Phase I dose-escalation study to examine the safety and tolerability of LY2603618, a checkpoint 1 kinase inhibitor, administered 1 day after pemetrexed 500 mg/m2 every 21 days in patients with cancer

PubMed Central

Iyengar, Tara; Ramanathan, Ramesh K.; Lewandowski, Karen; Anthony, Stephen P.; Donehower, Ross C.; Westin, Eric; Hurt, Karla; Hynes, Scott M.; McKane, Scott

2013-01-01

Summary Purpose This phase I study aims at assessing the safety and tolerability of LY2603618, a selective inhibitor of Checkpoint Kinase 1, in combination with pemetrexed and determining the maximum tolerable dose and the pharmacokinetic parameters. Experimental design This was an open-label, multicenter, dose-escalation study in patients with advanced solid tumors. Increasing doses of LY2603618 (40–195 mg/m2) were combined with 500 mg/m2 of pemetrexed. LY2603618 was administered on Days 1 and 9 and pemetrexed on Day 8 in a 28-day cycle. For all subsequent 21-day cycles, pemetrexed was administered on Day 1 and LY2603618 on Day 2. Anti-tumor activity was evaluated as per Response Evaluation Criteria in Solid Tumors 1.0. Results A total of 31 patients were enrolled into six cohorts (three at 40 mg/m2 over 4.5-hour infusion, 1-hour infusion in subsequent cohorts: three each at 40 mg/m2, 70 mg/m2, and 195 mg/m2; 13 at 105 mg/m2; six at 150 mg/m2). Four patients experienced a dose-limiting toxicity: diarrhea (105 mg/m2); reversible infusion-related reaction (150 mg/m2); thrombocytopenia (195 mg/m2); and fatigue (195 mg/m2). The maximum tolerated dose was defined as 150 mg/m2. The pharmacokinetic data demonstrated that the exposure of LY2603618 increased in a dose-dependent manner, displayed a suitable half-life for maintaining required human exposures while minimizing the intra- and inter-cycle accumulation, and was unaffected by the pemetrexed administration. The pharmacokinetic-defined biologically efficacious dose was achieved at doses ≥105 mg/m2. Conclusion LY2603618 administered approximately 24 h after pemetrexed showed acceptable safety and pharmacokinetic profiles. PMID:22492020

Phase I dose-escalation study to examine the safety and tolerability of LY2603618, a checkpoint 1 kinase inhibitor, administered 1 day after pemetrexed 500 mg/m(2) every 21 days in patients with cancer.

PubMed

Weiss, Glen J; Donehower, Ross C; Iyengar, Tara; Ramanathan, Ramesh K; Lewandowski, Karen; Westin, Eric; Hurt, Karla; Hynes, Scott M; Anthony, Stephen P; McKane, Scott

2013-02-01

This phase I study aims at assessing the safety and tolerability of LY2603618, a selective inhibitor of Checkpoint Kinase 1, in combination with pemetrexed and determining the maximum tolerable dose and the pharmacokinetic parameters. This was an open-label, multicenter, dose-escalation study in patients with advanced solid tumors. Increasing doses of LY2603618 (40-195 mg/m(2)) were combined with 500 mg/m(2) of pemetrexed. LY2603618 was administered on Days 1 and 9 and pemetrexed on Day 8 in a 28-day cycle. For all subsequent 21-day cycles, pemetrexed was administered on Day 1 and LY2603618 on Day 2. Antitumor activity was evaluated as per Response Evaluation Criteria in Solid Tumors 1.0. A total of 31 patients were enrolled into six cohorts (three at 40 mg/m(2) over 4.5-hour infusion, 1-hour infusion in subsequent cohorts: three each at 40 mg/m(2), 70 mg/m(2), and 195 mg/m(2); 13 at 105 mg/m(2); six at 150 mg/m(2)). Four patients experienced a dose-limiting toxicity: diarrhea (105 mg/m(2)); reversible infusion-related reaction (150 mg/m(2)); thrombocytopenia (195 mg/m(2)); and fatigue (195 mg/m(2)). The maximum tolerated dose was defined as 150 mg/m(2). The pharmacokinetic data demonstrated that the exposure of LY2603618 increased in a dose-dependent manner, displayed a suitable half-life for maintaining required human exposures while minimizing the intra- and inter-cycle accumulation, and was unaffected by the pemetrexed administration. The pharmacokinetic-defined biologically efficacious dose was achieved at doses ≥105 mg/m(2). LY2603618 administered approximately 24 h after pemetrexed showed acceptable safety and pharmacokinetic profiles.

Safety, efficacy and pharmacokinetics of neratinib (HKI-272) in Japanese patients with advanced solid tumors: a Phase 1 dose-escalation study.

PubMed

Ito, Yoshinori; Suenaga, Mitsukuni; Hatake, Kiyohiko; Takahashi, Shunji; Yokoyama, Masahiro; Onozawa, Yusuke; Yamazaki, Kentaro; Hironaka, Shuichi; Hashigami, Kiyoshi; Hasegawa, Hirotaka; Takenaka, Nobuko; Boku, Narikazu

2012-04-01

Neratinib (HKI-272), a potent, irreversible, small-molecule, orally administered, pan-ErbB inhibitor that blocks signal transduction via inhibition of three epidermal growth factor receptors [ErbB1, ErbB2 (Her2) and ErbB4], is being developed for the treatment of solid tumors, including breast cancer. This Phase 1 dose-escalation study assessed the safety, tolerability, maximum-tolerated dose, antitumor activity and pharmacokinetics of neratinib in Japanese patients with advanced solid tumors. Patients received neratinib 80, 160, 240 or 320 mg orally; each patient enrolled in only one dose cohort. Patients received a single dose in week 1, followed by daily continuous doses. Blood samples collected were on days 1 and 21 for pharmacokinetic analyses. Twenty-one patients were enrolled (3 breast cancer; 17 colorectal cancer; 1 gastric cancer). Neratinib-related adverse events (all grades) included diarrhea (20 patients), fatigue (14 patients), nausea and abdominal pain (9 patients each) and anorexia (8 patients). Grade ≥3 neratinib-related adverse events in two or more patients were diarrhea and anorexia (two patients each). Dose-limiting toxicities were diarrhea and anorexia (two patients, 320 mg dose). The maximum-tolerated dose and recommended dose was neratinib 240 mg once daily. Of 21 evaluable patients, 2 with breast cancer had partial response, 3 had stable disease ≥24 weeks, 7 had stable disease ≥16 weeks and 9 had progressive disease. Pharmacokinetic analyses indicated that neratinib exposures increased with dose. The safety, efficacy and pharmacokinetic profiles of neratinib are consistent with those reported for non-Japanese patients and warrant further investigation of neratinib in Japanese patients with solid tumors.

On the monitoring and implications of growing damages caused by manufacturing defects in composite structures

NASA Astrophysics Data System (ADS)

Schagerl, M.; Viechtbauer, C.; Hörrmann, S.

2015-07-01

Damage tolerance is a classical safety concept for the design of aircraft structures. Basically, this approach considers possible damages in the structure, predicts the damage growth under applied loading conditions and predicts the following decrease of the structural strength. As a fundamental result the damage tolerance approach yields the maximum inspection interval, which is the time a damage grows from a detectable to a critical level. The above formulation of the damage tolerance safety concept targets on metallic structures where the damage is typically a simple fatigue crack. Fiber-reinforced polymers show a much more complex damage behavior, such as delaminationsin laminated composites. Moreover, progressive damage in composites is often initiated by manufacturing defects. The complex manufacturing processes for composite structures almost certainly yield parts with defects, e.g. pores in the matrix or undulations of fibers. From such defects growing damages may start after a certain time of operation. The demand to simplify or even avoid the inspection of composite structures has therefore led to a comeback of the traditional safe-life safety concept. The aim of the so-called safe-life flaw tolerance concept is a structure that is capable of carrying the static loads during operation, despite significant damages and after a representative fatigue load spectrum. A structure with this property does not need to be inspected, respectively monitored at all during its service life. However, its load carrying capability is thereby not fully utilized. This article presents the possible refinement of the state-of-the-art safe-life flaw tolerance concept for composite structures towards a damage tolerance approach considering also the influence of manufacturing defects on damage initiation and growth. Based on fundamental physical relations and experimental observations the challenges when developing damage growth and residual strength curves are discussed.

Phase I/II study of sorafenib in combination with temsirolimus for recurrent glioblastoma or gliosarcoma: North American Brain Tumor Consortium study 05-02

PubMed Central

Lee, Eudocia Q.; Kuhn, John; Lamborn, Kathleen R.; Abrey, Lauren; DeAngelis, Lisa M.; Lieberman, Frank; Robins, H. Ian; Chang, Susan M.; Yung, W. K. Alfred; Drappatz, Jan; Mehta, Minesh P.; Levin, Victor A.; Aldape, Kenneth; Dancey, Janet E.; Wright, John J.; Prados, Michael D.; Cloughesy, Timothy F.; Gilbert, Mark R.; Wen, Patrick Y.

2012-01-01

The activity of single-agent targeted molecular therapies in glioblastoma has been limited to date. The North American Brain Tumor Consortium examined the safety, pharmacokinetics, and efficacy of combination therapy with sorafenib, a small molecule inhibitor of Raf, vascular endothelial growth factor receptor 2, and platelet-derived growth factor receptor–β, and temsirolimus (CCI-779), an inhibitor of mammalian target of rapamycin. This was a phase I/II study. The phase I component used a standard 3 × 3 dose escalation scheme to determine the safety and tolerability of this combination therapy. The phase II component used a 2-stage design; the primary endpoint was 6-month progression-free survival (PFS6) rate. Thirteen patients enrolled in the phase I component. The maximum tolerated dosage (MTD) for combination therapy was sorafenib 800 mg daily and temsirolimus 25 mg once weekly. At the MTD, grade 3 thrombocytopenia was the dose-limiting toxicity. Eighteen patients were treated in the phase II component. At interim analysis, the study was terminated and did not proceed to the second stage. No patients remained progression free at 6 months. Median PFS was 8 weeks. The toxicity of this combination therapy resulted in a maximum tolerated dose of temsirolimus that was only one-tenth of the single-agent dose. Minimal activity in recurrent glioblastoma multiforme was seen at the MTD of the 2 combined agents. PMID:23099651

Heavy metals in aromatic spices by inductively coupled plasma-mass spectrometry.

PubMed

Bua, Daniel Giuseppe; Annuario, Giovanni; Albergamo, Ambrogina; Cicero, Nicola; Dugo, Giacomo

2016-09-01

Objective of this study was to determine the content of Cd, Hg, As and Pb in common spices traded in the Italian market, using inductively coupled plasma-mass spectrometry (ICP-MS). The results were compared with the maximum limits established by the national Legislative Decree (LD) no. 107 implementing the Council Directive 88/388/EEC and by international organisations, such as Food and Agriculture Organization (FAO) and World Health Organization (WHO). Food safety for spices was assessed considering the tolerable weekly intake (TWI) and the provisional tolerable weekly intake (PTWI), respectively, for Cd and Hg and the 95% lower confidence limit of the benchmark dose of 1% extra risk (BMDL01) for As and Pb. Investigated elements in all samples were within the maximum limits as set by the national and international normative institutions. Nevertheless, the heavy metal content of some spices exceeded the PTWI, TWI and BMDL01, which needs attention when considering consumer's health.

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.

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.

Safety and Pharmacokinetics of Multiple 750-Milligram Doses of Intravenous Levofloxacin in Healthy Volunteers

PubMed Central

Chow, Andrew T.; Fowler, Cynthia; Williams, R. Rex; Morgan, Nancy; Kaminski, Susan; Natarajan, Jaya

2001-01-01

The safety and pharmacokinetics of a once-daily high intravenous dose of levofloxacin (750 mg) in 18 healthy volunteers were studied in a double-blind, randomized, placebo-controlled, single-center parallel group study. Levofloxacin was well tolerated, and higher maximum concentration of drug in serum and area under the concentration-time curve values were achieved. For difficult-to-treat infections, high daily doses of levofloxacin may be beneficial, and intravenous administration may be preferred in certain clinical settings, such as when treating patients in intensive care units, warranting further evaluation. PMID:11408234

Safety and pharmacokinetics of multiple 750-milligram doses of intravenous levofloxacin in healthy volunteers.

PubMed

Chow, A T; Fowler, C; Williams, R R; Morgan, N; Kaminski, S; Natarajan, J

2001-07-01

The safety and pharmacokinetics of a once-daily high intravenous dose of levofloxacin (750 mg) in 18 healthy volunteers were studied in a double-blind, randomized, placebo-controlled, single-center parallel group study. Levofloxacin was well tolerated, and higher maximum concentration of drug in serum and area under the concentration-time curve values were achieved. For difficult-to-treat infections, high daily doses of levofloxacin may be beneficial, and intravenous administration may be preferred in certain clinical settings, such as when treating patients in intensive care units, warranting further evaluation.

Intravenous Single-Dose Toxicity of Redaporfin-Based Photodynamic Therapy in Rodents

PubMed Central

Rocha, Luis B.; Schaberle, Fábio; Dąbrowski, Janusz M.; Simões, Sérgio; Arnaut, Luis G.

2015-01-01

We assessed the tolerability and safety in rodents of a single intravenous (i.v.) dose of redaporfin, a novel photosensitizer for Photodynamic Therapy (PDT) of cancer. Two approaches were used to evaluate acute toxicity: (i) a dose escalation study in BALB/c mice to evaluate the maximum tolerated dose of redaporfin; and (ii) a safety toxicology study in Wistar rats, of a single dose of redaporfin, with or without illumination, to evaluate possible signs of systemic toxicity. Redaporfin formulation was well tolerated by mice, with no signs of adverse reactions up to 75 mg/kg. In rats, there were no relevant changes, except for a significant, but transient, increase in the blood serum markers for hepatic function and muscle integrity, and also on neutrophil counts, observed after the application of light. The overall results showed that redaporfin-PDT is very well tolerated. No abnormalities were observed, including reactions at the injection site or skin phototoxicity, although the animals were maintained in normal indoor lighting. Redaporfin also showed a high efficacy in the treatment of male BALB/c mice with subcutaneously implanted colon (CT26) tumours. Vascular-PDT with 1.5 mg/kg redaporfin and a light dose of 74 J/cm2 led to the complete tumour regression in 83% of the mice. PMID:26670231

Open-label, dose-titration tolerability study of atomoxetine hydrochloride in Korean, Chinese, and Taiwanese adults with attention-deficit/hyperactivity disorder.

