal migration and one patient led to surgery because of balloon fragmentation

A 24-Week, Open-Label Extension Study to Investigate the Long-term Safety, Tolerability, and Efficacy of 13.3 mg/24 h Rivastigmine Patch in Patients With Severe Alzheimer Disease.

PubMed

Farlow, Martin R; Grossberg, George T; Sadowsky, Carl H; Meng, Xiangyi; Velting, Drew M

2015-01-01

The long-term safety, tolerability, and efficacy of high-dose 13.3 mg/24 h rivastigmine patch in severe Alzheimer disease was evaluated in a 24-week, open-label extension to the double-blind ACTION study. Safety and tolerability, and efficacy on the Alzheimer's Disease Cooperative Study-Activities of Daily Living scale-Severe Impairment Version (ADCS-ADL-SIV), Severe Impairment Battery (SIB), and ADCS-Clinical Global Impression of Change (ADCS-CGIC) were assessed. Overall, 197 patients continued on 13.3 mg/24 h patch; 199 uptitrated from 4.6 mg/24 h to 13.3 mg/24 h patch. The incidence of adverse events (AEs), serious AEs and discontinuations due to AEs was similar in patients who continued on, and patients who uptitrated to, 13.3 mg/24 h patch (AEs: 57.9% and 59.8%; serious AEs: 16.2% and 16.1%; discontinuations: 11.2% and 12.1%, respectively). Larger mean changes from double-blind baseline were observed in patients uptitrated on the ADCS-ADL-SIV (-4.6; SD=8.7) and SIB (-7.0; SD=16.6), than those who continued on 13.3 mg/24 h patch (-3.9; SD=8.0 and -4.7; SD=16.8, respectively). ADCS-CGIC scores were comparable. There were no clinically relevant between-group differences in safety and tolerability. Greater decline was observed in patients with delayed uptitration to high-dose 13.3 mg/24 h patch than patients who continued on high-dose patch.

Mechanisms of food processing and storage-related stress tolerance in Clostridium botulinum.

PubMed

Dahlsten, Elias; Lindström, Miia; Korkeala, Hannu

2015-05-01

Vegetative cultures of Clostridium botulinum produce the extremely potent botulinum neurotoxin, and may jeopardize the safety of foods unless sufficient measures to prevent growth are applied. Minimal food processing relies on combinations of mild treatments, primarily to avoid deterioration of the sensory qualities of the food. Tolerance of C. botulinum to minimal food processing is well characterized. However, data on effects of successive treatments on robustness towards further processing is lacking. Developments in genetic manipulation tools and the availability of annotated genomes have allowed identification of genetic mechanisms involved in stress tolerance of C. botulinum. Most studies focused on low temperature, and the importance of various regulatory mechanisms in cold tolerance of C. botulinum has been demonstrated. Furthermore, novel roles in cold tolerance were shown for metabolic pathways under the control of these regulators. A role for secondary oxidative stress in tolerance to extreme temperatures has been proposed. Additionally, genetic mechanisms related to tolerance to heat, low pH, and high salinity have been characterized. Data on genetic stress-related mechanisms of psychrotrophic Group II C. botulinum strains are scarce; these mechanisms are of interest for food safety research and should thus be investigated. This minireview encompasses the importance of C. botulinum as a food safety hazard and its central physiological characteristics related to food-processing and storage-related stress. Special attention is given to recent findings considering genetic mechanisms C. botulinum utilizes in detecting and countering these adverse conditions. Copyright © 2014 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

Avoiding and tolerating latency in large-scale next-generation shared-memory multiprocessors

NASA Technical Reports Server (NTRS)

Probst, David K.

1993-01-01

A scalable solution to the memory-latency problem is necessary to prevent the large latencies of synchronization and memory operations inherent in large-scale shared-memory multiprocessors from reducing high performance. We distinguish latency avoidance and latency tolerance. Latency is avoided when data is brought to nearby locales for future reference. Latency is tolerated when references are overlapped with other computation. Latency-avoiding locales include: processor registers, data caches used temporally, and nearby memory modules. Tolerating communication latency requires parallelism, allowing the overlap of communication and computation. Latency-tolerating techniques include: vector pipelining, data caches used spatially, prefetching in various forms, and multithreading in various forms. Relaxing the consistency model permits increased use of avoidance and tolerance techniques. Each model is a mapping from the program text to sets of partial orders on program operations; it is a convention about which temporal precedences among program operations are necessary. Information about temporal locality and parallelism constrains the use of avoidance and tolerance techniques. Suitable architectural primitives and compiler technology are required to exploit the increased freedom to reorder and overlap operations in relaxed models.

Insect Venom Immunotherapy: Analysis of the Safety and Tolerance of 3 Buildup Protocols Frequently Used in Spain.

PubMed

Gutiérrez Fernández, D; Moreno-Ancillo, A; Fernández Meléndez, S; Domínguez-Noche, C; Gálvez Ruiz, P; Alfaya Arias, T; Carballada González, F; Alonso Llamazares, A; Marques Amat, L; Vega Castro, A; Antolín Amérigo, D; Cruz Granados, S; Ruiz León, B; Sánchez Morillas, L; Fernández Sánchez, J; Soriano Gomis, V; Borja Segade, J; Dalmau Duch, G; Guspi Bori, R; Miranda Páez, A

2016-01-01

Hymenoptera venom immunotherapy (VIT) is an effective treatment but not one devoid of risk, as both local and systemic adverse reactions may occur, especially in the initial phases. We compared the tolerance to 3 VIT buildup protocols and analyzed risk factors associated with adverse reactions during this phase. We enrolled 165 patients divided into 3 groups based on the buildup protocol used (3, 4, and 9 weeks). The severity of systemic reactions was evaluated according to the World Allergy Organization model. Results were analyzed using exploratory descriptive statistics, and variables were compared using analysis of variance. Adverse reactions were recorded in 53 patients (32%) (43 local and 10 systemic). Local reactions were immediate in 27 patients (63%) and delayed in 16 (37%). The severity of the local reaction was slight/moderate in 15 patients and severe in 13. Systemic reactions were grade 1-2. No significant association was found between the treatment modality and the onset of local or systemic adverse reactions or the type of local reaction. We only found a statistically significant association between severity of the local reaction and female gender. As for the risk factors associated with systemic reactions during the buildup phase, we found no significant differences in values depending on the protocol used or the insect responsible. The buildup protocols compared proved to be safe and did not differ significantly from one another. In the population studied, patients undergoing the 9-week schedule presented no systemic reactions. Therefore, this protocol can be considered the safest approach.

Randomized, double-blind study of the safety, tolerability, and efficacy of tafenoquine versus mefloquine for malaria prophylaxis in nonimmune subjects.

PubMed

Nasveld, Peter E; Edstein, Michael D; Reid, Mark; Brennan, Leonard; Harris, Ivor E; Kitchener, Scott J; Leggat, Peter A; Pickford, Philip; Kerr, Caron; Ohrt, Colin; Prescott, William

2010-02-01

This study represents the first phase III trial of the safety, tolerability, and effectiveness of tafenoquine for malaria prophylaxis. In a randomized (3:1), double-blinded study, Australian soldiers received weekly malaria prophylaxis with 200 mg tafenoquine (492 subjects) or 250 mg mefloquine (162 subjects) for 6 months on a peacekeeping deployment to East Timor. After returning to Australia, tafenoquine-receiving subjects received a placebo and mefloquine-receiving subjects received 30 mg primaquine daily for 14 days. There were no clinically significant differences between hematological and biochemical parameters of the treatment groups. Treatment-related adverse events for the two groups were similar (tafenoquine, 13.4%; mefloquine, 11.7%). Three subjects on tafenoquine (0.6%) and none on mefloquine discontinued prophylaxis because of possible drug-related adverse events. No diagnoses of malaria occurred for either group during deployment, but 4 cases (0.9%) and 1 case (0.7%) of Plasmodium vivax infection occurred among the tafenoquine and mefloquine groups, respectively, up to 20 weeks after discontinuation of medication. In a subset of subjects recruited for detailed safety assessments, treatment-related mild vortex keratopathy was detected in 93% (69 of 74) of tafenoquine subjects but none of the 21 mefloquine subjects. The vortex keratopathy was not associated with any effect on visual acuity and was fully resolved in all subjects by 1 year. Tafenoquine appears to be safe and well tolerated as malaria prophylaxis. Although the volunteers' precise exposure to malaria could not be proven in this study, tafenoquine appears to be a highly efficacious drug for malaria prophylaxis.

Randomized, Double-Blind Study of the Safety, Tolerability, and Efficacy of Tafenoquine versus Mefloquine for Malaria Prophylaxis in Nonimmune Subjects▿

PubMed Central

Nasveld, Peter E.; Edstein, Michael D.; Reid, Mark; Brennan, Leonard; Harris, Ivor E.; Kitchener, Scott J.; Leggat, Peter A.; Pickford, Philip; Kerr, Caron; Ohrt, Colin; Prescott, William

2010-01-01

This study represents the first phase III trial of the safety, tolerability, and effectiveness of tafenoquine for malaria prophylaxis. In a randomized (3:1), double-blinded study, Australian soldiers received weekly malaria prophylaxis with 200 mg tafenoquine (492 subjects) or 250 mg mefloquine (162 subjects) for 6 months on a peacekeeping deployment to East Timor. After returning to Australia, tafenoquine-receiving subjects received a placebo and mefloquine-receiving subjects received 30 mg primaquine daily for 14 days. There were no clinically significant differences between hematological and biochemical parameters of the treatment groups. Treatment-related adverse events for the two groups were similar (tafenoquine, 13.4%; mefloquine, 11.7%). Three subjects on tafenoquine (0.6%) and none on mefloquine discontinued prophylaxis because of possible drug-related adverse events. No diagnoses of malaria occurred for either group during deployment, but 4 cases (0.9%) and 1 case (0.7%) of Plasmodium vivax infection occurred among the tafenoquine and mefloquine groups, respectively, up to 20 weeks after discontinuation of medication. In a subset of subjects recruited for detailed safety assessments, treatment-related mild vortex keratopathy was detected in 93% (69 of 74) of tafenoquine subjects but none of the 21 mefloquine subjects. The vortex keratopathy was not associated with any effect on visual acuity and was fully resolved in all subjects by 1 year. Tafenoquine appears to be safe and well tolerated as malaria prophylaxis. Although the volunteers' precise exposure to malaria could not be proven in this study, tafenoquine appears to be a highly efficacious drug for malaria prophylaxis. PMID:19995933

Toward Human-Carnivore Coexistence: Understanding Tolerance for Tigers in Bangladesh.

PubMed

Inskip, Chloe; Carter, Neil; Riley, Shawn; Roberts, Thomas; MacMillan, Douglas

2016-01-01

Fostering local community tolerance for endangered carnivores, such as tigers (Panthera tigris), is a core component of many conservation strategies. Identification of antecedents of tolerance will facilitate the development of effective tolerance-building conservation action and secure local community support for, and involvement in, conservation initiatives. We use a stated preference approach for measuring tolerance, based on the 'Wildlife Stakeholder Acceptance Capacity' concept, to explore villagers' tolerance levels for tigers in the Bangladesh Sundarbans, an area where, at the time of the research, human-tiger conflict was severe. We apply structural equation modeling to test an a priori defined theoretical model of tolerance and identify the experiential and psychological basis of tolerance in this community. Our results indicate that beliefs about tigers and about the perceived current tiger population trend are predictors of tolerance for tigers. Positive beliefs about tigers and a belief that the tiger population is not currently increasing are both associated with greater stated tolerance for the species. Contrary to commonly-held notions, negative experiences with tigers do not directly affect tolerance levels; instead, their effect is mediated by villagers' beliefs about tigers and risk perceptions concerning human-tiger conflict incidents. These findings highlight a need to explore and understand the socio-psychological factors that encourage tolerance towards endangered species. Our research also demonstrates the applicability of this approach to tolerance research to a wide range of socio-economic and cultural contexts and reveals its capacity to enhance carnivore conservation efforts worldwide.

Preclinical safety profile of trastuzumab emtansine (T-DM1): Mechanism of action of its cytotoxic component retained with improved tolerability

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

Poon, Kirsten Achilles, E-mail: achilles.kirsten@gene.com; Flagella, Kelly; Beyer, Joseph

2013-12-01

Trastuzumab emtansine (T-DM1) is the first antibody-drug conjugate (ADC) approved for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. The therapeutic premise of ADCs is based on the hypothesis that targeted delivery of potent cytotoxic drugs to tumors will provide better tolerability and efficacy compared with non-targeted delivery, where poor tolerability can limit efficacious doses. Here, we present results from preclinical studies characterizing the toxicity profile of T-DM1, including limited assessment of unconjugated DM1. T-DM1 binds primate ErbB2 and human HER2 but not the rodent homolog c-neu. Therefore, antigen-dependent and non-antigen-dependent toxicity was evaluated in monkeysmore » and rats, respectively, in both single- and repeat-dose studies; toxicity of DM1 was assessed in rats only. T-DM1 was well tolerated at doses up to 40 mg/kg (∼ 4400 μg DM1/m{sup 2}) and 30 mg/kg (∼ 6000 μg DM1/m{sup 2}) in rats and monkeys, respectively. In contrast, DM1 was only tolerated up to 0.2 mg/kg (1600 μg DM1/m{sup 2}). This suggests that at least two-fold higher doses of the cytotoxic agent are tolerated in T-DM1, supporting the premise of ADCs to improve the therapeutic index. In addition, T-DM1 and DM1 safety profiles were similar and consistent with the mechanism of action of DM1 (i.e., microtubule disruption). Findings included hepatic, bone marrow/hematologic (primarily platelet), lymphoid organ, and neuronal toxicities, and increased numbers of cells of epithelial and phagocytic origin in metaphase arrest. These adverse effects did not worsen with chronic dosing in monkeys and are consistent with those reported in T-DM1-treated patients to date. - Highlights: • T-DM1 was well tolerated in preclinical studies in rats and cynomolgus monkeys. • T-DM1 is associated with bone marrow/hematologic, hepatic, and neuronal toxicities. • T-DM1 toxicities are related to DM1 mechanisms of action and

Safe Physical Activity Environments--To What Extent Are Local Government Authorities Auditing the Safety of Grassed Sporting Grounds?

ERIC Educational Resources Information Center

Otago, Leonie; Swan, Peter; Donaldson, Alex; Payne, Warren; Finch, Caroline

2009-01-01

Physical activity (PA) participation is influenced by the safety of the settings in which it is undertaken. This study describes the grounds assessment practices of Local Government Authorities (LGAs) in Victoria, Australia to ensure the safety of grassed sporting grounds. It also makes recommendations for improving these practices to maximise the…

78 FR 67048 - Prothioconazole; Pesticide Tolerances

Federal Register 2010, 2011, 2012, 2013, 2014

2013-11-08

... code 111). Animal production (NAICS code 112). Food manufacturing (NAICS code 311). Pesticide manufacturing (NAICS code 32532). B. How can I get electronic access to other related information? You may... Assessment and Determination of Safety Section 408(b)(2)(A)(i) of FFDCA allows EPA to establish a tolerance...

[Safety and tolerability of psychotropic medications in childhood: preliminary data of a pharmacovigilance study].

PubMed

Magazù, A; Masi, G; Germanò, E; Gagliostro, M S; Siracusano, R; Arcoraci, V; Spina, E; Gagliano, A

2014-06-01

The aim of this study was to evaluate adverse drug reactions (ADRs) of psychotropic medications in childhood. One hundred and two children and adolescents (M 82.4%, F 17.6%) followed-up at the Division of Child Neurology and Psychiatry at the University of Messina, and at the Scientific Institute Child Neurology and Psychiatry, IRCCS Stella Maris, Calambrone, Pisa, were recruited between January 2009 and December 2011. All participants met DSM-IV diagnostic criteria for psychiatric disorders. The data were collected using a recording sheet for ADRs. An electronic database was also used. The recording sheet was designed to note all relevant information about drug treatment and ADRs according to AIFA (Agenzia Italiana del Farmaco) suggestions. The most prescribed drugs were: risperidone (19.6%), aripiprazole (18.4%) and valproic acid (14.8%). The ADRs more frequently recorded had been: weight gain (12.6%), sleepiness (8.4%), and irritability (6.7%). None of recorded ADRs were classified as "serious". This study can provide a basic model to collect information on safety and tolerability of psychotropic drugs in childhood.

A controlled, randomized, head-to-head comparison of the Prolieve thermodilatation System versus the Targis System for benign prostatic hyperplasia: safety, procedural tolerability, and clinical results.

PubMed

Shore, Neal D; Sethi, Parminder S

2010-09-01

Compare safety and tolerability of the Prolieve(®) System with the Targis(®) System using objective and subjective measures. Thirty-four men with symptomatic benign prostatic hyperplasia (BPH) were randomized to a single treatment with either the Prolieve or Targis system; 30 were treated and then followed for 6 months. After post-treatment bladder fill with ≥200 mL saline, patients were catheterized if they could not void after 2 hours or had a postvoid residual >150 mL. Catheter use, visual analog scale (VAS) tolerability scores, American Urological Association scores, and safety were assessed. After treatment, 15/16 (94%) Prolieve patients remained catheter-free compared with 3/14 (21%) Targis patients (P = 0.0001). Foley catheter indwelling time was 58.8 hours for the one Prolieve patient compared with 103.9 hrs (range 54-270 h) for the Targis patients (n = 9). Targis patients' catheterization requirements were: Seven Foley only, two intermittent self-catheters only, and two needing both. Intermittent self-catheterization continued for 1 month in two Targis patients. VAS tolerability scores were 24% to 50% lower during Prolieve treatment vs Targis (P < 0.05). Mean AUA scores for Prolieve improved from 21.2 at baseline to 12.3 and 7.9 at week 2 and month 6, respectively; for Targis, AUA scores improved from 22.9 at baseline to 17.9 and 10.9, respectively (P > 0.05). Overall, the incidence of device-related adverse events was 31% (Prolieve) compared with 64% (Targis) (P > 0.05)-most prevalently, urinary retention, dysuria, and hematuria. No device-related serious adverse events occurred. Prolieve provided enhanced near-term therapeutic benefit over Targis as assessed by catheterization, tolerability, and symptom relief, which may assist physician and patient decision-making when selecting an office-based transurethral microwave therapy option for patients.

BIOMARKERS OF OPERATIONAL TOLERANCE IN SOLID ORGAN TRANSPLANTATION

PubMed Central

Heidt, Sebastiaan; Wood, Kathryn J.

2012-01-01

Introduction Long-term immunosuppressive therapy represents a huge burden on transplant recipients, but currently cannot be omitted. Improving long-term transplant outcome by immunosuppressive drug withdrawal may be achieved in patients who have developed (partial) immunological unresponsiveness towards their graft, either spontaneously or through tolerance induction. Reliable biomarkers are essential to define such immunological unresponsiveness and will facilitate controlled immunosuppressive drug weaning as well as provide surrogate end-points for tolerance induction trials. Areas covered Tolerance biomarkers have been defined for both liver and kidney transplantation and can accurately identify operationally tolerant transplant recipients retrospectively. These two tolerance fingerprints are remarkably different, indicating the involvement of distinct mechanisms. Limited data suggest that tolerance biomarkers can be detected in immunosuppressed transplant recipients. Whether these patients can safely have their immunosuppressive drugs withdrawn needs to be established. Expert opinion Mechanistic interpretation of the kidney transplant tolerance biomarker profile dominated by B cell markers remains a challenge in light of experimental evidence suggesting the pivotal involvement of regulatory T cells. Therefore, defining animal models that resemble human transplant tolerance is crucial in understanding the underlying mechanisms. Additionally, to ensure patient safety while monitoring for tolerance, it is essential to develop biomarkers to non-invasively detect early signs of rejection as well. PMID:22988481

Safety and tolerability of denosumab for the treatment of postmenopausal osteoporosis

PubMed Central

Lewiecki, E Michael

2011-01-01

Denosumab is a fully human monoclonal antibody to receptor activator of nuclear factor kappa-B ligand (RANKL), a cytokine member of the tumor necrosis factor family that is the principal regulator of osteoclastic bone resorption. Postmenopausal osteoporosis (PMO) is a systemic skeletal disease associated with high levels of RANKL, resulting in a high rate of bone remodeling and an imbalance of bone resorption over bone formation. By inhibiting RANKL in women with PMO, denosumab reduces the rate of bone remodeling, thereby increasing bone mineral density, improving bone strength, and reducing the risk of fractures. In clinical trials of women with osteoporosis and low bone mineral density, denosumab has been well tolerated, with overall rates of adverse events and serious adverse events in women treated with denosumab similar to those receiving placebo. In the largest clinical trial of denosumab for the treatment of women with PMO, there was a significantly greater incidence of cellulitis reported as a serious adverse event, with no difference in the overall incidence of cellulitis, and a significantly lower incidence of the serious adverse event of concussions with denosumab compared with placebo. The evidence supports a favorable balance of benefits versus risks of denosumab for the treatment of PMO. Assessments of the long-term safety of denosumab are ongoing. Denosumab 60 mg subcutaneously every 6 months is an approved treatment for women with PMO who are at high risk for fracture. PMID:22279412

Toward Human-Carnivore Coexistence: Understanding Tolerance for Tigers in Bangladesh

PubMed Central

Inskip, Chloe; Roberts, Thomas; MacMillan, Douglas

2016-01-01

Fostering local community tolerance for endangered carnivores, such as tigers (Panthera tigris), is a core component of many conservation strategies. Identification of antecedents of tolerance will facilitate the development of effective tolerance-building conservation action and secure local community support for, and involvement in, conservation initiatives. We use a stated preference approach for measuring tolerance, based on the ‘Wildlife Stakeholder Acceptance Capacity’ concept, to explore villagers’ tolerance levels for tigers in the Bangladesh Sundarbans, an area where, at the time of the research, human-tiger conflict was severe. We apply structural equation modeling to test an a priori defined theoretical model of tolerance and identify the experiential and psychological basis of tolerance in this community. Our results indicate that beliefs about tigers and about the perceived current tiger population trend are predictors of tolerance for tigers. Positive beliefs about tigers and a belief that the tiger population is not currently increasing are both associated with greater stated tolerance for the species. Contrary to commonly-held notions, negative experiences with tigers do not directly affect tolerance levels; instead, their effect is mediated by villagers’ beliefs about tigers and risk perceptions concerning human-tiger conflict incidents. These findings highlight a need to explore and understand the socio-psychological factors that encourage tolerance towards endangered species. Our research also demonstrates the applicability of this approach to tolerance research to a wide range of socio-economic and cultural contexts and reveals its capacity to enhance carnivore conservation efforts worldwide. PMID:26760035

A 4-week study assessing the pharmacokinetics, pharmacodynamics, safety, and tolerability of the glucagon receptor antagonist PF-06291874 administered as monotherapy in subjects with type 2 diabetes mellitus.

PubMed

Bergman, Arthur; Tan, Beesan; Somayaji, Veena R; Calle, Roberto A; Kazierad, David J

2017-04-01

The glucagon receptor antagonist PF-06291874 has demonstrated robust glucose reductions in subjects with type 2 diabetes mellitus (T2DM) on background metformin. This study assessed the pharmacokinetics, pharmacodynamics, safety, and tolerability of PF-06291874 administered as monotherapy in subjects with T2DM. After a ≥4-week antidiabetic therapy washout period, 172 subjects were randomized to placebo or PF-06291874 15, 35, 75, or 150mg once daily for 28days. Mean daily glucose (MDG), fasting plasma glucose (FPG), and predefined safety endpoints were assessed at baseline and day 28. Dose-dependent reductions (placebo-adjusted) from baseline in MDG ranged from 40.3 to 68.8mg/dL and in FPG from 27.1 to 57.2mg/dL after 28days of dosing with PF-06291874. There were no significant changes in low-density lipoprotein cholesterol at doses ≤75mg relative to placebo. Small, dose-dependent increases in alanine aminotransferase and aspartate aminotransferase were observed; however, the incidence of these values >3×upper limit of normal was similar across doses. PF-06291874 exposures were consistent with previous studies and PF-06291874 was well tolerated, with minimal incidence of hypoglycemia. PF-06291874 as monotherapy was well tolerated and produced robust reductions in plasma glucose following 4weeks of dosing in subjects with T2DM. Copyright © 2017 Elsevier B.V. All rights reserved.

Transplantation Tolerance through Hematopoietic Chimerism: Progress and Challenges for Clinical Translation

PubMed Central

Mahr, Benedikt; Granofszky, Nicolas; Muckenhuber, Moritz; Wekerle, Thomas

2017-01-01

The perception that transplantation of hematopoietic stem cells can confer tolerance to any tissue or organ from the same donor is widely accepted but it has not yet become a treatment option in clinical routine. The reasons for this are multifaceted but can generally be classified into safety and efficacy concerns that also became evident from the results of the first clinical pilot trials. In comparison to standard immunosuppressive therapies, the infection risk associated with the cytotoxic pre-conditioning necessary to allow allogeneic bone marrow engraftment and the risk of developing graft-vs.-host disease (GVHD) constitute the most prohibitive hurdles. However, several approaches have recently been developed at the experimental level to reduce or even overcome the necessity for cytoreductive conditioning, such as costimulation blockade, pro-apoptotic drugs, or Treg therapy. But even in the absence of any hazardous pretreatment, the recipients are exposed to the risk of developing GVHD as long as non-tolerant donor T cells are present. Total lymphoid irradiation and enriching the stem cell graft with facilitating cells emerged as potential strategies to reduce this peril. On the other hand, the long-lasting survival of kidney allografts, seen with transient chimerism in some clinical series, questions the need for durable chimerism for robust tolerance. From a safety point of view, loss of chimerism would indeed be favorable as it eliminates the risk of GVHD, but also complicates the assessment of tolerance. Therefore, other biomarkers are warranted to monitor tolerance and to identify those patients who can safely be weaned off immunosuppression. In addition to these safety concerns, the limited efficacy of the current pilot trials with approximately 40–60% patients becoming tolerant remains an important issue that needs to be resolved. Overall, the road ahead to clinical routine may still be rocky but the first successful long-term patients and progress

Switching to aripiprazole in outpatients with schizophrenia experiencing insufficient efficacy and/or safety/tolerability issues with risperidone: a randomized, multicentre, open-label study.

PubMed

Ryckmans, V; Kahn, J P; Modell, S; Werner, C; McQuade, R D; Kerselaers, W; Lissens, J; Sanchez, R

2009-05-01

This study evaluated the safety/tolerability and effectiveness of aripiprazole titrated-dose versus fixed-dose switching strategies from risperidone in patients with schizophrenia experiencing insufficient efficacy and/or safety/tolerability issues. Patients were randomized to an aripiprazole titrated-dose (starting dose 5 mg/day) or fixed-dose (dose 15 mg/day) switching strategy with risperidone down-tapering. Primary endpoint was rate of discontinuation due to adverse events (AEs) during the 12-week study. Secondary endpoints included positive and negative syndrome scale (PANSS), clinical global impressions - improvement of illness scale (CGI-I), preference of medication (POM), subjective well-being under neuroleptics (SWN-K) and GEOPTE (Grupo Español para la Optimización del Tratamiento de la Esquizofrenia) scales. Rates of discontinuations due to AEs were similar between titrated-dose and fixed-dose strategies (3.5% vs. 5.0%; p=0.448). Improvements in mean PANSS total scores were similar between aripiprazole titrated-dose and fixed-dose strategies (-14.8 vs. -17.2; LOCF), as were mean CGI-I scores (2.9 vs. 2.8; p=0.425; LOCF) and SWN-K scores (+8.6 vs.+10.3; OC,+7.8 vs.+9.8; LOCF). Switching can be effectively and safely achieved through a titrated-dose or fixed-dose switching strategy for aripiprazole, with down-titration of risperidone.

SAFETY AND TOLERABILITY OF LOW DOSE NALTREXONE THERAPY IN CHILDREN WITH MODERATE TO SEVERE CROHN’S DISEASE: A PILOT STUDY

PubMed Central

Smith, Jill P.; Field, Douglas; Bingaman, Sandra; Evans, Robert; Mauger, David

2012-01-01

Background There is an unmet need for safe and effective medicines to treat children with Crohn’s disease. Recently, investigations have shown an association between endogenous opioid peptides and inflammatory cells. Aims The aims of this study were to evaluate the safety and tolerability of an opioid antagonist, naltrexone, in children with moderate to severe Crohn’s disease. Methods A pilot clinical trial was conducted in children with moderate to severe Crohn’s disease. Fourteen subjects with a mean age of 12.3 years (8–17, range) were enrolled. Children were randomized to placebo or naltrexone 0.1 mg/kg orally for 8 weeks followed by open-labeled treatment with 8 additional weeks of naltrexone. Safety and toxicity were monitored by physical examinations and blood chemistries. Clinical activity was assessed by the PCDAI (Pediatric Crohn’s Disease Activity Index) and Quality of life was monitored by the Impact III survey. Results Oral naltrexone was well tolerated without any serious adverse events in children with moderate to severe Crohn’s disease. PCDAI scores significantly decreased from pretreatment values (34.2±3.3) with an eight-week course of naltrexone therapy (21.7±3.9) (p=0.005). Twenty-five percent of those treated with naltrexone were considered in remission (score < 10) and 67% had improved with mild disease activity (decrease PCDAI score by at least 10 points) at the end of the study. Systemic and social quality of life improved with naltrexone treatment (p=0.035). Conclusions Naltrexone therapy appears safe with limited toxicity when given to children with Crohn’s disease and may reduce disease activity. PMID:23188075

Phase I study evaluating the safety, tolerability and pharmacokinetics of a novel oral dissolvable film containing dexamethasone versus Fortecortin dexamethasone tablets.

PubMed

Diamant, Zuzana; Samuelsson Palmgren, Gabriella; Westrin, Bengt; Bjermer, Leif

2017-01-01

Introduction : Systemic corticosteroids are anti-inflammatory agents with dexamethasone among the most potent in the class. Within (respiratory) allergy, systemic corticosteroids are usually applied in medical emergencies. In these situations, patients may experience physical or logistic problems taking tablets. To fulfil a practical unmet need for outpatients, Dexa ODF, an oral dissolvable film containing dexamethasone, was developed. Objectives : We compared the safety, tolerability and pharmacokinetics (PK) of Dexa ODF with Fortecortin tablets in healthy subjects. Methods : Thirty subjects participated in this open label, two-way, cross-over study, consisting of two treatment visits separated by 5-10 days. On both treatment visits, subjects randomly received one single dose of Dexa ODF (one strip; 8 mg dexamethasone) or one single dose of Fortecortin (two 4 mg tablets). Safety evaluations and blood sampling for PK were conducted until 48 h post-dose and bioequivalence analysis was performed on AUC(0-t), AUC(0-∞) and Cmax. Results : All subjects were dosed. Forty-five adverse events (AEs) were reported by 17 subjects and approximately 50% were deemed 'possibly treatment related' (14 on Dexa ODF; 12 on Fortecortin) with no significant difference between treatments. For all three bioequivalence parameters the 90% CIs were within the acceptance limits of bioequivalence (0.8;1.25). Conclusion : We demonstrated good tolerability and bioequivalence of Dexa ODF (8 mg dexamethasone) compared to Fortecortin tablets (2 × 4 mg dexamethasone). Dexa ODF is currently under development as an innovative treatment for use within respiratory and allergic conditions, including emergencies.

Efficacy, tolerability, and safety of aripiprazole once-monthly versus other long-acting injectable antipsychotic therapies in the maintenance treatment of schizophrenia: a mixed treatment comparison of double-blind randomized clinical trials.

PubMed

Majer, Istvan M; Gaughran, Fiona; Sapin, Christophe; Beillat, Maud; Treur, Maarten

2015-01-01

Treatment with long-acting injectable (LAI) antipsychotic medication is an important element of relapse prevention in schizophrenia. Recently, the intramuscular once-monthly formulation of aripiprazole received marketing approval in Europe and the United States for schizophrenia. This study aimed to compare aripiprazole once-monthly with other LAI antipsychotics in terms of efficacy, tolerability, and safety. A systematic literature review was conducted to identify relevant double-blind randomized clinical trials of LAIs conducted in the maintenance treatment of schizophrenia. MEDLINE, MEDLINE In-Process, Embase, the Cochrane Library, PsycINFO, conference proceedings, clinical trial registries, and the reference lists of key review articles were searched. The literature search covered studies dating from January 2002 to May 2013. Studies were required to have ≥24 weeks of follow-up. Patients had to be stable at randomization. Studies were not eligible for inclusion if efficacy of acute and maintenance phase treatment was not reported separately. Six trials were identified (0.5% of initially identified studies), allowing comparisons of aripiprazole once-monthly, risperidone LAI, paliperidone palmitate, olanzapine pamoate, haloperidol depot, and placebo. Data extracted included study details, study duration, the total number of patients in each treatment arm, efficacy, tolerability, and safety outcomes. The efficacy outcome contained the number of patients that experienced a relapse, tolerability outcomes included the number of patients that discontinued treatment due to treatment-related adverse events (AEs), and that discontinued treatment due to reasons other than AEs (e.g., loss to follow-up). Safety outcomes included the incidence of clinically relevant weight gain and extrapyramidal symptoms. Data were analyzed by applying a mixed treatment comparison competing risks model (efficacy) and using binary models (safety). There was no statistically significant

Nuclear Localization of Haa1, Which Is Linked to Its Phosphorylation Status, Mediates Lactic Acid Tolerance in Saccharomyces cerevisiae

PubMed Central

Sugiyama, Minetaka; Akase, Shin-Pei; Nakanishi, Ryota; Horie, Hitoshi; Kaneko, Yoshinobu

2014-01-01

Improvement of the lactic acid resistance of the yeast Saccharomyces cerevisiae is important for the application of the yeast in industrial production of lactic acid from renewable resources. However, we still do not know the precise mechanisms of the lactic acid adaptation response in yeast and, consequently, lack effective approaches for improving its lactic acid tolerance. To enhance our understanding of the adaptation response, we screened for S. cerevisiae genes that confer enhanced lactic acid resistance when present in multiple copies and identified the transcriptional factor Haa1 as conferring resistance to toxic levels of lactic acid when overexpressed. The enhanced tolerance probably results from increased expression of its target genes. When cells that expressed Haa1 only from the endogenous promoter were exposed to lactic acid stress, the main subcellular localization of Haa1 changed from the cytoplasm to the nucleus within 5 min. This nuclear accumulation induced upregulation of the Haa1 target genes YGP1, GPG1, and SPI1, while the degree of Haa1 phosphorylation observed under lactic acid-free conditions decreased. Disruption of the exportin gene MSN5 led to accumulation of Haa1 in the nucleus even when no lactic acid was present. Since Msn5 was reported to interact with Haa1 and preferentially exports phosphorylated cargo proteins, our results suggest that regulation of the subcellular localization of Haa1, together with alteration of its phosphorylation status, mediates the adaptation to lactic acid stress in yeast. PMID:24682296

Highway Safety Program Manual: Volume 14: Pedestrian Safety.

ERIC Educational Resources Information Center

National Highway Traffic Safety Administration (DOT), Washington, DC.

Volume 14 of the 19-volume Highway Safety Program Manual (which provides guidance to State and local governments on preferred highway safety practices) concentrates on pedestrian safety. The purpose and objectives of a pedestrian safety program are outlined. Federal authority in the area of pedestrian safety and policies regarding a safety program…

The safety and tolerability of vortioxetine: Analysis of data from randomized placebo-controlled trials and open-label extension studies

PubMed Central

Baldwin, David S; Chrones, Lambros; Florea, Ioana; Nielsen, Rebecca; Nomikos, George G; Palo, William; Reines, Elin

2016-01-01

The safety and tolerability of vortioxetine in adults with major depressive disorder was assessed. Tolerability was based on the nature, incidence and severity of treatment-emergent adverse events (TEAEs) during acute (6/8) week treatment in 11 randomized, double-blind placebo-controlled short-term studies in major depressive disorder: six with an active reference. Symptoms following discontinuation were assessed through the Discontinuation-Emergent Signs and Symptoms checklist in three studies. Long-term (⩽52 weeks) tolerability was evaluated in five open-label extension studies. Patients (n =5701) were acutely treated with either placebo (n=1817), vortioxetine (5–20mg/day; n=3018), venlafaxine XR (225mg/day; n=113) or duloxetine (60mg/day; n=753). The withdrawal rate due to TEAEs during treatment with vortioxetine (5–20mg/day) was 4.5–7.8%, compared with placebo (3.6%), venlafaxine XR (14.2%) or duloxetine (8.8%). Common TEAEs (incidence ⩾5% and >2 × placebo) with vortioxetine (5–20mg/day) were nausea (20.9–31.2%) and vomiting (2.9–6.5%). For vortioxetine (5–20mg/day), the incidence of TEAEs associated with insomnia was 2.0–5.1% versus 4.0% for placebo, and with sexual dysfunction 1.6–1.8% versus 1.0% for placebo. Discontinuation symptoms as assessed by the mean Discontinuation-Emergent Signs and Symptoms total score after abrupt discontinuation were comparable to placebo in the first and second week. Vortioxetine had no effect relative to placebo on clinical laboratory parameters, body weight, heart rate or blood pressure. Vortioxetine showed no clinically relevant effect on ECG parameters, including the QTcF interval. In long-term treatment, no new types of TEAEs were seen; the mean weight gain was 0.7–0.8kg. Thus, vortioxetine (5–20mg/day) appears safe and generally well tolerated in the treatment of major depressive disorder. PMID:26864543

The safety and tolerability of vortioxetine: Analysis of data from randomized placebo-controlled trials and open-label extension studies.

PubMed

Baldwin, David S; Chrones, Lambros; Florea, Ioana; Nielsen, Rebecca; Nomikos, George G; Palo, William; Reines, Elin

2016-03-01

The safety and tolerability of vortioxetine in adults with major depressive disorder was assessed. Tolerability was based on the nature, incidence and severity of treatment-emergent adverse events (TEAEs) during acute (6/8) week treatment in 11 randomized, double-blind placebo-controlled short-term studies in major depressive disorder: six with an active reference. Symptoms following discontinuation were assessed through the Discontinuation-Emergent Signs and Symptoms checklist in three studies. Long-term (⩽52 weeks) tolerability was evaluated in five open-label extension studies. Patients (n =5701) were acutely treated with either placebo (n=1817), vortioxetine (5-20mg/day; n=3018), venlafaxine XR (225mg/day; n=113) or duloxetine (60mg/day; n=753). The withdrawal rate due to TEAEs during treatment with vortioxetine (5-20mg/day) was 4.5-7.8%, compared with placebo (3.6%), venlafaxine XR (14.2%) or duloxetine (8.8%). Common TEAEs (incidence ⩾5% and >2 × placebo) with vortioxetine (5-20mg/day) were nausea (20.9-31.2%) and vomiting (2.9-6.5%). For vortioxetine (5-20mg/day), the incidence of TEAEs associated with insomnia was 2.0-5.1% versus 4.0% for placebo, and with sexual dysfunction 1.6-1.8% versus 1.0% for placebo. Discontinuation symptoms as assessed by the mean Discontinuation-Emergent Signs and Symptoms total score after abrupt discontinuation were comparable to placebo in the first and second week. Vortioxetine had no effect relative to placebo on clinical laboratory parameters, body weight, heart rate or blood pressure. Vortioxetine showed no clinically relevant effect on ECG parameters, including the QTcF interval. In long-term treatment, no new types of TEAEs were seen; the mean weight gain was 0.7-0.8kg. Thus, vortioxetine (5-20mg/day) appears safe and generally well tolerated in the treatment of major depressive disorder. © The Author(s) 2016.

Safety and tolerability of a live oral Salmonella typhimurium vaccine candidate in SIV-infected nonhuman primates.

PubMed

Ault, Alida; Tennant, Sharon M; Gorres, J Patrick; Eckhaus, Michael; Sandler, Netanya G; Roque, Annelys; Livio, Sofie; Bao, Saran; Foulds, Kathryn E; Kao, Shing-Fen; Roederer, Mario; Schmidlein, Patrick; Boyd, Mary Adetinuke; Pasetti, Marcela F; Douek, Daniel C; Estes, Jacob D; Nabel, Gary J; Levine, Myron M; Rao, Srinivas S

2013-12-02

Nontyphoidal Salmonella (NTS) serovars are a common cause of acute food-borne gastroenteritis worldwide and can cause invasive systemic disease in young infants, the elderly, and immunocompromised hosts, accompanied by high case fatality. Vaccination against invasive NTS disease is warranted where the disease incidence and mortality are high and multidrug resistance is prevalent, as in sub-Saharan Africa. Live-attenuated vaccines that mimic natural infection constitute one strategy to elicit protection. However, they must particularly be shown to be adequately attenuated for consideration of immunocompromised subjects. Accordingly, we examined the safety and tolerability of an oral live attenuated Salmonella typhimurium vaccine candidate, CVD 1921, in an established chronic simian immunodeficiency virus (SIV)-infected rhesus macaque model. We evaluated clinical parameters, histopathology, and measured differences in mucosal permeability to wild-type and vaccine strains. Compared to the wild-type S. typhimurium strain I77 in both SIV-infected and SIV-uninfected nonhuman primate hosts, this live-attenuated vaccine shows reduced shedding and systemic spread, exhibits limited pathological disease manifestations in the digestive tract, and induces low levels of cellular infiltration in tissues. Furthermore, wild-type S. typhimurium induces increased intestinal epithelial damage and permeability, with infiltration of neutrophils and macrophages in both SIV-infected and SIV-uninfected nonhuman primates compared to the vaccine strain. Based on shedding, systemic spread, and histopathology, the live-attenuated S. typhimurium strain CVD 1921 appears to be safe and well-tolerated in the nonhuman primate model, including chronically SIV-infected rhesus macaques. Copyright © 2013. Published by Elsevier Ltd.