PubMed

Takahashi, Michihiro; Goto, Taro; Takita, Yasushi; Chung, Sang-Keun; Wang, Yufeng; Gau, Susan Shur-Fen

2014-03-01

The primary objective of this study was to assess the overall safety and tolerability of atomoxetine in Korean, Chinese, and Taiwanese adults with attention-deficit/hyperactivity disorder (ADHD). A total of 44 patients aged ≥18 years who met the Conners' Adult ADHD Diagnostic Interview for DSM-IV diagnostic criteria for ADHD were enrolled from China, Korea, and Taiwan. In this open-label, dose-escalation study, patients received atomoxetine orally once daily over a period of eight weeks, starting at 40 mg/day (one week) up to a maximum dosage of 120 mg/day. Tolerability was evaluated by rate of discontinuation due to adverse events. Safety was assessed by recording all adverse events, laboratory tests, vital signs, and electrocardiograms. ADHD symptoms were evaluated by the Conners' Adult ADHD Rating Scale-Investigator Rated: Screening Version (CAARS-Inv:SV) for efficacy assessment. Thirty-four patients (77.3%) completed the study. Atomoxetine was well tolerated with a discontinuation rate of 2.3% (1/44) due to adverse events. The most commonly reported adverse events were nausea, dizziness, and somnolence. The mean change from baseline to endpoint in CAARS-Inv:SV total ADHD symptom score was -12.5 (P < 0.001). A significant reduction in the CAARS-Inv:SV subscales (inattentive, hyperactive/impulsive, and ADHD index score, P < 0.001) was observed. This is the first atomoxetine clinical trial in adult patients with ADHD in China, Korea, and Taiwan. Atomoxetine was well tolerated in doses of up to 120 mg/day with no unknown safety concerns. Copyright © 2012 Blackwell Publishing Asia Pty Ltd.

Phase I study of afatinib combined with nintedanib in patients with advanced solid tumours.

PubMed

Bahleda, Rastislav; Hollebecque, Antoine; Varga, Andrea; Gazzah, Anas; Massard, Christophe; Deutsch, Eric; Amellal, Nadia; Farace, Françoise; Ould-Kaci, Mahmoud; Roux, Flavien; Marzin, Kristell; Soria, Jean-Charles

2015-11-17

This Phase I study evaluated continuous- and intermittent-dosing (every other week) of afatinib plus nintedanib in patients with advanced solid tumours. In the dose-escalation phase (n=45), maximum tolerated doses (MTDs) were determined for continuous/intermittent afatinib 10, 20, 30 or 40 mg once daily plus continuous nintedanib 150 or 200 mg twice daily. Secondary objectives included safety and efficacy. Clinical activity of continuous afatinib plus nintedanib at the MTD was further evaluated in an expansion phase (n=25). The most frequent dose-limiting toxicities were diarrhoea (11%) and transaminase elevations (7%). Maximum tolerated doses were afatinib 30 mg continuously plus nintedanib 150 mg, and afatinib 40 mg intermittently plus nintedanib 150 mg. Treatment-related adverse events (mostly Grade⩽3) included diarrhoea (98%), asthenia (64%), nausea (62%) and vomiting (60%). In the dose-escalation phase, two patients had partial responses (PRs) and 27 (60%) had stable disease (SD). In the expansion phase, one complete response and three PRs were observed (all non-small cell lung cancer), with SD in 13 (52%) patients. No pharmacokinetic interactions were observed. MTDs of continuous or intermittent afatinib plus nintedanib demonstrated a manageable safety profile with proactive management of diarrhoea. Antitumour activity was observed in patients with solid tumours.

Safety and efficacy of caffeine-augmented ECT in elderly depressives: a retrospective study.

PubMed

Kelsey, M C; Grossberg, G T

1995-07-01

Prior studies have shown that in younger depressives undergoing ECT whose seizure durations declined despite maximum settings on three different ECT devices, pretreatment with caffeine lengthened seizures and resulted in clinical improvement. Caffeine (half life, 140-270 minutes) was well tolerated even in patients with pre-existing cardiovascular disease. The purpose of this retrospective study was to determine the safety and efficacy of caffeine augmented ECT in elderly depressed patients. The charts of 14 elderly depressives (average age 75.6, range 59-83; 2 males, 12 females) who received caffeine-augmented ECT were reviewed. Patients pre- and post-ECT medications, blood pressure, pulse, and seizure times (cuff and EEG) for each ECT performed were noted. The following conclusions were drawn from our study: (1) Caffeine definitely increases the seizure length and was useful in our setting when the energy settings could not be increased anymore. (2) Caffeine augmentation inconsistently causes an increase in pulse rate, on average, in the elderly. (3) Caffeine inconsistently produces an increase in mean arterial pressure. (4) Caffeine did not consistently produce an increase in the maximum rate-pressure product. We conclude from this study that caffeine-augmented ECT is safe and effective in increasing seizure duration in the elderly. However, more research needs to be done to determine optimal dosing and tolerability.

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.

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

PubMed

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

2015-09-01

Hypomethylating agents are used to treat cancers driven by aberrant DNA methylation, but their short half-life might limit their activity, particularly in patients with less proliferative diseases. Guadecitabine (SGI-110) is a novel hypomethylating dinucleotide of decitabine and deoxyguanosine resistant to degradation by cytidine deaminase. We aimed to assess the safety and clinical activity of subcutaneously given guadecitabine in patients with acute myeloid leukaemia or myelodysplastic syndrome. In this multicentre, open-label, phase 1 study, patients from nine North American medical centres with myelodysplastic syndrome or acute myeloid leukaemia that was refractory to or had relapsed after standard treatment were randomly assigned (1:1) to receive subcutaneous guadecitabine, either once-daily for 5 consecutive days (daily × 5), or once-weekly for 3 weeks, in a 28-day treatment cycle. Patients were stratified by disease. A 3 + 3 dose-escalation design was used in which we treated patients with guadecitabine doses of 3-125 mg/m(2) in separate dose-escalation cohorts. A twice-weekly treatment schedule was added to the study after a protocol amendment. The primary objective was to assess safety and tolerability of guadecitabine, determine the maximum tolerated and biologically effective dose, and identify the recommended phase 2 dose of guadecitabine. Safety analyses included all patients who received at least one dose of guadecitabine. Pharmacokinetic and pharmacodynamic analyses to determine the biologically effective dose included all patients for whom samples were available. This study is registered with ClinicalTrials.gov, number NCT01261312. Between Jan 4, 2011, and April 11, 2014, we enrolled and treated 93 patients: 35 patients with acute myeloid leukaemia and nine patients with myelodysplastic syndrome in the daily × 5 dose-escalation cohorts, 28 patients with acute myeloid leukaemia and six patients with myelodysplastic syndrome in the once-weekly dose-escalation cohorts, and 11 patients with acute myeloid leukaemia and four patients with myelodysplastic syndrome in the twice-weekly dose-escalation cohorts. The most common grade 3 or higher adverse events were febrile neutropenia (38 [41%] of 93 patients), pneumonia (27 [29%] of 93 patients), thrombocytopenia (23 [25%] of 93 patients), anaemia (23 [25%] of 93 patients), and sepsis (16 [17%] of 93 patients). The most common serious adverse events were febrile neutropenia (29 [31%] of 93 patients), pneumonia (26 [28%] of 93 patients), and sepsis (16 [17%] of 93 patients). Six of the 74 patients with acute myeloid leukaemia and six of the 19 patients with myelodysplastic syndrome had a clinical response to treatment. Two dose-limiting toxicities were noted in patients with myelodysplastic syndrome at 125 mg/m(2) daily × 5, thus the maximum tolerated dose in patients with myelodysplastic syndrome was 90 mg/m(2) daily × 5. The maximum tolerated dose was not reached in patients with acute myeloid leukaemia. Potent dose-related DNA demethylation occurred on the daily × 5 regimen, reaching a plateau at 60 mg/m(2) (designated as the biologically effective dose). Guadecitabine given subcutaneously at 60 mg/m(2) daily × 5 is well tolerated and is clinically and biologically active in patients with myelodysplastic syndrome and acute myeloid leukaemia. Guadecitabine 60 mg/m(2) daily × 5 is the recommended phase 2 dose, and these findings warrant further phase 2 studies. Astex Pharmaceuticals, Stand Up To Cancer. Copyright © 2015 Elsevier Ltd. All rights reserved.

Pharmacokinetics and safety of single doses of drisapersen in non-ambulant subjects with Duchenne muscular dystrophy: Results of a double-blind randomized clinical trial

PubMed Central

Flanigan, Kevin M.; Voit, Thomas; Rosales, Xiomara Q.; Servais, Laurent; Kraus, John E.; Wardell, Claire; Morgan, Allison; Dorricott, Susie; Nakielny, Joanna; Quarcoo, Naashika; Liefaard, Lia; Drury, Tom; Campion, Giles; Wright, Padraig

2014-01-01

Duchenne muscular dystrophy (DMD) is a progressive, lethal neuromuscular disorder caused by the absence of dystrophin protein due to mutations of the dystrophin gene. Drisapersen is a 2′-O-methyl-phosphorothioate oligonucleotide designed to skip exon 51 in dystrophin pre-mRNA to restore the reading frame of the mRNA. This study assessed safety, tolerability, and pharmacokinetics of drisapersen after a single subcutaneous administration in non-ambulatory subjects. Eligible subjects were non-ambulant boys aged ≥9 years, in wheelchairs for ≥1 to ≤4 years, with a diagnosis of DMD resulting from a mutation correctable by drisapersen treatment. Four dose cohorts were planned (3, 6, 9 and 12 mg/kg), but study objectives were met with the 9 mg/kg dose. Less than proportional increase in exposure was demonstrated over the 3–9 mg/kg dose range, though post hoc analysis showed dose proportionality was more feasible over the 3–6 mg/kg range. Single doses of drisapersen at 3 and 6 mg/kg did not result in significant safety or tolerability concerns; however, at the 9 mg/kg dose, pyrexia and transient elevations in inflammatory parameters were seen. The maximum tolerated dose of 6 mg/kg drisapersen was identified for further characterization in multiple dose studies in the non-ambulant DMD population. PMID:24321374

Phase I Trial and Pharmacokinetic Study of Lexatumumab in Pediatric Patients With Solid Tumors

PubMed Central

Merchant, Melinda S.; Geller, James I.; Baird, Kristin; Chou, Alexander J.; Galli, Susana; Charles, Ava; Amaoko, Martha; Rhee, Eunice H.; Price, Anita; Wexler, Leonard H.; Meyers, Paul A.; Widemann, Brigitte C.; Tsokos, Maria; Mackall, Crystal L.

2012-01-01

Purpose Lexatumumab is an agonistic, fully human monoclonal antibody against tumor necrosis factor–related apoptosis-inducing ligand receptor 2 with preclinical evidence of activity in pediatric solid tumors. Patients and Methods This phase I dose-escalation study examined the safety, tolerability, pharmacokinetics, and immunogenicity of lexatumumab at doses up to, but not exceeding, the adult maximum-tolerated dose (3, 5, 8, and 10 mg/kg), administered once every 2 weeks to patients age ≤ 21 years with recurrent or progressive solid tumors. Results Twenty-four patients received a total of 56 cycles of lexatumumab over all four planned dose levels. One patient had grade 2 pericarditis consistent with radiation recall, and one patient developed grade 3 pneumonia with hypoxia during the second cycle. Five patients experienced stable disease for three to 24 cycles. No patients experienced complete or partial response, but several showed evidence of antitumor activity, including one patient with recurrent progressive osteosarcoma who experienced resolution of clinical symptoms and positron emission tomography activity, ongoing more than 1 year off therapy. One patient with hepatoblastoma showed a dramatic biomarker response. Conclusion Pediatric patients tolerate 10 mg/kg of lexatumumab administered once every 14 days, the maximum-tolerated dose identified in adults. The drug seems to mediate some clinical activity in pediatric solid tumors and may work with radiation to enhance antitumor effects. PMID:23071222

A safety vs efficiency trade-off identified in the hydraulic pathway of grass leaves is decoupled from photosynthesis, stomatal conductance and precipitation.

PubMed

Ocheltree, Troy W; Nippert, Jesse B; Prasad, P V Vara

2016-04-01

A common theme in plant physiological research is the trade-off between stress tolerance and growth; an example of this trade-off at the tissue level is the safety vs efficiency hypothesis, which suggests that plants with the greatest resistance to hydraulic failure should have low maximum hydraulic conductance. Here, we quantified the leaf-level drought tolerance of nine C4 grasses as the leaf water potential at which plants lost 50% (P50 × RR ) of maximum leaf hydraulic conductance (Ksat ), and compared this trait with other leaf-level and whole-plant functions. We found a clear trade-off between Ksat and P50 × RR when Ksat was normalized by leaf area and mass (P = 0.05 and 0.01, respectively). However, no trade-off existed between P50 × RR and gas-exchange rates; rather, there was a positive relationship between P50 × RR and photosynthesis (P = 0.08). P50 × RR was not correlated with species distributions based on precipitation (P = 0.70), but was correlated with temperature during the wettest quarter of the year (P < 0.01). These results suggest a trade-off between safety and efficiency in the hydraulic system of grass leaves, which can be decoupled from other leaf-level functions. The unique physiology of C4 plants and adaptations to pulse-driven systems may provide mechanisms that could decouple hydraulic conductance from other plant functions. © 2015 The Authors. New Phytologist © 2015 New Phytologist Trust.

High lenticular tolerance to ultraviolet radiation-B by pigmented guinea-pig; application of a safety limit strategy for UVR-induced cataract.

PubMed

Mody, Vino C; Kakar, Manoj; Söderberg, Per G; Löfgren, Stefan

2012-05-01

The purpose of this study was to determine a threshold measure, maximum tolerable dose (MTD), for avoidance of UVR-B-induced cataract in the pigmented guinea-pig. Thirty pupil-dilated anesthetized young female guinea-pigs, divided into five equal groups, received between 0 and 84.9 kJ/m(2) unilateral UVR-B. Lens extraction and in vitro lens photography occurred 24 hr after exposure. Measurement of intensity of lens light scattering served as quantifying tool for the degree of cataract. Data analysis included regression, using a second order polynomial model. The applied MTD concept was based on the UVR-B dose-response curve obtained for the pigmented guinea-pig. A smaller number of pigmented guinea-pigs, pigmented rats and albino rats underwent morphometric analysis of the anterior segment geometry. All eyes exposed to UVR-B developed cataract in the anterior subcapsular region. MTD for avoidance of UVR-B-induced cataract was 69.0 kJ/m(2) in the pigmented guinea-pig. Iris was considerably thicker in the guinea-pig than in the rats. Lens blockage by the dilated iris was lowest in the guinea-pig. Maximum tolerable dose for avoidance of UVR-B-induced cataract in the pigmented guinea-pig was 69.0 kJ/m(2), over 10-fold higher than the threshold 5 kJ/m(2) obtained by Pitts et al. in the pigmented rabbit. Maximum tolerable dose is an appropriate method for estimation of toxicity for UVR-B-induced cataract in the guinea-pig. The pigmented guinea-pig is significantly less sensitive to UVR-B exposure than the pigmented rabbit and pigmented rat. © 2010 The Authors. Journal compilation © 2010 Acta Ophthalmol.

Pupillography as a sensitive, noninvasive biomarker in healthy volunteers: first-in-man study of BAY 63-9044, a new 5-HT1A-receptor agonist with dopamine agonistic properties.

PubMed

Wensing, Georg; Haase, Claus; Brendel, Erich; Böttcher, Michael Friedrich

2007-12-01

BAY 63-9044 is a new full 5-HT(1A)-agonist with functional dopamine agonist properties aimed for the treatment of Parkinson's disease. This first-in-man study investigated the pharmacodynamics, safety and tolerability as well as the pharmacokinetics of BAY 63-9044 in a randomized, single-blind, placebo-controlled group-comparison dose escalation study. 45 healthy men received BAY 63-9044 as an oral solution in single doses of 0.25 mg, 0.5 mg, 1.2 mg, 2.5 mg and 5.0 mg. Pupil reaction (baseline pupil diameter (DIAM), constriction amplitude (CA)), body temperature, electroencephalography (EEG) and prolactin, cortisol and adrenocorticotrophic hormone (ACTH) served as pharmacodynamic measures and were monitored up to 24 h after drug intake. Safety, tolerability and plasma samples for determination of BAY 63-9044 were followed up to 72 h. Up to a dose of 2.5 mg, BAY 63-9044 was safe and well tolerated. Dose-limiting adverse events (nausea, vomiting, and dizziness) occurred in 5 out of 6 volunteers at the 5 mg dose. Adverse events resolved spontaneously in all but one volunteers who was treated with an antihistaminergic for vomiting. Dose-dependent changes of DIAM and CA were observed at doses higher than 0.5 mg and 1.2 mg, respectively. Body temperature showed a trend for reduction starting at C(max) in the highest two doses only. No clear effect was found on prolactin, cortisol and ACTH levels. The pharmacokinetics of BAY 63-9044 showed a dose-dependent increase with maximum plasma concentrations reached within 1 h. Plasma concentrations declined in a bi-phased manner with an apparent terminal half-life of 5.2-8.1 h. Up to the maximum tolerated dose (MTD) of 2.5 mg BAY 63-9044 was safe and well tolerated and showed predictable linear pharmacokinetics. Pupil reaction may serve as a non-invasive biomarker for pharmacodynamic effects of 5-HT(1A)-compounds with DIAM being the most sensitive parameter.

A two-dimensional biased coin design for dual-agent dose-finding trials.

PubMed

Sun, Zhichao; Braun, Thomas M

2015-12-01

Given the limited efficacy observed with single agents, there is growing interest in Phase I clinical trial designs that allow for identification of the maximum tolerated combination of two agents. Existing parametric designs may suffer from over- or under-parameterization. Thus, we have designed a nonparametric approach that can be easily understood and implemented for combination trials. We propose a two-stage adaptive biased coin design that extends existing methods for single-agent trials to dual-agent dose-finding trials. The basic idea of our design is to divide the entire trial into two stages and apply the biased coin design, with modification, in each stage. We compare the operating characteristics of our design to four competing parametric approaches via simulation in several numerical examples. Under all simulation scenarios we have examined, our method performs well in terms of identification of the maximum tolerated combination and allocation of patients relative to the performance of its competitors. In our design, stopping rule criteria and the distribution of the total sample size among the two stages are context-dependent, and both need careful consideration before adopting our design in practice. Efficacy is not a part of the dose-assignment algorithm, nor used to define the maximum tolerated combination. Our design inherits the favorable statistical properties of the biased coin design, is competitive with existing designs, and promotes patient safety by limiting patient exposure to toxic combinations whenever possible. © The Author(s) 2015.

Phase I study of afatinib combined with nintedanib in patients with advanced solid tumours

PubMed Central

Bahleda, Rastislav; Hollebecque, Antoine; Varga, Andrea; Gazzah, Anas; Massard, Christophe; Deutsch, Eric; Amellal, Nadia; Farace, Françoise; Ould-Kaci, Mahmoud; Roux, Flavien; Marzin, Kristell; Soria, Jean-Charles

2015-01-01

Background: This Phase I study evaluated continuous- and intermittent-dosing (every other week) of afatinib plus nintedanib in patients with advanced solid tumours. Methods: In the dose-escalation phase (n=45), maximum tolerated doses (MTDs) were determined for continuous/intermittent afatinib 10, 20, 30 or 40 mg once daily plus continuous nintedanib 150 or 200 mg twice daily. Secondary objectives included safety and efficacy. Clinical activity of continuous afatinib plus nintedanib at the MTD was further evaluated in an expansion phase (n=25). Results: The most frequent dose-limiting toxicities were diarrhoea (11%) and transaminase elevations (7%). Maximum tolerated doses were afatinib 30 mg continuously plus nintedanib 150 mg, and afatinib 40 mg intermittently plus nintedanib 150 mg. Treatment-related adverse events (mostly Grade ⩽3) included diarrhoea (98%), asthenia (64%), nausea (62%) and vomiting (60%). In the dose-escalation phase, two patients had partial responses (PRs) and 27 (60%) had stable disease (SD). In the expansion phase, one complete response and three PRs were observed (all non-small cell lung cancer), with SD in 13 (52%) patients. No pharmacokinetic interactions were observed. Conclusions: MTDs of continuous or intermittent afatinib plus nintedanib demonstrated a manageable safety profile with proactive management of diarrhoea. Antitumour activity was observed in patients with solid tumours. PMID:26512876

Safety and maximum tolerated dose of superselective intraarterial cerebral infusion of bevacizumab after osmotic blood-brain barrier disruption for recurrent malignant glioma. Clinical article.

PubMed

Boockvar, John A; Tsiouris, Apostolos J; Hofstetter, Christoph P; Kovanlikaya, Ilhami; Fralin, Sherese; Kesavabhotla, Kartik; Seedial, Stephen M; Pannullo, Susan C; Schwartz, Theodore H; Stieg, Philip; Zimmerman, Robert D; Knopman, Jared; Scheff, Ronald J; Christos, Paul; Vallabhajosula, Shankar; Riina, Howard A

2011-03-01

The authors assessed the safety and maximum tolerated dose of superselective intraarterial cerebral infusion (SIACI) of bevacizumab after osmotic disruption of the blood-brain barrier (BBB) with mannitol in patients with recurrent malignant glioma. A total of 30 patients with recurrent malignant glioma were included in the current study. The authors report no dose-limiting toxicity from a single dose of SIACI of bevacizumab up to 15 mg/kg after osmotic BBB disruption with mannitol. Two groups of patients were studied; those without prior bevacizumab exposure (naïve patients; Group I) and those who had received previous intravenous bevacizumab (exposed patients; Group II). Radiographic changes demonstrated on MR imaging were assessed at 1 month postprocedure. In Group I patients, MR imaging at 1 month showed a median reduction in the area of tumor enhancement of 34.7%, a median reduction in the volume of tumor enhancement of 46.9%, a median MR perfusion (MRP) reduction of 32.14%, and a T2-weighted/FLAIR signal decrease in 9 (47.4%) of 19 patients. In Group II patients, MR imaging at 1 month showed a median reduction in the area of tumor enhancement of 15.2%, a median volume reduction of 8.3%, a median MRP reduction of 25.5%, and a T2-weighted FLAIR decrease in 0 (0%) of 11 patients. The authors conclude that SIACI of mannitol followed by bevacizumab (up to 15 mg/kg) for recurrent malignant glioma is safe and well tolerated. Magnetic resonance imaging shows that SIACI treatment with bevacizumab can lead to reduction in tumor area, volume, perfusion, and T2-weighted/FLAIR signal.

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

PubMed

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

2012-02-01

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

A phase I dose-escalation study of selumetinib in combination with docetaxel or dacarbazine in patients with advanced solid tumors.

PubMed

LoRusso, Patricia M; Infante, Jeffrey R; Kim, Kevin B; Burris, Howard A; Curt, Gregory; Emeribe, Ugochi; Clemett, Delyth; Tomkinson, Helen K; Cohen, Roger B

2017-03-06

The RAS/RAF/MEK/ERK pathway is constitutively activated in many cancers. Selumetinib (AZD6244, ARRY-142886) is an oral, potent and highly selective, allosteric MEK1/2 inhibitor with a short half-life that has shown clinical activity as monotherapy in phase I and II studies of advanced cancer. Preclinical data suggest that selumetinib may enhance the activity of chemotherapeutic agents. We assessed the safety, tolerability, and pharmacokinetics (PK) of selumetinib (AZD6244, ARRY-142886) in combination with docetaxel or dacarbazine in patients with advanced solid tumors. This study was a phase I, open-label, multicenter study in patients aged ≥18 years with advanced solid tumors who were candidates for docetaxel or dacarbazine treatment. Part A of the study (dose escalation) evaluated safety, tolerability, PK, and maximum tolerated dose (MTD) of selumetinib twice daily (BID) with docetaxel 75 mg/m 2 or dacarbazine 1000 mg/m 2 administered every 21 days. Patients receiving docetaxel could be administered primary prophylactic granulocyte-colony stimulating factor according to standard guidelines. Part B of the study (dose expansion) further evaluated safety, tolerability, and PK in 12 additional patients at the MTD combinations determined in part A. A total of 35 patients received selumetinib plus docetaxel, and 25 received selumetinib plus dacarbazine. The MTD of selumetinib was 75 mg BID in combination with either docetaxel (two dose-limiting toxicity [DLT] events: neutropenia with fever, and thrombocytopenia) or dacarbazine (one DLT event: thrombocytopenia). Common adverse events occurring with each treatment combination were diarrhea, peripheral/periorbital edema, fatigue, and nausea. PK parameters for selumetinib and docetaxel or dacarbazine were similar when administered alone or in combination. Partial responses were reported in 6/35 patients receiving selumetinib plus docetaxel and 4/25 patients receiving selumetinib plus dacarbazine. The combinations of selumetinib plus docetaxel and selumetinib plus dacarbazine demonstrated manageable safety and tolerability profiles and preliminary signs of clinical activity in patients with advanced solid tumors. ClinicalTrials.gov NCT00600496; registered 8 July 2009.

An open-label, dose-titration tolerability study of atomoxetine hydrochloride in Japanese adults with attention-deficit/hyperactivity disorder.

PubMed

Takahashi, Michihiro; Takita, Yasushi; Goto, Taro; Ichikawa, Hironobu; Saito, Kazuhiko; Matsumoto, Hideo; Tanaka, Yasuo

2011-02-01

The main purpose of this first atomoxetine study in Japanese adults with attention-deficit/hyperactivity disorder (ADHD) was to investigate the tolerability of an 8-week treatment regimen. This was an open-label, dose escalation study conducted in 45 Japanese patients aged at least 18 years with DSM-IV-defined ADHD. Patients received atomoxetine orally for 8 weeks. Atomoxetine administration was started at 40 mg/day (7 days), and subsequently increased to a maximum dose of 120 mg/day. Tolerability was assessed by discontinuation rate due to adverse events. Adverse events, laboratory tests, vital signs and electrocardiograms were collected. In addition, ADHD symptoms were assessed by using the Japanese version of the Conners' Adult ADHD Rating Scale-Investigator Rated: Screening Version (CAARS-Inv:SV) scores. Thirty-nine patients completed the study period. Atomoxetine was well tolerated with a 6.7% (3/45) discontinuation rate due to nausea, malaise and anorexia. The most commonly reported adverse events were nausea, nasopharyngitis and headache; there were no unexpected safety concerns. No deaths or serious adverse events were reported. Mean CAARS-Inv:SV-J total ADHD symptom scores decreased in a time-dependent manner; the mean change from baseline to endpoint was -15.0 (P<0.001). This study showed that atomoxetine was well tolerated in these patients and suggested that atomoxetine at a maximum dose of 120 mg/day would be safe in Japanese ADHD patients. © 2011 The Authors. Psychiatry and Clinical Neurosciences © 2011 Japanese Society of Psychiatry and Neurology.

A randomized, controlled phase I/II study to evaluate the safety and efficacy of MGV354 for ocular hypertension or glaucoma.

PubMed

Stacy, Rebecca; Huttner, Kenneth; Watts, Jen; Peace, James; Wirta, David; Walters, Tom; Sall, Kenneth; Seaman, John; Ni, Xiao; Prasanna, Ganesh; Mogi, Muneto; Adams, Christopher; Yan, Jing-He; Wald, Michael; He, Yunsheng; Newton, Ronald; Kolega, Randall; Grosskreutz, Cynthia

2018-05-23

To assess the clinical safety, tolerability, and efficacy of topically administered MGV354, a soluble guanylate cyclase (sGC) activator, in patients with ocular hypertension (OH) or glaucoma DESIGN: Double-masked, randomized, and vehicle-controlled study METHODS: Parts 1 and 2 evaluated safety and tolerability to identify the maximum tolerated dose (MTD) of once daily MGV354 in 32 healthy volunteers (Part 1) and 16 patients with OH or glaucoma (Part 2) at a single clinical site. Part 3 was a multi-site trial that evaluated IOP-lowering efficacy of the MTD administered nightly for one week in 50 patients with minimum IOP of 24mm Hg at 8 AM, with a main outcome measure of mean diurnal IOP at Day 8 compared to baseline (ClinicalTrials.gov NCT02743780). There was no difference in favor of MGV354 for IOP lowering; change from Baseline to Day 8 in mean diurnal IOP was -0.6 mmHg for MGV354-treated patients and -1.1 mmHg for Vehicle-treated patients in Part 3, with a confidence interval of -0.7 to 1.7. The most common adverse events reported after MGV354 administration were conjunctival and ocular hyperemia. Overall, MGV354 0.1% demonstrated no statistically significant effect compared to Vehicle in lowering IOP based upon the study's main outcome measure. MGV354 produced ocular hyperemia consistent with its pharmacology. Copyright © 2018 Elsevier Inc. All rights reserved.

Sodium phenylbutyrate in Huntington's disease: a dose-finding study.

PubMed

Hogarth, Penelope; Lovrecic, Luca; Krainc, Dimitri

2007-10-15

Transcriptional dysregulation in Huntington's disease (HD) is mediated in part by aberrant patterns of histone acetylation. We performed a dose-finding study in human HD of sodium phenylbutyrate (SPB), a histone deacetylase inhibitor that ameliorates the HD phenotype in animal models. We used a dose-escalation/de-escalation design, using prespecified toxicity criteria and standard clinical and laboratory safety measures. The maximum tolerated dose was 15 g/day. At higher doses, toxicity included vomiting, lightheadedness, confusion, and gait instability. We saw no significant laboratory or electrocardiographic abnormalities. Gene expression changes in blood suggested an inverse dose-response. In conclusion, SPB at 12 to 15 g/day appears to be safe and well-tolerated in human HD. 2007 Movement Disorder Society

7 CFR 993.602 - Maximum tolerances.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 8 2010-01-01 2010-01-01 false Maximum tolerances. 993.602 Section 993.602 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing... CALIFORNIA Grade Regulations § 993.602 Maximum tolerances. In lieu of the provision prescribed in I C of...

Riociguat in patients with chronic thromboembolic pulmonary hypertension: results from an early access study.