Propulsion Health Monitoring for Enhanced Safety

NASA Technical Reports Server (NTRS)

Butz, Mark G.; Rodriguez, Hector M.

2003-01-01

This report presents the results of the NASA contract Propulsion System Health Management for Enhanced Safety performed by General Electric Aircraft Engines (GE AE), General Electric Global Research (GE GR), and Pennsylvania State University Applied Research Laboratory (PSU ARL) under the NASA Aviation Safety Program. This activity supports the overall goal of enhanced civil aviation safety through a reduction in the occurrence of safety-significant propulsion system malfunctions. Specific objectives are to develop and demonstrate vibration diagnostics techniques for the on-line detection of turbine rotor disk cracks, and model-based fault tolerant control techniques for the prevention and mitigation of in-flight engine shutdown, surge/stall, and flameout events. The disk crack detection work was performed by GE GR which focused on a radial-mode vibration monitoring technique, and PSU ARL which focused on a torsional-mode vibration monitoring technique. GE AE performed the Model-Based Fault Tolerant Control work which focused on the development of analytical techniques for detecting, isolating, and accommodating gas-path faults.

[Involvement of local dietetics professionals in risk communication program on food safety in municipal governments and their attitude towards the program].

PubMed

Akamatsu, Rie; Nomura, Marika; Horiguchi, Itsuko; Tanaka, Hisako; Marui, Eiji

2009-01-01

The objective of this study is to gather statistical references on food safety education that encourages competence of food choice from the view-point of food safety. A survey on the involvement of the risk communication program on food safety in municipal governments and the attitude of local dietetics professionals towards the program was conducted. In November, 2006, self-reported questionnaires were mailed to 1990 local dietetics professionals who worked in municipal governments in Japan. Descriptive statistics and cross tables were used for data analysis. 1162 questionnaires were mailed and 1130 available surveys were returned. Among the respondents, 41.5% answered that they inform the community about food safety, but 49.9% answered that they did not get information from the community. Most of the respondents answered that risk communication of food safety was important; 21.8% answered "extremely agree" and 62.3% answered "rather agree" on a scale of four from "extremely agree" to "do not agree". More than one-half of the dietetics professionals answered that their confidence in conducting risk communication was low; 20.5% answered "no confidence" and 52.5% answered "hardly have confidence" on a scale of four from "without confidence" to "with confidence". More than 80% of the respondents answered that they needed "professional knowledge" and "support from professional agencies". This study suggests that educating local dietetics professionals about professional knowledge on food safety, and obtaining support from special agencies will be essential in the upgrade of risk communication program on food safety in a community.

Analysis of typical fault-tolerant architectures using HARP

NASA Technical Reports Server (NTRS)

Bavuso, Salvatore J.; Bechta Dugan, Joanne; Trivedi, Kishor S.; Rothmann, Elizabeth M.; Smith, W. Earl

1987-01-01

Difficulties encountered in the modeling of fault-tolerant systems are discussed. The Hybrid Automated Reliability Predictor (HARP) approach to modeling fault-tolerant systems is described. The HARP is written in FORTRAN, consists of nearly 30,000 lines of codes and comments, and is based on behavioral decomposition. Using the behavioral decomposition, the dependability model is divided into fault-occurrence/repair and fault/error-handling models; the characteristics and combining of these two models are examined. Examples in which the HARP is applied to the modeling of some typical fault-tolerant systems, including a local-area network, two fault-tolerant computer systems, and a flight control system, are presented.

Statistical evaluation of the Local Lymph Node Assay.

PubMed

Hothorn, Ludwig A; Vohr, Hans-Werner

2010-04-01

In the Local Lymph Node Assay measured endpoints for each animal, such as cell proliferation, cell counts and/or lymph node weight should be evaluated separately. The primary criterion for a positive response is when the estimated stimulation index is larger than a specified relative threshold that is endpoint- and strain-specific. When the lower confidence limit for ratio-to-control comparisons is larger than a relevance threshold, a biologically relevant increase can be concluded according to the proof of hazard. Alternatively, when the upper confidence limit for ratio-to-control comparisons is smaller than a tolerable margin, harmlessness can be concluded according to a proof of safety. Copyright 2009 Elsevier Inc. All rights reserved.

[Efficacy, tolerability and safety of cannabinoids for chronic neuropathic pain: A systematic review of randomized controlled studies].

PubMed

Petzke, F; Enax-Krumova, E K; Häuser, W

2016-02-01

Recently published systematic reviews came to different conclusions with respect to the efficacy, tolerability and safety of cannabinoids for treatment of chronic neuropathic pain. A systematic search of the literature was carried out in MEDLINE, the Cochrane central register of controlled trials (CENTRAL) and clinicaltrials.gov up until November 2015. We included double-blind randomized placebo-controlled studies (RCT) of at least 2 weeks duration and with at least 9 patients per treatment arm comparing medicinal cannabis, plant-based or synthetic cannabinoids with placebo or any other active drug treatment in patients with chronic neuropathic pain. Clinical endpoints of the analyses were efficacy (more than 30 % or 50 % reduction of pain, average pain intensity, global improvement and health-related quality of life), tolerability (drop-out rate due to side effects, central nervous system and psychiatric side effects) and safety (severe side effects). Using a random effects model absolute risk differences (RD) were calculated for categorical data and standardized mean differences (SMD) for continuous variables. The methodological quality of RCTs was rated by the Cochrane risk of bias tool. We included 15 RCTs with 1619 participants. Study duration ranged between 2 and 15 weeks. Of the studies 10 used a plant-derived oromucosal spray with tetrahydrocannabinol/cannabidiol, 3 studies used a synthetic cannabinoid (2  with nabilone and 1  with dronabinol) and 2 studies used medicinal cannabis. The 13 studies with parallel or cross-over design yielded the following results with 95 % confidence intervals (CI): cannabinoids were superior to placebo in the reduction of mean pain intensity with SMD - 0.10 (95 % CI - 0.20- - 0.00, p = 0.05, 13 studies with 1565 participants), in the frequency of at least a 30 % reduction in pain with an RD of 0.10 [95 % CI 0.03-0.16, p = 0.004, 9 studies with 1346 participants, number needed to treat for

SafetyAnalyst

DOT National Transportation Integrated Search

2009-01-01

This booklet provides an overview of SafetyAnalyst. SafetyAnalyst is a set of software tools under development to help State and local highway agencies advance their programming of site-specific safety improvements. SafetyAnalyst will incorporate sta...

Radiation Tolerant Interfaces: Influence of Local Stoichiometry at the Misfit Dislocation on Radiation Damage Resistance of Metal/Oxide Interfaces

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

Shutthanandan, Vaithiyalingam; Choudhury, Samrat; Manandhar, Sandeep

To understand how variations in interface properties such as misfit-dislocation density and local chemistry affect radiation-induced defect absorption and recombination, we have explored a model system of CrxV1-x alloy epitaxial films deposited on MgO single crystals. By controlling film composition, the lattice mismatch with MgO was adjusted so that the misfit-dislocation density varies at the interface. These interfaces were exposed to irradiation and in situ results show that the film with a semi-coherent interface (Cr) withstands irradiation while V film, which has similar semi-coherent interface like Cr, showed the largest damage. Theoretical calculations indicate that, unlike at metal/metal interfaces, themore » misfit dislocation density does not dominate radiation damage tolerance at metal/oxide interfaces. Rather, the stoichiometry, and the precise location of the misfit-dislocation density relative to the interface, drives defect behavior. Together, these results demonstrate the sensitivity of defect recombination to interfacial chemistry and provide new avenues for engineering radiation-tolerant nanomaterials.« less

Highway Safety Program Manual: Volume 3: Motorcycle Safety.

ERIC Educational Resources Information Center

National Highway Traffic Safety Administration (DOT), Washington, DC.

Volume 3 of the 19-volume Highway Safety Program Manual (which provides guidance to State and local governments on preferred highway safety practices) concentrates on aspects of motorcycle safety. The purpose and specific objectives of a State motorcycle safety program are outlined. Federal authority in the highway safety area and general policies…

Dose escalation study to evaluate safety, tolerability and efficacy of intravenous etoposide phosphate administration in 27 dogs with multicentric lymphoma

PubMed Central

Hordeaux, Juliette; Bouchaert, Emmanuel; Gomes, Bruno

2017-01-01

Comparative oncology has shown that naturally occurring canine cancers are of valuable and translatable interest for the understanding of human cancer biology and the characterization of new therapies. This work was part of a comparative oncology project assessing a new, clinical-stage topoisomerase II inhibitor and comparing it with etoposide in dogs with spontaneous lymphoma with the objective to translate findings from dogs to humans. Etoposide is a topoisomerase II inhibitor widely used in various humans’ solid and hematopoietic cancer, but little data is available concerning its potential antitumor efficacy in dogs. Etoposide phosphate is a water-soluble prodrug of etoposide which is expected to be better tolerated in dogs. The objectives of this study were to assess the safety, the tolerability and the efficacy of intravenous etoposide phosphate in dogs with multicentric lymphoma. Seven dose levels were evaluated in a traditional 3+3 phase I design. Twenty-seven owned-dogs with high-grade multicentric lymphoma were enrolled and treated with three cycles of etoposide phosphate IV injections every 2 weeks. Adverse effects were graded according to the Veterinary Cooperative Oncology Group criteria. A complete end-staging was realized 45 days after inclusion. The maximal tolerated dose was 300 mg/m2. At this dose level, the overall response rate was 83.3% (n = 6, 3 PR and 2 CR). Only a moderate reversible gastrointestinal toxicity, no severe myelotoxicity and no hypersensitivity reaction were reported at this dose level. Beyond the characterization of etoposide clinical efficacy in dogs, this study underlined the clinical and therapeutic homologies between dog and human lymphomas. PMID:28505195

Safety, tolerability, and efficacy evaluation of the SlimME device for circumference reduction.

PubMed

Ferrando, Giovanni

2018-02-07

To assess the short- and long-term thermal impact of subclinical and clinical regimens of a single, non-invasive uniform ultrasound treatment session on subcutaneous adipose tissue (SAT). Prospective, open-label, single-arm, split-side study. Patients (n = 17) were subjected to uniform ultrasound treatment, delivered in a single session with the SlimME device. The device was set to one of four treatment regimens, which differed in their durations and energy fluences during the raise and maintenance phases. Up to six abdominal regions were treated, with six patients receiving a different treatment on each side of the abdomen. Safety was assessed by measuring skin surface temperature, evaluating expected skin responses immediately and 30 min after treatment and via patient ratings of pain and discomfort. Efficacy of raising and then maintaining SAT temperatures at 48°C, was determined by routinely measuring SAT temperatures during the treatment session and by histological analysis of samples collected 7 (n = 13) or 90 (n = 4) days after treatment. Trace to mild erythema was observed in up to 48% of the treated zones, which, in most cases, resolved within 30 minutes. No significant rise in mean skin surface temperature (≤26.5°C) was recorded following any of the four tested regimens. Overall, patients reported tolerability to treatment, with the highest mean pain score registered for the moderate and high intensity regimens (4.4 ± 1.5 and 4.9 ± 1.4, respectively). Mean SAT temperatures did not exceed 48.4 ± 2.5°C and were effectively maintained throughout the maintenance phase of the treatment session. Low-energy fluence led to localized fat coagulative necrotic lesions, surrounded by subacute rim of inflammation, while high-energy fluence induced fat coagulative necrosis alongside granulomatous panniculitis, which resolved within 90 days. The tested uniform ultrasound regimens elicited SAT temperature elevations, with a subsequent

Safety and tolerability profile of daclizumab in patients with relapsing-remitting multiple sclerosis: An integrated analysis of clinical studies.

PubMed

Giovannoni, Gavin; Kappos, Ludwig; Gold, Ralf; Khatri, Bhupendra O; Selmaj, Krzysztof; Umans, Kimberly; Greenberg, Steven J; Sweetser, Marianne; Elkins, Jacob; McCroskery, Peter

2016-09-01

Daclizumab has been evaluated in multicentre, randomised, double-blind studies for the treatment of patients with relapsing-remitting multiple sclerosis (RRMS). Safety and tolerability are key considerations in MS treatment selection, as they influence adherence to medication. Evaluate the safety of daclizumab in patients with RRMS from an integrated analysis of six clinical studies. Patients treated with at least one dose of subcutaneous daclizumab 150mg or 300mg monthly in three completed and three ongoing clinical studies were included in this integrated analysis. Cumulative incidence of treatment-emergent adverse events (AEs) was the primary endpoint. This analysis included 2236 patients with 5214 patient-years of exposure to daclizumab. The cumulative incidence of any AE was 84% and of any serious AE excluding MS relapse was 16%. The incidences of AEs when evaluated by 6-month intervals remained stable over the 6.5 years of maximum follow-up. Most AEs were mild or moderate in severity. An important safety concern associated with daclizumab therapy involved hepatic AEs (16%) and serum transaminase elevations at least three times the upper limit of normal (10%), most of which were asymptomatic, self-limiting, and non-recurring. Cumulative incidences of cutaneous, infectious, and gastrointestinal AEs were 33%, 59%, and 25%, respectively; most events either resolved spontaneously or were treated successfully with standard medical interventions and did not result in discontinuation of treatment. This integrated analysis demonstrates that treatment of RRMS with daclizumab for periods of up to 6.5 years is associated with an acceptable safety profile with no evidence of cumulative toxicity over time. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

The safety and tolerability of spironolactone in patients with mild to moderate chronic kidney disease

PubMed Central

Edwards, Nicola C; Steeds, Richard P; Chue, Colin D; Stewart, Paul M; Ferro, Charles J; Townend, Jonathan N

2012-01-01

AIM Mineralocorticoid receptor blockade (MRBs) in combination with angiotensin converting enzyme (ACE) inhibitors and angiotensin-II receptor blockade (ARBs) improve prognostic markers of cardiovascular and renal disease in early stage chronic kidney disease (CKD). Concerns relating to the safety and tolerability of MRBs in CKD may limit their use in a non clinical trial setting. METHODS In the Chronic Renal Impairment in Birmingham II study, 115 patients with non-diabetic early stage CKD (eGFR 30–89 ml/min/1.73m2) received 25 mg daily of spironolactone for 4 weeks before randomization to continuing treatment or placebo for a further 36 weeks. All patients were on ACE inhibitors and/or ARB therapy. Potassium and renal function were checked at weeks 1, 2, 4, 8, 16, 28 and 40. The incidence of hyperkalaemia, significant renal dysfunction (reduction eGFR ≥25%) and adverse effects was assessed. RESULTS After 40 weeks of treatment the incidence of serious hyperkalaemia (K+≥6.0 mmol/L) was <1%. A potassium 5.5–5.9 mmol/L occurred on ≥1 occasion over follow-up in 11 patients (nine on spironolactone) and was predicted by baseline potassium ≥5.0 mmol/L and eGFR ≤45 ml/min/1.73m2. Over follow-up, three patients experienced significant renal dysfunction but no patients withdrew due to intolerance or side effects. Changes in potassium, eGFR and systolic blood pressure were most apparent in the first 4 eeks. CONCLUSION Spironolactone was well tolerated in selected patients with early stage CKD. Strict monitoring over the first month of treatment followed by standard surveillance as for ACE inhibitors and ARBs is suggested. PMID:21950312

The safety and tolerability of spironolactone in patients with mild to moderate chronic kidney disease.

PubMed

Edwards, Nicola C; Steeds, Richard P; Chue, Colin D; Stewart, Paul M; Ferro, Charles J; Townend, Jonathan N

2012-03-01

Mineralocorticoid receptor blockade (MRBs) in combination with angiotensin converting enzyme (ACE) inhibitors and angiotensin-II receptor blockade (ARBs) improve prognostic markers of cardiovascular and renal disease in early stage chronic kidney disease (CKD). Concerns relating to the safety and tolerability of MRBs in CKD may limit their use in a non clinical trial setting. METHODS In the Chronic Renal Impairment in Birmingham II study, 115 patients with non-diabetic early stage CKD (eGFR 30-89ml/min/1.73m(2) ) received 25mg daily of spironolactone for 4 weeks before randomization to continuing treatment or placebo for a further 36 weeks. All patients were on ACE inhibitors and/or ARB therapy. Potassium and renal function were checked at weeks 1, 2, 4, 8, 16, 28 and 40. The incidence of hyperkalaemia, significant renal dysfunction (reduction eGFR ≥25%) and adverse effects was assessed. After 40 weeks of treatment the incidence of serious hyperkalaemia (K(+) ≥6.0mmol/L) was <1%. A potassium 5.5-5.9mmol/L occurred on ≥1 occasion over follow-up in 11 patients (nine on spironolactone) and was predicted by baseline potassium ≥5.0mmol/L and eGFR ≤45 ml/min/1.73m(2) . Over follow-up, three patients experienced significant renal dysfunction but no patients withdrew due to intolerance or side effects. Changes in potassium, eGFR and systolic blood pressure were most apparent in the first 4 eeks. Spironolactone was well tolerated in selected patients with early stage CKD. Strict monitoring over the first month of treatment followed by standard surveillance as for ACE inhibitors and ARBs is suggested. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

Safety, Tolerability and Pharmacokinetics of the Serotonin 5-HT6 Receptor Antagonist, SUVN-502, in Healthy Young Adults and Elderly Subjects.

PubMed

Nirogi, Ramakrishna; Mudigonda, Koteshwara; Bhyrapuneni, Gopinadh; Muddana, Nageswara Rao; Goyal, Vinod Kumar; Pandey, Santosh Kumar; Palacharla, Raghava Choudary

2018-05-01

SUVN-502, a selective 5-HT6 receptor antagonist, was found to be active in preclinical models of cognitive deterioration suggesting a potential role in the treatment of dementia related to Alzheimer's disease. The objective of this study was to characterize the safety, tolerability and pharmacokinetics of SUVN-502 in healthy young adults and elderly subjects following single and multiple oral doses. Single doses (5, 15, 50, 100 and 200 mg SUVN-502) and multiple doses (50, 100 and 130 mg SUVN-502 once daily for 7 days) were evaluated in healthy young adults and multiple doses (50 and 100 mg SUVN-502 once daily for 14 days) were evaluated in elderly subjects using randomized, double-blind, placebo-controlled, dose-escalating study designs. The effect of food, gender and age on SUVN-502 pharmacokinetics (100 mg single dose) was evaluated using an open-label, two-period, randomized, fed and fasted in a crossover design. SUVN-502 and M1 (major metabolite of SUVN-502) were monitored using validated analytical methods. SUVN-502 is safe and well tolerated up to the highest tested single dose of 200 mg in healthy young adults and multiple doses up to 130 mg for 7 days and 100 mg for 14 days in healthy young adults and elderly subjects, respectively. Exposures of SUVN-502 and M1 were more than dose-proportional over the evaluated dose range. Food and gender did not have a clinically meaningful effect on SUVN-502 exposure. The mean SUVN-502 total (AUC 0-∞ , and AUC 0-last ) and peak exposures (C max ) were 2.9- and 2.2-fold higher, respectively, in elderly subjects compared to young subjects. Steady-state was achieved for SUVN-502 and M1 within 7 days after once-daily dosing of SUVN-502. SUVN-502 exhibited an acceptable safety, tolerability and pharmacokinetic profile in healthy young adults and elderly subjects. Based on the above results, 50 and 100 mg once-daily doses of SUVN-502 were advanced to Phase 2 evaluation in patients with moderate AD.

Safety, tolerability, and pharmacokinetics of single oral doses of tofacitinib, a Janus kinase inhibitor, in healthy volunteers.

PubMed

Krishnaswami, Sriram; Boy, Mary; Chow, Vincent; Chan, Gary

2015-03-01

Tofacitinib is an oral Janus kinase inhibitor. This randomized, double-blind, parallel-group, placebo-controlled study was the first evaluation of tofacitinib in humans. The objectives were to characterize the safety and tolerability, pharmacokinetics (PK), and pharmacodynamics of escalating single tofacitinib doses in healthy subjects. Tofacitinib (0.1, 0.3, 1, 3, 10, 30, 60, and 100 mg) or placebo was administered as oral powder for constitution. For each dose, 7-9 subjects were randomized to tofacitinib and 3-5 subjects to placebo. Ninety-five males and females (age range 19-45) completed the study. Forty-nine treatment-emergent all-causality adverse events (AEs) were observed; nausea and headache were the most frequently reported. Tofacitinib PK was characterized by rapid absorption (time to peak serum concentration [Tmax ] 0.5-1 hour), rapid elimination (mean terminal half-lives 2.3-3.1 hours), and dose-proportional systemic exposures (peak serum concentration [Cmax ] and area under the serum concentration-time curve from time zero to infinity [AUC0-∞ ]). No appreciable correlation was observed between tofacitinib dose and lymphocyte subset counts. Single-dose tofacitinib up to 100 mg in healthy subjects had a safety profile of mostly mild AEs, and no deaths, serious AEs, severe AEs or discontinuations due to AEs. © 2014, The American College of Clinical Pharmacology.

Local rollback for fault-tolerance in parallel computing systems

DOEpatents

Blumrich, Matthias A [Yorktown Heights, NY; Chen, Dong [Yorktown Heights, NY; Gara, Alan [Yorktown Heights, NY; Giampapa, Mark E [Yorktown Heights, NY; Heidelberger, Philip [Yorktown Heights, NY; Ohmacht, Martin [Yorktown Heights, NY; Steinmacher-Burow, Burkhard [Boeblingen, DE; Sugavanam, Krishnan [Yorktown Heights, NY

2012-01-24

A control logic device performs a local rollback in a parallel super computing system. The super computing system includes at least one cache memory device. The control logic device determines a local rollback interval. The control logic device runs at least one instruction in the local rollback interval. The control logic device evaluates whether an unrecoverable condition occurs while running the at least one instruction during the local rollback interval. The control logic device checks whether an error occurs during the local rollback. The control logic device restarts the local rollback interval if the error occurs and the unrecoverable condition does not occur during the local rollback interval.

77 FR 73311 - Special Local Regulation and Safety Zone; America's Cup Sailing Events, San Francisco, CA...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-12-10

...-AA00; 1625-AA08 Special Local Regulation and Safety Zone; America's Cup Sailing Events, San Francisco... the 2013 America's Cup events. This document corrects those erroneous coordinates. DATES: Effective on... published a temporary final rule regulating the on-water activities associated with the ``Louis Vuitton Cup...

77 FR 46285 - Special Local Regulation and Safety Zone; America's Cup Sailing Events, San Francisco, CA

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-03

...] Special Local Regulation and Safety Zone; America's Cup Sailing Events, San Francisco, CA AGENCY: Coast... 2012 program calendar for the on-water activities associated with the ``2012 America's Cup World Series... waters of San Francisco Bay associated with the 34th America's Cup sailing events taking place adjacent...

77 FR 4501 - Special Local Regulation and Safety Zone; America's Cup Sailing Events, San Francisco, CA

Federal Register 2010, 2011, 2012, 2013, 2014

2012-01-30

...] RIN 1625-AA00; 1625-AA08 Special Local Regulation and Safety Zone; America's Cup Sailing Events, San... those portions of the ``America's Cup World Series,'' the ``Louis Vuitton Cup'' challenger selection series, and the ``America's Cup Finals Match'' sailing regattas that may be conducted in the waters of...

A study of safety and tolerability of rotatory vestibular input for preschool children

PubMed Central

Su, Wen-Ching; Lin, Chin-Kai; Chang, Shih-Chung

2015-01-01

The objectives of this study were to determine a safe rotatory vestibular stimulation input for preschool children and to study the effects of grade level and sex of preschool children during active, passive, clockwise, and counterclockwise rotation vestibular input. This study adopted purposive sampling with 120 children from three kindergarten levels (K1, K2, and K3) in Taiwan. The subjects ranged in age from 46 to 79 months of age (mean: 62.1 months; standard deviation =9.60). This study included testing with four types of vestibular rotations. The number, duration, and speed of rotations were recorded. The study found that the mean number of active rotations was 10.28; the mean duration of rotation was 24.17 seconds; and the mean speed was 2.29 seconds per rotation. The mean number of passive rotations was 23.04. The differences in number of rotations in clockwise, counterclockwise, active, and passive rotations were not statistically significant. Sex and grade level were not important related factors in the speed and time of active rotation. Different sexes, rotation methods (active, passive), and grades made significant differences in the number of rotations. The safety and tolerability of rotatory vestibular stimulation input data obtained in this study can provide useful reference data for therapists using sensory integration therapy. PMID:25657579

Performance and Safety of Lithium Ion Cells

NASA Technical Reports Server (NTRS)

Ratnakumar, B. V.; Smart, M. C.; Whitcanack, L.; Surampudi, S.; Marsh, R.

2001-01-01

This report evaluates the performance and safety of Lithium Ion (Li-Ion) cells when used in batteries. Issues discussed include the cycle life, energy efficiency, tolerance to higher charge voltage, tolerance to extended tapered charge voltage, charge on cycling, specific energy, low temperature discharge, low temperature charge, various charge characteristics, storage characteristics, and more of Li-Ion cells.

Applications of a damage tolerance analysis methodology in aircraft design and production

NASA Technical Reports Server (NTRS)

Woodward, M. R.; Owens, S. D.; Law, G. E.; Mignery, L. A.

1992-01-01

Objectives of customer mandated aircraft structural integrity initiatives in design are to guide material selection, to incorporate fracture resistant concepts in the design, to utilize damage tolerance based allowables and planned inspection procedures necessary to enhance the safety and reliability of manned flight vehicles. However, validated fracture analysis tools for composite structures are needed to accomplish these objectives in a timely and economical manner. This paper briefly describes the development, validation, and application of a damage tolerance methodology for composite airframe structures. A closed-form analysis code, entitled SUBLAM was developed to predict the critical biaxial strain state necessary to cause sublaminate buckling-induced delamination extension in an impact damaged composite laminate. An embedded elliptical delamination separating a thin sublaminate from a thick parent laminate is modelled. Predicted failure strains were correlated against a variety of experimental data that included results from compression after impact coupon and element tests. An integrated analysis package was developed to predict damage tolerance based margin-of-safety (MS) using NASTRAN generated loads and element information. Damage tolerance aspects of new concepts are quickly and cost-effectively determined without the need for excessive testing.

A cooperative transponder system for improved traffic safety, localizing road users in the 5 GHz band

NASA Astrophysics Data System (ADS)

Schaffer, B.; Kalverkamp, G.; Chaabane, M.; Biebl, E. M.

2012-09-01

We present a multi-user cooperative mobile transponder system which enables cars to localize pedestrians, bicyclists and other road users in order to improve traffic safety. The system operates at a center frequency of 5.768 GHz, offering the ability to test precision localization technology at frequencies close to the newly designated automotive safety related bands around 5.9 GHz. By carrying out a roundtrip time of flight measurement, the sensor can determine the distance from the onboard localization unit of a car to a road user who is equipped with an active transponder, employing the idea of a secondary radar and pulse compression. The onboard unit sends out a pseudo noise coded interrogation pulse, which is answered by one or more transponders after a short waiting time. Each transponder uses a different waiting time in order to allow for time division multiple access. We present the system setup as well as range measurement results, achieving an accuracy up to centimeters for the distance measurement and a range in the order of hundred meters. We also discuss the effect of clock drift and offset on distance accuracy for different waiting times and show how the system can be improved to further increase precision in a multiuser environment.

A skincare combined with combination of adapalene and benzoyl peroxide provides a significant adjunctive efficacy and local tolerance benefit in adult women with mild acne.

PubMed

Bouloc, A; Roo, E; Imko-Walczuk, B; Moga, A; Chadoutaud, B; Dréno, B

2017-10-01

Acne in adult women is an increasing reason for dermatological consultations. The aim of this study was to assess in adult women with mild acne the efficacy and tolerance of a daily adjunctive application of a skincare (Normaderm ® , Laboratoires Vichy, France) to a fixed combination of adapalene/benzoyl peroxide daily or every other evening and a standard emollient. Subjects were randomized to receive the fixed combination applied either every evening or every other evening and a daily application of the standard emollient and the test care or a once daily application of the fixed combination and the standard emollient alone. Clinical evaluations at Day 0, Day 45 and Day 90 included the count of acne lesions, assessment of clinical improvement and local tolerance. The quantitative lipid profile of the stratum corneum of the forehead was also determined. After 90 days of application, acne had improved in all 299 subjects with a statistically significant difference in favour of the test care regimens (P < 0.05). Moreover, skin quality, subject satisfaction, skin discomfort and sebum composition were in favour of these regimens. In conclusion, the tested skincare combined with a fixed adapalene and benzoyl peroxide combination provides a significant adjunctive efficacy and local tolerance benefit in adult women with mild acne. © 2017 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.

Damage Tolerance Analysis of a Pressurized Liquid Oxygen Tank

NASA Technical Reports Server (NTRS)

Forth, Scott C.; Harvin, Stephen F.; Gregory, Peyton B.; Mason, Brian H.; Thompson, Joe E.; Hoffman, Eric K.

2006-01-01

A damage tolerance assessment was conducted of an 8,000 gallon pressurized Liquid Oxygen (LOX) tank. The LOX tank is constructed of a stainless steel pressure vessel enclosed by a thermal-insulating vacuum jacket. The vessel is pressurized to 2,250 psi with gaseous nitrogen resulting in both thermal and pressure stresses on the tank wall. Finite element analyses were performed on the tank to characterize the stresses from operation. Engineering material data was found from both the construction of the tank and the technical literature. An initial damage state was assumed based on records of a nondestructive inspection performed on the tank. The damage tolerance analyses were conducted using the NASGRO computer code. This paper contains the assumptions, and justifications, made for the input parameters to the damage tolerance analyses and the results of the damage tolerance analyses with a discussion on the operational safety of the LOX tank.

Understanding Risk Tolerance and Building an Effective Safety Culture

NASA Technical Reports Server (NTRS)

Loyd, David

2018-01-01

Estimates range from 65-90 percent of catastrophic mishaps are due to human error. NASA's human factors-related mishaps causes are estimated at approximately 75 percent. As much as we'd like to error-proof our work environment, even the most automated and complex technical endeavors require human interaction... and are vulnerable to human frailty. Industry and government are focusing not only on human factors integration into hazardous work environments, but also looking for practical approaches to cultivating a strong Safety Culture that diminishes risk. Industry and government organizations have recognized the value of monitoring leading indicators to identify potential risk vulnerabilities. NASA has adapted this approach to assess risk controls associated with hazardous, critical, and complex facilities. NASA's facility risk assessments integrate commercial loss control, OSHA (Occupational Safety and Health Administration) Process Safety, API (American Petroleum Institute) Performance Indicator Standard, and NASA Operational Readiness Inspection concepts to identify risk control vulnerabilities.

78 FR 32990 - Special Local Regulation and Safety Zone; America's Cup Sailing Events, San Francisco, CA

Federal Register 2010, 2011, 2012, 2013, 2014

2013-06-03

...] Special Local Regulation and Safety Zone; America's Cup Sailing Events, San Francisco, CA AGENCY: Coast... ``Louis Vuitton Cup, Red Bull Youth America's Cup and the 34th America's Cup'' regatta scheduled from July... associated with the 34th America's Cup sailing events taking place adjacent to the City of San Francisco...

Safety and Tolerability of Panax ginseng Root Extract: A Randomized, Placebo-Controlled, Clinical Trial in Healthy Korean Volunteers

PubMed Central

Lee, Nam-Hun; Yoo, Sa-Ra; Kim, Hyeong-Geug; Cho, Jung-Hyo

2012-01-01

Abstract Objectives Panax ginseng has been extensively used as an adaptogen and is among the top 10 selling herbal supplements in the United States over the past decade. However, there have been few reports about the toxicity of P. ginseng in human studies. Given the lack of toxicological studies in human, this study investigated whether P. ginseng administration causes any noticeable toxic effects in healthy volunteers. Methods This study was designed as a randomized, double-blind, placebo-controlled, and parallel group trial in healthy volunteers. The subjects were required to be healthy, free from any significant disease, as assessed at screening by physical examination, medical history, and laboratory (hematological and biochemical) tests. Eligible subjects received P. ginseng extract (1 g/day or 2 g/day) or placebo over a 4-week period. Results Although mild adverse events, such as dyspepsia, hot flash, insomnia, and constipation, were reported in both P. ginseng and placebo group, no serious untoward reactions were reported following P. ginseng administration. Nonsignificant changes were observed in hematological and biochemical tests. Conclusions P. ginseng administration for 4 weeks was shown to be safe, tolerable, and free of any untoward toxic effect in healthy male and female volunteers. Future results from ongoing multicenter collaborative efforts to evaluate short- and long-term effects of P. ginseng may contribute to our current understanding of safety and tolerability of this herbal product. PMID:22909282

Injury tolerance of tibia for the car-pedestrian impact.

PubMed

Mo, Fuhao; Arnoux, Pierre Jean; Jure, Jean Jaques; Masson, Catherine

2012-05-01

Lower limbs are normally the first contacted body region during car-pedestrian accidents, and easily suffer serious injuries. The previous tibia bending tolerances for pedestrian safety were mainly developed from three-point bending tests on tibia mid-shaft. The tibia tolerances of other locations are still not investigated enough. In addition, tibia loading condition under the car-pedestrian impact should be explored to compare with the three-point bending. This work aims to investigate the injury tolerance of tibia fracture with combined experimental data and numerical simulation. Eleven new reported quasi-static bending tests of tibia mid-shaft, and additional eleven dynamic mid-shaft bending test results in the previous literature were used to define injury risk functions. Furthermore, to investigate the influence of tibia locations on bending tolerance, finite element simulations with lower limb model were implemented according to three-point bending and pedestrian impact conditions. The regressive curve of tibia bending tolerance was obtained from the simulations on the different impact locations, and indicated that tibia fracture tolerance could vary largely due to the impact locations for the car-pedestrian crash. Copyright © 2011 Elsevier Ltd. All rights reserved.

SafetyAnalyst : software tools for safety management of specific highway sites

DOT National Transportation Integrated Search

2010-07-01

SafetyAnalyst provides a set of software tools for use by state and local highway agencies for highway safety management. SafetyAnalyst can be used by highway agencies to improve their programming of site-specific highway safety improvements. SafetyA...

Safety and tolerability of different titration rates of retigabine (ezogabine) in patients with partial-onset seizures.

PubMed

Biton, Victor; Gil-Nagel, Antonio; Brodie, Martin J; Derossett, Sarah E; Nohria, Virinder

2013-11-01

Retigabine (RTG; international nonproprietary name)/ezogabine (EZG; US adopted name) is an antiepileptic drug (AED) that prolongs neuronal voltage-gated potassium-channel KCNQ2-5 (Kv 7.2-7.5) opening. This double-blind study evaluated different RTG/EZG dose-titration rates. Patients (N=73) with partial-onset seizures receiving concomitant AEDs were randomized to one of three titration groups, all of which were initiated at RTG/EZG 300mg/day divided into three equal doses. Fast-, medium-, and slow-titration groups received dose increments of 150mg/day every 2, 4, and 7 days, respectively, achieving the target dose of 1200mg/day after 13, 25, and 43 days, respectively. Safety assessments were performed throughout. Discontinuation rates due to treatment-emergent adverse events (TEAEs) were numerically higher in the fast- (10/23) and medium- (7/22) titration groups than in the slow-titration group (3/23) but statistical significance was achieved only for the high-titration group compared with the low-titration group (p=0.024). Stratified analysis, with concomitant AEDs divided into enzyme inducers (carbamazepine, phenytoin, oxcarbazepine) or noninducers, showed that the risk of discontinuation due primarily to TEAEs was significantly higher in the fast- (p=0.010) but not in the medium-titration group (p=0.078) when compared with the slow-titration group. Overall, the slow-titration rate appeared to be best tolerated and was used in further efficacy and safety studies with RTG/EZG. Copyright © 2013 Elsevier B.V. All rights reserved.

Progressive Fracture and Damage Tolerance of Composite Pressure Vessels

NASA Technical Reports Server (NTRS)

Chamis, Christos C.; Gotsis, Pascal K.; Minnetyan, Levon

1997-01-01

Structural performance (integrity, durability and damage tolerance) of fiber reinforced composite pressure vessels, designed for pressured shelters for planetary exploration, is investigated via computational simulation. An integrated computer code is utilized for the simulation of damage initiation, growth, and propagation under pressure. Aramid fibers are considered in a rubbery polymer matrix for the composite system. Effects of fiber orientation and fabrication defect/accidental damages are investigated with regard to the safety and durability of the shelter. Results show the viability of fiber reinforced pressure vessels as damage tolerant shelters for planetary colonization.

HEMATOPOIETIC STEM CELL INFUSION/TRANSPLANTATION FOR INDUCTION OF ALLOGRAFT TOLERANCE

PubMed Central

Granados, Jose M. Marino; Benichou, Gilles; Kawai, Tatsuo

2015-01-01

Purpose of review This review updates the current status of basic, preclinical, and clinical research on donor hematopoietic stem cell infusion for allograft tolerance induction. Recent findings Recent basic studies in mice provide evidence of significant involvement of both central deletional and peripheral regulatory mechanisms in induction and maintenance of allograft tolerance effected through a mixed chimerism approach with donor hematopoietic stem cell infusion. The presence of heterologous memory T cells in primates hampers the induction of persistent chimerism. Durable mixed chimerism, however, now has been recently induced in inbred major histocompatibility complex-mismatched swine, resulting in tolerance of vascularized composite tissue allografts. In clinical transplantation, allograft tolerance has been achieved in human leukocyte antigen-mismatched kidney transplantation after the induction of transient mixed chimerism or persistent full donor chimerism. Summary Tolerance induction in clinical kidney transplantation has been achieved by donor hematopoietic stem cell infusion. Improving the consistency and safety of tolerance induction and extending successful protocols to other organs, as well as to organs from deceased donors, are critical next steps to bringing tolerance to a wider range of clinical applications. PMID:25563992

Antigen-Specific Tolerance in Immunotherapy of Th2-Associated Allergic Diseases

PubMed Central

Smarr, Charles B.; Bryce, Paul J.; Miller, Stephen D.

2013-01-01

Allergic diseases are an increasing health concern, particularly in the developed world. The standard clinical approach to treatment of allergic disease focuses on allergen avoidance and symptom control but does little to address the underlying Th2 bias of disease. Specific immunotherapy (SIT) consisting of controlled administration of allergen, however, has been demonstrated to successfully induce desensitization and tolerance in an antigen-specific manner for a variety of Th2-mediated diseases. This review focuses on the mechanisms by which current SIT approaches induce tolerance as well as discussing attempts to modify the safety and efficacy of SIT. These refinements focus on three major aspects of SIT: the route of antigen administration, modification of the antigen to remove allergenic epitopes and reduce adverse events and choice of adjuvant used to induce tolerance and/or immune deviation from Th2 to Th1 and regulatory T cell (Treg) phenotypes. Synthesis of these recent developments in SIT provides considerable promise for more robust therapies with improved safety profiles to improve resolution of allergic disease and its associated costs. PMID:24099300

Safety and Tolerability of Essential Oil from Cinnamomum zeylanicum Blume Leaves with Action on Oral Candidosis and Its Effect on the Physical Properties of the Acrylic Resin

PubMed Central

Oliveira, Julyana de Araújo; da Silva, Ingrid Carla Guedes; Trindade, Leonardo Antunes; Lima, Edeltrudes Oliveira; Carlo, Hugo Lemes; Cavalcanti, Alessandro Leite; de Castro, Ricardo Dias

2014-01-01

The anti-Candida activity of essential oil from Cinnamomum zeylanicum Blume, as well as its effect on the roughness and hardness of the acrylic resin used in dental prostheses, was assessed. The safety and tolerability of the test product were assessed through a phase I clinical trial involving users of removable dentures. Minimum inhibitory concentration (MIC) and minimum fungicidal concentrations (MFC) were determined against twelve Candida strains. Acrylic resin specimens were exposed to artificial saliva (GI), C. zeylanicum (GII), and nystatin (GIII) for 15 days. Data were submitted to ANOVA and Tukey posttest (α = 5%). For the phase I clinical trial, 15 healthy patients used solution of C. zeylanicum at MIC (15 days, 3 times a day) and were submitted to clinical and mycological examinations. C. zeylanicum showed anti-Candida activity, with MIC = 625.0 µg/mL being equivalent to MFC. Nystatin caused greater increase in roughness and decreased the hardness of the material (P < 0.0001), with no significant differences between GI and GII. As regards the clinical trial, no adverse clinical signs were observed after intervention. The substance tested had a satisfactory level of safety and tolerability, supporting new advances involving the clinical use of essential oil from C. zeylanicum. PMID:25574178

Safety and Tolerability of SBRT after High-Dose External Beam Radiation to the Lung

PubMed Central

Owen, Dawn; Olivier, Kenneth R.; Song, Limin; Mayo, Charles S.; Miller, Robert C.; Nelson, Kathryn; Bauer, Heather; Brown, Paul D.; Park, Sean S.; Ma, Daniel J.; Garces, Yolanda I.