PubMed

McLaughlin, Vallerie V; Jansa, Pavel; Nielsen-Kudsk, Jens E; Halank, Michael; Simonneau, Gérald; Grünig, Ekkehard; Ulrich, Silvia; Rosenkranz, Stephan; Gómez Sánchez, Miguel A; Pulido, Tomás; Pepke-Zaba, Joanna; Barberá, Joan Albert; Hoeper, Marius M; Vachiéry, Jean-Luc; Lang, Irene; Carvalho, Francine; Meier, Christian; Mueller, Katharina; Nikkho, Sylvia; D'Armini, Andrea M

2017-12-28

Following positive results from the Phase III CHEST-1 study in patients with inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH), the Phase IIIb CTEPH early access study (EAS) was designed to assess the safety and tolerability of riociguat in real-world clinical practice, as well as to provide patients with early access to riociguat before launch. Riociguat is approved for the treatment of inoperable and persistent/recurrent CTEPH. We performed an open-label, uncontrolled, single-arm, early access study in which 300 adult patients with inoperable or persistent/recurrent CTEPH received riociguat adjusted from 1 mg three times daily (tid) to a maximum of 2.5 mg tid. Patients switching from unsatisfactory prior pulmonary arterial hypertension (PAH)-targeted therapy (n = 84) underwent a washout period of at least 3 days before initiating riociguat. The primary aim was to assess the safety and tolerability of riociguat, with World Health Organization functional class and 6-min walking distance (6MWD) as exploratory efficacy endpoints. In total, 262 patients (87%) completed study treatment and entered the safety follow-up (median treatment duration 47 weeks). Adverse events were reported in 273 patients (91%). The most frequently reported serious adverse events were syncope (6%), right ventricular failure (3%), and pneumonia (2%). There were five deaths, none of which was considered related to study medication. The safety and tolerability of riociguat was similar in patients switched from other PAH-targeted therapies and those who were treatment naïve. In patients with data available, mean ± standard deviation 6MWD had increased by 33 ± 42 m at Week 12 with no clinically relevant differences between the switched and treatment-naïve subgroups. Riociguat was well tolerated in patients with CTEPH who were treatment naïve, and in those who were switched from other PAH-targeted therapies. No new safety signals were observed. ClinicalTrials.org NCT01784562 . Registered February 4, 2013.

Safety of Accelerated Schedules of Subcutaneous Allergen Immunotherapy with House Dust Mite Extract in Patients with Atopic Dermatitis

PubMed Central

Kim, Myoung-Eun; Kim, Jeong-Eun; Sung, Joon-Mo; Lee, Jin-Woo; Choi, Gil-Soon

2011-01-01

The safety of accelerated schedules of allergen immunotherapy (ASAI) in patients with bronchial asthma (BA) has been reported but there are little data on the safety of ASAI for patients with atopic dermatitis (AD). In this study, we investigated the safety of ASAI in patients with AD. Sixty patients with AD and 18 patients with BA sensitized to house dust mites (HDM) were studied. A maximum maintenance dose of HDM extract, adsorbed to aluminum hydroxide, was administered to patients by subcutaneous injection with either a 3-day protocol (rush immunotherapy) or 1-day protocol (ultra-rush immunotherapy). Systemic reactions were observed 4 of 15 patients (26.7%) with AD during rush immunotherapy, 13 of 45 patients (28.9%) with AD during ultra-rush immunotherapy, and 4 of 18 patients (22.2%) with BA during rush immunotherapy (P > 0.05). No severe or near fatal systemic reactions occurred in 78 subjects of this study. Systemic reactions developed within 4 hr after administration of the maximum allergen dose in 20 of 21 patients (95.2%) with AD and BA who showed systemic reactions during rush or ultra-rush immunotherapy. In conclusion, ASAI was safe and well tolerated in patients with AD. ASAI can be a useful therapeutic option for AD. PMID:21935270

TOOTH (The Open study Of dental pulp stem cell Therapy in Humans): Study protocol for evaluating safety and feasibility of autologous human adult dental pulp stem cell therapy in patients with chronic disability after stroke.

PubMed

Nagpal, Anjali; Kremer, Karlea L; Hamilton-Bruce, Monica A; Kaidonis, Xenia; Milton, Austin G; Levi, Christopher; Shi, Songtao; Carey, Leeanne; Hillier, Susan; Rose, Miranda; Zacest, Andrew; Takhar, Parabjit; Koblar, Simon A

2016-07-01

Stroke represents a significant global disease burden. As of 2015, there is no chemical or biological therapy proven to actively enhance neurological recovery during the chronic phase post-stroke. Globally, cell-based therapy in stroke is at the stage of clinical translation and may improve neurological function through various mechanisms such as neural replacement, neuroprotection, angiogenesis, immuno-modulation, and neuroplasticity. Preclinical evidence in a rodent model of middle cerebral artery ischemic stroke as reported in four independent studies indicates improvement in neurobehavioral function with adult human dental pulp stem cell therapy. Human adult dental pulp stem cells present an exciting potential therapeutic option for improving post-stroke disability. TOOTH (The Open study Of dental pulp stem cell Therapy in Humans) will investigate the use of autologous stem cell therapy for stroke survivors with chronic disability, with the following objectives: (a) determine the maximum tolerable dose of autologous dental pulp stem cell therapy; (b) define that dental pulp stem cell therapy at the maximum tolerable dose is safe and feasible in chronic stroke; and (c) estimate the parameters of efficacy required to design a future Phase 2/3 clinical trial. TOOTH is a Phase 1, open-label, single-blinded clinical trial with a pragmatic design that comprises three stages: Stage 1 will involve the selection of 27 participants with middle cerebral artery ischemic stroke and the commencement of autologous dental pulp stem cell isolation, growth, and testing in sequential cohorts (n = 3). Stage 2 will involve the transplantation of dental pulp stem cell in each cohort of participants with an ascending dose and subsequent observation for a 6-month period for any dental pulp stem cell-related adverse events. Stage 3 will investigate the neurosurgical intervention of the maximum tolerable dose of autologous dental pulp stem cell followed by 9 weeks of intensive task-specific rehabilitation. Advanced magnetic resonance and positron emission tomography neuro-imaging, and clinical assessment will be employed to probe any change afforded by stem cell therapy in combination with rehabilitation. Nine participants will step-wise progress in Stage 2 to a dose of up to 10 million dental pulp stem cell, employing a cumulative 3 + 3 statistical design with low starting stem cell dose and subsequent dose escalation, assuming that an acceptable probability of dose-limiting complications is between 1 in 6 (17%) and 1 in 3 (33%) of patients. In Stage 3, another 18 participants will receive an intracranial injection with the maximum tolerable dose of dental pulp stem cell. The primary outcomes to be measured are safety and feasibility of intracranial administration of autologous human adult DPSC in patients with chronic stroke and determination of the maximum tolerable dose in human subjects. Secondary outcomes include estimation of the measures of effectiveness required to design a future Phase 2/3 clinical trial. © 2016 World Stroke Organization.

Hydraulics and life history of tropical dry forest tree species: coordination of species' drought and shade tolerance.

PubMed

Markesteijn, Lars; Poorter, Lourens; Bongers, Frans; Paz, Horacio; Sack, Lawren

2011-07-01

Plant hydraulic architecture has been studied extensively, yet we know little about how hydraulic properties relate to species' life history strategies, such as drought and shade tolerance. The prevailing theories seem contradictory. We measured the sapwood (K(s) ) and leaf (K(l) ) hydraulic conductivities of 40 coexisting tree species in a Bolivian dry forest, and examined associations with functional stem and leaf traits and indices of species' drought (dry-season leaf water potential) and shade (juvenile crown exposure) tolerance. Hydraulic properties varied across species and between life-history groups (pioneers vs shade-tolerant, and deciduous vs evergreen species). In addition to the expected negative correlation of K(l) with drought tolerance, we found a strong, negative correlation between K(l) and species' shade tolerance. Across species, K(s) and K(l) were negatively correlated with wood density and positively with maximum vessel length. Consequently, drought and shade tolerance scaled similarly with hydraulic properties, wood density and leaf dry matter content. We found that deciduous species also had traits conferring efficient water transport relative to evergreen species. Hydraulic properties varied across species, corresponding to the classical trade-off between hydraulic efficiency and safety, which for these dry forest trees resulted in coordinated drought and shade tolerance across species rather than the frequently hypothesized trade-off. © 2011 The Authors. New Phytologist © 2011 New Phytologist Trust.

A First-Time-In-Human Phase I Clinical Trial of Bispecific Antibody-Targeted, Paclitaxel-Packaged Bacterial Minicells

PubMed Central

Rosenthal, Mark; McArthur, Grant A.; Pattison, Scott T.; Pattison, Stacey L.; MacDiarmid, Jennifer; Brahmbhatt, Himanshu; Scott, Andrew M.

2015-01-01

Background We have harnessed a novel biological system, the bacterial minicell, to deliver cancer therapeutics to cancer cells. Preclinical studies showed that epidermal growth factor receptor (EGFR)-targeted, paclitaxel-loaded minicells (EGFRminicellsPac) have antitumor effects in xenograft models. To examine the safety of the minicell delivery system, we initiated a first-time-in-human, open-label, phase I clinical study of EGFRminicellsPac in patients with advanced solid tumors. Methodology Patients received 5 weekly infusions followed by a treatment free week. Seven dose levels (1x108, 1x109, 3x109, 1x1010, 1.5x1010, 2x1010, 5x1010) were evaluated using a 3+3 dose-escalation design. Primary objectives were safety, tolerability and determination of the maximum tolerated dose. Secondary objectives were assessment of immune/inflammatory responses and antitumor activity. Principal Findings Twenty eight patients were enrolled, 22 patients completed at least one cycle of EGFRminicellsPac; 6 patients did not complete a cycle due to rapidly progressive disease. A total of 236 doses was delivered over 42 cycles, with a maximum of 45 doses administered to a single patient. Most common treatment-related adverse events were rigors and pyrexia. No deaths resulted from treatment-related adverse events and the maximum tolerated dose was defined as 1x1010 EGFRminicellsPac. Surprisingly, only a mild self-limiting elevation in the inflammatory cytokines IL-6, IL-8 and TNFα and anti-inflammatory IL-10 was observed. Anti-LPS antibody titers peaked by dose 3 and were maintained at that level despite repeat dosing with the bacterially derived minicells. Ten patients (45%; n = 22) achieved stable disease as their best response. Conclusions/Significance This is the first study in humans of a novel biological system that can provide targeted delivery of a range of chemotherapeutic drugs to solid tumor cells. Bispecific antibody-targeted minicells, packaged with the chemotherapeutic paclitaxel, were shown to be safe in patients with advanced solid tumors with modest clinical efficacy observed. Further study in Phase II trials is planned. Trial Registration Australian New Zealand Clinical Trials Registry ACTRN12609000672257 PMID:26659127

Recommended energy and nutrients intakes in the European Union: 2008-2016

PubMed

García Gabarra, Antoni; Castellà Soley, Marta; Calleja Fernández, Alicia

2017-03-30

The aim of this document is to refl ect the changes happened in the European Union legislation and the opinions of the European Food Safety Authority in relation to the nutritional labeling on food, the reference values for energy, macronutrients and micronutrients, and the tolerable upper safe levels. The European legislation in force uses the labeling reference values established by the Scientific Committee on Food in 2003. There would be advisable an update of them from the reference values for vitamins and minerals established by the European Food Safety Authority. Equally, there would be good to include reference labeling values for polyunsaturated fatty acids, dietary fiber and choline, and specific reference labeling values for children from 6 to 36 months. For vitamins and minerals there would be desirable the revision of tolerable upper safe levels and the establishment of maximum amounts allowed in fortified food and food supplements in the European Union; its absence might represent a risk in some population groups for an excessive and unsafe intake of certain minerals and vitamins.

The tolerance efficiency of Panicum maximum and Helianthus annuus in TNT-contaminated soil and nZVI-contaminated soil.

PubMed

Jiamjitrpanich, Waraporn; Parkpian, Preeda; Polprasert, Chongrak; Laurent, François; Kosanlavit, Rachain

2012-01-01

This study was designed to compare the initial method for phytoremediation involving germination and transplantation. The study was also to determine the tolerance efficiency of Panicum maximum (Purple guinea grass) and Helianthus annuus (Sunflower) in TNT-contaminated soil and nZVI-contaminated soil. It was found that the transplantation of Panicum maximum and Helianthus annuus was more suitable than germination as the initiate method of nano-phytoremediation potting test. The study also showed that Panicum maximum was more tolerance than Helianthus annuus in TNT and nZVI-contaminated soil. Therefore, Panicum maximum in the transplantation method should be selected as a hyperaccumulated plant for nano-phytoremediation potting tests. Maximum tolerance dosage of Panicum maximum to TNT-concentration soil was 320 mg/kg and nZVI-contaminated soil was 1000 mg/kg in the transplantation method.

Safety and tolerability of veliparib combined with capecitabine plus radiotherapy in patients with locally advanced rectal cancer: a phase 1b study.

PubMed

Czito, Brian G; Deming, Dustin A; Jameson, Gayle S; Mulcahy, Mary F; Vaghefi, Houman; Dudley, Matthew W; Holen, Kyle D; DeLuca, Angela; Mittapalli, Rajendar K; Munasinghe, Wijith; He, Lei; Zalcberg, John R; Ngan, Samuel Y; Komarnitsky, Philip; Michael, Michael

2017-06-01

Further optimisation of present standard chemoradiation is needed in patients with locally advanced rectal cancer. Veliparib, an oral poly(ADP-ribose) polymerase inhibitor, has been shown to enhance the antitumour activity of chemotherapy and radiotherapy in preclinical models. We aimed to establish the maximum tolerated dose and establish the recommended phase 2 dose of veliparib combined with neoadjuvant capecitabine and radiotherapy. This phase 1b, open-label, multicentre, dose-escalation study was done at six hospitals (one in Australia and five in the USA). Patients were eligible if they were aged 18 years or more and were newly diagnosed with stage II to III locally advanced, resectable adenocarcinoma of the rectum with a distal tumour border of less than 12 cm from anal verge. Patients were ineligible if they had received anticancer therapy or surgery (except colostomy or ileostomy) 28 days or less before the first dose of study drug, previous pelvic radiotherapy, or previous treatment with poly (ADP-ribose) polymerase inhibitors. Enrolled patients received capecitabine (825 mg/m 2 orally twice daily) with radiotherapy (50·4 Gy in 1·8 Gy fractions daily, approximately 5 days consecutively per week for about 5·5 weeks). Veliparib (20-400 mg orally twice daily) was administered daily starting on day 2 of week 1 and continuing until 2 days after radiotherapy completion. Patients underwent total mesorectal excision 5-10 weeks after radiotherapy completion. The primary objectives were to establish the maximum tolerated dose and recommended phase 2 dose of veliparib plus capecitabine and radiotherapy, with an exposure-adjusted continual reassessment methodology. Efficacy and safety analyses were done per protocol. The reported study has completed accrual and all analyses are final. This trial is registered with ClinicalTrials.gov, number NCT01589419. Between June 12, 2012, and Jan 13, 2015, 32 patients received veliparib (22 in the dose-escalation group; ten in the safety expansion group); 31 were assessable for efficacy (<400 mg, n=16; 400 mg, n=15). During dose escalation, grade 2 dose-limiting toxic effects occurred in two patients; no grade 3-4 dose-limiting toxic effects were noted. Therefore, the maximum tolerated dose was not reached; the recommended phase 2 dose was selected as 400 mg twice daily. The most common treatment-emergent adverse events in all 32 patients were nausea (17 [53%]), diarrhoea (16 [50%]), and fatigue (16 [50%]). Grade 3 diarrhoea was noted in three (9%) of 32 patients; no grade 4 events were reported. Veliparib pharmacokinetics were dose proportional, with no effect on capecitabine pharmacokinetics. Tumour downstaging after surgery was noted in 22 (71%) of 31 patients; nine (29%) of 31 patients achieved a pathological complete response. Veliparib plus capecitabine and radiotherapy had an acceptable safety profile and showed a dose-proportional pharmacokinetic profile with no effect on the pharmacokinetics of capecitabine. Preliminary antitumour activity warrants further evaluation. AbbVie Inc. Copyright © 2017 Elsevier Ltd. All rights reserved.