2015-01-01

Purpose: Stereotactic body radiotherapy (SBRT) is commonly used to treat unresectable lung nodules. Given its relative safety and effective local control, SBRT has also been used to treat recurrent lung nodules after high-dose external beam radiation (EBRT) to the lung. The toxicity of such treatment is unknown. Methods and Materials: Between 2006 and 2012, 18 subjects at the Mayo Clinic with 27 recurrent lung nodules were treated with SBRT after receiving EBRT to the lung. Median local control, overall survival, and progression-free survival (PFS) were described. Acute toxicity and late toxicity (defined as toxicity ≥ and >90 days, respectively) were reported and graded as per standardized CTCAE 4.0 criteria. Results: The median age of patients treated was 68 years. Fifteen patients had recurrent lung cancer as their primary histology. Twelve patients received ≥60 Gy of conventional EBRT prior to SBRT. SBRT dose and fractionation varied; the most common prescriptions were 48 Gy/4, 54 Gy/3, and 50 Gy/5 fractions. Only four patients had SBRT planning target volumes (PTVs) that overlapped more than 50% of their prior EBRT PTV. Two patients developed local recurrence following SBRT. With a median follow up of 21.2 months, median SBRT-specific overall survival and PFS were 21.7 and 12.3 months, respectively. No grade ≥3 acute or late toxicities were noted. Conclusion: Stereotactic body radiotherapy may be a good salvage option for select patients with recurrent lung nodules following definitive EBRT to the chest. Toxicity is minimal and local control is excellent. PMID:25642416

Safety, Tolerability, and Pharmacokinetics of SMT C1100, a 2-Arylbenzoxazole Utrophin Modulator, following Single- and Multiple-Dose Administration to Pediatric Patients with Duchenne Muscular Dystrophy

PubMed Central

Ricotti, Valeria; Spinty, Stefan; Roper, Helen; Hughes, Imelda; Tejura, Bina; Robinson, Neil; Layton, Gary; Davies, Kay

2016-01-01

Purpose SMT C1100 is a utrophin modulator being evaluated as a treatment for Duchenne muscular dystrophy (DMD). This study, the first in pediatric DMD patients, reports the safety, tolerability and PK parameters of single and multiple doses of SMT C1100, as well as analyze potential biomarkers of muscle damage. Methods This multicenter, Phase 1 study enrolled 12 patients, divided equally into three groups (A–C). Group A were given 50 mg/kg on Days 1 and 11, and 50 mg/kg bid on Days 2 to 10. Group B and C received 100 mg/kg on Days 1 and 11; Group B and Group C were given 100 mg/kg bid and 100 mg/kg tid, respectively, on Days 2 to 10. A safety review was performed on all patients following the single dose and there was at least 2 weeks between each dose escalation, for safety and PK review. Adverse events (AEs) were monitored throughout the study. Results Most patients experienced mild AEs and there were no serious AEs. Two patients required analgesia for pain (headache, ear pain and toothache). One patient experienced moderate psychiatric AEs (abnormal behaviour and mood swings). Plasma concentrations of SMT C1100 at Days 1 and 11 indicated a high degree of patient variability regardless of dose. Unexpectedly the SMT C1100 levels were significantly lower than similar doses administered to healthy volunteers in an earlier clinical study. In general, individual baseline changes of creatine phosphokinase, alanine aminotransferase, aspartate aminotransferase levels fell with SMT C1100 dosing. Conclusions SMT C1100 was well tolerated in pediatric DMD patients. Trial Registration ClinicalTrials.gov NCT02383511 PMID:27055247

Sequential Treatment Initiation with Timothy Grass and Ragweed Sublingual Immunotherapy Tablets Followed by Simultaneous Treatment Is Well Tolerated.

PubMed

Maloney, Jennifer; Berman, Gary; Gagnon, Remi; Bernstein, David I; Nelson, Harold S; Kleine-Tebbe, Jörg; Kaur, Amarjot; Li, Qing; Nolte, Hendrik

2016-01-01

Dual treatment with grass and ragweed sublingual immunotherapy (SLIT) tablets has not been studied. To characterize the safety and tolerability of dual grass and ragweed SLIT-tablet administration. This open-label, multicenter trial (NCT02256553) enrolled North American adults (N = 102) allergic to grass and ragweed. The trial had 3 periods, each of 2 weeks duration. In period 1, subjects received once-daily timothy grass SLIT tablet (2800 bioequivalent allergen unit; Merck, Inc, Kenilworth, NJ/ALK, Hørsholm, Denmark). In period 2, subjects received a short ragweed SLIT tablet (12 Ambrosia artemisiifolia 1-U; Merck/ALK) every morning and a grass SLIT tablet every evening. In period 3, subjects received once-daily grass and ragweed SLIT tablets within 5 minutes (simultaneous intake). The primary end point was the proportion of subjects with 1 or more local swelling events in each period. Secondary end points were the proportion of subjects with 1 or more local adverse events (AEs), that discontinued the treatment because of AEs, and subjects with 1 or more local AEs requiring treatment. No severe swellings, systemic allergic reactions, asthma attacks, or reactions requiring epinephrine were reported. Most (99%) AEs were graded mild to moderate. The proportions of subjects with 1 or more local swelling events were 14%, 22%, and 15% for periods 1, 2, and 3, respectively. For periods 1, 2, and 3, the proportions of subjects with 1 or more local AEs were 71%, 69%, and 56%, respectively; the proportions discontinuing the treatment because of treatment-related AEs were 5%, 1%, and 2%, and the proportions with 1 or more local AEs requiring treatment were 4%, 4%, and 1%. In this trial, a 4-week sequential SLIT-tablet dosing schedule followed by simultaneous intake of timothy grass and ragweed tablets was well tolerated. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Newly Identified Wild Rice Accessions Conferring High Salt Tolerance Might Use a Tissue Tolerance Mechanism in Leaf.

PubMed

Prusty, Manas R; Kim, Sung-Ryul; Vinarao, Ricky; Entila, Frederickson; Egdane, James; Diaz, Maria G Q; Jena, Kshirod K

2018-01-01

leaf and the following Na + sequestration in leaf might be occurring independent of tonoplast-localized OsNHX1. The newly isolated wild rice accessions will be valuable materials for both rice improvement to salinity stress and the study of salt tolerance mechanism in plants.

Newly Identified Wild Rice Accessions Conferring High Salt Tolerance Might Use a Tissue Tolerance Mechanism in Leaf

PubMed Central

Prusty, Manas R.; Kim, Sung-Ryul; Vinarao, Ricky; Entila, Frederickson; Egdane, James; Diaz, Maria G. Q.; Jena, Kshirod K.

2018-01-01

+ sequestration in leaf might be occurring independent of tonoplast-localized OsNHX1. The newly isolated wild rice accessions will be valuable materials for both rice improvement to salinity stress and the study of salt tolerance mechanism in plants. PMID:29740456

Safety and tolerability of intrathecal liposomal cytarabine as central nervous system prophylaxis in patients with acute lymphoblastic leukemia.

PubMed

Valentin, Angelika; Troppan, Katharina; Pfeilstöcker, Michael; Nösslinger, Thomas; Linkesch, Werner; Neumeister, Peter

2014-08-01

Central nervous system recurrence in acute lymphoblastic leukemia (ALL) occurs in up to 15% of patients and is frequently associated with poor outcome. The purpose of our study was to evaluate the efficacy and safety of a slow-release liposomal formulation of cytarabine for intrathecal (IT) meningeal prophylaxis in patients suffering from ALL. Forty patients aged 20-77 years (median 36) were preventively treated with a total of 96 (range 1-6) single doses containing 50 mg of liposomal cytarabine on a compassionate use basis. After a median observation period of 23 months (range 2-118) only two patients experienced a combined medullary-leptomeningeal disease recurrence after primary diagnosis. Except for headache grade 2 in two patients, no specific toxicity attributable to IT liposomal cytarabine application was noted. Long-term neurological side effects were not observed. IT liposomal cytarabine therapy with concomitant dexamethasone appears to be feasible and well tolerated.

A prospective clinical study to evaluate the safety and performance of wireless localization of nonpalpable breast lesions using radiofrequency identification technology.

PubMed

Dauphine, Christine; Reicher, Joshua J; Reicher, Murray A; Gondusky, Christina; Khalkhali, Iraj; Kim, Michelle

2015-06-01

The purpose of this study was to evaluate the safety and performance of localizing nonpalpable breast lesions using radiofrequency identification technology. Twenty consecutive women requiring preoperative localization of a breast lesion were recruited. Subjects underwent placement of both a hook wire and a radiofrequency identification tag immediately before surgery. The radiofrequency identification tag was the primary method used by the operating surgeon to localize each lesion during excision, with the hook wire serving as backup in case of tag migration or failed localization. Successful localization with removal of the intended lesion was the primary outcome measured. Tag migration and postoperative infection were also noted to assess safety. Twenty patients underwent placement of a radiofrequency identification tag, 12 under ultrasound guidance and eight with stereotactic guidance. In all cases, the radiofrequency identification tag was successfully localized by the reader at the level of the skin before incision, and the intended lesion was removed along with the radiofrequency identification tag. There were no localization failures and no postoperative infections. Tag migration did not occur before incision, but in three cases, occurred as the lesion was being retracted with fingers to make the final cut along the deep surface of the specimen. In this initial clinical study, radiofrequency tags were safe and able to successfully localize nonpalpable breast lesions. Radiofrequency identification technology may represent an alternative method to hook wire localization.

Simulation of a G-tolerance curve using the pulsatile cardiovascular model

NASA Technical Reports Server (NTRS)

Solomon, M.; Srinivasan, R.

1985-01-01

A computer simulation study, performed to assess the ability of the cardiovascular model to reproduce the G tolerance curve (G level versus tolerance time) is reported. A composite strength duration curve derived from experimental data obtained in human centrifugation studies was used for comparison. The effects of abolishing automomic control and of blood volume loss on G tolerance were also simulated. The results provide additional validation of the model. The need for the presence of autonomic reflexes even at low levels of G is pointed out. The low margin of safety with a loss of blood volume indicated by the simulation results underscores the necessity for protective measures during Shuttle reentry.

Safety and tolerability of guadecitabine (SGI-110) in patients with myelodysplastic syndrome and acute myeloid leukaemia: a multicentre, randomised, dose-escalation phase 1 study.

PubMed

Issa, Jean-Pierre J; Roboz, Gail; Rizzieri, David; Jabbour, Elias; Stock, Wendy; O'Connell, Casey; Yee, Karen; Tibes, Raoul; Griffiths, Elizabeth A; Walsh, Katherine; Daver, Naval; Chung, Woonbok; Naim, Sue; Taverna, Pietro; Oganesian, Aram; Hao, Yong; Lowder, James N; Azab, Mohammad; Kantarjian, Hagop

2015-09-01

Hypomethylating agents are used to treat cancers driven by aberrant DNA methylation, but their short half-life might limit their activity, particularly in patients with less proliferative diseases. Guadecitabine (SGI-110) is a novel hypomethylating dinucleotide of decitabine and deoxyguanosine resistant to degradation by cytidine deaminase. We aimed to assess the safety and clinical activity of subcutaneously given guadecitabine in patients with acute myeloid leukaemia or myelodysplastic syndrome. In this multicentre, open-label, phase 1 study, patients from nine North American medical centres with myelodysplastic syndrome or acute myeloid leukaemia that was refractory to or had relapsed after standard treatment were randomly assigned (1:1) to receive subcutaneous guadecitabine, either once-daily for 5 consecutive days (daily × 5), or once-weekly for 3 weeks, in a 28-day treatment cycle. Patients were stratified by disease. A 3 + 3 dose-escalation design was used in which we treated patients with guadecitabine doses of 3-125 mg/m(2) in separate dose-escalation cohorts. A twice-weekly treatment schedule was added to the study after a protocol amendment. The primary objective was to assess safety and tolerability of guadecitabine, determine the maximum tolerated and biologically effective dose, and identify the recommended phase 2 dose of guadecitabine. Safety analyses included all patients who received at least one dose of guadecitabine. Pharmacokinetic and pharmacodynamic analyses to determine the biologically effective dose included all patients for whom samples were available. This study is registered with ClinicalTrials.gov, number NCT01261312. Between Jan 4, 2011, and April 11, 2014, we enrolled and treated 93 patients: 35 patients with acute myeloid leukaemia and nine patients with myelodysplastic syndrome in the daily × 5 dose-escalation cohorts, 28 patients with acute myeloid leukaemia and six patients with myelodysplastic syndrome in the once-weekly dose

Pattern size tolerance of reverse offset printing: a proximity deformation effect related to local PDMS slipping

NASA Astrophysics Data System (ADS)

Kusaka, Yasuyuki; Kanazawa, Shusuke; Koutake, Masayoshi; Ushijima, Hirobumi

2017-10-01

We investigated the shape integrity of silver nanoparticle ink patterns formed by reverse offset printing, focusing particularly on the proximity effect of neighbouring patterns due to the local deformation of a polydimethylsiloxane (PDMS) blanket during contact with a hard cliché. We performed printing tests using a cliché having circular patterns with smaller neighbouring circles located at various distances (2-20 µm), and the results revealed that as we decrease the thickness of PDMS and the inter-pattern gap distance, and as we increase the printing indentations, the shape integrity of the printed pattern was worsened. A complementary numerical simulation of PDMS deformations suggested that the pattern distortion during the contact with clichés was caused by the horizontal deformation of PDMS during the printing, which becomes a significant burden when the uplifted region of PDMS is closer to the gap distance of each pattern. Our analysis further indicates that during printing, there is slipping of the ink at the PDMS interface. In addition, we examined the effects of a synchronization mismatch in a roll-to-sheet printing on the pattern size tolerance. The magnitude of the size distortions was severely influenced not only by the mismatch ratio but also by the nip width. This result verifies the scraping of the ink accompanied by the slipping of the PDMS during the printing process, and thereby determines the size tolerance of printed patterns in reverse offset printing. Finally, we discuss the optimization of process parameters to ensure the size integrity of reverse offset printing.

Results of a Phase 2, Randomized,Vehicle-Controlled Study Evaluating the Efficacy,Tolerability, and Safety of Daily or Twice Daily SB204 for the Treatment of Acne Vulgaris.

PubMed

Eichenfield, Lawrence F; Gold, Linda Stein; Nahm, Walter K; Cook-Bolden, Fran E; Pariser, David M

2016-12-01

This randomized, double-blind, placebo-controlled, Phase 2 study compared efficacy, tolerability, and safety of SB204 once or twice daily to vehicle in the treatment of acne vulgaris. Eligible subjects were to be between 12 and 40 years old, have facial acne vulgaris with 25 to 70 non-inflammatory lesions, 20 to 40 inflammatory lesions, no more than 2 nodules, and a baseline Investigator's Global Assessment (IGA) score of moderate or severe. The co-primary efficacy endpoints were the absolute change in inflammatory and non-inflammatory lesion counts and IGA success rate (baseline to week 12). Safety assessments included reported adverse events (AEs), physical examinations, and laboratory testing. Tolerability was evaluated by the investigators based on the occurrence and severity of erythema, scaling, dryness, pruritus, and burning/stinging. A total of 213 subjects were randomized: 27 subjects to vehicle once daily; 29 subjects to vehicle twice daily; 53 subjects to SB204 2% twice daily; 52 subjects to SB204 4% once daily; and 52 subjects to SB204 4% twice daily. When compared to vehicle, treatment with all 3 SB204 regimens significantly reduced the absolute inflammatory lesion count and SB204 4% once daily reduced the absolute non-inflammatory lesion count. Treatment with SB204 4% once daily demonstrated a significant reduction in percent inflammatory lesions by week 4. There were no significant differences in the IGA success rates between groups at the end of treatment. All treatment regimens of SB204 were found to be safe and well tolerated. When compared to vehicle, SB204 2% and SB204 4% significantly decreased the absolute inflammatory lesion count and SB204 4% once daily also significantly decreased the absolute non-inflammatory lesion count in subjects with acne vulgaris treated for 12 weeks. Treatment with SB204 2% and 4% was found to be safe and well tolerated. J Drugs Dermatol. 2016;15(12):1496-1502.

Mast Cells Condition Dendritic Cells to Mediate Allograft Tolerance

PubMed Central

de Vries, Victor C.; Pino-Lagos, Karina; Nowak, Elizabeth C.; Bennett, Kathy A.; Oliva, Carla; Noelle, Randolph J.

2013-01-01

SUMMARY Peripheral tolerance orchestrated by regulatory T cells, dendritic cells (DCs), and mast cells (MCs) has been studied in several models including skin allograft tolerance. We now define a role for MCs in controlling DC behavior (“conditioning”) to facilitate tolerance. Under tolerant conditions, we show that MCs mediated a marked increase in tumor necrosis factor (TNFα)-dependent accumulation of graft-derived DCs in the dLN compared to nontolerant conditions. This increase of DCs in the dLN is due to the local production of granulocyte macrophage colony-stimulating factor (GM-CSF) by MCs that induces a survival advantage of graft-derived DCs. DCs that migrated to the dLN from the tolerant allograft were tolerogenic; i.e., they dominantly suppress T cell responses and control regional immunity. This study underscores the importance of MCs in conditioning DCs to mediate peripheral tolerance and shows a functional impact of peripherally produced TNFα and GM-CSF on the migration and function of tolerogenic DCs. PMID:22035846

Interpopulational variation in the cold tolerance of a broadly distributed marine copepod

PubMed Central

Wallace, Gemma T.; Kim, Tiffany L.; Neufeld, Christopher J.

2014-01-01

Latitudinal trends in cold tolerance have been observed in many terrestrial ectotherms, but few studies have investigated interpopulational variation in the cold physiology of marine invertebrates. Here, the intertidal copepod Tigriopus californicus was used as a model system to study how local adaptation influences the cold tolerance of a broadly distributed marine crustacean. Among five populations spanning 18° in latitude, the following three metrics were used to compare cold tolerance: the temperature of chill-coma onset, the chill-coma recovery time and post-freezing recovery. In comparison to copepods from warmer southern latitudes, animals from northern populations exhibited lower chill-coma onset temperatures, shorter chill-coma recovery times and faster post-freezing recovery rates. Importantly, all three metrics showed a consistent latitudinal trend, suggesting that any single metric could be used equivalently in future studies investigating latitudinal variation in cold tolerance. Our results agree with previous studies showing that populations within a single species can display strong local adaptation to spatially varying climatic conditions. Thus, accounting for local adaptation in bioclimate models will be useful for understanding how broadly distributed species like T. californicus will respond to anthropogenic climate change. PMID:27293662

Interpopulational variation in the cold tolerance of a broadly distributed marine copepod.

PubMed

Wallace, Gemma T; Kim, Tiffany L; Neufeld, Christopher J

2014-01-01

Latitudinal trends in cold tolerance have been observed in many terrestrial ectotherms, but few studies have investigated interpopulational variation in the cold physiology of marine invertebrates. Here, the intertidal copepod Tigriopus californicus was used as a model system to study how local adaptation influences the cold tolerance of a broadly distributed marine crustacean. Among five populations spanning 18° in latitude, the following three metrics were used to compare cold tolerance: the temperature of chill-coma onset, the chill-coma recovery time and post-freezing recovery. In comparison to copepods from warmer southern latitudes, animals from northern populations exhibited lower chill-coma onset temperatures, shorter chill-coma recovery times and faster post-freezing recovery rates. Importantly, all three metrics showed a consistent latitudinal trend, suggesting that any single metric could be used equivalently in future studies investigating latitudinal variation in cold tolerance. Our results agree with previous studies showing that populations within a single species can display strong local adaptation to spatially varying climatic conditions. Thus, accounting for local adaptation in bioclimate models will be useful for understanding how broadly distributed species like T. californicus will respond to anthropogenic climate change.

Safety, Tolerability, and Pharmacokinetics of Therapeutic and Supratherapeutic Doses of Tramadol Hydrochloride in Healthy Adults: A Randomized, Double-Blind, Placebo-Controlled Multiple-Ascending-Dose Study.

PubMed

DeLemos, Byron; Richards, Henry M; Vandenbossche, Joris; Ariyawansa, Jay; Natarajan, Jaya; Alexander, Binu; Ramakrishna, Tage; Murtaugh, Thomas; Stahlberg, Hans-Jürgen

2017-11-01

This randomized, double-blind, parallel-group multiple-ascending-dose study evaluated the safety, tolerability, and pharmacokinetics of tramadol hydrochloride in healthy adults to inform dosage and design for a subsequent QT/QTc study. Healthy men and women, 18 to 45 years old (inclusive), were sequentially assigned to the tramadol 200, 400, or 600 mg/day treatment cohort and within each cohort, randomized (4:1) to either tramadol or placebo every 6 hours for 9 oral doses. Of the 24 participants randomized to tramadol (n = 8/cohort), 22 (91.7%) completed the study. The AUC tau,ss of tramadol increased approximately 2.2- and 3.6-fold for the (+) enantiomer and 2.0- and 3.5-fold for the (-) enantiomer with increasing dose from 200 to 400  and 600 mg/day, whereas the C max,ss increased 2.1- and 3.3-fold for the (+) enantiomer and 2.0- and 3.2-fold for the (-) enantiomer. Overall, 21 participants (87.5%) participants reported ≥1 treatment-emergent adverse event; most frequent were nausea (17 of 24, 70.8%) and vomiting (7 of 24, 29.2%). Vomiting (affected participants and events) increased with increasing dose from 200 to 600 mg/day but was mild (5 of 24) or moderate (2 of 24) in severity. All tested dosage regimens of tramadol showed acceptable safety and tolerability profile for further investigation in a thorough QT/QTc study. © 2017, The American College of Clinical Pharmacology.

Gross mismatch between thermal tolerances and environmental temperatures in a tropical freshwater snail: climate warming and evolutionary implications.

PubMed

Polgar, Gianluca; Khang, Tsung Fei; Chua, Teddy; Marshall, David J

2015-01-01

The relationship between acute thermal tolerance and habitat temperature in ectotherm animals informs about their thermal adaptation and is used to assess thermal safety margins and sensitivity to climate warming. We studied this relationship in an equatorial freshwater snail (Clea nigricans), belonging to a predominantly marine gastropod lineage (Neogastropoda, Buccinidae). We found that tolerance of heating and cooling exceeded average daily maximum and minimum temperatures, by roughly 20°C in each case. Because habitat temperature is generally assumed to be the main selective factor acting on the fundamental thermal niche, the discordance between thermal tolerance and environmental temperature implies trait conservation following 'in situ' environmental change, or following novel colonisation of a thermally less-variable habitat. Whereas heat tolerance could relate to an historical association with the thermally variable and extreme marine intertidal fringe zone, cold tolerance could associate with either an ancestral life at higher latitudes, or represent adaptation to cooler, higher-altitudinal, tropical lotic systems. The broad upper thermal safety margin (difference between heat tolerance and maximum environmental temperature) observed in this snail is grossly incompatible with the very narrow safety margins typically found in most terrestrial tropical ectotherms (insects and lizards), and hence with the emerging prediction that tropical ectotherms, are especially vulnerable to environmental warming. A more comprehensive understanding of climatic vulnerability of animal ectotherms thus requires greater consideration of taxonomic diversity, ecological transition and evolutionary history. Copyright © 2014 Elsevier Ltd. All rights reserved.

Long-term safety, efficacy, and tolerability of imidafenacin in the treatment of overactive bladder: a review of the Japanese literature

PubMed Central

Masumori, Naoya

2013-01-01

Imidafenacin is an antimuscarinic agent with high affinity for the M3 and M1 muscarinic receptor subtypes and low affinity for the M2 subtype, and is used to treat overactive bladder. Several animal studies have demonstrated that imidafenacin has organ selectivity for the bladder over the salivary glands, colon, heart, and brain. In Phase I studies in humans, the approximately 2.9-hour elimination half-life of imidafenacin was shorter than that of other antimuscarinics such as tolterodine and solifenacin. Imidafenacin was approved for clinical use in overactive bladder in Japan in 2007 after a randomized, double-blind, placebo-controlled Phase II study and a propiverine-controlled Phase III study conducted in Japanese patients demonstrated that imidafenacin 0.1 mg twice daily was clinically effective for treating overactive bladder and was not inferior to propiverine for reduction of episodes of incontinence, with a better safety profile than propiverine. Several short-term clinical studies have demonstrated that imidafenacin also improves sleep disorders, nocturia, and nocturia-related quality of life. In addition, it is speculated that addon therapy with imidafenacin is beneficial for men with benign prostatic hyperplasia whose overactive bladder symptoms are not controlled by alpha-1 adrenoceptor antagonists. No cognitive impairment or influence of imidafenacin on the QTc interval has been observed. Although there have been very few relevant long-term clinical studies, the available information suggests the long-term efficacy, safety, and tolerability of imidafenacin, with less frequent severe adverse events, such as dry mouth and constipation. In addition, imidafenacin can be used safely for a long time even for cognitively vulnerable elderly patients with symptoms of overactive bladder. Thus, it is highly likely that imidafenacin is safe, efficacious, and tolerable to control symptoms of overactive bladder even over the long term. However, it remains unknown

Columbus safety and reliability

NASA Astrophysics Data System (ADS)

Longhurst, F.; Wessels, H.

1988-10-01

Analyses carried out to ensure Columbus reliability, availability, and maintainability, and operational and design safety are summarized. Failure modes/effects/criticality is the main qualitative tool used. The main aspects studied are fault tolerance, hazard consequence control, risk minimization, human error effects, restorability, and safe-life design.

Evaluation of local tolerance of the antiretroviral spermicide (WHI-07)-loaded gel-microemulsion in the porcine female reproductive tract.

PubMed

D'Cruz, Osmond J; Uckun, Fatih M

2008-04-01

The local tolerance of the antiretroviral spermicide, WHI-07 (5-bromo-6-methoxy-5,6-dihydro-3'-azidothymidine-5'-(p-bromophenyl)-methoxyalaninyl phosphate)-loaded gel-microemulsion was evaluated in a physiologically relevant and sensitive porcine model. Gilts (Duroc) in nonestrus stages of the reproductive cycle received either a single or a daily intravaginal application of 2.0% WHI-07 via a gel-microemulsion for 6 days. Cervicovaginal lavage (CVL) fluid was obtained for up to 72 h after a single exposure and the cellular profile and levels of inflammatory cytokines (IL-1beta, IL-8, IFN-gamma and TNF-alpha) were quantitated by flow cytometry and chemiluminescence-based multiplex immunoassay, respectively. The reproductive tract (vagina, cervix, uteri and Fallopian tubes) harvested on day 7 was scored histologically for evidence of mucosal irritation using a new scoring criterion for ten histological endpoints that reflect pathological changes in the epithelial/ subepithelial and vascular/perivascular compartments. When compared with irritant reactions caused by the detergent-type spermicide, benzalkonium chloride (BZK), the scatter profile of CVL immune cells and basal levels of proinflammatory cytokines (IL-1beta, IL-8, IFN-gamma and TNF-alpha) in CVL fluid were unaffected by intravaginal exposure to 2% WHI-07. Unlike BZK, endpoint histology of the proximal and distal regions of the reproductive tract from gilts treated with 2.0% WHI-07 via gel-microemulsion for 6 days did not result in mucosal irritation or alteration in the epithelium, subepithelium/lamina propria, vessels/perivascular tissues and underlying/surrounding muscles. Based on surrogate markers for inflammation, leukocyte profile and histologic data for local tolerance, repeated intravaginal administration of WHI-07 via gel-microemulsion as a prophylactic contraceptive is unlikely to cause vaginal irritation.

[HLA-G: from feto-maternal tolerance to organ acceptance].

PubMed

Carosella, Edgardo D

2014-01-01

HLA-G is a nonclassical class I molecule that differs from classical antigens by its restricted expression, very low polymorphism, expression of 7 different protein isoforms, and immune tolerance-inducing activity. HLA-G plays a key role in feto-maternal tolerance. Its interaction with three specific receptors expressed on immune cells (T, B, natural killer and antigen-presenting cells) allows it to act at all levels of the immune response. HLA-G can also be expressed by tumor cells and their microenvironment, endowing them with significant local tolerance. The same is true in some inflammatory and viral diseases.

Efficacy, tolerability, and safety of hypnosis in adult irritable bowel syndrome: systematic review and meta-analysis.

PubMed

Schaefert, Rainer; Klose, Petra; Moser, Gabriele; Häuser, Winfried

2014-06-01

To assess the efficacy, tolerability, and safety of hypnosis in adult irritable bowel syndrome by a meta-analysis of randomized controlled trials. Studies were identified by a literature search of the databases Allied and Complementary Medicine Database, Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, PubMed, PsycINFO, and Scopus (from inception to June 30, 2013). Primary outcomes were adequate symptom relief, global gastrointestinal score, and safety. Summary relative risks (RRs) with number needed to treat (NNT) and standardized mean differences (SMDs) with 95% confidence intervals (95% CIs) were calculated using random-effects models. Eight randomized controlled trials with a total of 464 patients and a median of 8.5 (7-12) hypnosis sessions over a median of 12 (5-12) weeks were included into the analysis. At the end of therapy, hypnosis was superior to control conditions in producing adequate symptom relief (RR, 1.69 [95% CI = 1.14-2.51]; NNT, 5 [3-10]) and in reducing global gastrointestinal score (SMD, 0.32 [95% CI = -0.56 to -0.08]). At long-term follow-up, hypnosis was superior to controls in adequate symptom relief (RR, 2.17 [95% CI = 1.22-3.87]; NNT, 3 [2-10]), but not in reducing global gastrointestinal score (SMD, -0.57 [-1.40 to 0.26]). One (0.4%) of 238 patients in the hypnosis group dropped out due to an adverse event (panic attack). This meta-analysis demonstrated that hypnosis was safe and provided long-term adequate symptom relief in 54% of patients with irritable bowel syndrome refractory to conventional therapy.

Using the Slug Mucosal Irritation Assay to Investigate the Tolerability of Tablet Excipients on Human Skin in the Context of the Use of a Nipple Shield Delivery System.

PubMed

Kendall, Richard; Lenoir, Joke; Gerrard, Stephen; Scheuerle, Rebekah L; Slater, Nigel K H; Tuleu, Catherine

2017-04-01

Neonates are particularly challenging to treat. A novel patented drug delivery device containing a rapidly disintegrating tablet held within a modified nipple shield (NSDS) was designed to deliver medication to infants during breastfeeding. However concerns exist around dermatological nipple tolerability with no pharmaceutical safety assessment guidance to study local tissue tolerance of the nipple and the areola. This is the first Slug Mucosal Irritation (SMI) study to evaluate irritancy potential of GRAS excipients commonly used to manufacture rapidly disintegrating immediate release solid oral dosage form METHODS: Zinc sulphate selected as the antidiarrheal model drug that reduces infant mortality, was blended with functional excipients at traditional levels [microcrystalline cellulose, sodium starch glycolate, croscarmellose sodium, magnesium stearate]. Slugs were exposed to blends slurried in human breast milk to assess their stinging, itching or burning potential, using objective values such as mucus production to categorize irritation potency RESULTS: Presently an in vivo assay, previously validated for prediction of ocular and nasal irritation, was used as an alternative to vertebrate models to anticipate the potential maternal dermatological tolerability issues to NSDS tablet components. The excipients did not elicit irritancy. However, mild irritancy was observed when zinc sulphate was present in blends. These promising good tolerability results support the continued investigation of these excipients within NSDS rapidly disintegrating tablet formulations. Topical local tolerance effects being almost entirely limited to irritation, the slug assay potentially adds to the existing preformulation toolbox, and may sit in between the in vitro and existing in vivo assays.

QTLs for tolerance of drought and breeding for tolerance of abiotic and biotic stress: an integrated approach.

PubMed

Dixit, Shalabh; Huang, B Emma; Sta Cruz, Ma Teresa; Maturan, Paul T; Ontoy, Jhon Christian E; Kumar, Arvind

2014-01-01

The coupling of biotic and abiotic stresses leads to high yield losses in rainfed rice (Oryza sativa L.) growing areas. While several studies target these stresses independently, breeding strategies to combat multiple stresses seldom exist. This study reports an integrated strategy that combines QTL mapping and phenotypic selection to develop rice lines with high grain yield (GY) under drought stress and non-stress conditions, and tolerance of rice blast. A blast-tolerant BC2F3-derived population was developed from the cross of tropical japonica cultivar Moroberekan (blast- and drought-tolerant) and high-yielding indica variety Swarna (blast- and drought-susceptible) through phenotypic selection for blast tolerance at the BC2F2 generation. The population was studied for segregation distortion patterns and QTLs for GY under drought were identified along with study of epistatic interactions for the trait. Segregation distortion, in favour of Moroberekan, was observed at 50 of the 59 loci. Majority of these marker loci co-localized with known QTLs for blast tolerance or NBS-LRR disease resistance genes. Despite the presence of segregation distortion, high variation for DTF, PH and GY was observed and several QTLs were identified under drought stress and non-stress conditions for the three traits. Epistatic interactions were also detected for GY which explained a large proportion of phenotypic variance observed in the population. This strategy allowed us to identify QTLs for GY along with rapid development of high-yielding purelines tolerant to blast and drought with considerably reduced efforts. Apart from this, it also allowed us to study the effects of the selection cycle for blast tolerance. The developed lines were screened at IRRI and in the target environment, and drought and blast tolerant lines with high yield were identified. With tolerance to two major stresses and high yield potential, these lines may provide yield stability in rainfed rice areas.

77 FR 50373 - Special Local Regulation and Safety Zone; America's Cup World Series Regattas, San Francisco Bay...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-21

...] RIN 1625-AA00; 1625-AA08 Special Local Regulation and Safety Zone; America's Cup World Series Regattas... Acronyms APA Administrative Procedure Act ACRM America's Cup Race Management DHS Department of Homeland... associated with the ``2012 America's Cup World Series'' regatta scheduled to occur August 21-26, 2012 (77 FR...

Safety and tolerability of repetitive transcranial magnetic stimulation in patients with pathologic positive sensory phenomena: a review of literature

PubMed Central

Muller, Paul A; Pascual-Leone, Alvaro; Rotenberg, Alexander

2013-01-01

BACKGROUND Repetitive transcranial magnetic stimulation (rTMS) is emerging as a valuable therapeutic and diagnostic tool. rTMS appears particularly promising for disorders characterized by positive sensory phenomena attributable to alterations in sensory cortex excitability. Among these are tinnitus, auditory and visual hallucinations, and pain syndromes. OBJECTIVE Despite studies addressing rTMS efficacy in suppression of positive sensory symptoms, the safety of stimulation of potentially hyperexcitable cortex has not been fully addressed. We performed a systematic literature review and metanalysis to describe the rTMS safety profile in these disorders. METHODS Using the PubMed database, we performed an English-language literature search from January 1985 to April 2011 to review all pertinent publications. Per study, we noted and listed pertinent details. From these data we also calculated a crude per-subject risk for each adverse event. RESULTS 106 publications (n = 1815 subjects) were identified with patients undergoing rTMS for pathologic positive sensory phenomena. Adverse events associated with rTMS were generally mild and occurred in 16.7% of subjects. Seizure was the most serious adverse event, and occurred in three patients with a 0.16% crude per-subject risk. The second most severe adverse event involved aggravation of sensory phenomena, occurring in 1.54%. CONCLUSIONS The published data suggest rTMS for the treatment or diagnosis of pathologic positive sensory phenomena appears to be a relatively safe and well-tolerated procedure. However, published data are lacking in systematic reporting of adverse events, and safety risks of rTMS in these patient populations will have to be addressed in future prospective trials. PMID:22322098

Outcomes studies of the gastrointestinal safety of cyclooxygenase-2 inhibitors.

PubMed

Scheiman, James M

2002-01-01

Short-term endoscopic studies of the highly selective cyclooxygenase-2 (COX-2) inhibitors (coxibs) rofecoxib and celecoxib have shown that these agents are well tolerated and have efficacy equivalent to nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) with fewer adverse effects on the upper gastrointestinal (GI) tract. These studies are limited, however, as the detection of endoscopic lesions is not well correlated with symptomatic ulcers and ulcer complications. Outcomes studies of the GI safety are, therefore, essential to understanding how coxibs are likely to perform in a clinical practice setting. Four large outcomes studies (Vioxx Gastrointestinal Outcomes Research, VIGOR; Assessment of Difference Between Vioxx and Naproxen to Ascertain Gastrointestinal Tolerability and Effectiveness trial, ADVANTAGE; Celecoxib Long-term Arthritis Safety Study, CLASS; and the Successive Celecoxib Efficacy and Safety Studies, SUCCESS) examined the GI safety of rofecoxib and celecoxib in over 39,000 patients with osteoarthritis or rheumatoid arthritis. Results of these studies showed that patients taking a supratherapeutic dose of rofecoxib or celecoxib had significantly lower rates of GI-related adverse events than those taking a nonselective NSAID (naproxen, ibuprofen, or diclofenac). Reduced risk of upper GI events was seen in patients with multiple risk factors and in patients using low-dose aspirin and corticosteroids concomitantly with a coxib. Results of large outcomes studies provide support for the COX-2 hypothesis and demonstrate the long-term safety and tolerability of coxibs.

CORAL REEFS. Genomic determinants of coral heat tolerance across latitudes.

PubMed

Dixon, Groves B; Davies, Sarah W; Aglyamova, Galina A; Meyer, Eli; Bay, Line K; Matz, Mikhail V

2015-06-26

As global warming continues, reef-building corals could avoid local population declines through "genetic rescue" involving exchange of heat-tolerant genotypes across latitudes, but only if latitudinal variation in thermal tolerance is heritable. Here, we show an up-to-10-fold increase in odds of survival of coral larvae under heat stress when their parents come from a warmer lower-latitude location. Elevated thermal tolerance was associated with heritable differences in expression of oxidative, extracellular, transport, and mitochondrial functions that indicated a lack of prior stress. Moreover, two genomic regions strongly responded to selection for thermal tolerance in interlatitudinal crosses. These results demonstrate that variation in coral thermal tolerance across latitudes has a strong genetic basis and could serve as raw material for natural selection. Copyright © 2015, American Association for the Advancement of Science.

CORSSTOL: Cylinder Optimization of Rings, Skin, and Stringers with Tolerance sensitivity

NASA Technical Reports Server (NTRS)

Finckenor, J.; Bevill, M.

1995-01-01

Cylinder Optimization of Rings, Skin, and Stringers with Tolerance (CORSSTOL) sensitivity is a design optimization program incorporating a method to examine the effects of user-provided manufacturing tolerances on weight and failure. CORSSTOL gives designers a tool to determine tolerances based on need. This is a decisive way to choose the best design among several manufacturing methods with differing capabilities and costs. CORSSTOL initially optimizes a stringer-stiffened cylinder for weight without tolerances. The skin and stringer geometry are varied, subject to stress and buckling constraints. Then the same analysis and optimization routines are used to minimize the maximum material condition weight subject to the least favorable combination of tolerances. The adjusted optimum dimensions are provided with the weight and constraint sensitivities of each design variable. The designer can immediately identify critical tolerances. The safety of parts made out of tolerance can also be determined. During design and development of weight-critical systems, design/analysis tools that provide product-oriented results are of vital significance. The development of this program and methodology provides designers with an effective cost- and weight-saving design tool. The tolerance sensitivity method can be applied to any system defined by a set of deterministic equations.

Fault-Tolerant Local-Area Network

NASA Technical Reports Server (NTRS)

Morales, Sergio; Friedman, Gary L.