Safety and pharmacokinetics of nintedanib and pirfenidone in idiopathic pulmonary fibrosis.

PubMed

Ogura, Takashi; Taniguchi, Hiroyuki; Azuma, Arata; Inoue, Yoshikazu; Kondoh, Yasuhiro; Hasegawa, Yoshinori; Bando, Masashi; Abe, Shinji; Mochizuki, Yoshiro; Chida, Kingo; Klüglich, Matthias; Fujimoto, Tsuyoshi; Okazaki, Kotaro; Tadayasu, Yusuke; Sakamoto, Wataru; Sugiyama, Yukihiko

2015-05-01

A randomised, double-blind, phase II, dose escalation trial was conducted to assess the safety, tolerability and pharmacokinetics of the tyrosine kinase inhibitor nintedanib, alone and when added to ongoing pirfenidone therapy, in Japanese patients with idiopathic pulmonary fibrosis. 50 Japanese patients were randomised to receive nintedanib or placebo in one of three cohorts (nintedanib 50 mg twice daily or 100 mg twice daily for 14 days, or 150 mg twice daily for 28 days). Patients receiving pirfenidone at inclusion were stratified to every nintedanib dose group and placebo. Adverse events were reported in nine out of 17 patients receiving nintedanib alone and 10 out of 21 patients receiving nintedanib added to pirfenidone. All adverse events were mild or moderate in intensity. Gastrointestinal disorders were the most common adverse event. Maximum plasma concentration and area under the curve at steady state for nintedanib and its metabolites tended to be lower when nintedanib was added to pirfenidone. Nintedanib had no effect on the pharmacokinetics of pirfenidone. In conclusion, further study is needed to evaluate the safety and tolerability profile of nintedanib when added to pirfenidone in patients with idiopathic pulmonary fibrosis. There was a trend toward lower exposure of nintedanib when it was added to pirfenidone. Copyright ©ERS 2015.

Safety and pharmacokinetics of veliparib extended-release in patients with advanced solid tumors: a phase I study.

PubMed

Werner, Theresa L; Sachdev, Jasgit; Swisher, Elizabeth M; Gutierrez, Martin; Kittaneh, Muaiad; Stein, Mark N; Xiong, Hao; Dunbar, Martin; Sullivan, Danielle; Komarnitsky, Philip; McKee, Mark; Tan, Antoinette R

2018-05-07

The poly(ADP-ribose) polymerase-1/2 inhibitor veliparib is active against tumors deficient in homologous DNA damage repair. The pharmacokinetics and safety of veliparib extended-release (ER) were evaluated in patients with advanced solid tumors. This phase I study assessed veliparib-ER up to 800 mg once daily or 600 mg twice daily. Dose-limiting toxicities (DLTs), recommended phase II dose (RP2D), and maximum tolerated dose (MTD) were assessed in cycle 1 and safety/tolerability during continuous administration (28-day cycles). Seventy-one patients (n = 53 ovarian, n = 17 breast, n = 1 prostate carcinoma) received veliparib; 50 had deleterious breast cancer susceptibility (BRCA) gene mutations. Single-dose veliparib-ER 200 mg (fasting) led to 58% lower peak concentration and similar area under the concentration-time curve compared with veliparib immediate-release (IR). Three patients experienced DLTs (grade 2: asthenia; grade 3: nausea/vomiting, seizure). RP2D and MTD for veliparib-ER were 400 mg BID. The most frequent adverse events (AEs) were nausea (78.9%) and vomiting (50.7%). The most common grade 3/4 treatment-related AEs were as follows: thrombocytopenia (7.0%), nausea, and anemia (4.2% each). Overall, 12 (27.3%) patients with ovarian and 10 (62.5%) patients with breast carcinoma had a partial response. Veliparib-ER, versus veliparib-IR, exhibited an improved pharmacokinetic profile and was well tolerated in patients with ovarian and BRCA-mutated breast cancers. © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Food Safety Legislation Regarding Of Aflatoxins Contamination

NASA Astrophysics Data System (ADS)

Ketney, Otto

2015-09-01

The main objective of the European Union (EU) is to reduce certain contaminants in foodstuffs to acceptable levels. The occurrence of aflatoxin B1 in food was considered to be one of the most important issues of global food security to protect the health of humans and animals, over 100 nations have established maximum tolerable levels for aflatoxin in food. Although EU legislation covers many aspects of food safety was not legally establish an integrated framework that could effectively combat and cover all sectors of the food chain. Monitoring and reporting levels of aflatoxins after controls are essential actions that assist to identify potential risks to human health. The review process for aflatoxin regulations is a complex activity involving many factors and stakeholders.

Bioactive nutrients - Time for tolerable upper intake levels to address safety.

PubMed

Yates, Allison A; Erdman, John W; Shao, Andrew; Dolan, Laurie C; Griffiths, James C

2017-03-01

There is increasing interest by consumers, researchers, and regulators into the roles that certain bioactive compounds, derived from plants and other natural sources, can play in health maintenance and promotion, and even prolonging a productive quality of life. Research has rapidly emerged suggesting that a wide range of compounds and mixtures in and from plants (such as fruits and vegetables, tea and cocoa) and animals (such as fish and probiotics) may exert substantial health benefits. There is interest in exploring the possibility of establishing recommended intakes or dietary guidance for certain bioactive substances to help educate consumers. A key aspect of establishing dietary guidance is the assessment of safety/toxicity of these substances. Toxicologists need to be involved in both the development of the safety framework and in the evaluation of the science to establish maximum intake/upper limits. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

A safety and pharmacokinetic trial assessing delivery of dapivirine from a vaginal ring in healthy women.

PubMed

Nel, Annalene; Haazen, Wouter; Nuttall, Jeremy; Romano, Joseph; Rosenberg, Zeda; van Niekerk, Neliëtte

2014-06-19

Women-initiated HIV-prevention products are urgently needed. To address this need, a trial was conducted to assess the safety and pharmacokinetics of a silicone elastomer matrix vaginal ring containing 25 mg of the antiretroviral drug dapivirine when used continuously for 28 consecutive days. A double-blind, randomized, placebo-controlled trial was conducted in 16 healthy, HIV-negative women, 18-40 years of age, who were randomized 1:1 to use either the active or matching placebo ring for 28 days. Participants were followed during and for 28 days after ring use for safety and pharmacokinetic evaluations. The dapivirine vaginal ring was safe and well tolerated with no differences in safety endpoints between the active and placebo ring. The concentration-time plots of dapivirine in vaginal fluid were indicative of a sustained release of dapivirine over the 28 days of use. Dapivirine vaginal fluid concentrations were highest near the ring, followed by the cervix and introïtus (mean Cmax of 80, 67 and 31 μg/g, respectively). Vaginal fluid concentrations of dapivirine on the day of ring removal (day 28) at all three collection sites exceeded by more than 3900-fold the IC99 for dapivirine in a tissue explant infection model. Plasma dapivirine concentrations were low (< 1 ng/ml) and remained well below those observed at the maximum tolerated dose for oral treatment (mean Cmax of 2286  ng/ml). The dapivirine vaginal ring has a safety and pharmacokinetic profile that supports its use as a sustained-release topical microbicide for HIV-1 prevention in women.

Phase I Trial of Bortezomib and Concurrent External Beam Radiation in Patients With Advanced Solid Malignancies

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

Pugh, Thomas J.; Chen Changhu; Rabinovitch, Rachel

Purpose: To determine the maximal tolerated dose of bortezomib with concurrent external beam radiation therapy in patients with incurable solid malignant tumors requiring palliative therapy. Methods and Materials: An open label, dose escalation, phase I clinical trial evaluated the safety of three dose levels of bortezomib administered intravenously (1.0 mg/m{sup 2}, 1.3 mg/m{sup 2}, and 1.6 mg/m{sup 2}/ dose) once weekly with concurrent radiation in patients with histologically confirmed solid tumors and a radiographically appreciable lesion suitable for palliative radiation therapy. All patients received 40 Gy in 16 fractions to the target lesion. Dose-limiting toxicity was the primary endpoint, definedmore » as any grade 4 hematologic toxicity, any grade {>=}3 nonhematologic toxicity, or any toxicity requiring treatment to be delayed for {>=}2 weeks. Results: A total of 12 patients were enrolled. Primary sites included prostate (3 patients), head and neck (3 patients), uterus (1 patient), abdomen (1 patient), breast (1 patient), kidney (1 patient), lung (1 patient), and colon (1 patient). The maximum tolerated dose was not realized with a maximum dose of 1.6 mg/m{sup 2}. One case of dose-limiting toxicity was appreciated (grade 3 urosepsis) and felt to be unrelated to bortezomib. The most common grade 3 toxicity was lymphopenia (10 patients). Common grade 1 to 2 events included nausea (7 patients), infection without neutropenia (6 patients), diarrhea (5 patients), and fatigue (5 patients). Conclusions: The combination of palliative external beam radiation with concurrent weekly bortezomib therapy at a dose of 1.6 mg/m{sup 2} is well tolerated in patients with metastatic solid tumors. The maximum tolerated dose of once weekly bortezomib delivered concurrently with radiation therapy is greater than 1.6 mg/m{sup 2}.« less

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. All rights reserved.

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.

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.

NBI‐98854, a selective monoamine transport inhibitor for the treatment of tardive dyskinesia: A randomized, double‐blind, placebo‐controlled study

PubMed Central

Jimenez, Roland; Hauser, Robert A.; Factor, Stewart A.; Burke, Joshua; Mandri, Daniel; Castro‐Gayol, Julio C.

2015-01-01

ABSTRACT Background Tardive dyskinesia is a persistent movement disorder induced by chronic neuroleptic exposure. NBI‐98854 is a novel, highly selective, vesicular monoamine transporter 2 inhibitor. We present results of a randomized, 6‐week, double‐blind, placebo‐controlled, dose‐titration study evaluating the safety, tolerability, and efficacy of NBI‐98854 for the treatment of tardive dyskinesia. Methods Male and female adult subjects with moderate or severe tardive dyskinesia were included. NBI‐98854 or placebo was given once per day starting at 25 mg and then escalated by 25 mg to a maximum of 75 mg based on dyskinesia and tolerability assessment. The primary efficacy endpoint was the change in Abnormal Involuntary Movement Scale from baseline at week 6 scored by blinded, central video raters. The secondary endpoint was the Clinical Global Impression of Change—Tardive Dyskinesia score assessed by the blinded investigator. Results Two hundred five potential subjects were screened, and 102 were randomized; 76% of NBI‐98854 subjects and 80% of placebo subjects reached the maximum allowed dose. Abnormal Involuntary Movement Scale scores for NBI‐98854 compared with placebo were significantly reduced (p = 0.0005). Active drug was also superior on the Clinical Global Impression of Change—Tardive Dyskinesia (p < 0.0001). Treatment‐emergent adverse event rates were 49% in the NBI‐98854 and 33% in the placebo subjects. The most common adverse events (active vs. placebo) were fatigue and headache (9.8% vs. 4.1%) and constipation and urinary tract infection (3.9% vs. 6.1%). No clinically relevant changes in safety assessments were noted. Conclusion NBI‐98854 significantly improved tardive dyskinesia and was well tolerated in patients. These results support the phase 3 clinical trials of NBI‐98854 now underway. © 2015 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. PMID:26346941

NBI-98854, a selective monoamine transport inhibitor for the treatment of tardive dyskinesia: A randomized, double-blind, placebo-controlled study.

PubMed

O'Brien, Christopher F; Jimenez, Roland; Hauser, Robert A; Factor, Stewart A; Burke, Joshua; Mandri, Daniel; Castro-Gayol, Julio C

2015-10-01

Tardive dyskinesia is a persistent movement disorder induced by chronic neuroleptic exposure. NBI-98854 is a novel, highly selective, vesicular monoamine transporter 2 inhibitor. We present results of a randomized, 6-week, double-blind, placebo-controlled, dose-titration study evaluating the safety, tolerability, and efficacy of NBI-98854 for the treatment of tardive dyskinesia. Male and female adult subjects with moderate or severe tardive dyskinesia were included. NBI-98854 or placebo was given once per day starting at 25 mg and then escalated by 25 mg to a maximum of 75 mg based on dyskinesia and tolerability assessment. The primary efficacy endpoint was the change in Abnormal Involuntary Movement Scale from baseline at week 6 scored by blinded, central video raters. The secondary endpoint was the Clinical Global Impression of Change-Tardive Dyskinesia score assessed by the blinded investigator. Two hundred five potential subjects were screened, and 102 were randomized; 76% of NBI-98854 subjects and 80% of placebo subjects reached the maximum allowed dose. Abnormal Involuntary Movement Scale scores for NBI-98854 compared with placebo were significantly reduced (p = 0.0005). Active drug was also superior on the Clinical Global Impression of Change-Tardive Dyskinesia (p < 0.0001). Treatment-emergent adverse event rates were 49% in the NBI-98854 and 33% in the placebo subjects. The most common adverse events (active vs. placebo) were fatigue and headache (9.8% vs. 4.1%) and constipation and urinary tract infection (3.9% vs. 6.1%). No clinically relevant changes in safety assessments were noted. NBI-98854 significantly improved tardive dyskinesia and was well tolerated in patients. These results support the phase 3 clinical trials of NBI-98854 now underway. © 2015 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Prospective, open, multicentre Phase I/II trial to assess safety and efficacy of neoadjuvant radiochemotherapy with docetaxel and cisplatin for esophageal carcinoma.

PubMed

Ma, Hong-Bing; Di, Zheng-Li; Wen, Jiao; Ke, Yue; Sun, Xiaodong; Ren, Juan

2015-02-01

Esophageal squamous cell carcinoma is increasingly treated with trimodality therapy. The objective of this Phase I/II clinical study is to assess the efficacy and safety of neoadjuvant radiochemotherapy with docetaxel and cisplatin and radiotherapy in patients with esophagectomy for locally advanced squamous cell carcinoma of the esophagus with neoadjuvant chemoradiotherapy. Patients with esophageal squamous cell carcinoma received radiochemotherapy (50 Gy/25 fractions during Weeks 1-5) using a three-dimensional conformal radiation therapy or intensity-modulated radiation therapy technique together with weekly docetaxel (20 mg/m(2) at dose levels 1 and 2, 25 mg/m(2) at dose level 3 on Weeks 1-5) and cisplatin (30 mg/m(2) at dose level 1, 40 mg/m(2) at dose levels 2 and 3 on Weeks 1-5) from January 2009 to December 2011. The dose-limiting toxicities and maximum tolerated dose were the primary endpoints and overall response rate and progression-free survival were the secondary endpoints. Over this timeframe, a total of 49 patients completed trimodality therapy. Thirteen patients were treated at dose level 1, 21 patients at dose level 2 and 15 patients at dose level 3.The maximum tolerated dose for docetaxel was 20 mg/m(2) and cisplatin 40 mg/m(2). The complete response or partial response was observed in 26.5% (13/49) of patients. Thirty-four patients (69.4%) were treated with neoadjuvant radiochemotherapy followed by surgical resection. The median progression-free survival and median overall survival for all patients (n = 49) were 8 and 17.2 months, respectively. The median overall survival was 27.5 months for patients treated at dose level 2. Neoadjuvant radiochemotherapy with docetaxel 20 mg/m(2) and cisplatin 40 mg/m(2) was effective and tolerable induction regimen in patients with esophageal tumors. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Critical factors and paths influencing construction workers' safety risk tolerances.

PubMed

Wang, Jiayuan; Zou, Patrick X W; Li, Penny P

2016-08-01

While workers' safety risk tolerances have been regarded as a main reason for their unsafe behaviors, little is known about why different people have different risk tolerances even when confronting the same situation. The aim of this research is to identify the critical factors and paths that influence workers' safety risk tolerance and to explore how they contribute to accident causal model from a system thinking perceptive. A number of methods were carried out to analyze the data collected through interviews and questionnaire surveys. In the first and second steps of the research, factor identification, factor ranking and factor analysis were carried out, and the results show that workers' safety risk tolerance can be influenced by four groups of factors, namely: (1) personal subjective perception; (2) work knowledge and experiences; (3) work characteristics; and (4) safety management. In the third step of the research, hypothetical influencing path model was developed and tested by using structural equation modeling (SEM). It is found that the effects of external factors (safety management and work characteristics) on risk tolerance are larger than that of internal factors (personal subjective perception and work knowledge & experiences). Specifically, safety management contributes the most to workers' safety risk tolerance through its direct effect and indirect effect; while personal subjective perception comes the second and can act as an intermedia for work characteristics. This research provides an in-depth insight of workers' unsafe behaviors by depicting the contributing factors as shown in the accident causal model developed in this research. Copyright © 2015 Elsevier Ltd. All rights reserved.

A first in human, safety, pharmacokinetics, and clinical activity phase I study of once weekly administration of the Hsp90 inhibitor ganetespib (STA-9090) in patients with solid malignancies

PubMed Central

2013-01-01

Background This phase I study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics and antitumor activity of ganetespib in patients with solid malignancies. Methods Patients were enrolled in cohorts of escalating ganetespib doses, given as 1 hour IV infusion, once weekly for 3 weeks, followed by a 1-week rest until disease progression or unacceptable toxicity. Endpoints included safety, pharmacokinetic and pharmacodynamic parameters and preliminary clinical activity. Results Fifty-three patients were treated at doses escalating from 7 to 259 mg/m2. The most common adverse events were Grade 1 and 2 diarrhea, fatigue, nausea or vomiting. Dose-limiting toxicities (DLT) observed were: one Grade 3 amylase elevation (150 mg/m2), one Grade 3 diarrhea and one Grade 3 and one Grade 4 asthenia (259 mg/m2). The MTD was 216 mg/m2 and the recommended phase 2 dose was established at 200 mg/m2 given IV at Days 1, 8, and 15 every 4 weeks. There was a linear relationship between dose and exposure. Plasma HSP70 protein levels remained elevated for over a week post treatment. Disease control rate (objective response and stable disease at ≥ 16 weeks) was 24.4%. Conclusions Ganetespib is well tolerated as a weekly infusion for 3 of every 4 weeks cycle. The recommended phase II dose is 200 mg/m2, and is associated with an acceptable tolerability profile. Trial registration NCT00687934 PMID:23530663

A Phase 1, Single-center, Double-blind, Placebo-controlled Study in Healthy Subjects to Assess the Safety, Tolerability, Clinical Effects, and Pharmacokinetics-Pharmacodynamics of Intravenous Cyclopropyl-methoxycarbonylmetomidate (ABP-700) after a Single Ascending Bolus Dose.

PubMed

Struys, Michel M R F; Valk, Beatrijs I; Eleveld, Douglas J; Absalom, Anthony R; Meyer, Peter; Meier, Sascha; den Daas, Izaak; Chou, Thomas; van Amsterdam, Kai; Campagna, Jason A; Sweeney, Steven P

2017-07-01

Cyclopropyl-methoxycarbonylmetomidate (ABP-700) is a new "soft" etomidate analog. The primary objectives of this first-in-human study were to describe the safety and efficacy of ABP-700 and to determine its maximum tolerated dose. Secondary objectives were to characterize the pharmacokinetics of ABP-700 and its primary metabolite (cyclopropyl-methoxycarbonyl acid), to assess the clinical effects of ABP-700, and to investigate the dose-response and pharmacokinetic/pharmacodynamic relationships. Sixty subjects were divided into 10 cohorts and received an increasing, single bolus of either ABP-700 or placebo. Safety was assessed by clinical laboratory evaluations, infusion-site reactions, continuous monitoring of vital signs, physical examination, adverse event monitoring, and adrenocorticotropic hormone stimulation testing. Clinical effects were assessed with modified observer's assessment of alertness/sedation and Bispectral Index monitoring. Pharmacokinetic parameters were calculated. Stopping criteria were met at 1.00 mg/kg dose. No serious adverse events were reported. Adverse events were dose-dependent and comprised involuntary muscle movement, tachycardia, and ventilatory effects. Adrenocorticotropic hormone stimulation evoked a physiologic cortisol response in all subjects, no different from placebo. Pharmacokinetics were dose-proportional. A three-compartment pharmacokinetic model described the data well. A rapid onset of anesthesia/sedation after bolus administration and also a rapid recovery were observed. A quantitative concentration-effect relationship was described for the modified observer's assessment of alertness/sedation and Bispectral Index. This first-in-human study of ABP-700 shows that ABP-700 was safe and well tolerated after single-bolus injections up to 1.00 mg/kg. Bolus doses of 0.25 and 0.35 mg/kg were found to provide the most beneficial clinical effect versus side-effect profile.

A randomized controlled trial of the efficacy and safety of saxagliptin as add-on therapy in patients with type 2 diabetes and inadequate glycaemic control on metformin plus a sulphonylurea.

PubMed

Moses, R G; Kalra, S; Brook, D; Sockler, J; Monyak, J; Visvanathan, J; Montanaro, M; Fisher, S A

2014-05-01

To evaluate the efficacy and safety of saxagliptin as add-on therapy in adults with type 2 diabetes with inadequate glycaemic control on metformin plus a sulphonylurea. In this 24-week, multicentre, randomized, parallel-group, double-blind study, outpatients aged ≥18 years with type 2 diabetes, body mass index ≤40 kg/m(2) and inadequate glycaemic control, received saxagliptin 5 mg or placebo once-daily added to background medication consisting of a stable maximum tolerated dose of metformin plus a sulphonylurea. The primary end point was change in glycated haemoglobin (HbA1c) from baseline to week 24. Safety and tolerability assessments included adverse events (AEs), hypoglycaemia and body weight. A total of 257 patients were randomized, treated and included in the safety analysis (saxagliptin, n = 129; placebo, n = 128); 255 were included in the efficacy analysis (saxagliptin, n = 127; placebo, n = 128). HbA1c reduction was greater with saxagliptin versus placebo [between-group difference in adjusted mean change from baseline, -0.66%; 95% confidence interval (CI), -0.86 to -0.47 (7 mmol/mol, -9.4 to -5.1); p < 0.0001]. The proportion of patients with ≥1 AE was 62.8% with saxagliptin and 71.7% with placebo. In the saxagliptin and placebo groups, rates of reported hypoglycaemia were 10.1 and 6.3%, respectively, and rates of confirmed hypoglycaemia (symptoms + glucose < 2.8 mmol/l) were 1.6 and 0%. Mean change in body weight was 0.2 kg for saxagliptin and -0.6 kg for placebo (p = 0.0272). Addition of saxagliptin 5 mg/day in patients inadequately controlled on metformin and sulphonylurea effectively improved glycaemic control and was well tolerated. © 2013 John Wiley & Sons Ltd.

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.

Safety, Pharmacokinetics, and Pharmacodynamics in Healthy Volunteers Treated With GDC-0853, a Selective Reversible Bruton's Tyrosine Kinase Inhibitor.

PubMed

Herman, Ann E; Chinn, Leslie W; Kotwal, Shweta G; Murray, Elaine R; Zhao, Rui; Florero, Marilyn; Lin, Alyse; Moein, Anita; Wang, Rena; Bremer, Meire; Kokubu, Serika; Serone, Adrian P; Hanze, Eva L; Viberg, Anders; Morimoto, Alyssa M; Winter, Helen R; Katsumoto, Tamiko R

2018-06-01

GDC-0853 is a small molecule inhibitor of Bruton's tyrosine kinase (BTK) that is highly selective and noncovalent, leading to reversible binding. In double-blind, randomized, and placebo-controlled phase I healthy volunteer studies, GDC-0853 was well tolerated, with no dose-limiting adverse events (AEs) or serious AEs. The maximum tolerated dose was not reached during dose escalation (≤600 mg, single ascending dose (SAD) study; ≤250 mg twice daily (b.i.d.) and ≤500 mg once daily, 14-day multiple ascending dose (MAD) study). Plasma concentrations peaked 1-3 hours after oral administration and declined thereafter, with a steady-state half-life ranging from 4.2-9.9 hours. Independent assays demonstrated dose-dependent BTK target engagement. Based on pharmacokinetic/pharmacodynamic (PK/PD) simulations, a once-daily dosing regimen (e.g., 100 mg, q.d.) is expected to maintain a high level of BTK inhibition over the dosing interval. Taken together, the safety and PK/PD data support GDC-0853 evaluation in rheumatoid arthritis, lupus, and other autoimmune or inflammatory indications. © 2018 American Society for Clinical Pharmacology and Therapeutics.

Intradetrusor Injections of Onabotulinum Toxin-A in Children With Urinary Incontinence due to Neurogenic Detrusor Overactivity Refractory to Antimuscarinic Treatment.

PubMed

Tarcan, Tufan; Akbal, Cem; Sekerci, Cağri A; Top, Tuncay; Simşek, Ferruh

2014-04-01

This was a prospective single-arm study to assess the efficacy and safety of intradetrusor injections of onabotulinum toxin-A in children with urinary incontinence associated with neurogenic detrusor overactivity due to myelomeningocele. All patients had failed the first-line treatment of a combination of oral antimuscarinics and intermittent catheterization. The study group consisted of 31 children with myelomeningocele with a mean age of 7.95 years (range, 5-3 years) who were followed up for a mean of 29 weeks. The amount of onabotulinum toxin A injected was 10 U/kg with a maximal dose of 300 U. There were 20 to 30 injection sites with rigid cystoscopic guidance under general anesthesia. Thirty of 31 patients reported dryness between intermittent catheterization intervals. The mean reduction in maximum detrusor pressure and the mean increase in maximum cystometric capacity from baseline were 53% and 51.5%, respectively, 6 weeks after injection. We found a 324% increase in mean bladder compliance and a 57% increase in mean intermittent catheterization volumes. The mean duration of efficacy was 28 weeks with a single injection and 36 weeks for repeated injections (minimum, 16 weeks; maximum, 52 weeks). The mean time interval between repeated onabotulinum toxin-A injections was 7 months (maximum, 13 months). Intradetrusor injections of onabotulinum toxin-A were well tolerated. Onabotulinum toxin-A injections into the bladder wall provide a significant symptomatic and urodynamic improvement in children with neurogenic detrusor overactivity due to myelomeningocele who are on intermittent catheterization. The treatment seems to be safe and very well tolerated.

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.

LJM716 in Japanese patients with head and neck squamous cell carcinoma or HER2-overexpressing breast or gastric cancer.

PubMed

Takahashi, Shunji; Kobayashi, Takayuki; Tomomatsu, Junichi; Ito, Yoshinori; Oda, Hisanobu; Kajitani, Tatsuhiro; Kakizume, Tomoyuki; Tajima, Takeshi; Takeuchi, Hiromi; Maacke, Heiko; Esaki, Taito

2017-01-01

Human epidermal growth factor receptor 3 (HER3) has been identified as an important component of many receptor tyrosine kinase-driven cancers. LJM716 is a human IgG monoclonal antibody that binds HER3, trapping it in an inactive conformation. In this study, a phase I dose escalation was performed with a primary objective to establish the maximum tolerated dose and/or the recommended dose of LJM716 in Japanese patients with selected advanced solid tumors. Secondary objectives included the evaluation of the safety and tolerability, preliminary antitumor activity, and pharmacokinetics of LJM716 in Japanese patients. LJM716 was administered intravenously at doses of 10, 20, or 40 mg/kg once weekly, in 28-day cycles, to 12 patients with HER2-amplified breast cancer or gastric cancer, or with esophageal squamous cell carcinoma or squamous cell carcinoma of the head and neck, regardless of HER2 status. The maximum tolerated dose was not reached, and the recommended dose was established at 40 mg/kg. No dose-limiting toxicities were observed in the first cycle. The most frequently reported adverse events were diarrhea, fatigue, stomatitis, pyrexia, and paronychia. One unconfirmed partial response was observed in a patient with breast cancer, and 50% of the patients achieved stable disease as the best overall response. Exposure increased with ascending dose, and half-life was estimated to be 11-14 days. No anti-LJM716 antibodies were detected. LJM716 was well tolerated in Japanese patients, and a degree of tumor shrinkage was observed. ClinicalTrials.gov NCT01911936.

A Phase I Trial of High-Dose Lenalidomide and Melphalan as Conditioning for Autologous Stem Cell Transplantation in Relapsed or Refractory Multiple Myeloma.