1988-01-01

Local-area network (LAN) for computers prevents single-point failure from interrupting communication between nodes of network. Includes two complete cables, LAN 1 and LAN 2. Microprocessor-based slave switches link cables to network-node devices as work stations, print servers, and file servers. Slave switches respond to commands from master switch, connecting nodes to two cable networks or disconnecting them so they are completely isolated. System monitor and control computer (SMC) acts as gateway, allowing nodes on either cable to communicate with each other and ensuring that LAN 1 and LAN 2 are fully used when functioning properly. Network monitors and controls itself, automatically routes traffic for efficient use of resources, and isolates and corrects its own faults, with potential dramatic reduction in time out of service.

Safety of local anaesthesia in dental patients taking oral anticoagulants: is it still controversial?

PubMed

Bajkin, Branislav V; Todorovic, Ljubomir M

2012-01-01

The aim of this study was to investigate the safety of local infiltration techniques and the inferior alveolar nerve block (IANB) in dental patients taking oral anticoagulants. A total of 352 patients were given a total of 560 injections of local anaesthetic (119 IANB and 441 others). The study group comprised 279 patients with therapeutic international normalised ratios (INRs), and the control group 73 patients who were taking oral anticoagulants but had subtherapeutic INR on the day of operation. Blood was aspirated 7 times (7.3%) during the IANB in the study group. However, there were no clinical signs of prolonged haemorrhage into the medial pterygoid muscle or pterygomandibular space after 96 IANB, including those from whom blood had been aspirated. Only two minor haematomas developed after multiple infiltrations in the lingual sulci. The results suggest that bleeding as a result of the use of local anaesthesia in patients with therapeutic INR is unlikely, provided that the IANB is done correctly. Copyright © 2010 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

Analysis of fault-tolerant neurocontrol architectures

NASA Technical Reports Server (NTRS)

Troudet, T.; Merrill, W.

1992-01-01

The fault-tolerance of analog parallel distributed implementations of a multivariable aircraft neurocontroller is analyzed by simulating weight and neuron failures in a simplified scheme of analog processing based on the functional architecture of the ETANN chip (Electrically Trainable Artificial Neural Network). The neural information processing is found to be only partially distributed throughout the set of weights of the neurocontroller synthesized with the backpropagation algorithm. Although the degree of distribution of the neural processing, and consequently the fault-tolerance of the neurocontroller, could be enhanced using Locally Distributed Weight and Neuron Approaches, a satisfactory level of fault-tolerance could only be obtained by retraining the degrated VLSI neurocontroller. The possibility of maintaining neurocontrol performance and stability in the presence of single weight of neuron failures was demonstrated through an automated retraining procedure of the neurocontroller based on a pre-programmed choice and sequence of the training parameters.

Tolerability of Crisaborole Ointment for Application on Sensitive Skin Areas: A Randomized, Double-Blind, Vehicle-Controlled Study in Healthy Volunteers.

PubMed

Zane, Lee T; Hughes, Matilda H; Shakib, Sepehr

2016-10-01

Inflammatory skin diseases such as atopic dermatitis (AD) and psoriasis often present in sensitive and thin-skinned areas that are at higher risk for topical treatment-related skin irritation (e.g., burning, stinging). Our objective was to address the need for topical treatments that can be safely applied to these areas. We assessed the local tolerability of crisaborole topical ointment when applied to sensitive and thin-skinned areas of healthy volunteers. In this phase I, randomized, double-blind, vehicle-controlled, single-center study, 32 subjects were randomized 3:1 to twice-daily application of crisaborole topical ointment, 2 %, (n = 24) or vehicle ointment (n = 8) for 21 days to 13 anatomic skin areas, including the face/hairline, genitals, extensor, and intertriginous areas. The primary endpoint was assessment of the frequency and severity of local tolerability symptoms (burning/stinging, erythema, and pruritus) using the Local Tolerability Scale. Overall, 98.8 % of all tolerability assessments had a grade of 0 (no signs/symptoms of irritation) and 0.1 % had a grade >1 (mild); no differences were observed in the frequency of local tolerability scores between treatment groups. The total frequency of local tolerability assessments graded >0 (none) was lower across all application sites with crisaborole ointment (0.0-2.2 %) than with vehicle ointment (2.4-7.1 %). Local tolerability did not change over time, and was comparable between sensitive and nonsensitive skin areas. Crisaborole ointment application to sensitive skin areas was well tolerated in healthy volunteers, supporting its potential role as a topical treatment alternative for patients with AD or psoriasis.

Safety in the Chemical Laboratory: Developing Departmental Safety Procedures.

ERIC Educational Resources Information Center

Renfrew, Malcolm M., Ed.; Palladino, George F.

1980-01-01

Presents rationale and guidelines for development of Safety Standard Operating Procedures (Safety SOP) specific for local conditions. Includes an outline of a Safety SOP developed for a department primarily focused on undergraduate education with a wide variety of expertise from common laborer to PhD with 20 years experience. (Author/JN)

Self-stabilizing byzantine-fault-tolerant clock synchronization system and method

NASA Technical Reports Server (NTRS)

Malekpour, Mahyar R. (Inventor)

2012-01-01

Systems and methods for rapid Byzantine-fault-tolerant self-stabilizing clock synchronization are provided. The systems and methods are based on a protocol comprising a state machine and a set of monitors that execute once every local oscillator tick. The protocol is independent of specific application specific requirements. The faults are assumed to be arbitrary and/or malicious. All timing measures of variables are based on the node's local clock and thus no central clock or externally generated pulse is used. Instances of the protocol are shown to tolerate bursts of transient failures and deterministically converge with a linear convergence time with respect to the synchronization period as predicted.

Safety and tolerability of vortioxetine (15 and 20 mg) in patients with major depressive disorder: results of an open-label, flexible-dose, 52-week extension study.

PubMed

Jacobsen, Paula L; Harper, Linda; Chrones, Lambros; Chan, Serena; Mahableshwarkar, Atul R

2015-09-01

Vortioxetine is approved for the treatment of adults with major depressive disorder. This open-label extension (OLE) study evaluated the safety and tolerability of vortioxetine in the long-term treatment of major depressive disorder patients, as well as evaluated its effectiveness using measures of depression, anxiety, and overall functioning. This was a 52-week, flexible-dose, OLE study in patients who completed one of three randomized, double-blind, placebo-controlled, 8-week vortioxetine trials. All patients were switched to 10 mg/day vortioxetine for week 1, then adjusted between 15 and 20 mg for the remainder of the study, but not downtitrated below 15 mg. Safety and tolerability were assessed on the basis of treatment-emergent adverse events (TEAEs), vital signs, laboratory values, physical examination, and the Columbia-Suicide Severity Rating Scale. Efficacy measures included the Montgomery-Åsberg Depression Rating Scale, the Hamilton Anxiety Scale, the Clinical Global Impression Scale-Severity of Illness, and the Sheehan Disability Scale. Of the 1075 patients enrolled, 1073 received at least one dose of vortioxetine and 538 (50.0%) completed the study. A total of 537 patients withdrew early, with 115 (10.7% of the original study population) withdrawing because of TEAEs. Long-term treatment with vortioxetine was well tolerated; the most common TEAEs (≥10%) were nausea and headache. Laboratory values, vital signs, and physical examinations revealed no trends of clinical concern. The mean Montgomery-Åsberg Depression Rating Scale total score was 19.9 at the start of the extension study and 9.0 after 52 weeks of treatment (observed cases). Similar improvements were observed with the Hamilton Anxiety Scale (Δ-4.2), the Clinical Global Impression Scale-Severity of Illness (Δ-1.2), and the Sheehan Disability Scale (Δ-4.7) total scores after 52 weeks of treatment (observed case). In this 52-week, flexible-dose OLE study, 15 and 20 mg vortioxetine

Safety and tolerability of vortioxetine (15 and 20 mg) in patients with major depressive disorder: results of an open-label, flexible-dose, 52-week extension study

PubMed Central

Jacobsen, Paula L.; Harper, Linda; Chrones, Lambros; Chan, Serena

2015-01-01

Vortioxetine is approved for the treatment of adults with major depressive disorder. This open-label extension (OLE) study evaluated the safety and tolerability of vortioxetine in the long-term treatment of major depressive disorder patients, as well as evaluated its effectiveness using measures of depression, anxiety, and overall functioning. This was a 52-week, flexible-dose, OLE study in patients who completed one of three randomized, double-blind, placebo-controlled, 8-week vortioxetine trials. All patients were switched to 10 mg/day vortioxetine for week 1, then adjusted between 15 and 20 mg for the remainder of the study, but not downtitrated below 15 mg. Safety and tolerability were assessed on the basis of treatment-emergent adverse events (TEAEs), vital signs, laboratory values, physical examination, and the Columbia-Suicide Severity Rating Scale. Efficacy measures included the Montgomery–Åsberg Depression Rating Scale, the Hamilton Anxiety Scale, the Clinical Global Impression Scale-Severity of Illness, and the Sheehan Disability Scale. Of the 1075 patients enrolled, 1073 received at least one dose of vortioxetine and 538 (50.0%) completed the study. A total of 537 patients withdrew early, with 115 (10.7% of the original study population) withdrawing because of TEAEs. Long-term treatment with vortioxetine was well tolerated; the most common TEAEs (≥10%) were nausea and headache. Laboratory values, vital signs, and physical examinations revealed no trends of clinical concern. The mean Montgomery–Åsberg Depression Rating Scale total score was 19.9 at the start of the extension study and 9.0 after 52 weeks of treatment (observed cases). Similar improvements were observed with the Hamilton Anxiety Scale (Δ−4.2), the Clinical Global Impression Scale-Severity of Illness (Δ−1.2), and the Sheehan Disability Scale (Δ−4.7) total scores after 52 weeks of treatment (observed case). In this 52-week, flexible-dose OLE study, 15 and 20�

Tolerance and Withdrawal From Prolonged Opioid Use in Critically Ill Children

PubMed Central

Anand, Kanwaljeet J. S.; Willson, Douglas F.; Berger, John; Harrison, Rick; Meert, Kathleen L.; Zimmerman, Jerry; Carcillo, Joseph; Newth, Christopher J. L.; Prodhan, Parthak; Dean, J. Michael; Nicholson, Carol

2012-01-01

OBJECTIVE After prolonged opioid exposure, children develop opioid-induced hyperalgesia, tolerance, and withdrawal. Strategies for prevention and management should be based on the mechanisms of opioid tolerance and withdrawal. PATIENTS AND METHODS Relevant manuscripts published in the English language were searched in Medline by using search terms “opioid,” “opiate,” “sedation,” “analgesia,” “child,” “infant-newborn,” “tolerance,” “dependency,” “withdrawal,” “analgesic,” “receptor,” and “individual opioid drugs.” Clinical and preclinical studies were reviewed for data synthesis. RESULTS Mechanisms of opioid-induced hyperalgesia and tolerance suggest important drug- and patient-related risk factors that lead to tolerance and withdrawal. Opioid tolerance occurs earlier in the younger age groups, develops commonly during critical illness, and results more frequently from prolonged intravenous infusions of short-acting opioids. Treatment options include slowly tapering opioid doses, switching to longer-acting opioids, or specifically treating the symptoms of opioid withdrawal. Novel therapies may also include blocking the mechanisms of opioid tolerance, which would enhance the safety and effectiveness of opioid analgesia. CONCLUSIONS Opioid tolerance and withdrawal occur frequently in critically ill children. Novel insights into opioid receptor physiology and cellular biochemical changes will inform scientific approaches for the use of opioid analgesia and the prevention of opioid tolerance and withdrawal. PMID:20403936

Artificial sweeteners and mixture of food additives cause to break oral tolerance and induce food allergy in murine oral tolerance model for food allergy.

PubMed

Yamashita, H; Matsuhara, H; Miotani, S; Sako, Y; Matsui, T; Tanaka, H; Inagaki, N

2017-09-01

Processed foods are part of daily life. Almost all processed foods contain food additives such as sweeteners, preservatives and colourants. From childhood, it is difficult to avoid consuming food additives. It is thought that oral tolerance for food antigens is acquired during early life. If tolerance fails, adverse immune responses to food proteins may occur. We hypothesized that food additives prevent acquisition of oral tolerance and aimed to verify the safety of food additives. We induced experimental oral tolerance in mice for ovalbumin (OVA), a food antigen, by previous oral treatment with OVA before sensitization with OVA injections. Food additives were administered at the induction of oral tolerance, and food allergy was induced by repeated administration of OVA. Symptoms of food allergy were defined as a change in body temperature and allergic diarrhoea. Saccharin sodium and a mixture of food additives inhibited acquisition of oral tolerance. Hypothermia and allergic diarrhoea with elevation of OVA-specific IgE were induced in the murine model of oral tolerance. Analyses of antigen-presenting cells in mesenteric lymph nodes showed that food additives affected their manner of migration. Additionally, food additives decreased the proportion of CD25 hi regulatory T cells among CD4 + T cells in the mesenteric lymph nodes. A large amount of food additives may prevent acquisition of oral tolerance. Intake of food additives in early life may increase the risk of food allergies. © 2017 John Wiley & Sons Ltd.

The safety of phosphodiesterase type 5 inhibitors for erectile dysfunction.

PubMed

Ventimiglia, Eugenio; Capogrosso, Paolo; Montorsi, Francesco; Salonia, Andrea

2016-01-01

Phosphodiesterase type 5 inhibitors (PDE5Is) are the leading drugs for the treatment of erectile dysfunction (ED), being recommended as a first line treatment by both the European and US urological guidelines. PDE5Is are highly effective as compared to placebo, well tolerated and have a very low, though not negligible, rate of severe treatment-related adverse events. This paper reviews the safety profile of currently available PDE5Is, comparing them in a broad spectrum ED population and outlining a number of real-life aspects of importance in the real-life everyday clinical setting. Guidelines unanimously agree in considering PDE5Is as first line treatments for ED when well-tolerated and not contraindicated. Despite the fact that no high-grade evidence comparing the efficacy and the safety for PDE5Is is currently available, published data seem to suggest that there are no major differences in their safety profiles. Moreover, although oral PDE5Is were shown to cause more AEs than placebo, they were generally mild and well tolerated.

A Phase I trial using local regional treatment, nonlethal irradiation, intratumoral and systemic polyinosinic-polycytidylic acid polylysine carboxymethylcellulose to treat liver cancer: in search of the abscopal effect

PubMed Central

de la Torre, Andrew N; Contractor, Sohail; Castaneda, Ismael; Cathcart, Charles S; Razdan, Dolly; Klyde, David; Kisza, Piotr; Gonzales, Sharon F; Salazar, Andres M

2017-01-01

Purpose To determine the safety of an approach to immunologically enhance local treatment of hepatocellular cancer (HCC) by combining nonlethal radiation, local regional therapy with intratumoral injection, and systemic administration of a potent Toll-like receptor (TLR) immune adjuvant. Methods Patients with HCC not eligible for liver transplant or surgery were subject to: 1) 3 fractions of 2-Gy focal nonlethal radiation to increase tumor antigen expression, 2) intra-/peri-tumoral (IT) injection of the TLR3 agonist, polyinosinic-polycytidylic acid polylysine carboxymethylcellulose (poly-ICLC), to induce an immunologic “danger” response in the tumor microenvironment with local regional therapy, and 3) systemic boosting of immunity with intramuscular poly-ICLC. Primary end points were safety and tolerability; secondary end points were progression-free survival (PFS) and overall survival (OS) at 6 months, 1 year, and 2 years. Results Eighteen patients with HCC not eligible for surgery or liver transplant were treated. Aside from 1 embolization-related severe adverse event, all events were ≤grade II. PFS was 66% at 6 months, 39% at 12 months, and 28% at 24 months. Overall 1-year survival was 69%, and 2-year survival 38%. In patients <60 years old, 2-year survival was 62.5% vs. 11.1% in patients aged >60 years (P<0.05). Several patients had prolonged PFS and OS. Conclusion Intra-tumoral injection of the TLR3 agonist poly-ICLC in patients with HCC is safe and tolerable when combined with local nonlethal radiation and local regional treatment. Further work is in progress to evaluate if this approach improves survival compared to local regional treatment alone and characterize changes in anticancer immunity. PMID:28848723

A Phase 1, open-label, multicentre study to compare the capsule and tablet formulations of AZD5363 and explore the effect of food on the pharmacokinetic exposure, safety and tolerability of AZD5363 in patients with advanced solid malignancies: OAK.

PubMed

Dean, Emma; Banerji, Udai; Schellens, Jan H M; Krebs, Matthew G; Jimenez, Begona; van Brummelen, Emilie; Bailey, Chris; Casson, Ed; Cripps, Diana; Cullberg, Marie; Evans, Stephen; Foxley, Andrew; Lindemann, Justin; Rugman, Paul; Taylor, Nigel; Turner, Guy; Yates, James; Lawrence, Peter

2018-05-01

AZD5363 is a potent pan-AKT inhibitor originally formulated as a capsule; a tablet was developed for patient convenience and manufacturing ease. This study assessed the PK comparability of both formulations (Part A) and the effect of food (Part B) on the PK/safety of the tablet. Adults with advanced solid tumours received AZD5363 480 mg bid in a partially fasted state by tablet (Week 1) and capsule (Week 2) in a '4-days-on/3-days-off' schedule (Part A). PK parameters were evaluated using pre-defined 90% CIs for AUCτ and C max ratios of 0.75-1.33 to assess comparability. In Part B, AZD5363 tablet was given to a new cohort of patients under the same conditions as Part A, except on the morning of PK assessment days, when it was administered after an overnight fast (Week 1) and standard meal (Week 2). In evaluable patients (N = 11), the geometric least-squares mean ratios (tablet:capsule) for AUCτ and C max were 0.90 (0.77-1.06) and 1.02 (0.86-1.20), respectively, demonstrating comparable PK in the partially fasted state. Tablet and capsule safety data were also comparable. Tablet PK profiles indicated later t max and lower C max after food versus overnight fast. Fed and fasted AUCτ and C max ratios were 0.89 (0.76-1.05) and 0.67 (0.55-0.82), respectively (N = 9). The safety/tolerability profile of the tablet was comparable between fed and fasted states. PK and safety/tolerability of AZD5363 tablet and capsule were comparable. Food did not affect the bioavailability of AZD5363, but reduced the absorption rate without discernibly affecting safety/tolerability.

Small-bore wire-guided chest drains: safety, tolerability, and effectiveness in pneumothorax, malignant effusions, and pleural empyema.

PubMed

Cafarotti, Stefano; Dall'Armi, Valentina; Cusumano, Giacomo; Margaritora, Stefano; Meacci, Elisa; Lococo, F; Vita, M L; Porziella, V; Bonassi, S; Cesario, Alfredo; Granone, Pierluigi

2011-03-01

The use of small-bore wire-guided chest drains for pleural effusions and pneumothorax has become popular; however, limited data are available on its efficacy and morbidity. The aim of this retrospective study is to measure, via the analysis of the so far largest reported cohort, the efficacy, safety, and tolerability of this approach in different clinical conditions. In the period from January 2002 to December 2008, 1092 patients have undergone the positioning of a small-bore wire-guided chest drain (12F) for the evidence of pneumothorax or pleural effusion and have been monitored over time for morbidity, pain at the time of insertion (measured via the visual analogue scale), and drain failure for misplacement or blockage. Patients with trauma were excluded from this study. Male/female ratio and mean age were respectively 418:674 and 55.85 ± 18.6. Three-hundred ninety-nine (36.5%) drains were inserted for pneumothorax, 324 (29.7%) for malignant effusion, 97 (8.9%) for empyema, and 272 (24.9%) for nonmalignant effusion. The pain experience was on average "very mild" (mean visual analogue scale = 4.6 mm). The overall drain failure rate was 12.9%. The percentage of successful cases was 93.8% in malignant effusion, 93% in pneumothorax, and 92.3% in nonmalignant effusion; in the cases of pathologically diagnosed empyema, drains were more likely to get blocked (74.2%). We recorded 1 serious complication within the malignant effusion group. Wire-guided 12F Seldinger-type drains are a well-tolerated and effective method of treating pneumothorax and uncomplicated pleural effusions (malignant and nonmalignant) with acceptable morbidity. The use of 12F small-bore chest drain is not indicated for the treatment of empyema. Copyright © 2011 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

Food-specific sublingual immunotherapy is well tolerated and safe in healthy dogs: a blind, randomized, placebo-controlled study.

PubMed

Maina, E; Pelst, M; Hesta, M; Cox, E

2017-01-18

Food allergies are increasing in prevalence but no treatment strategies are currently available to cure dogs with food allergy. Over the past decade, experimental food allergen-specific sublingual immunotherapy (FA-SLIT) has emerged as a potential treatment for food allergies in human medicine. However, FA-SLIT has not been investigated in dogs. Therefore, the objective of this study was to prospectively evaluate the safety, tolerability and dispenser sterility of FA-SLIT in healthy dogs before testing it in food allergic dogs. Eight experimental healthy beagle dogs, never orally exposed to peanut, were randomized in two groups to receive SLIT with peanut or placebo for 4 months. Subjects were monitored daily for local and systemic adverse effects. Blood samples for complete blood count and serum biochemistry, and urine for urinalysis were collected and the dogs' body weight was recorded at day 0, 35 and 119 of the SLIT treatment. Sera for the determination of peanut-specific IgG and IgE were collected at day 0, 35, 49, 70, 91, 105 and 119. Intradermal tests were performed before (day 0) and after (day 119) the experiment. The content of each dispenser used to administer treatment or placebo was tested for sterility after usage. In order to assess the presence or absence of sensitization, dogs were challenged 6 months after the end of the study with 2000 μg of peanut extract daily for 7 to 14 days. All dogs completed the study. The treatment did not provoke either local or systemic side-effects. Peanut-specific IgG significantly increased in treatment group. Even though a significant increase in peanut-specific IgE was also seen, intradermal tests were negative in all dogs before and after the experiment, and the challenge test did not trigger any adverse reactions in the treated dogs, which shows the protocol did not cause sensitization to peanut, but nevertheless primed the immune system as indicated by the humoral immune response. All dispenser solutions

Safety and accuracy of a new long-term subconjunctival glucose sensor.

PubMed

Hasslacher, Christoph; Auffarth, Gerd; Platten, Isabell; Rabsilber, Tanja; Smith, Beate; Kulozik, Felix; Knuth, Monika; Nikolaus, Katharina; Müller, Achim

2012-09-01

A new biosensor has been developed by EyeSense (Großostheim, Germany) that is placed into the conjunctiva of one eye to measure the glucose concentration of the surrounding tissue in a non-invasive manner. In the present study we investigated the correlation between glucose concentrations measured by the EyeSense implant and those determined by finger prick testing, as well as the tolerability and safety of the implant over a 16-week period. The study was performed in 28 diabetic patients. The biosensor was inserted under local anesthesia and sterile conditions. Correlations between capillary glucose measured by laboratory methods and interstitial glucose determined by the biosensor were investigated by inducing increases and decreases in glucose values between 60 and 300 mg/dL. Most patients experienced a mild subconjunctival hemorrhage postoperatively. Except for the minor sensation of the presence of foreign body, the implants were well tolerated. Three patients lost the ocular mini insert spontaneously, whereas there was a function failure of the insert in four patients. Error grid analysis showed that the percentage of data pairs in the acceptable ranges (zone A and B) was very high (>96%). However, there was a shift from zone A to zone B during observation. This was due primarily to an increase in the lag time between capillary and interstitial measured glucose. he present study demonstrates good tolerability and measurement performance of the biosensor. The reasons for an increase in the lag time are still unknown; local reactions may be involved. © 2012 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.

Altitude deviations: Breakdowns of an error-tolerant system

NASA Technical Reports Server (NTRS)

Palmer, Everett A.; Hutchins, Edwin L.; Ritter, Richard D.; Vancleemput, Inge

1993-01-01

Pilot reports of aviation incidents to the Aviation Safety Reporting System (ASRS) provide a window on the problems occurring in today's airline cockpits. The narratives of 10 pilot reports of errors made in the automation-assisted altitude-change task are used to illustrate some of the issues of pilots interacting with automatic systems. These narratives are then used to construct a description of the cockpit as an information processing system. The analysis concentrates on the error-tolerant properties of the system and on how breakdowns can occasionally occur. An error-tolerant system can detect and correct its internal processing errors. The cockpit system consists of two or three pilots supported by autoflight, flight-management, and alerting systems. These humans and machines have distributed access to clearance information and perform redundant processing of information. Errors can be detected as deviations from either expected behavior or as deviations from expected information. Breakdowns in this system can occur when the checking and cross-checking tasks that give the system its error-tolerant properties are not performed because of distractions or other task demands. Recommendations based on the analysis for improving the error tolerance of the cockpit system are given.

Chronic Obstructive Pulmonary Disease: Safety and Tolerability of Hyperpolarized 129Xe MR Imaging in Healthy Volunteers and Patients

PubMed Central

Martinez-Jimenez, Santiago; Cleveland, Zackary I.; Metz, Gregory M.; Beaver, Denise M.; Nouls, John C.; Kaushik, S. Sivaram; Firszt, Rafael; Willis, Christine; Kelly, Kevin T.; Wolber, Jan; Kraft, Monica; McAdams, H. Page

2012-01-01

Purpose: To evaluate the safety and tolerability of inhaling multiple 1-L volumes of undiluted hyperpolarized xenon 129 (129Xe) followed by up to a 16-second breath hold and magnetic resonance (MR) imaging. Materials and Methods: This study was approved by the institutional review board and was HIPAA compliant. Written informed consent was obtained. Forty-four subjects (19 men, 25 women; mean age, 46.1 years ± 18.8 [standard deviation]) were enrolled, consisting of 24 healthy volunteers, 10 patients with chronic obstructive pulmonary disease (COPD), and 10 age-matched control subjects. All subjects received three or four 1-L volumes of undiluted hyperpolarized 129Xe, followed by breath-hold MR imaging. Oxygen saturation, heart rate and rhythm, and blood pressure were continuously monitored. These parameters, along with respiratory rate and subjective symptoms, were assessed after each dose. Subjects’ serum biochemistry and hematology were recorded at screening and at 24-hour follow-up. A 12-lead electrocardiogram (ECG) was obtained at these times and also within 2 hours prior to and 1 hour after 129Xe MR imaging. Xenon-related symptoms were evaluated for relationship to subject group by using a χ2 test and to subject age by using logistic regression. Changes in vital signs were tested for significance across subject group and time by using a repeated-measures multivariate analysis of variance test. Results: The 44 subjects tolerated all xenon inhalations, no subjects withdrew, and no serious adverse events occurred. No significant changes in vital signs (P > .27) were observed, and no subjects exhibited changes in laboratory test or ECG results at follow-up that were deemed clinically important or required intervention. Most subjects (91%) did experience transient xenon-related symptoms, most commonly dizziness (59%), paresthesia (34%), euphoria (30%), and hypoesthesia (30%). All symptoms resolved without clinical intervention in 1.6 minutes ± 0.9. Conclusion

[Systemic approach to ecologic safety at objects with radiation jeopardy, involved into localization of low and medium radioactive waste].

PubMed

Veselov, E I

2011-01-01

The article deals with specifying systemic approach to ecologic safety of objects with radiation jeopardy. The authors presented stages of work and algorithm of decisions on preserving reliability of storage for radiation jeopardy waste. Findings are that providing ecologic safety can cover 3 approaches: complete exemption of radiation jeopardy waste, removal of more dangerous waste from present buildings and increasing reliability of prolonged localization of radiation jeopardy waste at the initial place. The systemic approach presented could be realized at various radiation jeopardy objects.

Efficacy, Safety and Tolerability of Augmentative rTMS in Treatment of Major Depressive Disorder (MDD): A Prospective Cohort Study in Croatia.

PubMed

Filipcic, Igor; Milovac, Zeljko; Sucic, Strahimir; Gajsak, Tomislav; Filipcic, Ivona Simunovic; Ivezic, Ena; Aljinovic, Vjekoslav; Orgulan, Ivana; Penic, Sandra Zecevic; Bajic, Zarko

2017-03-01

An increasing body of research suggest that repetitive Transcranial Magnetic Stimulation (rTMS) is effective and safe treatment option for patients with major depressive disorder (MDD). The Psychiatric Hospital "Sveti Ivan" has the first TMS laboratory with rTMS and deep TMS (dTMS) in Croatia. The objective of this study was to assess the efficacy, safety and tolerability of augmentative rTMS treatment vs standard treatment in Croatian patients with major depressive disorder (MDD). Total of 93 MDD patients were enrolled; 41 of them were treated by augmentative rTMS and 52 were treated by standard (psychopharmacotherapy and psychotherapy) therapy only. We delivered rTMS to the left dorsolateral prefrontal cortex at 120% motor threshold (10 Hz, 4-second train duration), 3000 pulses per session using a figure-eight coil, minimum of 20 sessions during four weeks. Our key outcome was the change in Hamilton Depression Scale (HAM-D17) result from baseline to 4 th week. Our secondary outcomes were changes in Hamilton Anxiety (HAM-A) and WHOQOL-BREF scales. After four weeks the changes of HAM-D17 and HAM-A results were significantly different between the group of patients treated by augmentative rTMS (48% and 53% decrease, respectively) and the group of patients treated by the standard therapy alone (24% and 30% decrease) (P=0.004, P=0.007). Absolute benefit increase defined as the difference between rates of remission (HAM-D17 ≤7) in rTMS and control group was 33% (P=0.001). Number of patients needed to treat with rTMS in order to achieve remission in one patient was NNT=3. In a group of patients treated with augmentative rTMS 21/41 (51%), and in control group 17/52 (33%) were responders (P=0.071). It seems that augmentative treatment with rTMS is more effective on depression and anxiety symptoms than standard therapy in MDD with equal safety and tolerability. Randomized, controlled studies are required to verify this finding.

First-in-human study assessing safety, tolerability and pharmacokinetics of BI 409306, a selective phosphodiesterase 9A inhibitor, in healthy males.

PubMed

Moschetti, Viktoria; Boland, Katja; Feifel, Ulrich; Hoch, Anja; Zimdahl-Gelling, Heike; Sand, Michael

2016-11-01

The aim of the present study was to investigate the safety, tolerability, dose proportionality and relative bioavailability of tablet and oral solution formulations of BI 409306 in healthy male subjects, and to compare the safety and pharmacokinetics in subjects who were extensive metabolizers (EMs) or poor metabolizers (PMs) of cytochrome P450 (CYP)-2C19. The present randomized, double-blind, placebo-controlled, single-centre study evaluated single rising doses of BI 409306 (0.5-500 mg) administered as a tablet or oral solution to EMs or PMs. Of 80 enrolled subjects (mean age 36.7 years), 79 (CYP2C19 EMs, 71; CYP2C19 PMs, eight) received treatment and completed the study. Adverse events (AEs) were mild to moderate in intensity. Overall, 17/71 (23.9%) EMs and 6/8 (75.0%) PMs experienced 28 and eight AEs, respectively, of which, 25 and seven AEs, respectively, were considered to be drug related. The most frequently reported AEs were nervous system and eye disorders; all occurred shortly (20-30 min) after administration and mostly resolved within 1-2 h. No serious AEs occurred. BI 409306 systemic absorption and elimination were rapid; peak plasma concentration (C max ) was reached <1 h after drug administration, and the half-life ranged from 0.99 h to 2.71 h. Both the tablet and oral solution resulted in similar exposures. In PMs, at dose levels of 10 mg and 100 mg, C max was 2.2-2.3-fold higher, and the area under the plasma concentration-time curve over the time interval 0 extrapolated to infinity was 4.1-5.0-fold higher compared with EMs. In healthy male subjects, BI 409306 was generally safe and well tolerated, with rapid absorption and elimination. Systemic exposure was higher in CYP2C19 PMs than EMs at the same dose level. © 2016 Boehringer Ingelheim. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Effect of extremes of body weight on the pharmacokinetics, pharmacodynamics, safety and tolerability of apixaban in healthy subjects

PubMed Central

Upreti, Vijay V; Wang, Jessie; Barrett, Yu Chen; Byon, Wonkyung; Boyd, Rebecca A; Pursley, Janice; LaCreta, Frank P; Frost, Charles E

2013-01-01

Aim Apixaban is an oral, direct, factor-Xa inhibitor approved for thromboprophylaxis in patients who have undergone elective hip or knee replacement surgery and for prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. This open label, parallel group study investigated effects of extremes of body weight on apixaban pharmacokinetics, pharmacodynamics, safety and tolerability. Method Fifty-four healthy subjects were enrolled [18 each into low (≤50 kg), reference (65–85 kg) and high (≥120 kg) body weight groups]. Following administration of a single oral dose of 10 mg apixaban, plasma and urine samples were collected for determination of apixaban pharmacokinetics and anti-factor Xa activity. Adverse events, vital signs and laboratory assessments were monitored. Results Compared with the reference body weight group, low body weight had approximately 27% [90% confidence interval (CI): 8–51%] and 20% (90% CI: 11–42%) higher apixaban maximum observed plasma concentration (Cmax) and area under the concentration–time curve extrapolated to infinity (AUC(0,∞)), respectively, and high body weight had approximately 31% (90% CI: 18–41%) and 23% (90% CI: 9–35%) lower apixaban Cmax and AUC(0,∞), respectively. Apixaban renal clearance was similar across the weight groups. Plasma anti-factor Xa activity showed a direct, linear relationship with apixaban plasma concentration, regardless of body weight group. Apixaban was well tolerated in this study. Conclusion The modest change in apixaban exposure is unlikely to require dose adjustment for apixaban based on body weight alone. However, caution is warranted in the presence of additional factors (such as severe renal impairment) that could increase apixaban exposure. PMID:23488672

Fault-tolerant dynamic task graph scheduling

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

Kurt, Mehmet C.; Krishnamoorthy, Sriram; Agrawal, Kunal

2014-11-16

In this paper, we present an approach to fault tolerant execution of dynamic task graphs scheduled using work stealing. In particular, we focus on selective and localized recovery of tasks in the presence of soft faults. We elicit from the user the basic task graph structure in terms of successor and predecessor relationships. The work stealing-based algorithm to schedule such a task graph is augmented to enable recovery when the data and meta-data associated with a task get corrupted. We use this redundancy, and the knowledge of the task graph structure, to selectively recover from faults with low space andmore » time overheads. We show that the fault tolerant design retains the essential properties of the underlying work stealing-based task scheduling algorithm, and that the fault tolerant execution is asymptotically optimal when task re-execution is taken into account. Experimental evaluation demonstrates the low cost of recovery under various fault scenarios.« less

Impacts of Larval Connectivity on Coral Heat Tolerance

NASA Astrophysics Data System (ADS)

Pinsky, M. L.; Kleypas, J. A.; Thompson, D. M.; Castruccio, F. S.; Curchitser, E. N.; Watson, J. R.

2016-02-01

The sensitivity of corals to elevated temperature depends on their acclimation and adaptation to the local maximum temperature regime. Through larval dispersal, however, coral populations can receive larvae from regions that are significantly warmer or colder. If these exogenous larvae carry genetic-based tolerances to colder or warmer temperatures, then the thermal sensitivity of the receiving population may be lower or higher, respectively. Using a high-resolution Regional Ocean Modeling System (ROMS) configuration for the Coral Triangle region, we quantify the potential role of connectivity in determining the thermal stress threshold (TST) of a typical broadcast spawner. The model results suggest that even with a pelagic larval dispersal period of only 10 days, many reefs receive larvae from reefs that are warmer or cooler than the local temperature, and that accounting for this connectivity improves bleaching predictions. This has important implications for conservation planning, because connectivity may allow some reefs to have an inherited heat tolerance that is higher or lower than would be predicted based on local conditions alone.

Safety and tolerability of SCH 530348 in patients undergoing non-urgent percutaneous coronary intervention: a randomised, double-blind, placebo-controlled phase II study.

PubMed

Becker, Richard C; Moliterno, David J; Jennings, Lisa K; Pieper, Karen S; Pei, Jinglan; Niederman, Alan; Ziada, Khaled M; Berman, Gail; Strony, John; Joseph, Diane; Mahaffey, Kenneth W; Van de Werf, Frans; Veltri, Enrico; Harrington, Robert A

2009-03-14

An antithrombotic drug is needed that safely reduces cardiovascular events in patients undergoing percutaneous coronary intervention (PCI). We therefore assessed the tolerability and safety of SCH 530348-an oral platelet protease-activated receptor-1 antagonist. We randomly assigned patients aged 45 years or older and undergoing non-urgent PCI or coronary angiography with planned PCI to an oral loading dose of SCH 530348 (10 mg, 20 mg, or 40 mg) or matching placebo in a 3:1 ratio in a multicentre international study. Those in the SCH 530348 group who subsequently underwent PCI (primary PCI cohort) continued taking an oral maintenance dose (0.5 mg, 1.0 mg, or 2.5 mg per day), and patients in the placebo group continued placebo for 60 days. The primary endpoint was the incidence of clinically significant major or minor bleeding according to the thrombolysis in myocardial infarction (TIMI) scale. Both investigators and patients were unaware of treatment allocation. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00132912. 257 patients were assigned to placebo and 773 to SCH 530348. The primary endpoint occurred in 2 (2%) of 129, 3 (3%) of 120, and 7 (4%) of 173 patients, respectively, in the SCH 530348 10 mg, 20 mg, and 40 mg groups compared with 5 (3%) of 151 patients in the placebo group (p=0.5786). TIMI major plus minor bleeding occurred in 3 (2%) of 136, 5 (4%) of 139, and 4 (3%) of 138 patients given SCH 530348 0.5 mg, 1.0 mg, and 2.5 mg once per day, respectively (p=0.7561). Oral SCH 530348 was generally well tolerated and did not cause increased TIMI bleeding, even when administered concomitantly with aspirin and clopidogrel. Further testing in phase III trials to accurately define the safety and efficacy of SCH 530348 is warranted.

Single Dose and Repeat Once-Daily Dose Safety, Tolerability and Pharmacokinetics of Valbenazine in Healthy Male Subjects.

PubMed

Luo, Rosa; Bozigian, Haig; Jimenez, Roland; Loewen, Gordon; O'Brien, Christopher F

2017-08-01

Valbenazine (VBZ) is a vesicular monoamine transporter 2 (VMAT2) inhibitor approved for the treatment of tardive dyskinesia. The safety, tolerability and pharmacokinetics of VBZ following single and repeat once-daily (QD) dosing were evaluated in 2 randomized, single-center, double-blind studies in healthy male subjects. In the first study, 2 cohorts of 8 subjects were administered single doses (SD) of placebo (PBO; N = 2/period) or VBZ (N = 6/period; 1, 2, 5, or 12.5 mg for Cohort 1 and 12.5, 25, 50, or 75 mg for Cohort 2) using a sequential escalation scheme. The second study consisted of 2 phases. In the initial phase, subjects were administered SD PBO (N = 2/period) or VBZ (N = 6/period; 75, 100, 125 or 150 mg) with sequential escalation. In the second phase, subjects received PBO, or 50 or 100 mg VBZ (N = 4:8:8) QD for 8 days (Cohort 1) or PBO or 50 mg VBZ (N = 6:6) QD for 8 days (Cohort 2). For both studies, plasma concentrations of VBZ and its active metabolite, NBI-98782, were determined. Safety was assessed throughout the studies. PK parameters were determined using noncompartmental methods. In both studies, VBZ was rapidly absorbed with peak concentrations typically observed within 1.5 hours. Peak NBI-98782 concentrations were typically observed at 4.0 to 9.0 hours. Terminal elimination half-life for both VBZ and NBI-98782 was ~20 hours. Across the 1 to 150 mg SD range evaluated across the studies, VBZ and NBI-98782 C max and AUC increased dose-proportionally from 50 to 150 mg and more than dose-proportionally from 1 to 50 mg. QD VBZ and NBI-98782 C max and AUC parameters were also dose-proportional between the 50 and 100 mg doses. Steady-state for both analytes appeared to be achieved by Day 8. The accumulation index was ~1.5 for VBZ and ~2.5 for NBI-98782. Peak to trough fluctuation was approximately 250% for VBZ and 70% for NBI-98782. Across both studies, NBI-98782 exposure was approximately 20%-30% that of VBZ based on molar ratios. In the first study

Single Dose and Repeat Once-Daily Dose Safety, Tolerability and Pharmacokinetics of Valbenazine in Healthy Male Subjects

PubMed Central

Luo, Rosa; Bozigian, Haig; Jimenez, Roland; Loewen, Gordon; O’Brien, Christopher F.

2017-01-01

Valbenazine (VBZ) is a vesicular monoamine transporter 2 (VMAT2) inhibitor approved for the treatment of tardive dyskinesia. The safety, tolerability and pharmacokinetics of VBZ following single and repeat once-daily (QD) dosing were evaluated in 2 randomized, single-center, double-blind studies in healthy male subjects. In the first study, 2 cohorts of 8 subjects were administered single doses (SD) of placebo (PBO; N = 2/period) or VBZ (N = 6/period; 1, 2, 5, or 12.5 mg for Cohort 1 and 12.5, 25, 50, or 75 mg for Cohort 2) using a sequential escalation scheme. The second study consisted of 2 phases. In the initial phase, subjects were administered SD PBO (N = 2/period) or VBZ (N = 6/period; 75, 100, 125 or 150 mg) with sequential escalation. In the second phase, subjects received PBO, or 50 or 100 mg VBZ (N = 4:8:8) QD for 8 days (Cohort 1) or PBO or 50 mg VBZ (N = 6:6) QD for 8 days (Cohort 2). For both studies, plasma concentrations of VBZ and its active metabolite, NBI-98782, were determined. Safety was assessed throughout the studies. PK parameters were determined using noncompartmental methods. In both studies, VBZ was rapidly absorbed with peak concentrations typically observed within 1.5 hours. Peak NBI-98782 concentrations were typically observed at 4.0 to 9.0 hours. Terminal elimination half-life for both VBZ and NBI-98782 was ~20 hours. Across the 1 to 150 mg SD range evaluated across the studies, VBZ and NBI-98782 Cmax and AUC increased dose-proportionally from 50 to 150 mg and more than dose-proportionally from 1 to 50 mg. QD VBZ and NBI-98782 Cmax and AUC parameters were also dose-proportional between the 50 and 100 mg doses. Steady-state for both analytes appeared to be achieved by Day 8. The accumulation index was ~1.5 for VBZ and ~2.5 for NBI-98782. Peak to trough fluctuation was approximately 250% for VBZ and 70% for NBI-98782. Across both studies, NBI-98782 exposure was approximately 20%–30% that of VBZ based on molar ratios. In the first study

DsSWEET17, a Tonoplast-Localized Sugar Transporter from Dianthus spiculifolius, Affects Sugar Metabolism and Confers Multiple Stress Tolerance in Arabidopsis.

PubMed

Zhou, Aimin; Ma, Hongping; Feng, Shuang; Gong, Shufang; Wang, Jingang

2018-05-24

Plant SWEETs (Sugars Will Eventually be Exported Transporters) affect the growth of plants by regulating the transport of sugar from source to sink and its intracellular transport between different organelles. In this study, DsSWEET17 from Dianthus spiculifolius was identified and characterized. Real-time quantitative PCR analysis revealed that the expression of DsSWEET17 was affected by exogenous application of fructose and glucose as well as under salt, osmotic, and oxidation stress. Colocalization experiments showed that the DsSWEET17-GFP (green fluorescent protein) fusion protein was localized to the FM4-64-labeled tonoplasts in Arabidopsis . Compared to the wild type, the transgenic Arabidopsis seedlings overexpressing DsSWEET17 had longer roots, greater fresh weight, and a faster root growth upon exogenous application of fructose. Furthermore, transgenic Arabidopsis seedlings had significantly higher fructose accumulation than was observed for the wild-type seedlings. The analysis of root length revealed that transgenic Arabidopsis had higher tolerance to salt, osmotic, and oxidative stresses. Taken together, our results suggest that DsSWEET17 may be a tonoplast sugar transporter, and its overexpression affects sugar metabolism and confers multiple stress tolerance in Arabidopsis .

Efficacy and safety of clindamycin-tretinoin gel versus clindamycin or tretinoin alone in acne vulgaris: a randomized, double-blind, vehicle-controlled study.

PubMed

Jarratt, Michael T; Brundage, Tom

2012-03-01

Topical combination therapy containing a retinoid and an antimicrobial is an effective treatment for acne vulgaris. To evaluate the efficacy and safety of a new topical formulation containing clindamycin phosphate 1.2% and tretinoin 0.025% solubilized in an aqueous-based gel (CT gel). 1,649 participants were randomized 2:2:2:1 to 12 weeks of double-blind treatment with CT gel, clindamycin, tretinoin, or vehicle gel administered once daily. Significantly more participants achieved 2-grade or greater improvement on the Investigator's Static Global Assessment score with CT gel versus clindamycin, tretinoin, or vehicle gel. CT gel produced a significantly greater reduction in absolute number of total lesions versus all other treatment groups, in total and noninflammatory lesions versus clindamycin, and in total and inflammatory lesions versus tretinoin. Local tolerability was similar to that of tretinoin alone; signs and symptoms of irritation were most notable at week 2. There were no more adverse events with CT gel than with tretinoin gel. CT gel is more effective than clindamycin or tretinoin monotherapy, with a safety and tolerability profile similar to that of tretinoin.

An Autonomous Distributed Fault-Tolerant Local Positioning System

NASA Technical Reports Server (NTRS)

Malekpour, Mahyar R.

2017-01-01

We describe a fault-tolerant, GPS-independent (Global Positioning System) distributed autonomous positioning system for static/mobile objects and present solutions for providing highly-accurate geo-location data for the static/mobile objects in dynamic environments. The reliability and accuracy of a positioning system fundamentally depends on two factors; its timeliness in broadcasting signals and the knowledge of its geometry, i.e., locations and distances of the beacons. Existing distributed positioning systems either synchronize to a common external source like GPS or establish their own time synchrony using a scheme similar to a master-slave by designating a particular beacon as the master and other beacons synchronize to it, resulting in a single point of failure. Another drawback of existing positioning systems is their lack of addressing various fault manifestations, in particular, communication link failures, which, as in wireless networks, are increasingly dominating the process failures and are typically transient and mobile, in the sense that they typically affect different messages to/from different processes over time.

The safety, tolerability, pharmacokinetics and cognitive effects of GSK239512, a selective histamine H₃ receptor antagonist in patients with mild to moderate Alzheimer's disease: a preliminary investigation.

PubMed

Nathan, Pradeep J; Boardley, Rebecca; Scott, Nicola; Berges, Alienor; Maruff, Paul; Sivananthan, Tharani; Upton, Neil; Lowy, Martin T; Nestor, Peter J; Lai, Robert

2013-03-01

The histamine H3 receptor plays a critical role in the negative neuromodulation of neurotransmitters involved in cognitive function. H3 receptor antagonists/inverse agonists have been shown to exert pro-cognitive effects in pre-clinical models. GSK239512 is a potent and selective H₃ receptor antagonist developed for the treatment of cognitive dysfunction in neurodegenerative disorders. In this study we examined the safety, tolerability, pharmacokinetics and pro-cognitive effects of GSK239512 (oral) in patients with mild to moderate Alzheimer's disease using ascending dose titration regimens. The study was conducted in two parts. Part A was a single-blind, placebo run-in, flexible dose titration over 9 days in two cohorts, each consisting of two patients. Part B was a double-blind, randomised, placebo controlled, parallel group, which investigated 3 flexible dose titration regimens over 4 weeks in 3 cohorts, each consisting of eight patients. Overall, the 5/10/20/40 μg and 10/20/40/80 μg regimens were well-tolerated. The regimen of 20/40/80/150 μg showed the poorest tolerability likely due to the higher starting dose. There were no clinically significant abnormalities in haematology, clinical chemistry, urinalysis parameters and cardiovascular parameters. GSK239512 had positive effects on tasks of attention and memory with effect sizes between 0.56 and 1.37. GSK239512 displayed asatisfactory level of tolerability in patients with Alzheimer's disease with evidence for positive effects on attention and memory. The findings suggest that a titration regimen with a starting dose of 5-10 μg and a maximum dose of 80 μg is likely to be a well-tolerated and potentially efficacious regimen for future clinical trials in patients with Alzheimer's disease. These findings await replication in a larger study.

Tolerating Zero Tolerance?

ERIC Educational Resources Information Center

Moore, Brian N.

2010-01-01

The concept of zero tolerance dates back to the mid-1990s when New Jersey was creating laws to address nuisance crimes in communities. The main goal of these neighborhood crime policies was to have zero tolerance for petty crime such as graffiti or littering so as to keep more serious crimes from occurring. Next came the war on drugs. In federal…

NASA System Safety Handbook. Volume 1; System Safety Framework and Concepts for Implementation

NASA Technical Reports Server (NTRS)

Dezfuli, Homayoon; Benjamin, Allan; Everett, Christopher; Smith, Curtis; Stamatelatos, Michael; Youngblood, Robert

2011-01-01

unrtainties represents a method of probabilistic thinking wherein the analyst and decision makers recognize possible outcomes other than the outcome perceived to be "most likely." Without this type of analysis, it is not possible to determine the worth of an analysis product as a basis for making decisions related to safety and mission success. In line with these considerations the handbook does not take a hazard-analysis-centric approach to system safety. Hazard analysis remains a useful tool to facilitate brainstorming but does not substitute for a more holistic approach geared to a comprehensive identification and understanding of individual risk issues and their contributions to aggregate safety risks. The handbook strives to emphasize the importance of identifying the most critical scenarios that contribute to the risk of not meeting the agreed-upon safety objectives and requirements using all appropriate tools (including but not limited to hazard analysis). Thereafter, emphasis shifts to identifying the risk drivers that cause these scenarios to be critical and ensuring that there are controls directed toward preventing or mitigating the risk drivers. To address these and other areas, the handbook advocates a proactive, analytic-deliberative, risk-informed approach to system safety, enabling the integration of system safety activities with systems engineering and risk management processes. It emphasizes how one can systematically provide the necessary evidence to substantiate the claim that a system is safe to within an acceptable risk tolerance, and that safety has been achieved in a cost-effective manner. The methodology discussed in this handbook is part of a systems engineering process and is intended to be integral to the system safety practices being conducted by the NASA safety and mission assurance and systems engineering organizations. The handbook posits that to conclude that a system is adequately safe, it is necessary to consider a set of safety claims that

Longitudinal Studies of a B Cell Derived Signature of Tolerance in Renal Transplant Recipients

PubMed Central

Newell, Kenneth A.; Asare, Adam; Sanz, Ignacio; Wei, Chungwen; Rosenberg, Alexander; Gao, Zhong; Kanaparthi, Sai; Asare, Smita; Lim, Noha; Stahly, Michael; Howell, Michael; Knechtle, Stuart; Kirk, Allan; Marks, William H.; Kawai, Tatsuo; Spitzer, Thomas; Tolkoff-Rubin, Nina; Sykes, Megan; Sachs, David H.; Cosimi, A. Benedict; Burlingham, William J.; Phippard, Deborah; Turka, Laurence A.

2016-01-01

Biomarkers of transplant tolerance would enhance the safety and feasibility of clinical tolerance trials and potentially facilitate management of patients receiving immunosuppression. To this end, we examined blood from spontaneously tolerant renal transplant recipients and patients enrolled in two interventional tolerance trials using flow cytometry and gene expression profiling. Using a previously reported tolerant cohort as well as newly identified tolerant patients we confirmed our previous finding that tolerance was associated with increased expression of B cell-associated genes relative to immunosuppressed patients. This was not accounted for merely by an increase in total B cell numbers, but was associated with the increased frequencies of transitional and naïve B cells. Moreover, serial measurements of gene expression demonstrated that this pattern persisted over several years although patients receiving immunosuppression also displayed an increase in the two most dominant tolerance-related B cell genes, IGKV1D-13 and IGLL-1, over time. Importantly, patients rendered tolerant via induction of transient mixed chimerism, and those weaned to minimal immunosuppression, showed similar increases in IGKV1D-13 as did spontaneously tolerant individuals. Collectively, these findings support the notion that alterations in B cells may be a common theme for tolerant kidney transplant recipients, and a useful monitoring tool in prospective trials. PMID:26461968

Error and attack tolerance of complex networks

NASA Astrophysics Data System (ADS)

Albert, Réka; Jeong, Hawoong; Barabási, Albert-László

2000-07-01

Many complex systems display a surprising degree of tolerance against errors. For example, relatively simple organisms grow, persist and reproduce despite drastic pharmaceutical or environmental interventions, an error tolerance attributed to the robustness of the underlying metabolic network. Complex communication networks display a surprising degree of robustness: although key components regularly malfunction, local failures rarely lead to the loss of the global information-carrying ability of the network. The stability of these and other complex systems is often attributed to the redundant wiring of the functional web defined by the systems' components. Here we demonstrate that error tolerance is not shared by all redundant systems: it is displayed only by a class of inhomogeneously wired networks, called scale-free networks, which include the World-Wide Web, the Internet, social networks and cells. We find that such networks display an unexpected degree of robustness, the ability of their nodes to communicate being unaffected even by unrealistically high failure rates. However, error tolerance comes at a high price in that these networks are extremely vulnerable to attacks (that is, to the selection and removal of a few nodes that play a vital role in maintaining the network's connectivity). Such error tolerance and attack vulnerability are generic properties of communication networks.

Selenium-tolerant diamondback moth disarms hyperaccumulator plantdefense

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

Freeman, J.L.; Quinn, C.F.; Marcus, M.A.

2006-11-20

Background Some plants hyperaccumulate the toxic element selenium (Se) to extreme levels, up to 1% of dry weight. The function of this intriguing phenomenon is obscure. Results Here, we show that the Se in the hyperaccumulator prince's plume (Stanleya pinnata) protects it from caterpillar herbivory because of deterrence and toxicity. In its natural habitat, however, a newly discovered variety of the invasive diamondback moth (Plutella xylostella) has disarmed this elemental defense. It thrives on plants containing highly toxic Se levels and shows no oviposition or feeding deterrence, in contrast to related varieties. Interestingly, a Se-tolerant wasp (Diadegma insulare) was foundmore » to parasitize the tolerant moth. The insect's Se tolerance mechanism was revealed by X-ray absorption spectroscopy and liquid chromatography--mass spectroscopy, which showed that the Se-tolerant moth and its parasite both accumulate methylselenocysteine, the same form found in the hyperaccumulator plant, whereas related sensitive moths accumulate selenocysteine. The latter is toxic because of its nonspecific incorporation into proteins. Indeed, the Se-tolerant diamondback moth incorporated less Se into protein. Additionally, the tolerant variety sequestered Se in distinct abdominal areas, potentially involved in detoxification and larval defense to predators. Conclusions Although Se hyperaccumulation protects plants from herbivory by some invertebrates, it can give rise to the evolution of unique Se-tolerant herbivores and thus provide a portal for Se into the local ecosystem. In a broader context, this study provides insight into the possible ecological implications of using Se-enriched crops as a source of anti-carcinogenic selenocompounds and for the remediation of Se-polluted environments.« less

Safety and convenience of once-weekly somapacitan in adult GH deficiency: a 26-week randomized, controlled trial.

PubMed

Johannsson, Gudmundur; Feldt-Rasmussen, Ulla; Håkonsson, Ida Holme; Biering, Henrik; Rodien, Patrice; Tahara, Shigeyuki; Toogood, Andrew; Rasmussen, Michael Højby

2018-05-01

Somapacitan is a reversible albumin-binding growth hormone (GH) derivative, developed for once-weekly administration. This study aimed to evaluate the safety of once-weekly somapacitan vs once-daily Norditropin ® . Local tolerability and treatment satisfaction were also assessed. 26-week randomized, controlled phase 3 safety and tolerability trial in six countries (Nbib2382939). Male or female patients aged 18-79 years with adult GH deficiency (AGHD), treated with once-daily GH for ≥6 months, were randomized to once-weekly somapacitan ( n  = 61) or once-daily Norditropin ( n  = 31) administered subcutaneously by pen. Both treatments were dose titrated for 8 weeks to achieve insulin-like growth factor I (IGF-I) standard deviation score (SDS) levels within the normal range, and then administered at a fixed dose. Outcome measures were adverse events (AEs), including injection site reactions; occurrence of anti-somapacitan/anti-GH antibodies and change in treatment satisfaction, assessed using the Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9). Mean IGF-I SDS remained between 0 and 2 SDS throughout the trial in both groups. AEs were mostly mild or moderate and transient in nature. The most common AEs were nasopharyngitis, headache and fatigue in both groups. More than 1500 somapacitan injections were administered and no clinically significant injection site reactions were reported. No anti-somapacitan or anti-GH antibodies were detected. The TSQM-9 score for convenience increased significantly more with somapacitan vs Norditropin ( P  = 0.0171). In this 26-week trial in patients with AGHD, somapacitan was well tolerated and no safety issues were identified. Once-weekly somapacitan was reported to be more convenient than once-daily Norditropin. © 2018 The authors.

Software Fault Tolerance: A Tutorial

NASA Technical Reports Server (NTRS)

Torres-Pomales, Wilfredo

2000-01-01

Because of our present inability to produce error-free software, software fault tolerance is and will continue to be an important consideration in software systems. The root cause of software design errors is the complexity of the systems. Compounding the problems in building correct software is the difficulty in assessing the correctness of software for highly complex systems. After a brief overview of the software development processes, we note how hard-to-detect design faults are likely to be introduced during development and how software faults tend to be state-dependent and activated by particular input sequences. Although component reliability is an important quality measure for system level analysis, software reliability is hard to characterize and the use of post-verification reliability estimates remains a controversial issue. For some applications software safety is more important than reliability, and fault tolerance techniques used in those applications are aimed at preventing catastrophes. Single version software fault tolerance techniques discussed include system structuring and closure, atomic actions, inline fault detection, exception handling, and others. Multiversion techniques are based on the assumption that software built differently should fail differently and thus, if one of the redundant versions fails, it is expected that at least one of the other versions will provide an acceptable output. Recovery blocks, N-version programming, and other multiversion techniques are reviewed.

Evaluation of the efficacy, tolerability, and safety of an over-the-counter acne regimen containing benzoyl peroxide and salicylic acid in subjects with acne.

PubMed

Kircik, Leon H; Gwazdauskas, Jennifer; Butners, Victoria; Eastern, Joseph; Green, Lawrence J

2013-03-01

Benzoyl peroxide (BPO) is a widely used over-the-counter (OTC) topical acne treatment often used in combination with salicylic acid (SA) to achieve better comedone control than that achieved with BPO alone. MaxClarity™ is an OTC acne treatment system comprising BPO and SA in an aqueous foam delivery vehicle, VersaFoam AF™. This paper describes 2 open-label, single-arm studies conducted to assess the efficacy, safety, tolerability, and patient preference of MaxClarity in the treatment of mild, moderate, and severe acne. Subjects applied MaxClarity twice daily for 8 weeks in study 402 and for 12 weeks in study 405. Reductions in all lesion types were seen throughout both studies. At week 8 (study 402), there was a mean reduction from baseline of -56.9 ± 32.7% in total lesions in subjects with mild, moderate, or severe acne. At week 12 (study 405), there was a reduction from baseline of -61.6 ± 22.0% in total lesions in subjects with moderate or severe acne. Overall, both studies demonstrated that MaxClarity is a generally well tolerated and effective treatment for mild, moderate, and severe acne.

Pirfenidone gel in patients with localized scleroderma: a phase II study.

PubMed

Rodríguez-Castellanos, Marco; Tlacuilo-Parra, Alberto; Sánchez-Enríquez, Sergio; Vélez-Gómez, Ezequiel; Guevara-Gutiérrez, Elizabeth

2015-01-28

Localized scleroderma is an inflammatory disease in its first stages and a fibrotic process in later stages, principally mediated by the transforming growth factor β. To date, there is no standard treatment. The objective of this study was to determine the effectiveness and safety of 8% pirfenidone gel in patients with localized scleroderma. This was an open phase II clinical trial that included 12 patients. Treatment with pirfenidone was indicated, three times daily for 6 months. Patients were evaluated clinically with the modified Localized Scleroderma Skin Severity Index (mLoSSI), as well with a durometer and histologically using hematoxylin and eosin stain and Masson's trichrome stain. The baseline mLoSSI average scores were 5.83 ± 4.80 vs. 0.83 ± 1.75 (P = 0.002) at 6 months. The initial durometer induration of the scleroderma plaques was 35.79 ± 9.10 vs. 32.47 ± 8.97 at 6 months (P = 0.05). We observed histopathological improvement with respect to epidermal atrophy, inflammation, dermal or adipose tissue fibrosis and annex atrophy from 12.25 ± 3.25 to 9.75 ± 4.35 (P = 0.032). The 8% pirfenidone gel application was well tolerated, and no side effects were detected. This is the first study on the therapeutic use of pirfenidone gel in localized scleroderma. It acts on both the inflammatory and the fibrotic phases. Considering its effectiveness, good safety profile and the advantage of topical application, pirfenidone is a treatment option in this condition.

Safety of antiobesity drugs

PubMed Central

Cheung, Tommy Tsang; Samaranayake, Nithushi Rajitha

2013-01-01

Obesity is a major health problem worldwide. Although diet and physical activity are crucial in the management of obesity, the long-term success rate is low. Therefore antiobesity drugs are of great interest, especially when lifestyle modification has failed. As obesity is not an immediate life-threatening disease, these drugs are required to be safe. Antiobesity drugs that have been developed so far have limited efficacies and considerable adverse effects affecting tolerability and safety. Therefore, most antiobesity drugs have been withdrawn. Fenfluramine and dexfenfluramine were withdrawn because of the potential damage to heart valves. Sibutramine was associated with an increase in major adverse cardiovascular events in the Sibutramine Cardiovascular Outcomes (SCOUT) trial and it was withdrawn from the market in 2010. Rimonabant was withdrawn because of significant psychiatric adverse effects. Orlistat was approved in Europe and the United States for long-term treatment of obesity, but many patients cannot tolerate its gastrointestinal side effects. Phentermine and diethylpropion can only be used for less than 12 weeks because the long-term safety of these drugs is unknown. Ephedrine and caffeine are natural substances but the effects on weight reduction are modest. As a result there is a huge unmet need for effective and safe antiobesity drugs. Recently lorcaserin and topiramate plus phentermine have been approved for the treatment of obesity but long-term safety data are lacking. PMID:25114779

A double-blind, placebo-controlled, ascending-dose, randomized study to evaluate the safety, tolerability and effects on cognition of AL-108 after 12 weeks of intranasal administration in subjects with mild cognitive impairment.

PubMed

Morimoto, Bruce H; Schmechel, Don; Hirman, Joe; Blackwell, Andrew; Keith, Julian; Gold, Michael

2013-01-01

AL-108-211 was a placebo-controlled, ascending-dose study that explored the safety, tolerability and efficacy of 12 weeks of treatment with AL-108 in subjects with amnestic mild cognitive impairment. A total of 144 subjects were randomized in a 2:1 drug:placebo ratio. Subjects were enrolled into the low-dose group or placebo and then to the high-dose group or placebo. Pooling of the placebo groups yielded 3 groups (approx. 48/group) whose baseline demographics and disease characteristics were well matched. AL-108 was generally safe and well tolerated. Analyses of efficacy data failed to detect a statistically significant difference between the treatment groups on the composite cognitive memory score. Analyses of the individual cognitive tasks identified signals of potential efficacy in 2 tests of memory and attention. These data suggest that AL-108 was generally safe, well tolerated and merits additional investigation as a treatment for Alzheimer's disease. Copyright © 2013 S. Karger AG, Basel.

Saxagliptin for the treatment of diabetes - a focus on safety.

PubMed

Cernea, Simona; Cahn, Avivit; Raz, Itamar

2016-05-01

The safety of agents used to treat type 2 diabetes (T2D), a chronic disease requiring life-long intervention, is of particular interest. Saxagliptin is a potent and selective DPP-4 inhibitor that has emerged as a therapeutic option for T2D. Its safety was assessed in a development program of 20 phase 2/3 randomized clinical trials and in SAVOR-TIMI 53 trial that evaluated the cardiovascular outcomes. In order to capture any further safety signals, mainly in the long-term, a post-marketing safety surveillance is ongoing. This paper discusses the tolerability and safety profile of the agent, including cardiovascular, renal, pancreatic, hepatic and bone adverse events. Saxagliptin is a safe therapeutic option for patients with T2D, with low risk of hypoglycemia and good tolerability. It demonstrated cardiovascular safety (including in patients with pre-existing cardiovascular disease and/or HF) and safety with respect to all-cause mortality and adverse events of special interest. In SAVOR-TIMI53, saxagliptin was associated with an unexpected increased risk of HF hospitalization, mainly in the first 12 months; a mechanistic explanation for this has not been found. Further research needs to elucidate the effect of antidiabetic drugs on the heart, by including biomarkers and echocardiographic sub-studies within large outcome trials.

Intrusion-Tolerant Location Information Services in Intelligent Vehicular Networks

NASA Astrophysics Data System (ADS)

Yan, Gongjun; Yang, Weiming; Shaner, Earl F.; Rawat, Danda B.

Intelligent Vehicular Networks, known as Vehicle-to-Vehicle and Vehicle-to-Roadside wireless communications (also called Vehicular Ad hoc Networks), are revolutionizing our daily driving with better safety and more infortainment. Most, if not all, applications will depend on accurate location information. Thus, it is of importance to provide intrusion-tolerant location information services. In this paper, we describe an adaptive algorithm that detects and filters the false location information injected by intruders. Given a noisy environment of mobile vehicles, the algorithm estimates the high resolution location of a vehicle by refining low resolution location input. We also investigate results of simulations and evaluate the quality of the intrusion-tolerant location service.

Opportunities Suspended: The Devastating Consequences of Zero Tolerance and School Discipline Policies. Report from a National Summit on Zero Tolerance [Proceedings] (Washington, DC, June 15-16, 2000).

ERIC Educational Resources Information Center

Harvard Civil rights Project, Cambridge, MA.

This report contends that public school administrators no longer rely on literal interpretations of states' and districts' zero tolerance policies and overzealously promote safety, inventing creative interpretations of the laws and using them to suspend and expel children based on relatively minor offenses. Minority students are disproportionately…

Assessment of efficacy, safety, and tolerability of 4-n-butylresorcinol 0.3% cream: an Indian multicentric study on melasma

PubMed Central

Madan Mohan, NT; Gowda, Adarsh; Jaiswal, Ashok Kumar; Sharath Kumar, BC; Shilpashree, P; Gangaboraiah, Bilugumba; Shamanna, Manjula

2016-01-01

Introduction Melasma is one of the commonly reported pigmentory disorders in the Indian population. Numerous therapeutic modalities are available. However, very few have produced complete satisfactory response. 4-n-Butylresorcinol 0.3% cream has recently been introduced in India as a new hypopigmenting agent. It is a resorcinol derivative and acts by inhibiting both tyrosinase and tyrosinase-related protein-1. Objective The available published literatures are with 4-n-butylresorcinol 0.1% cream, and there is paucity of clinical studies with 4-n-butylresorcinol 0.3% cream. Furthermore, considering the fact that Indian skin is more prone to irritation with hypopigmenting agents, our study explores the efficacy, safety, and tolerability of 4-n-butylresorcinol 0.3% cream in Indian subjects with melasma. Methods Fifty-two subjects with melasma participated in this open-label, single arm, observational study. All the patients were advised twice daily application of 4-n-butylresorcinol 0.3% cream for 8 weeks over the areas of melasma. Assessment parameters included modified Melasma Area Severity Index (mMASI) score. Digital photographs of all the patients at baseline, week 4, and week 8 were taken. During this 8-week study period, all the adverse events were observed and recorded. Results All the 52 subjects completed the study. Out of 52 subjects, 90.38% were females. The mean age of patients was 38.5±7.8 years. Mean ± standard error of MASI score measurements showed a significant decrease from baseline score of 14.73±0.59 to 11.09±0.53 after week 4 (P<0.001) and 6.48±0.43 at week 8 (P<0.001). The digital photographs of the study subjects taken at week 4 and week 8 also showed decrease in melasma pigmentation compared to baseline photograph and correlated with the changes in the mMASI score. The treatment was well tolerated by all the study subjects. No adverse reactions were reported throughout the study period. Conclusion Our data suggest that the 4-n

Safety, Tolerability, and Pharmacokinetics of Ribavirin in Hepatitis C Virus-Infected Patients with Various Degrees of Renal Impairment

PubMed Central

Wang, K.; Blotner, S.; Magnusson, M. O.; Wilkins, J. J.; Martin, P.; Solsky, J.; Nieforth, K.; Wat, C.; Grippo, J. F.

2013-01-01

Ribavirin (RBV) is an integral part of standard-of-care hepatitis C virus (HCV) treatments and many future regimens under investigation. The pharmacokinetics (PK), safety, and tolerability of RBV in chronically HCV-infected patients with renal impairment are not well defined and were the focus of an open-label PK study in HCV-infected patients receiving RBV plus pegylated interferon. Serial RBV plasma samples were collected over 12 h on day 1 of weeks 1 and 12 from patients with moderate renal impairment (creatinine clearance [CLCR], 30 to 50 ml/min; RBV, 600 mg daily), severe renal impairment (CLCR, <30 ml/min; RBV, 400 mg daily), end-stage renal disease (ESRD) (RBV, 200 mg daily), or normal renal function (CLCR, >80 ml/min; RBV, 800 to 1,200 mg daily). Of the 44 patients, 9 had moderately impaired renal function, 10 had severely impaired renal function, 13 had ESRD, and 12 had normal renal function. The RBV dose was reduced because of adverse events (AEs) in 71% and 53% of severe and moderate renal impairment groups, respectively. Despite this modification, patients with moderate and severe impairment had 12-hour (area under the concentration-time curve from 0 to 12 h [AUC0–12]) values 36% (38,452 ng · h/ml) and 25% (35,101 ng · h/ml) higher, respectively, than those with normal renal function (28,192 ng · h/ml). Patients with ESRD tolerated a 200-mg daily dose, and AUC0–12 was 20% lower (22,629 ng · h/ml) than in patients with normal renal function. PK modeling and simulation (M&S) indicated that doses of 200 mg or 400 mg alternating daily for patients with moderate renal impairment and 200 mg daily for patients with severe renal impairment were the most appropriate dose regimens in these patients. PMID:24080649

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.

I-25 truck safety improvements project : local evaluation report

DOT National Transportation Integrated Search

2004-12-29

The I-25 Truck Safety Improvements project (I-25 TSIP) is the result of a FY98 congressionally designated earmark to support improvements in transportation efficiency, promote safety, increase traffic flow, reduce emissions, improve traveler informat...

Primary (Month-6) Outcomes of the STOP-Uveitis Study: Evaluating the Safety, Tolerability, and Efficacy of Tocilizumab in Patients With Noninfectious Uveitis.

PubMed

Sepah, Yasir Jamal; Sadiq, Mohammad Ali; Chu, David S; Dacey, Mark; Gallemore, Ron; Dayani, Pouya; Hanout, Mostafa; Hassan, Muhammad; Afridi, Rubbia; Agarwal, Aniruddha; Halim, Muhammad Sohail; Do, Diana V; Nguyen, Quan Dong

2017-11-01

To report the primary endpoint analyses of the safety and efficacy of 2 different doses of intravenous (IV) infusions of tocilizumab (TCZ), an IL-6 inhibitor, in eyes with noninfectious intermediate uveitis, posterior uveitis, or panuveitis. Randomized, controlled, multicenter clinical trial. STOP-Uveitis is a randomized, open-label safety, efficacy, and bioactivity clinical trial conducted at 5 clinical centers across the United States. The study evaluated the role of TCZ in patients with noninfectious uveitis (NIU). Thirty-seven patients with NIU were randomized into one of 2 treatment groups in a ratio of 1:1. Group 1 received IV infusions of 4 mg/kg TCZ and group 2 received IV infusions of 8 mg/kg TCZ. Infusions were given every 4 weeks in both groups until month 6 (primary endpoint). Primary outcome measure was incidence and severity of systemic and ocular adverse events through month 6. Secondary outcome measures included mean change in visual acuity (VA), vitreous haze (VH), and central macular thickness (CMT) at month 6. A total of 37 patients were randomized in the study. At month 6, 43.5% of patients who had the potential for a 2-step decrease in VH demonstrated a 2-step decrease (40% in Group 1 and 46.1% in Group 2). Mean change in CMT was -83.88 ± 136.1 μm at month 6 (-131.5 ± 41.56 μm in Group 1 and -38.92 ± 13.7 μm in Group 2). Mean change in VA was +8.22 ± 11.83 ETDRS letters at month 6 (10.9 ± 14.6 in Group 1 and 5.5 ± 7.8 in Group 2). Repeated infusions of TCZ were well tolerated. Repeated IV administrations of TCZ are well tolerated. TCZ (both 4 and 8 mg/kg) is effective in improving VA and reducing VH and CMT in eyes with noninfectious intermediate uveitis, posterior uveitis, and panuveitis. Copyright © 2017 Elsevier Inc. All rights reserved.

21 CFR 170.22 - Safety factors to be considered.

Code of Federal Regulations, 2014 CFR

2014-04-01

...) FOOD ADDITIVES Food Additive Safety § 170.22 Safety factors to be considered. In accordance with... proposed use of a food additive will be safe: Except where evidence is submitted which justifies use of a... used; that is, a food additive for use by man will not be granted a tolerance that will exceed 1/100th...

Oral tolerance in neonates: from basics to potential prevention of allergic disease.

PubMed

Verhasselt, V

2010-07-01

Oral tolerance refers to the observation that prior feeding of an antigen induces local and systemic immune tolerance to that antigen. Physiologically, this process is probably of central importance for preventing inflammatory responses to the numerous dietary and microbial antigens present in the gut. Defective oral tolerance can lead to gut inflammatory disease, food allergies, and celiac disease. In the last two cases, the diseases develop early in life, stressing the necessity of understanding how oral tolerance is set up in neonates. This article reviews the parameters that have been outlined in adult animal models as necessary for tolerance induction and assesses whether these factors operate in neonates. In addition, we highlight the factors that are specific for this period of life and discuss how they could have an impact on oral tolerance. We pay particular attention to maternal influence on early oral tolerance induction through breast-feeding and outline the major parameters that could be modified to optimize tolerance induction in early life and possibly prevent allergic diseases.

Safety and tolerability of cladribine tablets in multiple sclerosis: the CLARITY (CLAdRIbine Tablets treating multiple sclerosis orallY) study.

PubMed

Cook, S; Vermersch, P; Comi, G; Giovannoni, G; Rammohan, K; Rieckmann, P; Sørensen, P Soelberg; Hamlett, A; Miret, M; Weiner, J; Viglietta, V; Musch, B; Greenberg, S J

2011-05-01

Cladribine is a synthetic deoxyadenosine analogue in development as an oral multiple sclerosis (MS) therapy. To report in detail the safety findings from the 96-week, phase III, double-blind CLARITY study, which evaluated treatment with cladribine tablets in relapsing-remitting MS. A total of 1,326 patients were randomized 1:1:1 to two short-course regimens of cladribine tablets (3.5 or 5.25 mg/kg cumulative dose over 96 weeks) or placebo. Safety assessments included monitoring for adverse events (AEs), routine physical and neurologic examinations and frequent laboratory parameter assessments. Of the randomized patients, 88.6% completed treatment with cladribine tablets versus 86.3% with placebo. Lymphopenia was the most commonly reported AE in patients treated with cladribine tablets and was anticipated based on the mechanism of action. The incidence of infections was 48.3% with cladribine tablets and 42.5% with placebo, with 99.1% and 99.0% rated mild-to-moderate by investigators. Herpes zoster infections developed in 20 (2.3%) cladribine-treated patients; all cases were dermatomal. There were no herpes zoster infections in the placebo group. Nine (1.0%) patients experienced events related to uterine leiomyomas in the cladribine tablets groups versus one (0.2%) with placebo. Three isolated cases of malignancy were reported in cladribine-treated patients during the study; a fourth was reported during post-study surveillance. A pre-malignant cervical carcinoma in situ was also reported. The incidence of malignancies during the study did not exceed the expected rate in a population standardized for country, gender and age. The safety and tolerability profile observed in the CLARITY study together with the reported efficacy support the potential for cladribine tablets as an MS therapy.

Randomised masked trial of the clinical safety and tolerability of MGO Manuka Honey eye cream for the management of blepharitis

PubMed Central

Craig, Jennifer P; Wang, Michael T M; Ganesalingam, Kalaivarny; Rupenthal, Ilva D; Swift, Simon; Loh, Chee Seang; Te Weehi, Leah; Cheung, Isabella M Y; Watters, Grant A

2017-01-01

Objective To assess the clinical safety and tolerability of a novel MGO Manuka Honey microemulsion (MHME) eye cream for the management of blepharitis in human subjects. Methods and analysis Twenty-five healthy subjects were enrolled in a prospective, randomised, paired-eye, investigator-masked trial. The MHME eye cream (Manuka Health New Zealand) was applied to the closed eyelids of one eye (randomised) overnight for 2 weeks. LogMAR visual acuity, eyelid irritation symptoms, ocular surface characteristics and tear film parameters were assessed at baseline, day 7 and day 14. Expression of markers of ocular surface inflammation (matrix metalloproteinase-9 and interleukin-6) and goblet cell function (MUC5AC) were quantified using impression cytology at baseline and day 14. Results There were no significant changes in visual acuity, eyelid irritation symptoms, ocular surface characteristics, tear film parameters and inflammatory marker expression during the 2-week treatment period in treated and control eyes (all p>0.05), and measurements did not differ significantly between eyes (all p>0.05). No major adverse events were reported. Two subjects experienced transient ocular stinging, presumably due to migration of the product into the eye, which resolved following aqueous irrigation. Conclusion The MHME eye cream application was found to be well tolerated in healthy human subjects and was not associated with changes in visual acuity, ocular surface characteristics, tear film parameters, expression of markers of inflammation or goblet cell function. The findings support future clinical efficacy trials in patients with blepharitis. Trial registration number ACTRN12616000540415 PMID:29354710

Pharmacokinetics, Safety, and Tolerability of a Single 500-mg or 1000-mg Intravenous Dose of Dalbavancin in Healthy Japanese Subjects.

PubMed

Scoble, Patrick J; Owens, Robert C; Puttagunta, Sailaja; Yen, Mark; Dunne, Michael W

2015-12-01

Dalbavancin is a novel, once-weekly glycopeptide antibiotic approved for treatment of acute bacterial skin infections. Given the importance of understanding any pharmacokinetic variability across different patient populations, a double-blind, placebo-controlled study was conducted to evaluate the pharmacokinetics, safety, and tolerability of a single 500-mg and a single 1000-mg intravenous dose of dalbavancin in healthy Japanese subjects. Ten subjects received intravenous dalbavancin 1000 mg, five subjects received intravenous dalbavancin 500 mg, and three subjects received intravenous placebo. After a single infusion of dalbavancin, the maximal plasma concentration (C max) and area under the plasma concentration-time curve (AUC) increased in a proportional manner from 500 mg to 1000 mg (C max: 157 μg/ml and 299 μg/ml; AUClast: 10,850 μg·h/ml and 22,679 μg·h/ml, on the 500-mg and 1000-mg regimens, respectively) with low inter-subject variability. The mean terminal phase half-life (t 1/2) was 204 and 193 h after the 500-mg and 1000-mg dose, respectively. Clearance and volume of distribution were similar for the two dose concentrations. Treatment-emergent adverse events reported were considered to be of mild intensity. There were no relevant changes in laboratory values or vital signs over time in subjects in either treatment group. Overall, dalbavancin 500 mg and dalbavancin 1000 mg, administered as a single 30-min infusion, was well tolerated in this population and resulted in plasma exposures similar to those in non-Asians.

Efficacy, safety and tolerability of rivastigmine capsules in patients with probable vascular dementia: the VantagE study.

PubMed

Ballard, C; Sauter, M; Scheltens, P; He, Y; Barkhof, F; van Straaten, E C W; van der Flier, W M; Hsu, C; Wu, S; Lane, R

2008-09-01

The aim was to evaluate the efficacy, safety and tolerability of rivastigmine capsules in patients diagnosed with probable vascular dementia (VaD). VantagE (Vascular Dementia trial studying Exelon) was a 24-week, multicentre, double-blind study. VaD patients aged 50-85 years were randomized to rivastigmine capsules (3-12 mg/day) or placebo. Efficacy assessments included global and cognitive performances, activities of daily living and neuropsychiatric symptoms. Adverse events were recorded. Additional exploratory analyses determined whether heterogeneity in pathologies and symptoms extended to differential treatment effects. NCT00099216. 710 patients were randomized. Rivastigmine demonstrated superiority over placebo on three measures of cognitive performance (Vascular Dementia Assessment Scale, Alzheimer's Disease Assessment Scale cognitive subscale, Mini-Mental State Examination; all p< or = 0.05, intent-to-treat population [ITT]), but not other outcomes. Predominant adverse events were nausea and vomiting. Exploratory analyses indicated that older patients (> or =75 years old), assumed more likely to also have Alzheimer's disease (AD) pathology, demonstrated significant cognitive responses to rivastigmine and a safety profile similar to that seen in AD patients. Younger patients, assumed less likely to have concomitant AD pathology, showed no efficacy response and were associated with slight elevations of blood pressure, cerebrovascular accidents and mortality. Rivastigmine-placebo differences in patients with, versus those without, medial temporal atrophy (also suggestive of concomitant AD) showed a numerical difference similar to that seen between the older versus younger patients, but did not attain statistical significance. Consistent with trials evaluating other cholinesterase inhibitors, rivastigmine did not provide consistent efficacy in probable VaD. The efficacy apparent on cognitive outcomes was derived from effects in older patients likely to have

Phase I clinical studies of the advanced glycation end-product (AGE)-breaker TRC4186: safety, tolerability and pharmacokinetics in healthy subjects.