PubMed

Mark, Tomer M; Guarneri, Danielle; Forsberg, Peter; Rossi, Adriana; Pearse, Roger; Perry, Arthur; Pekle, Karen; Tegnestam, Linda; Greenberg, June; Shore, Tsiporah; Gergis, Usama; Mayer, Sebastian; Van Besien, Koen; Ely, Scott; Jayabalan, David; Sherbenou, Daniel; Coleman, Morton; Niesvizky, Ruben

2017-06-01

Autologous stem cell transplantation (ASCT) conditioned with high-dose chemotherapy has long been established as the standard of care for eligible patients with newly diagnosed multiple myeloma. Despite recent therapeutic advances, high-dose melphalan (HDM) remains the chemotherapy regimen of choice in this setting. Lenalidomide (LEN) in combination with low-dose dexamethasone is recognized as a standard of care for patients with relapsed or refractory multiple myeloma (RRMM), and there is growing support for the administration of LEN as maintenance therapy post-ASCT. In view of the above, the present phase I clinical trial was designed to evaluate the safety and tolerability of high-dose LEN (HDLEN) in patients with RRMM, and to determine the maximum tolerated dose of HDLEN when added to HDM before ASCT. Despite administering HDLEN at doses of up to 350 mg/day, the maximum tolerated dose could not be determined, owing to an insufficient number of dose-limiting toxicities in the 21 patients enrolled in the trial. Conditioning with HDLEN plus HDM was associated with a favorable tolerability profile. Adverse events following ASCT were as expected with HDM. Median progression-free and overall survival were 10 months and 22 months, respectively, in this population of heavily pretreated patients. Our findings suggest that HDLEN in combination with HDM may offer significant potential as a conditioning regimen before ASCT in patients with RRMM. These preliminary findings are now being evaluated further in an ongoing phase II clinical trial. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Phase II Dose Escalation Study of Caspofungin for Invasive Aspergillosis ▿ §

PubMed Central

Cornely, O. A.; Vehreschild, J. J.; Vehreschild, M. J. G. T.; Würthwein, G.; Arenz, D.; Schwartz, S.; Heussel, C. P.; Silling, G.; Mahne, M.; Franklin, J.; Harnischmacher, U.; Wilkens, A.; Farowski, F.; Karthaus, M.; Lehrnbecher, T.; Ullmann, A. J.; Hallek, M.; Groll, A. H.

2011-01-01

Our objective was to evaluate the maximum tolerated dose of caspofungin for invasive aspergillosis (IA). The safety and pharmacokinetics of escalating dosages of caspofungin were investigated in IA. Eight patients each received caspofungin 70, 100, 150, or 200 mg once a day (QD). Dose-limiting toxicity (DLT) was defined as the same non-hematological treatment-related adverse event of grade ≥4 in 2 of 8 patients or ≥3 in 4 of 8 patients in a cohort. A total of 46 patients (median age, 61 years; 21 female; 89% with hematological malignancies) received caspofungin (9, 8, 9, and 20 patients in the 70-, 100-, 150-, and 200-mg cohorts) for a median of 24.5 days. Plasma pharmacokinetics were linear across the investigated dosages and followed a two-compartment model, with weight as the covariate on clearance and sex as the covariate on central volume of distribution. Simulated peak plasma concentrations at steady state ranged from 14.2 to 40.6 mg/liter (28%), trough concentrations from 4.1 to 11.8 mg/liter (58%), and area under the concentration-time curve from 175 to 500 mg/liter/h (32%) (geometric mean, geometric coefficient of variation). Treatment was well tolerated without dose-limiting toxicity. The rate of complete or partial responses was 54.3%, and the overall mortality at 12-week follow-up was 28.3%. In first-line treatment of invasive aspergillosis, daily doses of up to 200 mg caspofungin were well tolerated and the maximum tolerated dose was not reached. Pharmacokinetics was linear. Response rates were similar to those previously reported for voriconazole and liposomal amphotericin. PMID:21911573

Treatment of nonhealing diabetic foot ulcers with a platelet-derived growth factor gene-activated matrix (GAM501): results of a phase 1/2 trial.

PubMed

Mulder, Gerit; Tallis, Arthur J; Marshall, V Tracy; Mozingo, David; Phillips, Laurie; Pierce, Glenn F; Chandler, Lois A; Sosnowski, Barbara K

2009-01-01

The results from a Phase 1/2 study of a replication-defective adenovirus encoding human platelet-derived growth factor (PDGF)-B formulated in a bovine collagen (Ad-5PDGF-B; 2.6% collagen; GAM501) gel for nonhealing neuropathic diabetic foot ulcers is reported. The primary objectives of the study were to evaluate the safety, maximum-tolerated dose, and preliminary biological activity of GAM501. Fifteen patients enrolled into the study with chronic, nonhealing ulcers received either a single administration of GAM501 at one of three dose levels, or up to four administrations of GAM501 at 1-week intervals. All patients received standard of care treatment including debridement and were required to wear an off-loading shoe. GAM501 was found to be safe and well tolerated with no evidence of systemic or local toxicity at all doses so no maximum-tolerated dose was reached. Serum antibody titers to platelet-derived growth factor-B homodimer and collagen were negative and adenoviral DNA was not detected in the blood. In the 12 patients that completed the study, ulcer closure was observed by Month 3 in 10 patients, seven of whom received a single application of GAM501. In conclusion, GAM501 did not appear to have any toxicity at doses that showed biological activity. GAM501 holds promise as a potentially effective treatment for nonhealing diabetic foot ulcers.

Biomarker-guided clinical development of the first-in-class anti-inflammatory FPR2/ALX agonist ACT-389949.

PubMed

Stalder, Anna K; Lott, Dominik; Strasser, Daniel S; Cruz, Hans G; Krause, Andreas; Groenen, Peter M A; Dingemanse, Jasper

2017-03-01

The main objectives of these two phase I studies were to investigate safety and tolerability as well as the pharmacokinetic/pharmacodynamic profile of the novel potent and selective formyl peptide receptor type 2 (FPR2)/Lipoxin A 4 receptor (ALX) agonist ACT-389949. A challenge model was used to assess the drug's anti-inflammatory potential, with the aim of selecting a dosing regimen for future patient studies. Two double-blind, randomized phase I studies investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of ACT-389949 at different doses and dosing regimens. Drug exposure was correlated with target engagement markers such as receptor internalization and cytokine measurements. The effect of FPR2/ALX agonism on neutrophil migration was studied in a lipopolysaccharide (LPS) inhalation model. ACT-389949 was well tolerated. Maximum concentrations were reached around 2 h after dosing, with a mean terminal half-life of 29.3 h [95% confidence interval (CI) 25.5, 33.7]. After multiple-dose administration, exposure increased by 111% (95% CI 89, 136), indicating drug accumulation. Administration of ACT-389949 resulted in a dose-dependent, long-lasting internalization of FPR2/ALX into leukocytes. Pro- and anti-inflammatory cytokines were dose-dependently but transiently upregulated only after the first dose. No pharmacological effect on neutrophil count was observed in the LPS challenge test performed at steady state. FPR2/ALX agonism with ACT-389949 was shown to be safe and well tolerated in healthy subjects. Receptor internalization and downstream mediators pointed towards a desensitization of the system, which may explain the lack of effect on neutrophil recruitment in the LPS challenge model. © 2016 The British Pharmacological Society.

A multiscale model to evaluate the efficacy of anticancer therapies based on chimeric polypeptide nanoparticles

NASA Astrophysics Data System (ADS)

Paiva, L. R.; Martins, M. L.

2011-01-01

A multiscale model for tumor growth and its chemotherapy using conjugate nanoparticles is presented, and the corresponding therapeutic outcomes are evaluated. It is found that doxorubicin assembled into chimeric polypeptide nanoparticles cannot eradicate either vascularized primary tumors or avascular micrometastasis even administrated at loads close to their maximum tolerated doses. Furthermore, an effective and safety treatment demands for conjugate nanoparticles targeted to the malignant cells with much higher specificity and affinity than those currently observed in order to leave most of the normal tissues unaffected and to ensure a fast intracellular drug accumulation.

Phase I dose-escalation and pharmacokinetic study (TED 11576) of cabazitaxel in Japanese patients with castration-resistant prostate cancer.

PubMed

Mukai, Hirofumi; Takahashi, Shunji; Nozawa, Masahiro; Onozawa, Yusuke; Miyazaki, Jun; Ohno, Keiji; Suzuki, Kazuhiro

2014-04-01

The purpose of the study is to analyze the pharmacokinetic (PK) profile of cabazitaxel and evaluate its safety and tolerability as a 1-h IV infusion every 3 weeks in Japanese patients with castration-resistant prostate cancer (CRPC). Seventeen patients were treated with cabazitaxel at doses of 20 and 25 mg/m(2) for PK analyses. Dose escalation was performed only in the absence of dose-limiting toxicity (DLT). The maximum tolerated dose (MTD) was the highest dose at which less than 33 % of the patients developed DLT. Cabazitaxel exhibited a triphasic elimination profile with a long terminal half-life of 116 ± 29.0 or 113 ± 28.0 h after IV infusion of 20 or 25 mg/m(2) cabazitaxel, respectively. The major differences in the PK parameters of cabazitaxel and docetaxel were cabazitaxel's fairly high clearance rate, representing approximately half the hepatic flow, and its large volume of distribution at steady-state conditions. No DLT was observed during Cycle 1. Mild-to-moderate hematological adverse events (AEs), including neutropenia, and other AEs typically associated with taxanes were observed; all AEs were manageable. Cabazitaxel at 25 mg/m(2) every 3 weeks was selected as the MTD in Japanese patients. The PK parameters of cabazitaxel in Japanese CRPC patients were comparable with those previously determined in Caucasian subjects. The safety and tolerability of cabazitaxel were also comparable in both ethnic populations.

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...

Safety assessment of medium- and long-chain triacylglycerols containing 30% (w/w) medium-chain fatty acids in mice and rats.

PubMed

Zhou, Shengmin; Wang, Yueqiang; Jiang, Yuanrong; Yu, Liangli Lucy

2017-06-01

A novel medium- and long-chain triacylglycerols (MLCT), with 30% (w/w) medium-chain fatty acids (MCFA) was evaluated for its safety as a dietary fat in mice and rats. The subacute oral toxicity study showed that the maximum tolerated dose exceeded 54.33 g/kg body weight (kg bw)/day. In the 90-day feeding study, no dose-related adverse effects were observed in rats administered diets formulated with different levels of MLCT (2.0, 4.0, and 8.0 g/kg bw/day) as compared to the rapeseed oil control diet. Further safety assessment in pregnant rats did not reveal any significant difference relative to the control at a treatment level up to 8.0 g MLCT/kg bw/day. The results from this study indicated the safe use of MLCT with high contents of MCFA in food products for improving human health. Copyright © 2017 Elsevier Inc. All rights reserved.

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...

The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia.

PubMed

Stein, Eytan M; Garcia-Manero, Guillermo; Rizzieri, David A; Tibes, Raoul; Berdeja, Jesus G; Savona, Michael R; Jongen-Lavrenic, Mojca; Altman, Jessica K; Thomson, Blythe; Blakemore, Stephen J; Daigle, Scott R; Waters, Nigel J; Suttle, A Benjamin; Clawson, Alicia; Pollock, Roy; Krivtsov, Andrei; Armstrong, Scott A; DiMartino, Jorge; Hedrick, Eric; Löwenberg, Bob; Tallman, Martin S

2018-05-03

Pinometostat (EPZ-5676) is a first-in-class, small-molecule inhibitor of the histone methyltransferase DOT1L. In this phase 1 study, pinometostat was evaluated for safety and efficacy in adult patients with advanced acute leukemias, particularly those involving MLL rearrangements ( MLL-r ) resulting from 11q23 translocations. Fifty-one patients were enrolled into 6 dose escalation cohorts (n=26) and 2 expansion cohorts (n=25) at pinometostat doses of 54 and 90 mg/m 2 /day by continuous intravenous infusion in 28-day cycles. As a maximum tolerated dose was not established in the dose escalation phase, the expansion doses were selected based upon safety and clinical response data combined with pharmacodynamic evidence of reduction in H3K79 methylation during dose escalation. Across all dose levels, plasma pinometostat concentrations increased in an approximately dose-proportional fashion, reaching an apparent steady state by 4-8 hours after infusion, and rapidly decreased following treatment cessation. The most common adverse events, of any cause, were fatigue (39%), nausea (39%), constipation (35%), and febrile neutropenia (35%). Overall, 2 patients, both with t(11;19), experienced complete remissions at 54 mg/m 2 /day by continuous intravenous infusion, demonstrating proof of concept for delivering clinically meaningful responses through targeting DOT1L using single agent pinometostat in MLL-r leukemia patients. Administration of pinometostat was generally safe with the maximum tolerated dose not being reached, although efficacy as a single agent was modest. This study demonstrates the therapeutic potential for targeting DOT1L in MLL-r leukemia and lays the groundwork for future combination approaches in this patient population. This clinical trial is registered at www.clinicaltrials.gov as no. NCT01684150. Copyright © 2018 American Society of Hematology.

Safety evaluation of combination carboplatin and toceranib phosphate (Palladia) in tumour-bearing dogs: A phase I dose finding study.

PubMed

Wouda, R M; Hocker, S E; Higginbotham, M L

2018-03-01

Combining conventional cytotoxic maximum tolerated dose (MTD) chemotherapy with low-dose metronomic and/or anti-angiogenic agents is a exciting area of oncologic research. The objective of this study was to establish the MTD, safety and adverse event (AE) profile of 1 such drug combination. This prospective phase I dose-finding clinical trial assumed an open-label 3 + 3 cohort design. Client-owned dogs with 1 or more cytologically and/or histologically confirmed and macroscopically measurable, naive or recurrent, malignant tumours, were enrolled. No preference for tumour histology, grade or stage was expressed. Toceranib was administered at a dose of 2.75 mg kg -1 by mouth (PO) every other day (EOD), and carboplatin administered intravenously (IV) every 21 days at a starting dose of 200 mg m -2 . A total of 25% dose escalation was proposed for carboplatin, to a maximum of 300 mg m -2 . AEs were graded according to the Veterinary Cooperative Oncology Group's common terminology criteria for AEs (VCOG-CTCAE). Grade 3 haematologic or gastrointestinal AEs were nominated dose-limiting. Response to therapy was evaluated according to the VCOG's revised RECIST criteria. Eleven dogs were enrolled. Tumour histologies included sinonasal carcinoma, osteosarcoma, thyroid carcinoma, melanoma and apocrine gland anal sac adenocarcinoma. MTDs of carboplatin and toceranib were identified as 200 mg m -2 IV every 21 days and approximately 2.75 mg kg -1 PO EOD, respectively. The dose-limiting toxicity was neutropenia. Two dogs experienced a partial response, and 6 maintained stable disease. Combination carboplatin and toceranib chemotherapy was well-tolerated. Clinical benefit was observed in most cases. This protocol warrants further investigation in phase II/III trials. © 2017 John Wiley & Sons Ltd.

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

PubMed

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

2008-02-15

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

First human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers.