PubMed

Chandra, Kumar P; Shiwalkar, Ajay; Kotecha, Jignesh; Thakkar, Purav; Srivastava, Ambrish; Chauthaiwale, Vijay; Sharma, Sanjay K; Cross, Maurice R; Dutt, Chaitanya

2009-01-01

Advanced glycation end-products (AGEs) have been implicated in the pathogenesis of diabetic complications through a variety of mechanisms including endothelial dysfunction and structural abnormalities in the vasculature and myocardium. Reducing the AGEs burden and their ensuing pro-inflammatory, pro-oxidative and pro-coagulant effect with associated dysfunctional proteins in various target tissues may retard the progression of and even reverse diabetic macro- and microvascular complications. Pyridinium, 3-[[2-(methylsulfonyl) hydrazino] carbonyl]-1-[2-oxo-2-2-thienyl) ethyl]-chloride (TRC4186) has demonstrated AGE-breaking activities in in vitro experiments and improvement in the endothelial and myocardial function in animal models of diabetes mellitus with reduction of AGEs accumulation in tissues over time. The safety of TRC4186 has been established in in vitro and in vivo preclinical studies. Thus, this drug is being developed for the treatment of complications associated with diabetes. This investigation set out to evaluate the safety, tolerability and pharmacokinetics of TRC4186 in healthy human subjects after single and multiple ascending doses, fixed doses in elderly male and female subjects, and with food and different formulations of the compound. Four studies were conducted during phase I clinical development of TRC4186. These were: (i) a randomized, double-blind, placebo-controlled, single-dose, dose-ascending study in healthy male subjects with doses of TRC4186 ranging from 250 to 2500 mg administered as an oral solution (total six doses); (ii) a randomized, double-blind, placebo-controlled, multiple-dose, dose-ascending study in healthy male subjects with three doses of TRC4186 ranging from 500 to 2000 mg twice daily for 6 days with a final single dose on day 7; (iii) a randomized, open-label, three-way crossover study to assess the effect of food (fasted vs fed) and formulation (solution vs tablet) with TRC4186 500 mg; (iv) a randomized, double

Distributed asynchronous microprocessor architectures in fault tolerant integrated flight systems

NASA Technical Reports Server (NTRS)

Dunn, W. R.

1983-01-01

The paper discusses the implementation of fault tolerant digital flight control and navigation systems for rotorcraft application. It is shown that in implementing fault tolerance at the systems level using advanced LSI/VLSI technology, aircraft physical layout and flight systems requirements tend to define a system architecture of distributed, asynchronous microprocessors in which fault tolerance can be achieved locally through hardware redundancy and/or globally through application of analytical redundancy. The effects of asynchronism on the execution of dynamic flight software is discussed. It is shown that if the asynchronous microprocessors have knowledge of time, these errors can be significantly reduced through appropiate modifications of the flight software. Finally, the papear extends previous work to show that through the combined use of time referencing and stable flight algorithms, individual microprocessors can be configured to autonomously tolerate intermittent faults.

Conservatism of lizard thermal tolerances and body temperatures across evolutionary history and geography.

PubMed

Grigg, Joseph W; Buckley, Lauren B

2013-04-23

Species may exhibit similar thermal tolerances via either common ancestry or environmental filtering and local adaptation, if the species inhabit similar environments. We ask whether upper and lower thermal limits (critical thermal maxima and minima) and body temperatures are more strongly conserved across evolutionary history or geography for lizard populations distributed globally. We find that critical thermal maxima are highly conserved with location accounting for a higher proportion of the variation than phylogeny. Notably, thermal tolerance breadth is conserved across the phylogeny despite critical thermal minima showing little niche conservatism. Body temperatures observed during activity in the field show the greatest degree of conservatism, with phylogeny accounting for most of the variation. This suggests that propensities for thermoregulatory behaviour, which can buffer body temperatures from environmental variation, are similar within lineages. Phylogeny and geography constrain thermal tolerances similarly within continents, but variably within clades. Conservatism of thermal tolerances across lineages suggests that the potential for local adaptation to alleviate the impacts of climate change on lizards may be limited.

Libertas: rationale and study design of a multicentre, Phase II, double-blind, randomised, placebo-controlled investigation to evaluate the efficacy, safety and tolerability of locally applied NRL001 in patients with faecal incontinence.

PubMed

Siproudhis, L; Jones, D; Shing, R Ng Kwet; Walker, D; Scholefield, J H

2014-03-01

Faecal incontinence affects up to 8% of adults. Associated social isolation and subsequent depression can have devastating effects on quality of life (QoL). Faecal incontinence is an underreported health problem as the social isolation and stigma that patients experience makes it difficult for sufferers to discuss their condition with a physician. There have been few well-designed, placebo-controlled clinical trials of treatment for faecal incontinence and little clinical evidence is available to inform the most appropriate management strategies. Libertas, a robustly designed study will investigate the efficacy and safety of NRL001 (1R,2S-methoxamine), an α1 -adrenoceptor agonist, in the treatment of faecal incontinence. Libertas is a multicentre, Phase II, double-blind, randomised, placebo-controlled, parallel group study. Patient recruitment took place across 55 study centres in Europe. Patients suffering with faecal incontinence were randomised into four groups (approximately 110 each) to receive once daily self-administered doses of NRL001 (5, 7.5 or 10 mg or placebo in a suppository formulation) for 8 weeks. The primary objective of Libertas is to assess the impact of once daily administration of NRL001 on the severity and frequency of incontinence episodes as assessed by the Wexner score at 4 weeks, compared with placebo. Secondary outcomes include measures of efficacy of NRL001 compared with placebo following 8 weeks treatment; safety and tolerability; evaluation of plasma pharmacokinetics; establishment of any pharmacokinetic/pharmacodynamic relationship to adverse events; dose-response relationship; the efficacy of NRL001 therapy at 4 and 8 weeks assessed by the Vaizey score; and QoL using the Faecal Incontinence Quality of Life and the EQ-5D-5L Healthcare Questionnaires following 4 and 8 weeks NRL001 therapy. Overall patient satisfaction with the treatment will also be evaluated. This is the first randomised controlled study to investigate the efficacy

The salinity tolerant poplar database (STPD): a comprehensive database for studying tree salt-tolerant adaption and poplar genomics.

PubMed

Ma, Yazhen; Xu, Ting; Wan, Dongshi; Ma, Tao; Shi, Sheng; Liu, Jianquan; Hu, Quanjun

2015-03-17

Soil salinity is a significant factor that impairs plant growth and agricultural productivity, and numerous efforts are underway to enhance salt tolerance of economically important plants. Populus species are widely cultivated for diverse uses. Especially, they grow in different habitats, from salty soil to mesophytic environment, and are therefore used as a model genus for elucidating physiological and molecular mechanisms of stress tolerance in woody plants. The Salinity Tolerant Poplar Database (STPD) is an integrative database for salt-tolerant poplar genome biology. Currently the STPD contains Populus euphratica genome and its related genetic resources. P. euphratica, with a preference of the salty habitats, has become a valuable genetic resource for the exploitation of tolerance characteristics in trees. This database contains curated data including genomic sequence, genes and gene functional information, non-coding RNA sequences, transposable elements, simple sequence repeats and single nucleotide polymorphisms information of P. euphratica, gene expression data between P. euphratica and Populus tomentosa, and whole-genome alignments between Populus trichocarpa, P. euphratica and Salix suchowensis. The STPD provides useful searching and data mining tools, including GBrowse genome browser, BLAST servers and genome alignments viewer, which can be used to browse genome regions, identify similar sequences and visualize genome alignments. Datasets within the STPD can also be downloaded to perform local searches. A new Salinity Tolerant Poplar Database has been developed to assist studies of salt tolerance in trees and poplar genomics. The database will be continuously updated to incorporate new genome-wide data of related poplar species. This database will serve as an infrastructure for researches on the molecular function of genes, comparative genomics, and evolution in closely related species as well as promote advances in molecular breeding within Populus. The

Reirradiation of Prostate Cancer Local Failures After Previous Curative Radiation Therapy: Long-Term Outcome and Tolerance

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

Zilli, Thomas, E-mail: Thomas.Zilli@hcuge.ch; Faculty of Medicine, Geneva University, Geneva; Benz, Eileen

2016-10-01

Purpose: To evaluate the safety, feasibility, side-effect profile, and proof of concept of external beam radiation therapy (EBRT) with or without a brachytherapy (BT) boost for salvage of exclusive local failure after primary EBRT for prostate cancer. Methods and Materials: Fourteen patients with presumed exclusive local recurrence after primary EBRT with or without BT were considered eligible for reirradiation. The median normalized total dose in 2-Gy fractions (NTD{sub 2Gy}, α/β ratio = 1.5 Gy) was 74 Gy (range, 66-98.4 Gy) at first irradiation. Median time between the first irradiation and the reirradiation was 6.1 years (range, 4.7-10.2 years). Results: Between 2003 and 2008 salvage treatment was deliveredmore » with a median NTD{sub 2Gy} of 85.1 Gy (range, 70-93.4) to the prostate with EBRT with (n=10) or without (n=4) BT. Androgen deprivation was given to 12 patients (median time of 12 months). No grade ≥3 toxicity was observed during and within 6 weeks after RT. After a median follow-up of 94 months (range, 48-172 months) after salvage RT, 5-year grade ≥3 genitourinary and gastrointestinal toxicity-free survival figures were 77.9% ± 11.3% and 57.1% ± 13.2%, respectively. Four patients presented with combined grade 4 genitourinary/gastrointestinal toxicity. The 5-year biochemical relapse-free, local relapse-free, distant metastasis-free, and cancer-specific survival rates were 35.7% ± 12.8%, 50.0% ± 13.4%, 85.7% ± 9.4%, and 100%, respectively. Conclusion: Salvage whole-gland reirradiation for patients with a suspicion of exclusive local recurrence after initial RT may be associated with a high rate of severe radiation-induced side effects and poor long-term biochemical and local control.« less

Weapons in Schools and Zero-Tolerance Policies

ERIC Educational Resources Information Center

Losinski, Mickey; Katsiyannis, Antonis; Ryan, Joseph; Baughan, Cynthia

2014-01-01

Horrific events such as the fatal shooting of three high school students in Chardon, Ohio, in the winter of 2012 places tremendous pressure on state and local agencies to ensure that schools provide a safe and conducive learning environment for all students. To help curb school violence, schools have adopted zero-tolerance policies, which often…

Assessment of the short-term safety and tolerability of a quantified 80 % ethanol extract from the stem bark of Nauclea pobeguinii (PR 259 CT1) in healthy volunteers: a clinical phase I study.

PubMed

Mesia, Kahunu; Cimanga, Kanyanga; Tona, Lutete; Mampunza, Ma Miezi; Ntamabyaliro, Nsengi; Muanda, Tsobo; Muyembe, Tamfum; Totté, Jozef; Mets, Tony; Pieters, Luc; Vlietinck, Arnold

2011-01-01

The aim of this study was to evaluate the short-term safety and tolerability of an antimalarial herbal medicinal product (PR 259 CT1) consisting of a quantified 80 % ethanol extract from the stem bark of Nauclea pobeguinii when given orally to healthy adult male volunteers. The amount of the major alkaloid strictosamide in the extract was determined by a validated HPLC method and was shown to be 5.6 %. The herbal preparation was formulated in a gelatine capsule form containing 500 mg of PCR 259 CT1. A sample of 15 healthy male volunteers, selected using the Lot Quality Assurance of Sampling (LQAS) method, was eligible for inclusion after fulfillment of the inclusion criteria and clinical examination by a physician. The volunteers were treated in an outpatient clinic with a drug regimen of two 500 mg capsules three times daily (each eight hours) for seven days, during meals. Safety and tolerability were monitored clinically, haematologically, biochemically and by electrocardiographic (ECG) examination at days 0, 1, 3, 7 and 14. Adverse effects were recorded by self-reporting of the participants or by detection of abnormalities in clinical examinations by a physician. The oral administration of PR 259 CT1 at high doses of 2 × 500 mg/capsule/day for 7 days was found to induce no significant changes in the concentration levels of all investigated haematological, biochemical, electrocardiogram and vital sign parameters and physical characteristics after 14 days of treatment compared to those seen in the baseline data. The concentration levels of all evaluated parameters were within the normal limits as reported in the literature. All adverse events noted were mild and self-resolving including increase of appetite (33 %), headache (20 %) and nausea (20 %). Other minor side effects were insomnia, somnolence and asthenia (7 %). Thus, PR 259 CT1 presented a significant safety and tolerability in healthy volunteers to allow its further development by starting a phase II

Vedolizumab Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability Following Administration of a Single, Ascending, Intravenous Dose to Healthy Volunteers.

PubMed

Rosario, Maria; Wyant, Timothy; Leach, Timothy; Sankoh, Serap; Scholz, Catherine; Parikh, Asit; Fox, Irving; Feagan, Brian G

2016-11-01

Vedolizumab, a humanized monoclonal antibody against the α 4 β 7 integrin, is indicated for treatment of moderately to severely active ulcerative colitis or Crohn's disease. In this placebo-controlled, double-blind, randomized, single ascending-dose study, the pharmacokinetics, pharmacodynamics, safety, and tolerability of vedolizumab were evaluated in healthy volunteers. Forty-nine participants (in five cohorts) were randomly assigned in a 4:1 ratio to receive a single intravenous infusion of either vedolizumab (0.2, 0.5, 2.0, 6.0, or 10.0 mg/kg) or placebo. Blood samples were collected for measurement of vedolizumab serum concentrations and α 4 β 7 saturation on peripheral blood lymphocytes by vedolizumab. Pharmacokinetic parameters were computed using a non-compartmental approach. Adverse events were monitored. Vedolizumab maximum observed serum concentration (C max ) demonstrated dose proportionality over the dose range tested. Greater than dose-proportional increases in area under the serum concentration-time curve from time 0 to infinity (AUC 0-inf ) and shorter terminal elimination half-life (t 1/2 ) were observed from 0.2 to 2.0 mg/kg, suggestive of nonlinear pharmacokinetics at lower doses. At doses higher than 2.0 mg/kg, these parameters increased dose proportionally. Saturation of α 4 β 7 was at or near maximal levels (>90 %) at all doses and time points when vedolizumab was measurable in serum. A total of 21 of 39 (54 %) vedolizumab-treated participants were anti-drug antibody (ADA) positive, and 11 (28 %) were persistently ADA positive. Overall, no adverse event signals, including serious infections or malignancies, were apparent. Vedolizumab exhibited target-mediated disposition, characterized by a rapid, saturable, nonlinear elimination process at low concentrations and a slower linear elimination process at higher concentrations. Nearly complete α 4 β 7 saturation was observed at all doses. A single intravenous infusion of vedolizumab

Pharmacokinetics, Safety and Tolerability of Sacubitril/Valsartan (LCZ696) After Single-Dose Administration in Healthy Chinese Subjects.

PubMed

Han, Yi; Ayalasomayajula, Surya; Pan, Wei; Yang, Fan; Yuan, Yaozong; Langenickel, Thomas; Hinder, Markus; Kalluri, Sampath; Pal, Parasar; Sunkara, Gangadhar

2017-02-01

Sacubitril/valsartan (LCZ696) is a first-in-class angiotensin receptor neprilysin inhibitor (ARNI) and has been recently approved in several countries for the treatment of patients with heart failure and reduced ejection fraction. This was the first study conducted to characterise the pharmacokinetics of LCZ696 analytes (pro-drug sacubitril, active neprilysin inhibitor LBQ657 and valsartan) after single-dose administration of LCZ696 in healthy Chinese subjects. In this open-label, randomised, parallel-group study, following screening and baseline evaluation, eligible healthy subjects received single oral doses of LCZ696 50, 100, 200 or 400 mg. The pharmacokinetics, safety and tolerability of LCZ696 were assessed up to 72 h after dosing. A total of 40 healthy male subjects were enrolled, and all completed the study. Following oral administration, LCZ696 delivered systemic exposure to sacubitril, LBQ657 and valsartan with a median time to reach maximum plasma concentration (T max ) ranging from 0.50 to 1.25, 2.00 to 3.00 and 1.50 to 2.50 h, respectively, over the investigated dose range. The mean terminal elimination half-life (T 1/2 ) ranged from 0.89 to 1.35, 8.57 to 9.24 and 5.33 to 7.91 h for sacubitril, LBQ657 and valsartan, respectively. The area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUC 0-last ), and maximum plasma concentration (C max ) for LBQ657 increased dose proportionally over the entire dose range. Dose linear increase in the exposure was observed across the dose range for sacubitril and valsartan. LCZ696 was safe and well tolerated at all doses in this study. Adverse events of only mild intensity, which required no treatment, were reported in 6 (15 %) subjects. The pharmacokinetic profiles of LCZ696 analytes in Chinese subjects are similar to those reported previously in Caucasian subjects.

The demonstration of a theory-based approach to the design of localized patient safety interventions

PubMed Central

2013-01-01

Background There is evidence of unsafe care in healthcare systems globally. Interventions to implement recommended practice often have modest and variable effects. Ideally, selecting and adapting interventions according to local contexts should enhance effects. However, the means by which this can happen is seldom systematic, based on theory, or made transparent. This work aimed to demonstrate the applicability, feasibility, and acceptability of a theoretical domains framework implementation (TDFI) approach for co-designing patient safety interventions. Methods We worked with three hospitals to support the implementation of evidence-based guidance to reduce the risk of feeding into misplaced nasogastric feeding tubes. Our stepped process, informed by the TDF and key principles from implementation literature, entailed: involving stakeholders; identifying target behaviors; identifying local factors (barriers and levers) affecting behavior change using a TDF-based questionnaire; working with stakeholders to generate specific local strategies to address key barriers; and supporting stakeholders to implement strategies. Exit interviews and audit data collection were undertaken to assess the feasibility and acceptability of this approach. Results Following audit and discussion, implementation teams for each Trust identified the process of checking the positioning of nasogastric tubes prior to feeding as the key behavior to target. Questionnaire results indicated differences in key barriers between organizations. Focus groups generated innovative, generalizable, and adaptable strategies for overcoming barriers, such as awareness events, screensavers, equipment modifications, and interactive learning resources. Exit interviews identified themes relating to the benefits, challenges, and sustainability of this approach. Time trend audit data were collected for 301 patients over an 18-month period for one Trust, suggesting clinically significant improved use of pH and

Localized neuropathic pain: an expert consensus on local treatments

PubMed Central

Pickering, Gisèle; Martin, Elodie; Tiberghien, Florence; Delorme, Claire; Mick, Gérard

2017-01-01

Background Pain localization is one of the hallmarks for the choice of first-line treatment in neuropathic pain. This literature review has been conducted to provide an overview of the current knowledge regarding the etiology and pathophysiology of localized neuropathic pain (LNP), its assessment and the existing topical pharmacological treatments. Materials and methods Literature review was performed using Medline from 2010 to December 2016, and all studies involving LNP and treatments were examined. A multidisciplinary expert panel of five pain specialists in this article reports a consensus on topical approaches that may be recommended to alleviate LNP and on their advantages in clinical practice. Results Successive international recommendations have included topical 5% lidocaine and 8% capsaicin for LNP treatment. The expert panel considers that these compounds can be a first-line treatment for LNP, especially in elderly patients and patients with comorbidities and polypharmacy. Regulatory LNP indications should cover the whole range of LNP and not be restricted to specific etiologies or sites. Precautions for the use of plasters must be followed cautiously. Conclusion Although there is a real need for more randomized controlled trials for both drugs, publications clearly demonstrate excellent risk/benefit ratios, safety, tolerance and continued efficacy throughout long-term treatment. A major advantage of both plasters is that they have proven efficacy and may reduce the risk of adverse events such as cognitive impairment, confusion, somnolence, dizziness and constipation that are often associated with systemic neuropathic pain treatment and reduce the quality of life. Topical modalities also may be used in combination with other drugs and analgesics with limited drug–drug interactions. PMID:29066862

Hybrid routing technique for a fault-tolerant, integrated information network

NASA Technical Reports Server (NTRS)

Meredith, B. D.

1986-01-01

The evolutionary growth of the space station and the diverse activities onboard are expected to require a hierarchy of integrated, local area networks capable of supporting data, voice, and video communications. In addition, fault-tolerant network operation is necessary to protect communications between critical systems attached to the net and to relieve the valuable human resources onboard the space station of time-critical data system repair tasks. A key issue for the design of the fault-tolerant, integrated network is the development of a robust routing algorithm which dynamically selects the optimum communication paths through the net. A routing technique is described that adapts to topological changes in the network to support fault-tolerant operation and system evolvability.

Safety interventions on the labor and delivery unit.

PubMed

Kacmar, Rachel M

2017-06-01

The present review highlights recent advances in efforts to improve patient safety on labor and delivery units and well tolerated care for pregnant patients in general. Recent studies in obstetric patient safety have a broad focus but repetitive themes for interdisciplinary training include: simulating critical events, having open multidisciplinary communication, frequent reviews of cases of maternal morbidity, and implementing maternal early warning systems. The National Partnership for Maternal Safety is also active in promoting care bundles across many topics on maternal safety. A culture of safety is the goal for all obstetric units. Achieving that ideal requires multidisciplinary collaboration, frequent reassessment for areas of improvement, and a culture of openness to change when improvement opportunities arise.

Long-term safety and efficacy of sapropterin: the PKUDOS registry experience.

PubMed

Longo, Nicola; Arnold, Georgianne L; Pridjian, Gabriella; Enns, Gregory M; Ficicioglu, Can; Parker, Susan; Cohen-Pfeffer, Jessica L

2015-04-01

The Phenylketonuria (PKU) Demographics, Outcomes and Safety (PKUDOS) registry is designed to provide longitudinal safety and efficacy data on subjects with PKU who are (or have been) treated with sapropterin dihydrochloride. The PKUDOS population consists of 1189 subjects with PKU: N = 504 who were continuously exposed to sapropterin from date of registry enrollment, N = 211 who had intermittent exposure to the drug, and N = 474 with some other duration of exposure. Subjects continuously exposed to sapropterin showed an average 34% decrease in blood phenylalanine (Phe)--from 591 ± 382 μmol/L at baseline to 392 ± 239 μmol/L (p = 0.0009) after 5 years. This drop in blood Phe was associated with an increase in dietary Phe tolerance [from 1000 ± 959 mg/day (pre-sapropterin baseline) to 1539 ± 840 mg/day after 6 years]. Drug-related adverse events (AEs) were reported in 6% of subjects, were mostly considered non-serious, and were identified in the gastrointestinal, respiratory, and nervous systems. Serious drug-related AEs were reported in ≤ 1% of subjects. Similar safety and efficacy data were observed for children<4 years. Long-term data from the PKUDOS registry suggest that sapropterin has a tolerable safety profile and that continuous use is associated with a significant and persistent decrease in blood Phe and improvements in dietary Phe tolerance. Copyright © 2015. Published by Elsevier Inc.

A survey on table tolerances and couch overrides in radiotherapy

PubMed Central

Chinsky, Bonnie; Patel, Rakesh; Panfil, Joshua; Surucu, Murat

2016-01-01

The purpose of this study was to survey current departmental policies on treatment couch overrides and the values of table tolerances used clinically. A 25‐question electronic survey on couch overrides and tolerances was sent to full members of the American Association of Physicists in Medicine (AAPM). The first part of the survey asked participants if table overrides were allowed at their institution, who was allowed to perform these overrides, and if imaging was required with overrides. The second part of the survey asked individuals to provide table tolerance data for the following treatment sites: brain/head and neck (H&N), lung, breast, abdomen/pelvis and prostate. Each site was further divided into IMRT/VMAT and 3D conformal techniques. Spaces for free‐text were provided, allowing respondents to enter any table tolerance data they were unable to specify under the treatment sites listed. A total of 361 individuals responded, of which approximately half participated in the couch tolerances portion of the survey. Overall, 86% of respondents’ institutions allow couch tolerance overrides at treatment. Therapists were the most common staff members permitted to perform overrides, followed by physicists, dosimetrists, and physicians, respectively. Of the institutions allowing overrides, 34% reported overriding daily. More than half of the centers document the override and/or require a setup image to radiographically verify the treatment site. With respect to table tolerances, SRS/SBRT table tolerances were the tightest, while clinical setup table tolerances were the largest. There were minimal statistically significant differences between IMRT/VMAT and 3D conformal table tolerances. Our results demonstrated that table overrides are relatively common in radiotherapy despite being a potential safety concern. Institutions should review their override policy and table tolerance values in light of the practices of other institutions. Careful attention to these

Long-term safety and tolerability of saxagliptin add-on therapy in older patients (aged ≥65 years) with type 2 diabetes

PubMed Central

Iqbal, Nayyar; Allen, Elsie; Öhman, Peter

2014-01-01

Background Treatment decisions for older patients with type 2 diabetes mellitus must balance glycemic control and adverse event risk. The objective of this study was to evaluate the long-term safety and tolerability of saxagliptin 5 mg as add-on therapy to common antihyperglycemic drugs in patients aged ≥65 years and <65 years. Methods Pooled adverse event data from three placebo-controlled trials of 76–206 weeks’ duration in older (≥65 years) and younger (<65 years) patients receiving saxagliptin 5 mg or matching placebo added to metformin, glyburide, or a thiazolidinedione were analyzed. Measurements were calculated from day of first dose to specified event or last dose and included time at risk for adverse events, treatment-related adverse events, serious adverse events, adverse events leading to discontinuation, and events of special interest. Weighted incidence rates (number of events/total time) and incidence rate ratios (saxagliptin/placebo) with 95% confidence intervals were calculated (Mantel-Haenszel test). Results A total of 205 older (mean age 69 years; saxagliptin, n=99; placebo, n=106) and 1,055 younger (mean age 52 years; saxagliptin, n=531; placebo, n=524) patients were assessed. Regardless of age category, the adverse event incidence rates were generally similar between treatments, with confidence intervals for incidence rate ratios bridging 1. Treatment-related adverse events occurred in 36 older patients receiving saxagliptin versus 32 receiving placebo (incidence rate 34.1 versus 27.1 per 100 person-years) and in 150 younger patients in both treatment groups (incidence rate 24.0 versus 27.8 per 100 person-years). With saxagliptin versus placebo, serious adverse events occurred in eight versus 14 older (incidence rate 5.7 versus 9.9 per 100 person-years) and 49 versus 44 younger patients (incidence rate 6.5 versus 6.6 per 100 person-years). There were two deaths (one patient ≥65 years) with saxagliptin and six (none aged ≥65 years

Long-term safety and tolerability of saxagliptin add-on therapy in older patients (aged ≥ 65 years) with type 2 diabetes.

PubMed

Iqbal, Nayyar; Allen, Elsie; Öhman, Peter

2014-01-01

Treatment decisions for older patients with type 2 diabetes mellitus must balance glycemic control and adverse event risk. The objective of this study was to evaluate the long-term safety and tolerability of saxagliptin 5 mg as add-on therapy to common antihyperglycemic drugs in patients aged ≥ 65 years and <65 years. Pooled adverse event data from three placebo-controlled trials of 76-206 weeks' duration in older (≥ 65 years) and younger (<65 years) patients receiving saxagliptin 5 mg or matching placebo added to metformin, glyburide, or a thiazolidinedione were analyzed. Measurements were calculated from day of first dose to specified event or last dose and included time at risk for adverse events, treatment-related adverse events, serious adverse events, adverse events leading to discontinuation, and events of special interest. Weighted incidence rates (number of events/total time) and incidence rate ratios (saxagliptin/placebo) with 95% confidence intervals were calculated (Mantel-Haenszel test). A total of 205 older (mean age 69 years; saxagliptin, n=99; placebo, n=106) and 1,055 younger (mean age 52 years; saxagliptin, n=531; placebo, n=524) patients were assessed. Regardless of age category, the adverse event incidence rates were generally similar between treatments, with confidence intervals for incidence rate ratios bridging 1. Treatment-related adverse events occurred in 36 older patients receiving saxagliptin versus 32 receiving placebo (incidence rate 34.1 versus 27.1 per 100 person-years) and in 150 younger patients in both treatment groups (incidence rate 24.0 versus 27.8 per 100 person-years). With saxagliptin versus placebo, serious adverse events occurred in eight versus 14 older (incidence rate 5.7 versus 9.9 per 100 person-years) and 49 versus 44 younger patients (incidence rate 6.5 versus 6.6 per 100 person-years). There were two deaths (one patient ≥ 65 years) with saxagliptin and six (none aged ≥ 65 years) with placebo. Older patients

Efficacy, safety, and tolerability of augmentation pharmacotherapy with aripiprazole for treatment-resistant depression in late life: a randomized placebo-controlled trial

PubMed Central

Lenze, Eric J.; Mulsant, Benoit H.; Blumberger, Daniel M.; Karp, Jordan F.; Newcomer, John W.; Anderson, Stewart J.; Dew, Mary Amanda; Butters, Meryl A.; Stack, Jacqueline A.; Begley, Amy E.; Reynolds, Charles F.

2015-01-01

Summary Background Treatment-resistant major depressive disorder is common and potentially life-threatening in older persons, in whom little is known about the benefits and risks of augmentation pharmacotherapy. Methods We conducted a multi-site, placebo-controlled, randomized clinical trial to test the efficacy and safety of aripiprazole augmentation for older adults with treatment-resistant depression. We treated 468 participants aged 60 and older with current major depressive episode with venlafaxine extended-release (ER); 96 (20.5%) did not complete this open phase, 191 (40.8%) remitted, and 181 (38.7%) did not remit and were randomized to 12 weeks of double-blind augmentation with aripiprazole or placebo. The computer-generated randomization was done in blocks and stratified by site. The primary endpoint was remission, defined as Montgomery-Asberg Depression Rating Scale scores ≤10 (and at least two points below the score at the start of the randomized phase) at both of the final two consecutive visits. We also assessed resolution of suicidal ideation, and safety and tolerability with cardiometabolic and neurological measures. Analyses were conducted according to the intention-to-treat principle. This trial is registered with ClinicalTrials.gov, number NCT00892047. Findings Older adults on aripiprazole had a higher remission rate than those on placebo (44% versus 29%; odds ratio [OR]=2.0, 95% CI 1.1–3.7, p=0.03; number needed to treat [NNT]=6.6 [95% CI 3.5–81.8]). Overall, remission was stable during 12 additional weeks of continuation treatment. The resolution of suicidal ideation was more marked with aripiprazole than with placebo. Akathisia was the most common adverse effect (27% of participants on aripiprazole). Compared to placebo, aripiprazole was also associated with more Parkinsonism but not with treatment-emergent suicidal ideation, QTc prolongation, or increases in adiposity, glucose, insulin, or lipids. Interpretation In older adults who fail

Dendritic cells in oral tolerance in the gut.

PubMed

Rescigno, Maria

2011-09-01

Oral tolerance is a process that allows generation of systemic unresponsiveness to food antigens. Hence if the same antigen is introduced systemically even under immunogenic conditions it does not induce immune responsiveness. Dendritic cells (DCs) have been identified as essential players in this process. DCs in the gut are located in a strategic position as they can interact directly with luminal antigens or indirectly after their transcytosis across epithelial cells. DCs can then migrate to associated lymphoid tissues to induce tolerance. Antigen presenting cells in the gut are specialized in function and have divided their labour so that there are cells capable to migrate to the draining mesenteric lymph node for induction of T regulatory cells, while other subsets are resident and are required to enforce tolerance locally in the gut after food antigen exposure. In this review, I shall summarize the characteristics of antigen presenting cells in the gut and their involvement in oral tolerance induction. In addition, I will also emphasize that tolerance to food allergens may be contributed by plasmacytoid DCs in the liver that participate to the elimination or anergy of allergen-specific CD8 T cells. Hence specialized functions are associated to different subsets of antigen presenting cells and different organs. © 2011 Blackwell Publishing Ltd.

Long-term safety, tolerability, and efficacy of α1-adrenergic blocker in young men with primary bladder neck obstruction: results from a single centre in China.

PubMed

Li, Bing; Gao, Wansheng; Dong, Chuanjiang; Han, Xiaomin; Li, Shuqiang; Jia, Renfeng; Xiao, Chuanguo

2012-06-01

Primary bladder neck obstruction (PBNO) is a nonneurogenic voiding disorder and frequently overlooked in young men. Prior studies have reported the efficacy of α-blockers only in the short-term for male patients with PBNO. We hereby report our long-term results using α1-blocker therapy in young men with PBNO. Between January 2005 and December 2009, PBNO was diagnosed in 30 young men (mean age 27.3 years, range 18-35) at our institution. Doxazosin 4 mg once daily was administered for at least 12 months. Safety and tolerability were assessed, and efficacy was evaluated from International Prostate Symptom Score (I-PSS), Quality of Life (QOL), uroflowmetry, and post-void residual following 3- and 12-month treatment. Successful treatment was defined as at least 3 ml per second increase in the maximum flow rate and more than a 40% decrease in I-PSS. In all 30 patients, Mean symptom duration was 26.4 (3-65) months. The most common symptoms were hesitancy (93.3%), weak stream (76.7%), and frequency (66.7%). A total of 24 patients (80%, 24/30) successfully completed the 12 month of treatment. The medication period was 15.2 months, and follow-up duration was 16.3 months. Doxazosin was safe and well tolerated. The efficacy of doxazosin was maintained over the 12-month treatment period. Relative to baseline, there were reductions in the number of mean I-PSS (from 17.7 ± 4.2 to 10.4 ± 4.8), mean QOL (from 4.2 ± 1.1 to 2.4 ± 1.3), and mean post-void residual urine (from 79.3 ± 33.4 to 47.1 ± 21.3), and an increase in mean maximum flow rate (from 11.4 ± 2.9 to 15.1 ± 3.2 ml) after 12-month treatment. Treatment was successful in 16 patients (66.7%, 16/24) according to the improvement in both symptoms and maximum urine flow. α1-blocker therapy displayed a favorable safety, tolerability, and efficacy profile during 12-month treatment in young male patients with PBNO.

33 CFR 100.35 - Special local regulations.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 33 Navigation and Navigable Waters 1 2011-07-01 2011-07-01 false Special local regulations. 100.35... MARINE PARADES SAFETY OF LIFE ON NAVIGABLE WATERS § 100.35 Special local regulations. (a) The Commander... authorized to promulgate such special local regulations as he or she deems necessary to insure safety of life...

Safety and tolerability of olanzapine compared with other antipsychotics in the treatment of elderly patients with schizophrenia: a naturalistic study.

PubMed

Ciudad, Antonio; Montes, José-Manuel; Olivares, José-Manuel; Gómez, Juan-Carlos

2004-09-01

To evaluate the safety and tolerability of olanzapine in the treatment of elderly patients with schizophrenia. A total of 135 outpatients with schizophrenia > or =60 years of age were treated with olanzapine (n = 105) or another antipsychotic (n = 30) and followed up for 6 months. Safety measures included the recording of spontaneous adverse events and extrapyramidal symptoms (EPS). Clinical status and effectiveness of the medications were measured using the Clinical Global Impressions-Severity of Illness and the Global Assessment of Function (GAF) scales. Quality of life was assessed by means of the Spanish version of the EuroQol. The Awad scale was applied to evaluate patients' subjective attitude towards medication. The incidence of overall adverse events and EPS was non-significantly lower in patients treated with olanzapine than in patients treated with other antipsychotics. The use of anticholinergic drugs was significantly lower (P = 0.04) in patients treated with olanzapine. Both groups of patients experienced similar improvements in Clinical Global Impressions-Severity and GAF scores. Non-significantly greater improvement in the acceptance of medication occurred at endpoint in olanzapine-treated patients than in control patients as measured by the Awad scale. The improvement in the EuroQol quality of life scale achieved at the end of study did not differ between both treatment groups. Results from this naturalistic study showed that olanzapine was as safe and effective as other antipsychotic drugs in the treatment of elderly patients with schizophrenia.

Advanced I&C for Fault-Tolerant Supervisory Control of Small Modular Reactors

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

Cole, Daniel G.

In this research, we have developed a supervisory control approach to enable automated control of SMRs. By design the supervisory control system has an hierarchical, interconnected, adaptive control architecture. A considerable advantage to this architecture is that it allows subsystems to communicate at different/finer granularity, facilitates monitoring of process at the modular and plant levels, and enables supervisory control. We have investigated the deployment of automation, monitoring, and data collection technologies to enable operation of multiple SMRs. Each unit's controller collects and transfers information from local loops and optimize that unit’s parameters. Information is passed from the each SMR unitmore » controller to the supervisory controller, which supervises the actions of SMR units and manage plant processes. The information processed at the supervisory level will provide operators the necessary information needed for reactor, unit, and plant operation. In conjunction with the supervisory effort, we have investigated techniques for fault-tolerant networks, over which information is transmitted between local loops and the supervisory controller to maintain a safe level of operational normalcy in the presence of anomalies. The fault-tolerance of the supervisory control architecture, the network that supports it, and the impact of fault-tolerance on multi-unit SMR plant control has been a second focus of this research. To this end, we have investigated the deployment of advanced automation, monitoring, and data collection and communications technologies to enable operation of multiple SMRs. We have created a fault-tolerant multi-unit SMR supervisory controller that collects and transfers information from local loops, supervise their actions, and adaptively optimize the controller parameters. The goal of this research has been to develop the methodologies and procedures for fault-tolerant supervisory control of small modular reactors. To

Efficacy and safety of superficial chemical peeling in treatment of active acne vulgaris*

PubMed Central

Al-Talib, Hassanain; Al-khateeb, Alyaa; Hameed, Ayad; Murugaiah, Chandrika

2017-01-01

Acne vulgaris is an extremely common condition affecting the pilosebaceous unit of the skin and characterized by presence of comedones, papules, pustules, nodules, cysts, which might result in permanent scars. Acne vulgaris commonly involve adolescents and young age groups. Active acne vulgaris is usually associated with several complications like hyper or hypopigmentation, scar formation and skin disfigurement. Previous studies have targeted the efficiency and safety of local and systemic agents in the treatment of active acne vulgaris. Superficial chemical peeling is a skin-wounding procedure which might cause some potentially undesirable adverse events. This study was conducted to review the efficacy and safety of superficial chemical peeling in the treatment of active acne vulgaris. It is a structured review of an earlier seven articles meeting the inclusion and exclusion criteria. The clinical assessments were based on pretreatment and post-treatment comparisons and the role of superficial chemical peeling in reduction of papules, pustules and comedones in active acne vulgaris. This study showed that almost all patients tolerated well the chemical peeling procedures despite a mild discomfort, burning, irritation and erythema have been reported; also the incidence of major adverse events was very low and easily manageable. In conclusion, chemical peeling with glycolic acid is a well-tolerated and safe treatment modality in active acne vulgaris while salicylic acid peels is a more convenient for treatment of darker skin patients and it showed significant and earlier improvement than glycolic acid PMID:28538881

Efficacy and safety of superficial chemical peeling in treatment of active acne vulgaris.

PubMed

Al-Talib, Hassanain; Al-Khateeb, Alyaa; Hameed, Ayad; Murugaiah, Chandrika

2017-01-01

Acne vulgaris is an extremely common condition affecting the pilosebaceous unit of the skin and characterized by presence of comedones, papules, pustules, nodules, cysts, which might result in permanent scars. Acne vulgaris commonly involve adolescents and young age groups. Active acne vulgaris is usually associated with several complications like hyper or hypopigmentation, scar formation and skin disfigurement. Previous studies have targeted the efficiency and safety of local and systemic agents in the treatment of active acne vulgaris. Superficial chemical peeling is a skin-wounding procedure which might cause some potentially undesirable adverse events. This study was conducted to review the efficacy and safety of superficial chemical peeling in the treatment of active acne vulgaris. It is a structured review of an earlier seven articles meeting the inclusion and exclusion criteria. The clinical assessments were based on pretreatment and post-treatment comparisons and the role of superficial chemical peeling in reduction of papules, pustules and comedones in active acne vulgaris. This study showed that almost all patients tolerated well the chemical peeling procedures despite a mild discomfort, burning, irritation and erythema have been reported; also the incidence of major adverse events was very low and easily manageable. In conclusion, chemical peeling with glycolic acid is a well-tolerated and safe treatment modality in active acne vulgaris while salicylic acid peels is a more convenient for treatment of darker skin patients and it showed significant and earlier improvement than glycolic acid.

Tolerance engineering in bacteria for the production of advanced biofuels and chemicals.

PubMed

Mukhopadhyay, Aindrila

2015-08-01

During microbial production of solvent-like compounds, such as advanced biofuels and bulk chemicals, accumulation of the final product can negatively impact the cultivation of the host microbe and limit the production levels. Consequently, improving solvent tolerance is becoming an essential aspect of engineering microbial production strains. Mechanisms ranging from chaperones to transcriptional factors have been used to obtain solvent-tolerant strains. However, alleviating growth inhibition does not invariably result in increased production. Transporters specifically have emerged as a powerful category of proteins that bestow tolerance and often improve production but are difficult targets for cellular expression. Here we review strain engineering, primarily as it pertains to bacterial solvent tolerance, and the benefits and challenges associated with the expression of membrane-localized transporters in improving solvent tolerance and production. Copyright © 2015 Elsevier Ltd. All rights reserved.

The Limits of Tolerance: Convicted Alcohol-Impaired Drivers Share Experiences Driving Under the Influence

PubMed Central

Lapham, Sandra C

2010-01-01

Most people are aware that regular alcohol drinkers can become tolerant to the effects of alcohol. Tolerance can lessen the outward manifestations of intoxication, and this poses challenges for the drinker and other observers, including law enforcement officers. On the basis of a National Institutes of Health-funded longitudinal study examining a cohort of convicted alcohol-impaired drivers, this article presents commentary regarding this phenomenon in offenders convicted of driving under the influence and the implications for traffic safety. PMID:20740113

Recent Advances in Durability and Damage Tolerance Methodology at NASA Langley Research Center

NASA Technical Reports Server (NTRS)

Ransom, J. B.; Glaessgen, E. H.; Raju, I. S.; Harris, C. E.

2007-01-01

Durability and damage tolerance (D&DT) issues are critical to the development of lighter, safer and more efficient aerospace vehicles. Durability is largely an economic life-cycle design consideration whereas damage tolerance directly addresses the structural airworthiness (safety) of the vehicle. Both D&DT methodologies must address the deleterious effects of changes in material properties and the initiation and growth of damage that may occur during the vehicle s service lifetime. The result of unanticipated D&DT response is often manifested in the form of catastrophic and potentially fatal accidents. As such, durability and damage tolerance requirements must be rigorously addressed for commercial transport aircraft and NASA spacecraft systems. This paper presents an overview of the recent and planned future research in durability and damage tolerance analytical and experimental methods for both metallic and composite aerospace structures at NASA Langley Research Center (LaRC).

Aviation safety/automation program overview

NASA Technical Reports Server (NTRS)

Morello, Samuel A.

1990-01-01

The goal is to provide a technology base leading to improved safety of the national airspace system through the development and integration of human-centered automation technologies for aircraft crews and air traffic controllers. Information on the problems, specific objectives, human-automation interaction, intelligent error-tolerant systems, and air traffic control/cockpit integration is given in viewgraph form.

A Dose Escalation and Pharmacodynamic Study of Triapine and Radiation in Patients With Locally Advanced Pancreas Cancer

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

Martin, Ludmila Katherine; Grecula, John; Jia, Guang

2012-11-15

Purpose: Triapine, a novel inhibitor of the M2 subunit of ribonucleotide reductase (RR), is a potent radiosensitizer. This phase 1 study, sponsored by the National Cancer Institute Cancer Therapy Evaluation Program, assessed the safety and tolerability of triapine in combination with radiation (RT) in patients with locally advanced pancreas cancer (LAPCA). Methods and Materials: We evaluated 3 dosage levels of triapine (24 mg/m{sup 2}, 48 mg/m{sup 2}, 72 mg/m{sup 2}) administered with 50.4 Gy of RT in 28 fractions. Patients with LAPCA received triapine thrice weekly, every other week during the course of RT. Dose-limiting toxicity (DLT) was assessed duringmore » RT and for 4 weeks after its completion. Dynamic contrast-enhanced magnetic resonance imaging and serum RR levels were evaluated as potential predictors for early response. Results: Twelve patients were treated. Four patients (1 nonevaluable) were enrolled at dosage level 1 (DL1), 3 patients at DL2, and 5 patients (2 nonevaluable) at DL3. No DLTs were observed, and the maximum tolerated dose was not reached. Two patients (17%) achieved partial response, and 6 patients (50%) had stable disease. One patient underwent R0 resection after therapy. Ninety-two percent of patients (100% at DL3) experienced freedom from local tumor progression. In 75% of patients who eventually experienced progression, metastases developed without local progression. RR levels did not seem to predict outcome. In 4 patients with available data, dynamic contrast-enhanced magnetic resonance imaging may predict early response or resistance to therapy. Conclusion: The combination of triapine at 72 mg/m{sup 2} 3 times weekly every other week and standard RT is tolerable with interesting activity in patients with LAPCA.« less

Bone marrow chimerism as a strategy to produce tolerance in solid organ allotransplantation.

PubMed

Hu, Min; Alexander, Stephen I; Yi, Shounan

2016-12-01

Clinical transplant tolerance has been most successfully achieved combining hematopoietic chimerism with kidney transplantation. This review outlines this strategy in animal models and human transplantation, and possible clinical challenges. Kidney transplant tolerance has been achieved through chimerism in several centers beginning with Massachusetts General Hospital's success with mixed chimerism in human leukocyte antigen (HLA)-mismatched patients and the Stanford group with HLA-matched patients, and the more recent success of the Northwestern protocol achieving full chimerism. This has challenged the original view that stable mixed chimerism is necessary for organ graft tolerance. However, among the HLA-mismatched kidney transplant-tolerant patients, loss of mixed chimerism does not lead to renal-graft rejection, and the development of host Foxp3+ regulatory T cells has been observed. Recent animal models suggest that graft tolerance through bone marrow chimerism occurs through both clonal deletion and regulatory immune cells. Further, Tregs have been shown to improve chimerism in animal models. Animal studies continue to suggest ways to improve our current clinical strategies. Advances in chimerism protocols suggest that tolerance may be clinically achievable with relative safety for HLA-mismatched kidney transplants.

Experimental evolution reveals high insecticide tolerance in Daphnia inhabiting farmland ponds

PubMed Central

Jansen, Mieke; Coors, Anja; Vanoverbeke, Joost; Schepens, Melissa; De Voogt, Pim; De Schamphelaere, Karel A C; De Meester, Luc

2015-01-01

Exposure of nontarget populations to agricultural chemicals is an important aspect of global change. We quantified the capacity of natural Daphnia magna populations to locally adapt to insecticide exposure through a selection experiment involving carbaryl exposure and a control. Carbaryl tolerance after selection under carbaryl exposure did not increase significantly compared to the tolerance of the original field populations. However, there was evolution of a decreased tolerance in the control experimental populations compared to the original field populations. The magnitude of this decrease was positively correlated with land use intensity in the neighbourhood of the ponds from which the original populations were sampled. The genetic change in carbaryl tolerance in the control rather than in the carbaryl treatment suggests widespread selection for insecticide tolerance in the field associated with land use intensity and suggests that this evolution comes at a cost. Our data suggest a strong impact of current agricultural land use on nontarget natural Daphnia populations. PMID:26029258

T cell priming versus T cell tolerance induced by synthetic peptides

PubMed Central

1995-01-01

It is well known that synthetic peptides are able to both induce and tolerize T cells. We have examined the parameters leading either to priming or tolerance of CD8+ cytotoxic T lymphocytes (CTL) in vivo with a major histocompatibility complex class I (H-2 Db) binding peptide derived from the glycoprotein (GP aa33-41) of lymphocytic choriomeningitis virus (LCMV). By varying dose, route, and frequency of LCMV GP peptide application, we found that a single local subcutaneous injection of 50-500 micrograms peptide emulsified in incomplete Freund's adjuvant protected mice against LCMV infection, whereas repetitive and systemic intraperitoneal application of the same dose caused tolerance of LCMV-specific CTL. The peptide-induced tolerance was transient in euthymic mice but permanent in thymectomized mice. These findings are relevant for a selective use of peptides as a therapeutic approach: peptide-induced priming of T cells for vaccination and peptide-mediated T cell tolerance for intervention in immunopathologies and autoimmune diseases. PMID:7540654

Comparing Safety and Efficacy of "Third-Generation" Antiepileptic Drugs: Long-Term Extension and Post-marketing Treatment.

PubMed

Kwok, Charlotte S; Johnson, Emily L; Krauss, Gregory L

2017-11-01

Four "third-generation" antiepileptic drugs (AEDs) were approved for adjunctive treatment of refractory focal onset seizures during the past 10 years. Long-term efficacy and safety of the drugs were demonstrated in large extension studies and in reports of subgroups of patients not studied in pivotal trials. Reviewing extension study and post-marketing outcome series for the four newer AEDs-lacosamide, perampanel, eslicarbazepine acetate and brivaracetam-can guide clinicians in treating and monitoring patients. AED extension studies evaluate treatment retention, drug tolerability, and drug safety during individualized treatment with flexible dosing and thus provide information not available in rigid pivotal trials. Patient retention in the studies ranged from 75 to 80% at 1 year and from 36 to 68% at 2-year treatment intervals. Safety findings were generally similar to those of pivotal trials, with no major safety risks identified and with several specific adverse drug effects, such as hyponatremia, reported. The third-generation AEDs, some through new mechanisms and others with improved tolerability compared to related AEDs, provide new options in efficacy and tolerability.

SafetyAnalyst Testing and Implementation

DOT National Transportation Integrated Search

2009-03-01

SafetyAnalyst is a software tool developed by the Federal Highway Administration to assist state and local transportation agencies on analyzing safety data and managing their roadway safety programs. This research report documents the major tasks acc...

Pharmacokinetics, pharmacodynamics, safety and tolerability of an intravaginal ring releasing anastrozole and levonorgestrel in healthy premenopausal women: a Phase 1 randomized controlled trial.

PubMed

Schultze-Mosgau, M-H; Waellnitz, K; Nave, R; Klein, S; Kraetzschmar, J; Rautenberg, T; Schmitz, H; Rohde, B

2016-08-01

What are suitable doses of the aromatase inhibitor anastrozole (ATZ) and the progestin levonorgestrel (LNG), when delivered to the systemic circulation by an intravaginal ring (IVR), for further clinical development as a potential new therapy for the treatment of endometriosis? Anticipated targets for pharmacokinetics, pharmacodynamics and safety/tolerability were achieved for both drug components of the IVR at the doses investigated, supporting selection of the doses to be investigated in Phase 2 studies. Aromatase is a key enzyme in the biosynthesis of estrogens and is known to increase local levels of estradiol (E2) at extragonadal sites. Up-regulation of aromatase expression has been demonstrated in endometriotic lesions and the use of oral aromatase inhibitors has been shown to reduce endometriosis-associated pelvic pain in small-scale clinical trials. This Phase 1, randomized, multicentre, parallel-group, three-arm, open-label study assessed the pharmacokinetics, pharmacodynamics, safety and tolerability of various IVRs intended for systemic drug delivery. After screening, healthy, ovulating women aged 18-35 years were randomized to use IVRs releasing one of the three ATZ/LNG dose combinations (in vitro nominal daily drug release rates on Day 29: ATZ/LNG 500 µg/20 µg [low dose], ATZ/LNG 1000 µg/30 µg [mid dose] or ATZ/LNG 1500 µg/40 µg [high dose]) for two consecutive 28-day wearing periods without a treatment break. Sixty women were included in the per protocol set. The primary variables were plasma concentrations of ATZ and LNG at the end of each treatment period and the mean size of largest follicle-like structures (FLSs) over 56 days. Serum concentrations of several hormones were also evaluated, with emphasis on E2 levels. At the end of the first treatment period, geometric mean plasma concentrations of LNG and ATZ, respectively, were 0.228 and 12.5 µg/l for the low dose, 0.269 and 19.8 µg/l for the mid dose and 0.384 and 37.3 µg/l for the high

An open-label extension study to investigate the long-term safety and tolerability of THC/CBD oromucosal spray and oromucosal THC spray in patients with terminal cancer-related pain refractory to strong opioid analgesics.

PubMed

Johnson, Jeremy R; Lossignol, Dominique; Burnell-Nugent, Mary; Fallon, Marie T

2013-08-01

Chronic pain in patients with advanced cancer poses a serious clinical challenge. The Δ9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray (U.S. Adopted Name, nabiximols; Sativex(®)) is a novel cannabinoid formulation currently undergoing investigation as an adjuvant therapy for this treatment group. This follow-up study investigated the long-term safety and tolerability of THC/CBD spray and THC spray in relieving pain in patients with advanced cancer. In total, 43 patients with cancer-related pain experiencing inadequate analgesia despite chronic opioid dosing, who had participated in a previous three-arm (THC/CBD spray, THC spray, or placebo), two-week parent randomized controlled trial, entered this open-label, multicenter, follow-up study. Patients self-titrated THC/CBD spray (n=39) or THC spray (n=4) to symptom relief or maximum dose and were regularly reviewed for safety, tolerability, and evidence of clinical benefit. The efficacy end point of change from baseline in mean Brief Pain Inventory-Short Form scores for "pain severity" and "worst pain" domains showed a decrease (i.e., improvement) at each visit in the THC/CBD spray patients. Similarly, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 scores showed a decrease (i.e., improvement) from baseline in the domains of insomnia, pain, and fatigue. No new safety concerns associated with the extended use of THC/CBD spray arose from this study. This study showed that the long-term use of THC/CBD spray was generally well tolerated, with no evidence of a loss of effect for the relief of cancer-related pain with long-term use. Furthermore, patients who kept using the study medication did not seek to increase their dose of this or other pain-relieving medication over time, suggesting that the adjuvant use of cannabinoids in cancer-related pain could provide useful benefit. Copyright © 2013 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc

Zero Tolerance: A Stage Adaptation of an Investigative Report on School Safety

ERIC Educational Resources Information Center

Goldstein, Tara; Wickett, Jocelyn

2009-01-01

In May 2007, 15-year-old Jordan Manners was shot and killed in the hallway of his Toronto school. In June 2007, the Toronto District School Board commissioned an investigation into school safety, which resulted in a report entitled "The Road to Health: A Final Report on School Safety." In February 2008, in an attempt to provoke…

Grapevine and Arabidopsis Cation-Chloride Cotransporters Localize to the Golgi and Trans-Golgi Network and Indirectly Influence Long-Distance Ion Transport and Plant Salt Tolerance1[OPEN

PubMed Central

Henderson, Sam W.; Wege, Stefanie; Qiu, Jiaen; Blackmore, Deidre H.; Walker, Amanda R.; Tyerman, Stephen D.; Walker, Rob R.; Gilliham, Matthew

2015-01-01

Plant cation-chloride cotransporters (CCCs) have been implicated in conferring salt tolerance. They are predicted to improve shoot salt exclusion by directly catalyzing the retrieval of sodium (Na+) and chloride (Cl−) ions from the root xylem. We investigated whether grapevine (Vitis vinifera [Vvi]) CCC has a role in salt tolerance by cloning and functionally characterizing the gene from the cultivar Cabernet Sauvignon. Amino acid sequence analysis revealed that VviCCC shares a high degree of similarity with other plant CCCs. A VviCCC-yellow fluorescent protein translational fusion protein localized to the Golgi and the trans-Golgi network and not the plasma membrane when expressed transiently in tobacco (Nicotiana benthamiana) leaves and Arabidopsis (Arabidopsis thaliana) mesophyll protoplasts. AtCCC-green fluorescent protein from Arabidopsis also localized to the Golgi and the trans-Golgi network. In Xenopus laevis oocytes, VviCCC targeted to the plasma membrane, where it catalyzed bumetanide-sensitive 36Cl–, 22Na+, and 86Rb+ uptake, suggesting that VviCCC (like AtCCC) belongs to the Na+-K+-2Cl– cotransporter class of CCCs. Expression of VviCCC in an Arabidopsis ccc knockout mutant abolished the mutant’s stunted growth phenotypes and reduced shoot Cl– and Na+ content to wild-type levels after growing plants in 50 mm NaCl. In grapevine roots, VviCCC transcript abundance was not regulated by Cl– treatment and was present at similar levels in both the root stele and cortex of three Vitis spp. genotypes that exhibit differential shoot salt exclusion. Our findings indicate that CCC function is conserved between grapevine and Arabidopsis, but neither protein is likely to directly mediate ion transfer with the xylem or have a direct role in salt tolerance. PMID:26378102

A Two-Phase Pilot Study to Evaluate the Safety and Tolerability of an In Situ Polymerizing Collagen.

PubMed

Inglefield, Christopher; Rone-McCrate, Rebecca; Brooks, Robert; Zhu, Jiaxun; Grant, Sheila; DeVore, Dale P

2017-09-01

Demand for collagen-based fillers has declined primarily because of limited long-term clinical benefit and the introduction of hyaluronic acid compositions. In situ polymerizing collagen is a noncrosslinked solution of porcine collagen containing a collagenase shield that undergoes fibrillogenesis on injected into tissues forming a natural matrix. Conduct a prospective, single-center, dual-phase open-label study in 8 subjects to evaluate the safety, tolerability, and efficacy of the porcine collagen composition. In Phase I, potential hypersensitivity of the collagen composition was evaluated after skin testing in the back (men) or forearms of subjects (women). In Phase II, subjects showing no signs of hypersensitivity received collagen injections into the nasolabial area followed by evaluation at 1, 4, 8, and 12 weeks using the Global Aesthetic Improvement Scale. None of the subjects had signs of hypersensitivity and all continued in Phase II. The treating physician(s) reported no post-treatment adverse events. Improvement of the nasolabial fold was observed by the physicians and confirmed by assessment of high-resolution photographs and Global Aesthetic Improvement Scale scores over the 12-week treatment were maintained. In this pilot clinical study in situ polymerizing collagen was shown to be safe and effective throughout the 3-month study period.

Need for Tolerances and Tolerance Exemptions for Minimum Risk Pesticides

EPA Pesticide Factsheets

The ingredients used in minimum risk products used on food, food crops, food contact surfaces, or animal feed commodities generally have a tolerance or tolerance exemption. Learn about tolerances and tolerance exemptions for minimum risk ingredients.

Biophysics, environmental stochasticity, and the evolution of thermal safety margins in intertidal limpets.

PubMed

Denny, M W; Dowd, W W

2012-03-15

As the air temperature of the Earth rises, ecological relationships within a community might shift, in part due to differences in the thermal physiology of species. Prediction of these shifts - an urgent task for ecologists - will be complicated if thermal tolerance itself can rapidly evolve. Here, we employ a mechanistic approach to predict the potential for rapid evolution of thermal tolerance in the intertidal limpet Lottia gigantea. Using biophysical principles to predict body temperature as a function of the state of the environment, and an environmental bootstrap procedure to predict how the environment fluctuates through time, we create hypothetical time-series of limpet body temperatures, which are in turn used as a test platform for a mechanistic evolutionary model of thermal tolerance. Our simulations suggest that environmentally driven stochastic variation of L. gigantea body temperature results in rapid evolution of a substantial 'safety margin': the average lethal limit is 5-7°C above the average annual maximum temperature. This predicted safety margin approximately matches that found in nature, and once established is sufficient, in our simulations, to allow some limpet populations to survive a drastic, century-long increase in air temperature. By contrast, in the absence of environmental stochasticity, the safety margin is dramatically reduced. We suggest that the risk of exceeding the safety margin, rather than the absolute value of the safety margin, plays an underappreciated role in the evolution of thermal tolerance. Our predictions are based on a simple, hypothetical, allelic model that connects genetics to thermal physiology. To move beyond this simple model - and thereby potentially to predict differential evolution among populations and among species - will require significant advances in our ability to translate the details of thermal histories into physiological and population-genetic consequences.

Underestimation of the efficacy, effectiveness, tolerability, and safety of weekly low-dose methotrexate in information presented to physicians and patients.

PubMed

Pincus, T; Furer, V; Sokka, T

2010-01-01

Ten specific examples of the underestimation of the efficacy, effectiveness and tolerability, and overestimation of adverse events of weekly, low-dose methotrexate, administered with folic acid, in treatment of rheumatic diseases are summarised. These examples include: 1) meta-analyses of clinical trials suggest that methotrexate has an efficacy similar to other disease-modifying anti-rheumatic drugs (DMARDs); 2) information in textbooks and websites may overstate adverse events and drug interactions associated with weekly low-dose methotrexate; 3) information presented to patients when filling a prescription for methotrexate understates 'side effects' of RA and overstates those of methotrexate; 4) an admonition to patients to refrain entirely from consumption of alcohol while taking methotrexate may be unnecessary; 5) frequent blood testing in patients who take methotrexate may be overused; 6) eligibility of only a small minority of patients for clinical trials to compare biologic agents and methotrexate; 7) Step-up design in most comparisons of biologic agents with methotrexate includes only patients who had experienced an incomplete response to methotrexate; 8) in parallel design trials, the efficacy of biologic agents is not substantially greater than that of methotrexate; 9) low, inflexible dosage schedules of methotrexate and requirement for withdrawal with minimal liver function abnormalities in many clinical trials may underestimate efficacy, effectiveness, tolerability and safety; 10) interpretation of clinical trial results may overstate the clinical significance of lower radiographic progression in patients treated with biologic agents versus patients treated with methotrexate. More accurate interpretation of information for physicians and other health professionals, as well as patients, concerning use of weekly low-dose methotrexate in contemporary care could improve care and outcomes for patients with RA and other rheumatic diseases.

Safety and tolerance of ester-C compared with regular ascorbic acid.

PubMed

Gruenwald, Joerg; Graubaum, Hans-Joachim; Busch, Regina; Bentley, Christine

2006-01-01

The goal of this randomized, double-blind crossover clinical trial in 50 healthy volunteers sensitive to acidic foods was to evaluate whether Ester-C calcium ascorbate causes fewer epigastric adverse effects than are produced by regular ascorbic acid (AA). Volunteers were randomly separated into 2 groups of 25. The study comprised an observation period of 9 days (phase 1 medication for 3 consecutive days, washout phase for 3 consecutive days, phase 2 medication for 3 consecutive days). Participants took 1000 mg vitamin C as Ester-C during phase 1 of the study followed by 1000 mg of vitamin C as AA during phase 2, or vice versa. During the course of the study, 3 examinations for the evaluation of epigastric adverse effects were performed (on days 0, 3, and 9). Participants used a diary to record epigastric adverse effects on a daily basis. In total, 28 (56%) of 50 participants reported 88 epigastric adverse effects of mild to moderate intensity. Of these 88 adverse effects, 33 (37.5%) occurred after intake of Ester-C and 55 (62.5%) were noted after intake of AA. The tolerability of Ester-C was rated "very good" by 72% of participants, whereas AA was rated "very good" by only 54%. This difference is statistically significant (P<.05). Investigators concluded that Ester-C compared with AA caused significantly fewer epigastric adverse effects in participants sensitive to acidic foods and that Ester-C is much better tolerated.

Development and analysis of the Software Implemented Fault-Tolerance (SIFT) computer

NASA Technical Reports Server (NTRS)

Goldberg, J.; Kautz, W. H.; Melliar-Smith, P. M.; Green, M. W.; Levitt, K. N.; Schwartz, R. L.; Weinstock, C. B.

1984-01-01

SIFT (Software Implemented Fault Tolerance) is an experimental, fault-tolerant computer system designed to meet the extreme reliability requirements for safety-critical functions in advanced aircraft. Errors are masked by performing a majority voting operation over the results of identical computations, and faulty processors are removed from service by reassigning computations to the nonfaulty processors. This scheme has been implemented in a special architecture using a set of standard Bendix BDX930 processors, augmented by a special asynchronous-broadcast communication interface that provides direct, processor to processor communication among all processors. Fault isolation is accomplished in hardware; all other fault-tolerance functions, together with scheduling and synchronization are implemented exclusively by executive system software. The system reliability is predicted by a Markov model. Mathematical consistency of the system software with respect to the reliability model has been partially verified, using recently developed tools for machine-aided proof of program correctness.

77 FR 53144 - Nitric Acid; Exemption From the Requirement of a Tolerance

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-31

... Cosmetic Act (FFDCA), requesting establishment of an exemption from the requirement of a tolerance. This... ingredients. IV. Aggregate Risk Assessment and Determination of Safety Section 408(c)(2)(A)(i) of FFDCA allows... to assess the hazards of and to make a determination on aggregate exposure for nitric acid including...

Safety, Pharmacokinetics, and Immunogenicity of Obiltoxaximab After Intramuscular Administration to Healthy Humans.

PubMed

Nagy, Christa F; Leach, Timothy S; King, Alex; Guttendorf, Robert

2017-11-10

Inhalational anthrax is a highly lethal infection caused by Bacillus anthracis and a serious bioterrorism threat. Protective antigen (PA) is a critical component required for the virulence of Bacillus anthracis. Obiltoxaximab, a high-affinity monoclonal antibody that neutralizes PA, is approved in the United States for intravenous use for the treatment of inhalational anthrax in combination with appropriate antibacterial drugs and for prophylaxis of inhalational anthrax when alternative therapies are not available or appropriate. Here, we explored the safety, pharmacokinetics (PK), and immunogenicity of obiltoxaximab administered by intramuscular injection at doses of 4, 8, 16, 20, and 24 mg/kg in healthy humans. Systemic exposures were approximately dose proportional, maximum serum concentrations were observed after 6-9 days, and terminal half-life ranged from 16 to 23 days. Average absolute intramuscular bioavailability was 64%. Obiltoxaximab was well tolerated, and local tolerability was acceptable up to 24 mg/kg intramuscularly, up to 6 injections per dose, and up to 5 mL per injection. No injection-site abscesses or hypersensitivity reactions occurred; no subjects developed treatment-emergent antitherapeutic antibodies over the study period of 71 days. © 2017, The American College of Clinical Pharmacology.

Pharmacokinetic Profile, Safety, and Tolerability of Crisaborole Topical Ointment, 2% in Adolescents with Atopic Dermatitis: An Open-Label Phase 2a Study.

PubMed

Tom, Wynnis L; Van Syoc, Merrie; Chanda, Sanjay; Zane, Lee T

2016-01-01

Phosphodiesterase-4 (PDE4) is an emerging target in treating inflammatory skin diseases. Crisaborole topical ointment, 2% is a novel, boron-based, topical PDE4 inhibitor under investigation for treatment of mild to moderate atopic dermatitis (AD). Adolescent patients aged 12 to 17 years with treatable AD lesions involving ≥ 10% to ≤ 35% body surface area (BSA) were enrolled into a phase 2a, open-label study comprising pharmacokinetic (PK), safety, tolerability, and efficacy assessments. Crisaborole topical ointment, 2% was applied twice daily to affected areas for 28 days, with dosage based on baseline treatable BSA. PK blood samples were collected on days 1, 2, 4, 6, 8, and 9. Safety assessments included adverse events (AEs), laboratory parameters, and vital signs. Efficacy assessments included the Investigator's Static Global Assessment (ISGA) score and severity of AD signs and symptoms. Twenty-three patients were enrolled; 22 completed the study (1 patient discontinued due to an AE [application site dermatitis]). PK analysis demonstrated limited exposure to crisaborole topical ointment, 2% after 8 days of dosing. Ten patients reported a total of 19 AEs, most commonly application site pain and nasopharyngitis (3 patients each). There were no clinically meaningful changes in laboratory or vital sign parameters. Efficacy was demonstrated by reductions in mean ISGA and AD sign and symptom severity scores. At day 29, eight patients (35%) had achieved an ISGA score ≤ 1 with ≥ 2-grade improvement. Mean treatable BSA declined from 17.6% to 8.2%. These results provide preliminary evidence for the limited systemic exposure, safety, and effectiveness of crisaborole topical ointment, 2% in adolescents with mild to moderate AD. © 2016 Wiley Periodicals, Inc.

A comparative study on the immunogenicity, safety and tolerance of purified duck embryo vaccine (PDEV) manufactured in India (Vaxirab) and Switzerland (Lyssavac-N): a randomized simulated post-exposure study in healthy volunteers.

PubMed

Mahendra, Bangalore Jayakrishnappa; Madhusudana, Shampur Narayan; Ashwathnarayana, Doddabele Hanumanthaiah; Sampath, Gadey; datta, Soma Subhra; Sudarshan, Mysore Kalappa; Venkatesh, Gonibeedu Manjunatah; Muhamuda, Kader; Bilagumba, Gangaboraiah; Shamanna, Manjula

2007-12-05

Purified duck embryo vaccine (PDEV, Vaxirab) for rabies prophylaxis is now indigenously manufactured in India under technology transfer from Berna Biotech who made the original PDEV (Lyssavac). In the present study we have compared the two vaccines in terms of safety, immunogenicity and tolerance. The study was conducted in 220 adult healthy volunteers. It was observed that both vaccines produced neutralizing antibody titers (as determined by rapid fluorescent focus inhibition test, RFFIT) more than 0.5 IU/mL (minimum level for seroconversion) on all days tested but the titers on days 90 and 180 were significantly higher with Lyssavac. The adverse reactions produced were slightly more with Lysssavac but both vaccines were well tolerated. In conclusion, the indigenously produced PDEV (Vaxirab) was found to be equally safe and immunogenic as the original PDEV (Lyssavac) manufactured at Switzerland.

(In)Tolerable Zero Tolerance Policy

ERIC Educational Resources Information Center

Dickerson, Sean L.

2014-01-01

The spread of zero tolerance policies for school-based scenarios flourished under President William J. Clinton who wanted to close a loophole in the Guns-Free School Zones Act of 1990. Expansion in the coverage of zero tolerance policy to offenses outside the initial scope of weapon and drug offenses has led to a disproportional ratio of African…

Pesticide tolerance in amphibians: induced tolerance in susceptible populations, constitutive tolerance in tolerant populations

PubMed Central

Hua, Jessica; Morehouse, Nathan I; Relyea, Rick

2013-01-01

The role of plasticity in shaping adaptations is important to understanding the expression of traits within individuals and the evolution of populations. With increasing human impacts on the environment, one challenge is to consider how plasticity shapes responses to anthropogenic stressors such as contaminants. To our knowledge, only one study (using mosquitoes) has considered the possibility of induced insecticide tolerance. Using populations of wood frogs (Lithobates sylvaticus) located close to and far from agricultural fields, we discovered that exposing some populations of embryos and hatchlings to sublethal concentrations of the insecticide carbaryl induced higher tolerance to a subsequent lethal concentration later in life. Interestingly, the inducible populations were located >800 m from agricultural areas and were the most susceptible to the insecticide. In contrast, the noninducible populations were located close to agricultural areas and were the least susceptible. We also found that sublethal concentrations of carbaryl induced higher tadpole AChE concentrations in several cases. This is the first study to demonstrate inducible tolerance in a vertebrate species and the pattern of inducible and constitutive tolerance among populations suggests the process of genetic assimilation. PMID:24187585

Basking behavior predicts the evolution of heat tolerance in Australian rainforest lizards.

PubMed

Muñoz, Martha M; Langham, Gary M; Brandley, Matthew C; Rosauer, Dan F; Williams, Stephen E; Moritz, Craig

2016-11-01

There is pressing urgency to understand how tropical ectotherms can behaviorally and physiologically respond to climate warming. We examine how basking behavior and thermal environment interact to influence evolutionary variation in thermal physiology of multiple species of lygosomine rainforest skinks from the Wet Tropics of northeastern Queensland, Australia (AWT). These tropical lizards are behaviorally specialized to exploit canopy or sun, and are distributed across marked thermal clines in the AWT. Using phylogenetic analyses, we demonstrate that physiological parameters are either associated with changes in local thermal habitat or to basking behavior, but not both. Cold tolerance, the optimal sprint speed, and performance breadth are primarily influenced by local thermal environment. Specifically, montane lizards are more cool tolerant, have broader performance breadths, and higher optimum sprinting temperatures than their lowland counterparts. Heat tolerance, in contrast, is strongly affected by basking behavior: there are two evolutionary optima, with basking species having considerably higher heat tolerance than shade skinks, with no effect of elevation. These distinct responses among traits indicate the multiple selective pressures and constraints that shape the evolution of thermal performance. We discuss how behavior and physiology interact to shape organisms' vulnerability and potential resilience to climate change. © 2016 The Author(s). Evolution © 2016 The Society for the Study of Evolution.

Safety, Tolerability, and Antihypertensive Effect of SER100, an Opiate Receptor-Like 1 (ORL-1) Partial Agonist, in Patients With Isolated Systolic Hypertension.

PubMed

Kantola, Ilkka; Scheinin, Mika; Gulbrandsen, Trygve; Meland, Nils; Smerud, Knut T

2017-11-01

The purpose of the present trial was to evaluate safety, tolerability, and effect on systolic blood pressure (SBP) of SER100 in a small group of patients with isolated systolic hypertension (ISH) in treatment with at least 1 antihypertensive drug. Eligible patients were randomized to either SER100 (10 mg) or placebo in a crossover design, and 2 doses were given subcutaneously (SC), 8 hours apart, on 2 consecutive days. On all treatment days patients were monitored with an ambulatory blood pressure measurement device for 12 daytime hours. Seventeen patients completed treatment. There were no serious or severe adverse events. Relative to placebo SER100 induced an average reduction of SBP during the 2 treatment days of 7.0 mm Hg (P = 0.0032), whereas the average reduction of diastolic blood pressure (DBP) over the same period was 3.8 mm Hg (P = 0.0011). For patients with ISH, this short-term cross-over study of SC SER100 demonstrated an acceptable safety profile and consistent, significant lowering of SBP and DBP. As initial clinical proof of concept for a new class of drugs, a nociceptin agonist peptide, the results were encouraging and warrant further research. © 2016, The American College of Clinical Pharmacology.

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

PubMed

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

2012-09-01

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

Fault-tolerant logical gates in quantum error-correcting codes

NASA Astrophysics Data System (ADS)

Pastawski, Fernando; Yoshida, Beni

2015-01-01

Recently, S. Bravyi and R. König [Phys. Rev. Lett. 110, 170503 (2013), 10.1103/PhysRevLett.110.170503] have shown that there is a trade-off between fault-tolerantly implementable logical gates and geometric locality of stabilizer codes. They consider locality-preserving operations which are implemented by a constant-depth geometrically local circuit and are thus fault tolerant by construction. In particular, they show that, for local stabilizer codes in D spatial dimensions, locality-preserving gates are restricted to a set of unitary gates known as the D th level of the Clifford hierarchy. In this paper, we explore this idea further by providing several extensions and applications of their characterization to qubit stabilizer and subsystem codes. First, we present a no-go theorem for self-correcting quantum memory. Namely, we prove that a three-dimensional stabilizer Hamiltonian with a locality-preserving implementation of a non-Clifford gate cannot have a macroscopic energy barrier. This result implies that non-Clifford gates do not admit such implementations in Haah's cubic code and Michnicki's welded code. Second, we prove that the code distance of a D -dimensional local stabilizer code with a nontrivial locality-preserving m th -level Clifford logical gate is upper bounded by O (LD +1 -m) . For codes with non-Clifford gates (m >2 ), this improves the previous best bound by S. Bravyi and B. Terhal [New. J. Phys. 11, 043029 (2009), 10.1088/1367-2630/11/4/043029]. Topological color codes, introduced by H. Bombin and M. A. Martin-Delgado [Phys. Rev. Lett. 97, 180501 (2006), 10.1103/PhysRevLett.97.180501; Phys. Rev. Lett. 98, 160502 (2007), 10.1103/PhysRevLett.98.160502; Phys. Rev. B 75, 075103 (2007), 10.1103/PhysRevB.75.075103], saturate the bound for m =D . Third, we prove that the qubit erasure threshold for codes with a nontrivial transversal m th -level Clifford logical gate is upper bounded by 1 /m . This implies that no family of fault-tolerant codes with

Efficacy, safety, Low density lipoprotein cholesterol lowering, and calculated 10-year cardiovascular risk reduction of alirocumab and evolocumab in addition to maximal tolerated cholesterol lowering therapy: a post-commercialization study.

PubMed

Shah, Parth; Glueck, Charles J; Goldenberg, Naila; Min, Sarah; Mahida, Chris; Schlam, Ilana; Rothschild, Matan; Huda, Ali; Wang, Ping

2017-01-23

Efficacy and safety of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, alirocumab (ALI) and evolocumab (EVO) have previously been evaluated through controlled clinical trials with selective patient groups. Post-commercially, in patients with heterozygous familial hypercholesterolemia (HeFH) and/or cardiovascular disease (CVD) with suboptimal LDL cholesterol (LDLC) lowering on maximal tolerated cholesterol lowering therapy, we assessed efficacy and safety of ALI and EVO. Post-commercially, we started 25 patients on ALI 75 mg, 15 on ALI 150 mg, and 32 on EVO 140 mg bi-weekly added to entry LDLC lowering regimen, with follow-up for a median 24 weeks. History, physical exam, demographics, and adverse event data were collected. Changes in LDLC and AHA and NIH calculated 10-year CVD risks were assessed on ALI and EVO. Of 72 patients, 25 had HeFH only, 25 CVD only, 22 had both, median age was 65 years, 63% females, 38% males, 86% Caucasian, 11% African-Americans, 17% diabetics, 63% on anti-hypertensives, and 7% smokers. At entry, 30 (42%) were on a statin and 42 (58%) could not tolerate any statins. At 24-weeks, median LDLC decreased on ALI 75 mg from 117 to 62 mg/dL (-54%), on ALI 150 mg from 175 to 57 mg/dL (-63%), and on EVO 140 mg from 165 to 69 mg/dL (-63%), p <0.0001 for all. Absolute and percent LDLC reduction did not differ (p >.05) between ALI 150 and EVO 140 mg, but were less on ALI 75 mg vs ALI 150 mg and EVO 140 mg (p <.05). Percent reductions in 10-year CVD risks by AHA and NIH calculators, respectively were ALI 75 mg -22 and -44%, ALI 150 mg -31 and -50%, and EVO 140 mg -29 and -56%, p ≤.002 for all. The three most common adverse events included flu-like myositis 10%, respiratory tract symptoms 8%, and injection site reaction 6%. In patients with HeFH and/or CVD, LDLC was lowered by 63% on EVO and ALI 150 mg, and 54% on ALI 75 mg. Adverse events were minimal and tolerable. ALI and EVO represent paradigm shifts

Safety and efficacy of targeted hyperthermia treatment utilizing gold nanorod therapy in spontaneous canine neoplasia.

PubMed

Schuh, Elizabeth M; Portela, Roberta; Gardner, Heather L; Schoen, Christian; London, Cheryl A

2017-10-02

Hyperthermia is an established anti-cancer treatment but is limited by tolerance of adjacent normal tissues. Parenteral administration of gold nanorods (NRs) as a photosensitizer amplifies the effects of hyperthermia treatment while sparing normal tissues. This therapy is well tolerated and has demonstrated anti-tumor effects in mouse models. The purpose of this phase 1 study was to establish the safety and observe the anti-tumor impact of gold NR enhanced (plasmonic) photothermal therapy (PPTT) in client owned canine patients diagnosed with spontaneous neoplasia. Seven dogs underwent gold NR administration and subsequent NIR PPTT. Side effects were mild and limited to local reactions to NIR laser. All of the dogs enrolled in the study experienced stable disease, partial remission or complete remission. The overall response rate (ORR) was 28.6% with partial or complete remission of tumors at study end. PPTT utilizing gold nanorod therapy can be safely administered to canine patients. Further studies are needed to determine the true efficacy in a larger population of canine cancer patients and to and identify those patients most likely to benefit from this therapy.

Safety, tolerability, and immunogenicity of a recombinant toxic shock syndrome toxin (rTSST)-1 variant vaccine: a randomised, double-blind, adjuvant-controlled, dose escalation first-in-man trial.

PubMed

Schwameis, Michael; Roppenser, Bernhard; Firbas, Christa; Gruener, Corina S; Model, Nina; Stich, Norbert; Roetzer, Andreas; Buchtele, Nina; Jilma, Bernd; Eibl, Martha M

2016-09-01

Staphylococcal toxic shock syndrome is a superantigen-driven potentially life-threatening disease affecting mainly young and otherwise healthy individuals. Currently, no specific treatment or preventive measure is available. We aimed to assess the safety, tolerability, and immunogenicity of a recombinant detoxified toxic shock syndrome toxin-1 variant (rTSST-1v) vaccine in adult volunteers. In this randomised, double-blind, adjuvant-controlled, dose-escalation first-in-human trial, healthy adults aged 18-64 years were enrolled from the Medical University of Vienna, Austria. Participants were randomly assigned (2:1 and 3:1) by block randomisation (block sizes of three and 12) to receive increasing doses of rTSST-1v (100 ng to 30 μg) or the adjuvant comparator aluminium hydroxide (Al(OH)3) (200 μg, 600 μg, or 1 mg). Investigators and participants were masked to group allocation. The per-protocol population received a booster immunisation 42 days after the first vaccination. The primary endpoint was safety and tolerability of rTSST-1v. The per-protocol population included all participants who had adhered to the study protocol without any major protocol deviations. The per-protocol population was the primary analysis population for immunogenicity. The trial is registered with EudraCT, number 2013-003716-50, and ClinicalTrials.gov, number NCT02340338. Between Aug 19, 2014, and April 14, 2015, 46 participants were enrolled (safety population), of whom three were assigned to cohort 1 (two to receive 100 ng rTSST-1v and one to receive 200 μg Al(OH)3), three to cohort 2 (two to receive 300 ng rTSST-1v and one to receive 600 μg Al(OH)3), four to cohort 3 (three to receive 1 μg rTSST-1v and one to receive 1 mg Al(OH)3), 12 to cohort 4 (nine to receive 3 μg rTSST-1v and three to receive 1 mg Al(OH)3), 12 to cohort 5 (nine to receive 10 μg rTSST-1v and three to receive 1 mg Al(OH)3), and 12 to cohort 6 (nine to receive 300 μg rTSST-1v and three to receive 1 mg Al(OH)3

Tolerability, Safety, and Benefits of Risperidone in Children and Adolescents with Autism: 21-Month Follow-up After 8-Week Placebo-Controlled Trial

PubMed Central

Rettiganti, Mallikarjuna; Nagaraja, Haikady N.; Hollway, Jill A.; McCracken, James; McDougle, Christopher J.; Tierney, Elaine; Scahill, Lawrence; Arnold, L. Eugene; Hellings, Jessica; Posey, David J.; Swiezy, Naomi B.; Ghuman, Jaswinder; Grados, Marco; Shah, Bhavik; Vitiello, Benedetto

2015-01-01

Abstract Objective: Risperidone has demonstrated efficacy for acute (8 week) and intermediate length (6 month) management of severe irritability and aggression in children and adolescents with autism. Less is known about the long-term effects of risperidone exposure in this population. We examined the tolerability, safety, and therapeutic benefit of risperidone exposure over a 1–2 year follow-up period. Methods: In a naturalistic study, 84 children and adolescents 5–17 years of age (from an original sample of 101) were assessed an average of 21.4 months after initial entry into a placebo-controlled 8 week trial of risperidone for children and adolescents with autism and severe irritability. They were assessed at baseline and at follow-up on safety and tolerability measures (blood, urinalysis, electrocardiogram [ECG], medical history, vital signs, neurological symptoms, other adverse events), developmental measures (adaptive behavior, intelligence quotient [IQ]), and standardized rating instruments. Treatment over the follow-up period, after completion of protocol participation, was uncontrolled. Statistical analyses assessed outcome over time with or without prolonged risperidone therapy. Results: Two-thirds of the 84 subjects continued to receive risperidone (mean 2.47 mg/day, S.D. 1.29 mg). At follow-up, risperidone was associated with more enuresis, more excessive appetite, and more weight gain, but not more adverse neurological effects. No clinically significant events were noted on blood counts, chemistries, urinalysis, ECG, or interim medical history. Regardless of drug condition at follow-up, there was considerable improvement in maladaptive behavior compared with baseline, including core symptoms associated with autism. Height and weight gains were elevated with risperidone. Social skills on Vineland Adaptive Behavior Scale (VABS) improved with risperidone. Parent-rated Aberrant Behavior Checklist (ABC) Irritability subscale scores were reduced in

Evaluation of Vaginal Drug Levels and Safety of a Locally Administered Glycerol Monolaurate Cream in Rhesus Macaques.

PubMed

Kirtane, Ameya R; Rothenberger, Meghan K; Frieberg, Abby; Nephew, Karla; Schultz-Darken, Nancy; Schmidt, Thomas; Reimann, Thomas; Haase, Ashley T; Panyam, Jayanth

2017-07-01

The human immunodeficiency virus epidemic affects millions of people worldwide. As women are more vulnerable to infection, female-controlled interventions can help control the spread of the disease significantly. Glycerol monolaurate (GML), an inexpensive and safe compound, has been shown to protect against simian immunodeficiency virus infection when applied vaginally. However, on account of its low aqueous solubility, fabrication of high-dose formulations of GML has proven difficult. We describe the development of a vaginal cream that could be loaded with up to 35% GML. Vaginal drug levels and safety of 3 formulations containing increasing concentrations of GML (5%w/w, 15%w/w, and 35%w/w) were tested in rhesus macaques after vaginal administration. GML concentration in the vaginal tissue increased as the drug concentration in the cream increased, with 35% GML cream resulting in tissue concentration of ∼0.5 mg/g, albeit with high interindividual variability. Compared with the vehicle control, none of the GML creams had any significant effect on the vaginal flora and cytokine (macrophage inflammatory protein 3α and interleukin 8) levels, suggesting that high-dose GML formulations do not induce local adverse effects. In summary, we describe the development of a highly loaded vaginal cream of GML, and vaginal drug levels and safety after local administration in macaques. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Glovebox and Experiment Safety

NASA Astrophysics Data System (ADS)

Maas, Gerard

2005-12-01

Human spaceflight hardware and operations must comply with NSTS 1700.7. This paper discusses how a glovebox can help.A short layout is given on the process according NSTS/ISS 13830, explaining the responsibility of the payload organization, the approval authority of the PSRP and the defined review phases (0 till III).Amongst others, the following requirement has to be met:"200.1 Design to Tolerate Failures. Failure tolerance is the basic safety requirement that shall be used to control most payload hazards. The payload must tolerate a minimum number of credible failures and/or operator errors determined by the hazard level. This criterion applies when the loss of a function or the inadvertent occurrence of a function results in a hazardous event.200.1a Critical Hazards. Critical hazards shall be controlled such that no single failure or operator error can result in damage to STS/ISS equipment, a nondisabling personnel injury, or the use of unscheduled safing procedures that affect operations of the Orbiter/ISS or another payload.200.1b Catastrophic Hazards. Catastrophic hazards shall be controlled such that no combination of two failures or operator errors can result in the potential for a disabling or fatal personnel injury or loss of the Orbiter/ISS, ground facilities or STS/ISS equipment."For experiments in material science, biological science and life science that require real time operator manipulation, the above requirement may be hard or impossible to meet. Especially if the experiment contains substances that are considered hazardous when released into the habitable environment. In this case operation of the experiment in a glovebox can help to comply.A glovebox provides containment of the experiment and at the same time allows manipulation and visibility to the experiment.The containment inside the glovebox provides failure tolerance because the glovebox uses a negative pressure inside the working volume (WV). The level of failure tolerance is dependent of

TED: A Tolerant Edit Distance for segmentation evaluation.

PubMed

Funke, Jan; Klein, Jonas; Moreno-Noguer, Francesc; Cardona, Albert; Cook, Matthew

2017-02-15

In this paper, we present a novel error measure to compare a computer-generated segmentation of images or volumes against ground truth. This measure, which we call Tolerant Edit Distance (TED), is motivated by two observations that we usually encounter in biomedical image processing: (1) Some errors, like small boundary shifts, are tolerable in practice. Which errors are tolerable is application dependent and should be explicitly expressible in the measure. (2) Non-tolerable errors have to be corrected manually. The effort needed to do so should be reflected by the error measure. Our measure is the minimal weighted sum of split and merge operations to apply to one segmentation such that it resembles another segmentation within specified tolerance bounds. This is in contrast to other commonly used measures like Rand index or variation of information, which integrate small, but tolerable, differences. Additionally, the TED provides intuitive numbers and allows the localization and classification of errors in images or volumes. We demonstrate the applicability of the TED on 3D segmentations of neurons in electron microscopy images where topological correctness is arguable more important than exact boundary locations. Furthermore, we show that the TED is not just limited to evaluation tasks. We use it as the loss function in a max-margin learning framework to find parameters of an automatic neuron segmentation algorithm. We show that training to minimize the TED, i.e., to minimize crucial errors, leads to higher segmentation accuracy compared to other learning methods. Copyright © 2016. Published by Elsevier Inc.

A randomized double-masked study to compare the ocular safety, tolerability, and efficacy of bromfenac 0.075% compared with vehicle in cataract surgery subjects

PubMed Central

Hosseini, Kamran; Walters, Thomas; DaVanzo, Robert; Lindstrom, Richard L

2016-01-01

Purpose The aim of this study was to evaluate the safety, tolerability, and efficacy of a low-dose version of bromfenac 0.075% in DuraSite® (bromfenac 0.075%) compared with DuraSite® vehicle (vehicle) alone for the treatment of postoperative inflammation and ocular pain after cataract surgery. Methods A multicenter, double-masked, vehicle-controlled, parallel-group clinical trial of 240 subjects randomized in a 2:1 ratio to bromfenac 0.075% or vehicle was conducted. Subjects were dosed BID beginning 1 day before the cataract surgery, the day of surgery, and 14 days after surgery. A slit lamp biomicroscopy examination was performed to evaluate the signs of inflammation, including anterior chamber cells (ACC) and anterior chamber flare (ACF). The primary efficacy variable was the proportion of subjects with an ACC grade of 0 at Day 15. Secondary efficacy endpoints included the proportion of subjects who achieved a pain score of 0 at each postsurgical visual analog scale (VAS) assessment and the proportion of subjects with an ACF grade of 0 at Day 15. Results At Day 15, proportionally more subjects in the bromfenac 0.075% group than in the vehicle group had an ACC grade of 0 (57.1% vs 18.8%, respectively; P<0.001). At each of the postsurgical time points (Days 1, 8, 15, and 29), proportionally more bromfenac 0.075%-treated subjects (76.8%, 90.5%, 92.9%, and 85.1%, respectively) had no pain (a VAS score of 0) compared with the vehicle-treated subjects (48.2%, 38.8%, 42.4%, and 47.1%, respectively), and at each time point, these differences in proportions were statistically significant (P<0.001). More subjects in the bromfenac 0.075% group had complete ACF resolution (151/167; 90.4%) compared to those in the vehicle group (54/85; 63.5%). There were no new safety signals reported. Conclusion Bromfenac 0.075% in DuraSite is safe, well tolerated, and effective at reducing inflammation and preventing pain associated with cataract surgery. PMID:27920490

Oxycodone recycling: a novel hypothesis of opioid tolerance development in humans.

PubMed

Linares, Oscar A; Fudin, Jeffrey; Schiesser, William E; Linares, Annemarie Daly; Boston, Raymond C

2014-09-01

We hypothesize that oxycodone (OC) recycling promotes sustained synaptic OC content, which prolongs OC's exposure to local μ-opioid receptors (μORs). In that way, OC recycling gives rise to OC tolerance in humans. To pilot test our hypothesis, we developed a whole-body OC mass transport tolerance recovery model. The model derived quantifiable measure of tolerance is TΩ. TΩ estimates OC's tolerance recovery in days; It is defined as the rate of recovery of OC's pharmacologic response after OC is stopped. We studied a random sample of five opioid intolerant healthy male subjects with no history of opioid or illicit drug use, or comorbidities in silico. Subjects were age 24.5 ± 2.3 yr (all values mean ± SD), weight 93 ± 20 kg, and CYP2D6 EM phenotype. Each subject was studied under two experimental conditions: (1) administration of a single oral dose of OC 12 ± 7 mg; and, after complete washout of OC from the intravascular pool, (2) administration of repetitive oral OC doses every 4h for 5 half-lives (t1/2 = 4.5h)-after which time steady-state was assumed. Repetitive OC dose TΩ fell 61% compared to single OC dose TΩ (5.2 ± 1.1 vs. 3.5 ± 0.7 days, p = 0.001). The fall in TΩ was associated with a significant 3-fold increase in extravascular OC content, which was accompanied by 2-fold increase in OC spillover from the extravascular pool, into the intravascular pool. Thus, the model predicted that a single dose of orally administered OC could give rise to tolerance. This is consistent with the widely held view of acute opioid tolerance. In addition, the dynamic changes accompanying repetitive OC dosing suggested that local unbound OC gave rise to both higher extravascular OC content and increased OC spillover. This reflects that OC stimulated endocytosis of μORs was accompanied by a reduction in the availability OC responsive neuroeffector cell surface μOR binding sites. We conclude that our hypothesis extends current concepts of opioid tolerance

Immune tolerance: a synopsis of the international experience.

PubMed

Di Michele, D M

1998-07-01

Because of the increased morbidity and cost of care associated with inhibitor development, immune tolerance therapy (ITT) is of crucial value in the care of haemophilia. The 24-year experience with this modality, primarily in the treatment of factor VIII inhibitors, has included the use of both high and low doses of clotting factor, with and without immune modulation. Overall success rates for ITT in haemophilia A have been similar (63-83%), while median time to IT has been variable (1.2-24 months). The role of type and purity of clotting factor used remains unclear. Three immune tolerance registries have suggested the potential importance of treatment parameters such as pre-induction inhibitor titer and daily factor dose in the prediction of successful outcome. Ultimately, prospective randomized studies of ITT are required to definitively compare therapeutic regimens with respect to efficacy, safety, and cost effectiveness.

Fault-tolerant Control of a Cyber-physical System

NASA Astrophysics Data System (ADS)

Roxana, Rusu-Both; Eva-Henrietta, Dulf

2017-10-01

Cyber-physical systems represent a new emerging field in automatic control. The fault system is a key component, because modern, large scale processes must meet high standards of performance, reliability and safety. Fault propagation in large scale chemical processes can lead to loss of production, energy, raw materials and even environmental hazard. The present paper develops a multi-agent fault-tolerant control architecture using robust fractional order controllers for a (13C) cryogenic separation column cascade. The JADE (Java Agent DEvelopment Framework) platform was used to implement the multi-agent fault tolerant control system while the operational model of the process was implemented in Matlab/SIMULINK environment. MACSimJX (Multiagent Control Using Simulink with Jade Extension) toolbox was used to link the control system and the process model. In order to verify the performance and to prove the feasibility of the proposed control architecture several fault simulation scenarios were performed.

76 FR 57907 - Tolerances for Residues of New Animal Drugs in Food; Progesterone

Federal Register 2010, 2011, 2012, 2013, 2014

2011-09-19

.... Sheep are considered a minor species for human food safety assessment, and the updated allowable... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration 21 CFR Part 556 [Docket No. FDA-2011-N-0003] Tolerances for Residues of New Animal Drugs in Food; Progesterone AGENCY: Food and...

Safety and tolerability of subcutaneous trastuzumab for the adjuvant treatment of human epidermal growth factor receptor 2-positive early breast cancer: SafeHer phase III study's primary analysis of 2573 patients.

PubMed

Gligorov, J; Ataseven, B; Verrill, M; De Laurentiis, M; Jung, K H; Azim, H A; Al-Sakaff, N; Lauer, S; Shing, M; Pivot, X

2017-09-01

To assess the safety and tolerability of adjuvant subcutaneous trastuzumab (Herceptin ® SC, H SC), delivered from an H SC Vial via hand-held syringe (Cohort A) or single-use injection device (Cohort B), with or without chemotherapy, for human epidermal growth factor receptor 2 (HER2)-positive stage I to IIIC early breast cancer (EBC) in the phase III SafeHer study (NCT01566721). Patients received 600 mg fixed-dose H SC every 3 weeks for 18 cycles. The chemotherapy partner was at the investigators' discretion (H SC monotherapy was limited to ≤10% of the population). Data from the first H SC dose until 28 days (plus a 5-day window) after the last dose are presented. Results are descriptive. In the overall population, 2282/2573 patients (88.7%) experienced adverse events (AEs). Of the above, 128 (5.0%) patients experienced AEs leading to study drug discontinuation; 596 (23.2%) experienced grade ≥ 3 AEs and 326 (12.7%) experienced serious AEs. Grade ≥ 3 cardiac disorders were reported in 24 patients (0.9%), including congestive heart failure in eight (0.3%). As expected, the AE rates varied according to the timing of chemotherapy in both cohorts, with higher rates in concurrent versus sequential chemotherapy subgroups. In the concurrent chemotherapy subgroup, AEs were more common during the actual period of concurrent chemotherapy compared with the period when patients did not receive concurrent chemotherapy. SafeHer confirms the safety and tolerability of the H SC 600 mg fixed dose for 1 year (every 3 weeks for 18 cycles) as adjuvant therapy with concurrent or sequential chemotherapy for HER2-positive EBC. These primary analysis results are consistent with the known safety profile for intravenous H and H SC. Copyright © 2017 Elsevier Ltd. All rights reserved.

Preclinical Pharmacokinetics and First-in-Human Pharmacokinetics, Safety, and Tolerability of Velpatasvir, a Pangenotypic Hepatitis C Virus NS5A Inhibitor, in Healthy Subjects

PubMed Central

German, Polina; Kearney, Brian P.; Yang, Cheng Yong; Brainard, Diana; Link, John; McNally, John; Han, LingLing; Ling, John; Mathias, Anita

2017-01-01

ABSTRACT Preclinical characterization of velpatasvir (VEL; GS-5816), an inhibitor of the hepatitis C virus (HCV) NS5A protein, demonstrated that it has favorable in vitro and in vivo properties, including potent antiviral activity against hepatitis C virus genotype 1 to 6 replicons, good metabolic stability, low systemic clearance, and adequate bioavailability and physicochemical properties, to warrant clinical evaluation. The phase 1 (first-in-human) study evaluated the safety, tolerability, and pharmacokinetics of VEL in healthy human subjects following administration of single and multiple (n = 7) once-daily ascending doses and of VEL in the presence and absence of food. Following administration of single and multiple doses, VEL was safe and well tolerated when administered at up to 450 mg and when administered with food. The pharmacokinetic behavior of VEL observed in humans was generally in agreement with that seen during preclinical characterization. Following administration of multiple doses, VEL trough concentrations were significantly greater than the protein-adjusted half-maximal (50%) effective concentration of VEL against HCV genotype 1 to 6 replicons at all evaluated doses greater than 5 mg. The pharmacokinetics of VEL were not significantly affected by administration with food. Collectively, the results of this study support the further clinical investigation of VEL administered once daily as part of a regimen with other pangenotypic direct-acting antivirals for the treatment of HCV infection. PMID:28193657

Phase I Study of Concomitant Pemetrexed and Cisplatin Plus External Beam Radiation Therapy in Patients with Locally Advanced or Metastatic Esophageal or Gastroesophageal Junction Carcinomas.

PubMed

Elquza, Emad; Babiker, Hani M; Howell, Krisha J; Kovoor, Andrew I; Brown, Thomas David; Patel, Hitendra; Malangone, Steven A; Borad, Mitesh J; Dragovich, Tomislav

2016-01-01

To establish the maximum tolerated dose (MTD) and safety profile of bi-weekly Pemetrexed (PEM) when combined with weekly cisplatin (CDDP) and standard dose external beam radiation (EBRT) in patients with locally advanced or metastatic esophageal and gastroesophageal junction (GEJ) carcinomas. We conducted an open label, single institution, phase I dose escalation study designed to evaluate up to 15-35 patients with advanced or metastatic esophageal and GEJ carcinomas. 10 patients were treated with bi-weekly PEM, weekly CDDP, and EBRT. The MTD of bi-weekly PEM was determined to be 500 mg/m(2).

Efficacy and Safety of Low-Dose-Rate Endorectal Brachytherapy as a Boost to Neoadjuvant Chemoradiation in the Treatment of Locally Advanced Distal Rectal Cancer: A Phase-II Clinical Trial

PubMed Central

Omidvari, Shapour; Zohourinia, Shadi; Ansari, Mansour; Ghahramani, Leila; Zare-Bandamiri, Mohammad; Mosalaei, Ahmad; Ahmadloo, Niloofar; Pourahmad, Saeedeh; Nasrolahi, Hamid; Hamedi, Sayed Hasan

2015-01-01

Purpose Despite advances in rectal cancer treatment over the last decade, local control and risk of late side effects due to external beam radiation therapy (EBRT) remain as concerns. The present study aimed to investigate the efficacy and the safety of low-dose-rate endorectal brachytherapy (LDRBT) as a boost to neoadjuvant chemoradiation for use in treating locally advanced distal rectal adenocarcinomas. Methods This phase-II clinical trial included 34 patients (as the study arm) with newly diagnosed, locally advanced (clinical T3-T4 and/or N1/N2, M0) lower rectal cancer. For comparative analysis, 102 matched patients (as the historical control arm) with rectal cancer were also selected. All the patients were treated with LDRBT (15 Gy in 3 fractions) and concurrent chemoradiation (45-50.4 Gy). Concurrent chemotherapy consisted of oxaliplatin 130 mg/m2 intravenously on day 1 plus oral capecitabine 825 mg/m2 twice daily during LDRBT and EBRT. Results The study results revealed a significant differences between the study arm and the control arm in terms in the pathologic tumor size (2.1 cm vs. 3.6 cm, P = 0.001), the pathologic tumor stage (35% T3-4 vs. 65% T3-4, P = 0.003), and the pathologic complete response (29.4% vs. 11.7%, P < 0.028). Moreover, a significantly higher dose of EBRT (P = 0.041) was found in the control arm, and a longer time to surgery was observed in the study arm (P < 0.001). The higher rate of treatment-related toxicities, such as mild proctitis and anemia, in the study arm was tolerable and easily manageable. Conclusion A boost of LDRBT can optimize the pathologic complete response, with acceptable toxicities, in patients with distal rectal cancer. PMID:26361613

Efficacy and Safety of Low-Dose-Rate Endorectal Brachytherapy as a Boost to Neoadjuvant Chemoradiation in the Treatment of Locally Advanced Distal Rectal Cancer: A Phase-II Clinical Trial.

PubMed

Omidvari, Shapour; Zohourinia, Shadi; Ansari, Mansour; Ghahramani, Leila; Zare-Bandamiri, Mohammad; Mosalaei, Ahmad; Ahmadloo, Niloofar; Pourahmad, Saeedeh; Nasrolahi, Hamid; Hamedi, Sayed Hasan; Mohammadianpanah, Mohammad

2015-08-01

Despite advances in rectal cancer treatment over the last decade, local control and risk of late side effects due to external beam radiation therapy (EBRT) remain as concerns. The present study aimed to investigate the efficacy and the safety of low-dose-rate endorectal brachytherapy (LDRBT) as a boost to neoadjuvant chemoradiation for use in treating locally advanced distal rectal adenocarcinomas. This phase-II clinical trial included 34 patients (as the study arm) with newly diagnosed, locally advanced (clinical T3-T4 and/or N1/N2, M0) lower rectal cancer. For comparative analysis, 102 matched patients (as the historical control arm) with rectal cancer were also selected. All the patients were treated with LDRBT (15 Gy in 3 fractions) and concurrent chemoradiation (45-50.4 Gy). Concurrent chemotherapy consisted of oxaliplatin 130 mg/m(2) intravenously on day 1 plus oral capecitabine 825 mg/m(2) twice daily during LDRBT and EBRT. The study results revealed a significant differences between the study arm and the control arm in terms in the pathologic tumor size (2.1 cm vs. 3.6 cm, P = 0.001), the pathologic tumor stage (35% T3-4 vs. 65% T3-4, P = 0.003), and the pathologic complete response (29.4% vs. 11.7%, P < 0.028). Moreover, a significantly higher dose of EBRT (P = 0.041) was found in the control arm, and a longer time to surgery was observed in the study arm (P < 0.001). The higher rate of treatment-related toxicities, such as mild proctitis and anemia, in the study arm was tolerable and easily manageable. A boost of LDRBT can optimize the pathologic complete response, with acceptable toxicities, in patients with distal rectal cancer.

Efficacy and Safety of Alirocumab Versus Ezetimibe Over 2 Years (from ODYSSEY COMBO II).

PubMed

El Shahawy, Mahfouz; Cannon, Christopher P; Blom, Dirk J; McKenney, James M; Cariou, Bertrand; Lecorps, Guillaume; Pordy, Robert; Chaudhari, Umesh; Colhoun, Helen M

2017-09-15

The proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab has been shown to substantially reduce low-density lipoprotein cholesterol (LDL-C). Demonstrating whether efficacy and safety are maintained over a long duration of exposure is vital for clinical decision-making. The COMBO II trial compared the efficacy and safety of alirocumab versus ezetimibe over 2 years. A prespecified first analysis was reported at 52 weeks. Here we report the final end-of-study data (on-treatment) and evaluate post hoc the safety profile with longer versus shorter duration of alirocumab exposure. Patients (n = 720) on maximally tolerated statin dose were treated with alirocumab (75/150 mg every 2 weeks) or ezetimibe (10 mg/day). Overall mean adherence for both treatment groups during the first and second year was >97%. At 2 years, LDL-C was reduced by 49% (alirocumab) versus 17% (ezetimibe; p <0.0001), and LDL-C <70 mg/dl was achieved by 73% of alirocumab-treated versus 40% of ezetimibe-treated patients. Overall safety was similar in both treatment groups at 2 years and during the first versus the second year. Local injection-site reactions were reported by 2.5% (alirocumab) versus 0.8% (ezetimibe) during the first year, and 0.2% versus 0.5% during the second year, indicating early occurrence during prolonged alirocumab exposure. Two consecutive calculated LDL-C values <25 mg/dl were observed in 28% of alirocumab-treated patients (vs 0.4% with ezetimibe). Persistent anti-drug antibody responses were observed in 1.3% (6 of 454) of alirocumab-treated versus 0.4% (1 of 231) of ezetimibe-treated patients. Neutralizing antibodies (that inhibit binding in vitro) were observed in 1.5% (7 of 454) of alirocumab-treated patients (0 with ezetimibe), mostly at isolated time points. Alirocumab sustained substantial LDL-C reductions and was well tolerated up to 2 years in the COMBO II trial. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Long-Term Tolerability and Safety of Pharmacological Treatment of Adult Attention-Deficit/Hyperactivity Disorder: A 6-Year Prospective Naturalistic Study.

PubMed

Edvinsson, Dan; Ekselius, Lisa

2018-06-20

Attention-deficit/hyperactivity disorder (ADHD) is a behavioral disorder typically treated with stimulants and atomoxetine. Data on long-term tolerability and safety of such pharmacological treatment in subjects diagnosed in adulthood are limited. A cohort of adults diagnosed with ADHD according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria was followed-up on an average of 6 years after first evaluation. Of 168 adults, 112 (67%) who initiated medication were available for follow-up. Data were obtained from patient record data, self-report forms, and a telephone interview. Of the 112 participants assessed, 57 (51%) were still on treatment with methylphenidate (MPH) at follow-up and 55 (49%) had discontinued. The 3 leading reasons for discontinuing treatment with MPH were lack of effect (29%), elevated mood or hypomania (11%), and losing contact with the prescribing physician (9%). The most common adverse effects in subjects still on treatment with MPH were decreased appetite (28%), dry mouth (24%), anxiousness/restlessness and increased pulse frequency (19% each), decreased sexual desire (17%), and perspiration (15%). Subjects still on treatment reported increased quality of life, a higher level of functioning, and a greater understanding of their way of functioning from those being close compared with nonmedicated subjects. The high attrition rate underscores the need for further research to identify possible modes to increase retention to treatment. Those diagnosed with ADHD and on long-term treatment with stimulants experience mild and tolerable adverse effects.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal.

The safety and tolerability of rotigotine transdermal system over a 6-year period in patients with early-stage Parkinson's disease.

PubMed

Giladi, Nir; Boroojerdi, Babak; Surmann, Erwin

2013-09-01

This open-label extension (SP716; NCT00599196) of a 6-month, double-blind, randomized study (SP513) investigated the safety and tolerability of rotigotine transdermal system over up to ~6 years in patients with Parkinson's disease (PD; early-stage PD at double-blind enrollment). Eligible patients completing the 6-month study received optimal dose open-label rotigotine (≤ 16 mg/24 h) for up to ~6 years. Adjunctive levodopa was permitted. Primary outcomes included adverse events (AEs) and extent of rotigotine exposure. Analysis of adjunctive levodopa use, dyskinesias [unified Parkinson's disease rating scale (UPDRS) IV], and efficacy (UPDRS II + III total score) were also assessed. Of 381 patients enrolled in the open-label extension, 52 % were still in the study at time of closure; 24 % withdrew because of AEs and 6 % because of lack of efficacy. Patients received rotigotine for a median duration of 1,564.5 days (~4 years, 3 months; range 5-2, 145 days). 69 % of patients started supplemental levodopa; median time to levodopa was 485 days (~1 year, 4 months). Most common AEs (% per patient-year) were somnolence (18 %), application site reactions (12 %), nausea (9 %), peripheral edema (7 %), and fall (7 %). AEs indicative of impulsive-compulsive behavior were recorded in 25 (7 %) patients. Dyskinesias were experienced by 65 (17 %) patients; the majority [47 of 65 (72 %)] reported first dyskinesia after starting levodopa. Mean UPDRS II + III total scores remained below double-blind baseline for 4 years (assessment of all patients). In conclusion, rotigotine was generally well tolerated for up to ~6 years in patients with early-stage PD. The AEs reported were in line with previous studies of rotigotine transdermal system, with typical dopaminergic side effects and application site reactions seen.

S-adenosyl methionine (SAM) attenuates the development of tolerance to analgesic activity of morphine in rats.

PubMed

Katyal, Jatinder; Kumar, Hemant; Joshi, Dinesh; Gupta, Yogendra Kumar

2017-04-03

Development of tolerance to analgesic effect, on chronic administration of morphine, limits its clinical usefulness in pain management. S-adenosyl methionine (SAM) used for arthritis and approved as a supplement in many countries including United States was evaluated for reducing morphine tolerance. Male 'Wistar' rats were used. The analgesic activity was determined using tail flick analgesiometer (Columbus Instruments, USA). Rats given morphine (7mg/kg), intraperitoneally (i.p.), once daily for 5days developed tolerance to analgesic effect. To evaluate the effect of SAM on morphine tolerance, SAM 800mg/kg was administered orally (p.o.), 45min prior to each dose of morphine. The analgesic activity of SAM and opioidergic component in its activity was also evaluated. Co-administration of morphine and SAM reversed morphine tolerance. SAM exhibited analgesic effect after repeated administration which was reversed by naloxone administration. Since safety of SAM on chronic use is documented it can be a good option in morphine tolerance. Role in drug addiction and withdrawal should also be evaluated. Copyright © 2017 Elsevier B.V. All rights reserved.

Safety of liposuction using exclusively tumescent local anesthesia in 3,240 consecutive cases.

PubMed

Habbema, Louis

2009-11-01

Many surgeons consider liposuction using tumescent local anesthesia (TLA) to be a safe technique, but when TLA has been combined with other techniques, such as general anesthesia or intravenous medication, or when the guidelines associated with TLA have been violated, serious complications and deaths have occurred. This has resulted in uncertainty concerning the safety of liposuction using TLA, which this article seeks to resolve. To investigate whether liposuction using TLA is a safe procedure. The same surgeon performed liposuction using exclusively TLA in 3,240 procedures. Detailed records were kept of the complications that occurred. In a series of 3,240 procedures, no deaths occurred, and no complications requiring hospitalization were experienced. In nine cases, complications developed that needed further action. Liposuction using exclusively TLA is a proven safe procedure provided that the existing guidelines are meticulously followed.

Safety, tolerability and potential efficacy of injection of autologous adipose-derived stromal vascular fraction in the fingers of patients with systemic sclerosis: an open-label phase I trial.

PubMed

Granel, Brigitte; Daumas, Aurélie; Jouve, Elisabeth; Harlé, Jean-Robert; Nguyen, Pierre-Sébastien; Chabannon, Christian; Colavolpe, Nathalie; Reynier, Jean-Charles; Truillet, Romain; Mallet, Stéphanie; Baiada, Antoine; Casanova, Dominique; Giraudo, Laurent; Arnaud, Laurent; Veran, Julie; Sabatier, Florence; Magalon, Guy

2015-12-01

In patients with systemic sclerosis (scleroderma, SSc), impaired hand function greatly contributes to disability and reduced quality of life, and is insufficiently relieved by currently available therapies. Adipose tissue-derived stromal vascular fraction (SVF) is increasingly recognised as an easily accessible source of regenerative cells with therapeutic potential in ischaemic or autoimmune diseases. We aimed to measure for the first time the safety, tolerability and potential efficacy of autologous SVF cells local injections in patients with SSc with hand disability. We did an open-label, single arm, at one study site with 6-month follow-up among 12 female SSc patients with Cochin Hand Function Scale score >20/90. Autologous SVF was obtained from lipoaspirates, using an automated processing system, and subsequently injected into the subcutaneous tissue of each finger in contact with neurovascular pedicles. Primary outcome was the number and the severity of adverse events related to SVF-based therapy. Secondary endpoints were changes in hand disability and fibrosis, vascular manifestations, pain and quality of life from baseline to 2 and 6 months after cell therapy. All enrolled patients had surgery, and there were no dropouts or patients lost to follow-up. No severe adverse events occurred during the procedure and follow-up. Four minor adverse events were reported and resolved spontaneously. A significant improvement in hand disability and pain, Raynaud's phenomenon, finger oedema and quality of life was observed. This study outlines the safety of the autologous SVF cells injection in the hands of patients with SSc. Preliminary assessments at 6 months suggest potential efficacy needing confirmation in a randomised placebo-controlled trial on a larger population. GFRS (Groupe Francophone de Recherche sur la Sclérodermie). NCT01813279. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to

Safety, tolerability, and bioavailability of topical SAR 1118, a novel antagonist of lymphocyte function-associated antigen-1: a phase 1b study.

PubMed

Paskowitz, D M; Nguyen, Q D; Gehlbach, P; Handa, J T; Solomon, S; Stark, W; Shaikh, O; Semba, C; Gadek, T R; Do, D V

2012-07-01

A growing body of evidence points to a role for inflammation mediated by lymphocyte function-associated antigen-1 (LFA-1) and its ligand intercellular adhesion molecule-1 in the pathogenesis of diabetic macular oedema. This phase 1b clinical trial assessed the safety, tolerability, and pharmacokinetics of topically administered SAR 1118, a novel LFA-1 antagonist, in human subjects. In this prospective, randomized, double-masked trial, 13 subjects scheduled for vitrectomy received one of three concentrations of topical SAR 1118 (0.1, 1.0, or 5.0%) twice daily for 1 week before surgery. Undiluted aqueous and vitreous samples were collected at surgery and analysed for the concentration of the medication. All subjects completed the entire course of medication. The only adverse events reported were instillation site irritation (4/13, 31%) and dysgeusia (3/13, 23%). These were mild and transient, occurring at the highest dose. Mean concentrations (ng/ml) of SAR 1118 in the aqueous humour were 0.25, 37.2, and 101.1 for the 0.1%, 1.0%, and 5.0% dose groups, respectively. SAR 1118 was below the level of detection (0.5 ng/ml) for all vitreous samples except in a single subject who had a history of prior vitrectomy and a dislocated intraocular lens. Topical SAR 1118 was safe and well tolerated, and dose-dependent levels of drug were detected in aqueous. However, vitreous levels were below the threshold of detection with the concentrations tested. Further investigation of this medication for posterior segment applications would require intravitreal delivery or chemical modification of the drug.

Noise tolerant spatiotemporal chaos computing.

PubMed

Kia, Behnam; Kia, Sarvenaz; Lindner, John F; Sinha, Sudeshna; Ditto, William L

2014-12-01

We introduce and design a noise tolerant chaos computing system based on a coupled map lattice (CML) and the noise reduction capabilities inherent in coupled dynamical systems. The resulting spatiotemporal chaos computing system is more robust to noise than a single map chaos computing system. In this CML based approach to computing, under the coupled dynamics, the local noise from different nodes of the lattice diffuses across the lattice, and it attenuates each other's effects, resulting in a system with less noise content and a more robust chaos computing architecture.

Noise tolerant spatiotemporal chaos computing

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

Kia, Behnam; Kia, Sarvenaz; Ditto, William L.

We introduce and design a noise tolerant chaos computing system based on a coupled map lattice (CML) and the noise reduction capabilities inherent in coupled dynamical systems. The resulting spatiotemporal chaos computing system is more robust to noise than a single map chaos computing system. In this CML based approach to computing, under the coupled dynamics, the local noise from different nodes of the lattice diffuses across the lattice, and it attenuates each other's effects, resulting in a system with less noise content and a more robust chaos computing architecture.

Comprehensive safety document/product.

DOT National Transportation Integrated Search

2013-06-01

With 100 counties and more than 800 cities, towns, and township governments in North Carolina, there is a tremendous need to : disseminate road safety information at the local level. For safety gains to be made in NC communities there needs to be bot...

Gastrointestinal safety and tolerance of ibuprofen at maximum over-the-counter dose.

PubMed

Doyle, G; Furey, S; Berlin, R; Cooper, S; Jayawardena, S; Ashraf, E; Baird, L

1999-07-01

Delineation of non-steroidal anti-inflammatory drug (NSAID) gastrointestinal toxicity has largely depended on retrospective epidemiologic studies which demonstrate that lower doses of NSAIDs pose a lower risk of gastrointestinal toxicity. Ibuprofen, a propionic acid NSAID, has, in most such studies, exhibited a favourable profile in terms of gastrointestinal bleeding. Since 1984, ibuprofen has been available as a non-prescription analgesic/antipyretic with a limit of 1200 mg/day for 10 days of continuous use. Trials and spontaneously reported adverse experiences suggest that gastrointestinal symptoms and bleeding are rare. This study prospectively evaluated the gastrointestinal tolerability, as compared to placebo, of the maximum non-prescription dose and duration of ibuprofen use in healthy subjects representative of a non-prescription analgesic user population. Gastrointestinal adverse experiences were similar in the placebo and ibuprofen groups (67 out of 413, 16% with placebo vs. 161 out of 833, 19% with ibuprofen). There was no difference between the two groups in the proportion discontinuing due to a gastrointestinal event. Gastrointestinal adverse experiences reported by >/= 1% of subjects were: dyspepsia, abdominal pain, nausea, diarrhoea, flatulence, and constipation. Seventeen (1.4%) subjects had positive occult blood tests: their frequency was comparable between treatments. When used as directed to treat episodic pain, non-prescription ibuprofen at the maximum dose of 1200 mg/day for 10 days, is well-tolerated.

Lubiprostone, a locally acting chloride channel activator, in adult patients with chronic constipation: a double-blind, placebo-controlled, dose-ranging study to evaluate efficacy and safety.

PubMed

Johanson, J F; Ueno, R

2007-06-01

Lubiprostone, a locally acting type-2 chloride channel activator, induces intestinal fluid secretion. To assess efficacy and safety of oral lubiprostone at multiple doses for the treatment of chronic constipation. A total of 129 patients with chronic constipation were randomized to receive lubiprostone (24, 48 or 72 mcg/day) or placebo for 3 weeks. Spontaneous bowel movement (SBM) frequency, rescue medication use, symptom assessments and adverse events (AEs) were tracked. Over the double-blinded period, mean SBM frequencies were higher for lubiprostone groups (5.1-6.1) vs. placebo (3.8) and the overall difference was statistically significant (P = 0.046). SBM frequencies at week 1 were significantly higher in patients taking lubiprostone 48 or 72 mcg/day (P < or = 0.003) and, at week 2, all three lubiprostone doses yielded significantly higher SBM rates vs. placebo (P < or = 0.020). Significantly larger proportions of patients taking lubiprostone 48 and 72 mcg/day also experienced a SBM on the first treatment day (P < or = 0.009). The most common AEs were nausea, headache and diarrhoea. Lubiprostone improved SBM rates in a dose-dependent manner. AEs were tolerable for most patients. Increased AE severity at 72 mcg/day did not provide a clear risk-to-benefit advantage compared with lubiprostone 48 mcg/day, the dose chosen for subsequent Phase 3 studies.

Bioinformatics approach of salt tolerance gene in mangrove plant Rhizophora stylosa

NASA Astrophysics Data System (ADS)

Basyuni, M.; Sumardi

2017-01-01

This study descibes bioinformatics approach on the analyze of the salt tolerance genes in mangrove plant, Rhizophora stylosa on DDBJ/EMBL/GenBank as well as similarity, phylogenetic, potential peptide, and subcellular localization. The DNA sequence between salt tolerance gene from R. stylosa exhibited 42-11% between themselves The target peptide value of mitochondria varied from 0.163 to 0.430, indicated it was possible to exist. These results suggested the importance of understanding the diversity and functional of properties of the different amino acids in mangrove OSC genes. To clarify the relationship among the salt-tolerant genes in R. stylosa, a phylogenetic tree was constructed. The phylogenetic tree shows that there are three clusters, first branch of Cu/Zn SOD and reverse transcriptase genes, the second branch consists of the majority genes and the last group was MAP3K alpha protein kinase only. The present study, therefore, suggested that salt tolerance genes form distinct clusters in the tree.

Non-Clinical Safety Evaluation of Intranasal Iota-Carrageenan

PubMed Central

Hebar, Alexandra; Koller, Christiane; Seifert, Jan-Marcus; Chabicovsky, Monika; Bodenteich, Angelika; Bernkop-Schnürch, Andreas; Grassauer, Andreas; Prieschl-Grassauer, Eva

2015-01-01