PubMed

Stevens, Misty W; Henry, Ralph L; Owens, S Michael; Schutz, Ralph; Gentry, W Brooks

2014-01-01

This first-in-human study examined the safety and pharmacokinetics of ch-mAb7F9, an anti-methamphetamine monoclonal antibody, in healthy volunteers. Single, escalating doses of ch-mAb7F9 over the range of 0.2 to 20 mg/kg were administered to 42 subjects who were followed for 147 d. Safety was measured by physical examinations, adverse events, vital signs, electrocardiograms, and clinical laboratory testing. Serum ch-mAb7F9 concentration and immunogenicity analyses were performed. There were no serious adverse reactions or discontinuations from the study due to adverse events. No trends emerged in the frequency, relatedness, or severity of adverse events with increased dose or between active and placebo treated subjects. Ch-mAb7F9 displayed expected IgG pharmacokinetic parameters, including a half-life of 17-19 d in the 3 highest dose groups and volume of distribution of 5-6 L, suggesting the antibody is confined primarily to the vascular compartment. Four (12.5%) of the 32 subjects receiving ch-mAb7F9 were confirmed to have developed a human anti-chimeric antibody response by the end of the study; however, this response did not appear to be dose related. Overall, no apparent safety or tolerability concerns were identified; a maximum tolerated dose was not reached in this Phase 1 study. Ch-mAb7F9 therefore appears safe for human administration.

A novel design for a dose finding, safety, and drug interaction study of an antiepileptic drug (retigabine) in early clinical development.

PubMed

Sachdeo, Rajesh; Partiot, Arnaud; Biton, Victor; Rosenfeld, William E; Nohria, Virinder; Tompson, Debra; DeRossett, Sarah; Porter, Roger J

2014-06-01

To obtain information on the acceptable doses of the antiepileptic drug (AED) retigabine (RTG), the maximum tolerated dose (MTD), drug interactions, safety and tolerability, and preliminary evidence of efficacy when administered as adjunctive therapy and as monotherapy. Study 202 was an open-label, add-on study in patients with partial or generalized epilepsy treated with valproic acid (VPA), carbamazepine (CBZ), phenytoin (PHT), or topiramate (TPM) as monotherapy. Following baseline assessments, patients entered a dose titration phase of 28 – 56 days. The initial daily RTG dose was 100 or 200 mg (2 or 3 × daily). The RTG dose was increased every 1 - 2 weeks by 50 - 200 mg to a maximum of 1,600 mg/day. Once the RTG MTD had been attained, patients entered a 14-day maintenance period. Following this, the patient's background AED dose could be reduced, with the possibility of achieving RTG monotherapy. The final dosing regimen attained was maintained for an additional 14 days. Patients who completed study 202 could choose to continue treatment with RTG (with or without other AEDs) in study 208, the long-term extension of study 202. Safety assessments included adverse event (AE) monitoring, clinical laboratory evaluations, electrocardiograms, and physical and neurologic examinations. Patients' seizure diaries to assess the frequency and type of seizures, the percentage change in seizure rate, and the responder rate (>= 50% reduction in seizure rate from baseline) were evaluated. 60 patients (mean age 37.2, range 16 - 64 years) were enrolled in study 202, and 47 (78%) continued treatment with RTG in the extension study (208). In study 202, the most commonly reported AEs were: dizziness (53%), asthenia (42%), somnolence (33%), nausea (27%), speech disorder (27%), and tremor (27%). In the extension study, AEs were similar and included dizziness, somnolence, diplopia, feeling "drunk", confusion, fatigue, and dysarthria. The median percent reductions in 28-day seizure rate, relative to baseline in Studies 202 and 208, were ~ 20% and 47%, respectively. RTG did not alter the pharmacokinetics of the four monotherapy AEDs investigated. CBZ and PHT increased RTG clearance by 27% and 36%, respectively, whereas TPM and VPA had no effect on RTG clearance. Studies 202 and 208 provided critical information on RTG safety and tolerability, and reductions in seizure rates towards the design and conduct of subsequent pivotal clinical trials. Likewise, information regarding the appropriate dosage of RTG with VPA, CBZ, PHT, or TPM was obtained, which permitted the subsequent pivotal trials to be performed appropriately. *Currently at Shire Pharmaceuticals, Behavioral Health Business Unit, Wayne, PA, USA **Currently at University of Pennsylvania, Department of Neurology, Philadelphia, PA, USA.

Safety and tolerability of the first-in-class agent CPI-613 in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer: a single-centre, open-label, dose-escalation, phase 1 trial.

PubMed

Alistar, Angela; Morris, Bonny B; Desnoyer, Rodwige; Klepin, Heidi D; Hosseinzadeh, Keyanoosh; Clark, Clancy; Cameron, Amy; Leyendecker, John; D'Agostino, Ralph; Topaloglu, Umit; Boteju, Lakmal W; Boteju, Asela R; Shorr, Rob; Zachar, Zuzana; Bingham, Paul M; Ahmed, Tamjeed; Crane, Sandrine; Shah, Riddhishkumar; Migliano, John J; Pardee, Timothy S; Miller, Lance; Hawkins, Gregory; Jin, Guangxu; Zhang, Wei; Pasche, Boris

2017-06-01

Pancreatic cancer statistics are dismal, with a 5-year survival of less than 10%, and more than 50% of patients presenting with metastatic disease. Metabolic reprogramming is an emerging hallmark of pancreatic adenocarcinoma. CPI-613 is a novel anticancer agent that selectively targets the altered form of mitochondrial energy metabolism in tumour cells, causing changes in mitochondrial enzyme activities and redox status that lead to apoptosis, necrosis, and autophagy of tumour cells. We aimed to establish the maximum tolerated dose of CPI-613 when used in combination with modified FOLFIRINOX chemotherapy (comprising oxaliplatin, leucovorin, irinotecan, and fluorouracil) in patients with metastatic pancreatic cancer. In this single-centre, open-label, dose-escalation phase 1 trial, we recruited adult patients (aged ≥18 years) with newly diagnosed metastatic pancreatic adenocarcinoma from the Comprehensive Cancer Center of Wake Forest Baptist Medical Center (Winston-Salem, NC, USA). Patients had good bone marrow, liver and kidney function, and good performance status (Eastern Cooperative Oncology Group [ECOG] performance status 0-1). We studied CPI-613 in combination with modified FOLFIRINOX (oxaliplatin at 65 mg/m 2 , leucovorin at 400 mg/m 2 , irinotecan at 140 mg/m 2 , and fluorouracil 400 mg/m 2 bolus followed by 2400 mg/m 2 over 46 h). We applied a two-stage dose-escalation scheme (single patient and traditional 3+3 design). In the single-patient stage, one patient was accrued per dose level. The starting dose of CPI-613 was 500 mg/m 2 per day; the dose level was then escalated by doubling the previous dose if there were no adverse events worse than grade 2 within 4 weeks attributed as probably or definitely related to CPI-613. The traditional 3+3 dose-escalation stage was triggered if toxic effects attributed as probably or definitely related to CPI-613 were grade 2 or worse. The dose level for CPI-613 for the first cohort in the traditional dose-escalation stage was the same as that used in the last cohort of the single-patient dose-escalation stage. The primary objective was to establish the maximum tolerated dose of CPI-613 (as assessed by dose-limiting toxicities). This trial is registered with ClinicalTrials.gov, number NCT01835041, and is closed to recruitment. Between April 22, 2013, and Jan 8, 2016, we enrolled 20 patients. The maximum tolerated dose of CPI-613 was 500 mg/m 2 . The median number of treatment cycles given at the maximum tolerated dose was 11 (IQR 4-19). Median follow-up of the 18 patients treated at the maximum tolerated dose was 378 days (IQR 250-602). Two patients enrolled at a higher dose of 1000 mg/m 2 , and both had a dose-limiting toxicity. Two unexpected serious adverse events occurred, both for the first patient enrolled. Expected serious adverse events were: thrombocytopenia, anaemia, and lymphopenia (all for patient number 2; anaemia and lymphopenia were dose-limiting toxicities); hyperglycaemia (in patient number 7); hypokalaemia, hypoalbuminaemia, and sepsis (patient number 11); and neutropenia (patient number 20). No deaths due to adverse events were reported. For the 18 patients given the maximum tolerated dose, the most common grade 3-4 non-haematological adverse events were hyperglycaemia (ten [55%] patients), hypokalaemia (six [33%]), peripheral sensory neuropathy (five [28%]), diarrhoea (five [28%]), and abdominal pain (four [22%]). The most common grade 3-4 haematological adverse events were neutropenia (five [28%] of 18 patients), lymphopenia (five [28%]), anaemia (four [22%], and thrombocytopenia in three [17%]). Sensory neuropathy (all grade 1-3) was recorded in 17 (94%) of the 18 patients and was managed with dose de-escalation or discontinuation per standard of care. No patients died while on active treatment; 11 study participants died, with cause of death as terminal pancreatic cancer. Of the 18 patients given the maximum tolerated dose, 11 (61%) achieved an objective (complete or partial) response. A maximum tolerated dose of CPI-613 was established at 500 mg/m 2 when used in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer. The findings of clinical activity will require validation in a phase 2 trial. Comprehensive Cancer Center of Wake Forest Baptist Medical Center. Copyright © 2017 Elsevier Ltd. All rights reserved.

Pharmacokinetics, Safety, and 48-Week Efficacy of Oral Raltegravir in HIV-1–Infected Children Aged 2 Through 18 Years

PubMed Central

Nachman, Sharon; Zheng, Nan; Acosta, Edward P.; Teppler, Hedy; Homony, Brenda; Graham, Bobbie; Fenton, Terence; Xu, Xia; Wenning, Larissa; Spector, Stephen A.; Frenkel, Lisa M.; Alvero, Carmelita; Worrell, Carol; Handelsman, Edward; Wiznia, Andrew; Moultrie, Harry; Kindra, Gurpreet; Sanders, Margaret Ann; Williams, Ruth; Jensen, Jennifer; Acevedo, Midnela; Fabregas, Lizbeth; Jurgrau, Andrea; Foca, Marc; Higgins, Alice; Deville, Jaime G.; Nielsen-Saines, Karin; Carter, Michele F.; Swetnam, John; Wilson, Joan; Donnelly, Margaret; Akleh, Siham; Rigaud, Mona; Kaul, Aditya; Patel, Nehali; Gaur, Aditya; Utech, L. Jill; Cardoso, Edmundo; Moreira, Ana Maria; Santos, Breno; Bobat, Raziya; Mngqibisa, Rosie; Burey, Marlene; Abadi, Jacob; Rosenberg, Michael; Luzuriaga, Katherine; Picard, Donna; Pagano-Therrien, Jessica; Dittmer, Sylvia; Ndiweni, Hilda Ntatule; Patel, Amisha; DelRey, Michelle; McMullen-Jackson, Chivon; Paul, Mary E.; Melvin, Ann; Venema-Weiss, Corry; Lane, Jenna; Beneri, Christy; Ferraro, Denise; Infanzon, Erin; McAuley, James B; Aziz, Mariam; McNichols, Maureen; Pelton, Stephen; McLaud, Deb; Clarke, Diana; Zeichner, Steven; Akar, Arezou; Thompson, Deidre; Douglas, Steven D.; Rutstein, Richard M.; Vincent, Carol A.; Vachon, Mary Elizabeth; Cavallo, Martha; Purswani, Murli Udharam; Masheto, Gaerolwe; Ogwu, Anthony; Kakhu, Tebogo; Viani, Rolando M.; Darcey, Anita,; Norris, Kimberly; Burchett, Sandra K.; Kneut, Catherine; Karthas, Nancy; Casey, Denise; Emmanuel, Patricia; Lujan-Zilbermann, Jorge; Rana, Sohail; Houston, Patricia; Mengistab, Mulu; Rathore, Mobeen; Mirza, Ayesha; Gayton, Tabetha; Barr, Emily; Dunn, Jennifer; Hahn, Kerry; Eysallenne, Zulma; Howard, F. Sholar; Graham, Kathleen; Negra, Marinella Della; Queiroz, Wladimir; Lian, Yu Ching; Wara, Diane; Ruel, Ted; VanDyke, Russell; Reilly, Patricia; Bradford, Sheila; van Rensburg, Anita Janse; Dobbels, Els; Bester, Marietjie; Bamji, Mahrukh; Paul, Santa; Sarza, Mirala; Kovacs, Andrea; Homans, James; Spencer, LaShonda; Hofer, Cristna; Abreu, Thalita; Oliveira, Ricardo; Joao, Esau C.; Pinto, Jorge; Ferreira, Flavia; Kakehasi, Fabiana; Cervi, Maria Celia; Isaac, Marcia De Lima; Losso, Marcelo H.; Stankievich, Erica; Foradori, Irene; Tucker, Diane; Church, Joseph; Belzer, Marvin; Hopkins, Johns; Ellen, Jonathan; Agwu, Allison; Laurel, Borkovic

2014-01-01

Background. IMPAACT P1066 is a phase I/II open-label multicenter trial to evaluate pharmacokinetics, safety, tolerability, and efficacy of multiple raltegravir formulations in human immunodeficiency virus (HIV)–infected youth. Methods. Dose selection for each cohort (I: 12 to <19 years; II: 6 to <12 years; and III: 2 to <6 years) was based on review of short-term safety (4 weeks) and intensive pharmacokinetic evaluation. Safety data through weeks 24 and 48, and grade ≥3 or serious adverse events (AEs) were assessed. The primary virologic endpoint was achieving HIV RNA <400 copies/mL or ≥1 log10 reduction between baseline and week 24. Results. The targeted pharmacokinetic parameters (AUC0-12h and C12h) were achieved for each cohort, allowing dose selection for 2 formulations. Of 96 final dose subjects, there were 15 subjects with grade 3 or higher clinical AEs (1 subject with drug-related [DR] psychomotor hyperactivity and insomnia); 16 subjects with grade 3 or higher laboratory AEs (1 with DR transaminase elevation); 14 subjects with serious clinical AEs (1 with DR rash); and 1 subjects with serious laboratory AEs (1 with DR transaminase increased). There were no discontinuations due to AEs and no DR deaths. Favorable virologic responses at week 48 were observed in 79.1% of patients, with a mean CD4 increase of 156 cells/µL (4.6%). Conclusions. Raltegravir as a film-coated tablet 400 mg twice daily (6 to <19 years, and ≥25 kg) and chewable tablet 6 mg/kg (maximum dose 300 mg) twice daily (2 to <12 years) was well tolerated and showed favorable virologic and immunologic responses. Clinical Trials Registration NCT00485264. PMID:24145879

A randomised, single-blind, single-dose, three-arm, parallel-group study in healthy subjects to demonstrate pharmacokinetic equivalence of ABP 501 and adalimumab

PubMed Central

Kaur, Primal; Chow, Vincent; Zhang, Nan; Moxness, Michael; Kaliyaperumal, Arunan; Markus, Richard

2017-01-01

Objective To demonstrate pharmacokinetic (PK) similarity of biosimilar candidate ABP 501 relative to adalimumab reference product from the USA and European Union (EU) and evaluate safety, tolerability and immunogenicity of ABP 501. Methods Randomised, single-blind, single-dose, three-arm, parallel-group study; healthy subjects were randomised to receive ABP 501 (n=67), adalimumab (USA) (n=69) or adalimumab (EU) (n=67) 40 mg subcutaneously. Primary end points were area under the serum concentration-time curve from time 0 extrapolated to infinity (AUCinf) and the maximum observed concentration (Cmax). Secondary end points included safety and immunogenicity. Results AUCinf and Cmax were similar across the three groups. Geometrical mean ratio (GMR) of AUCinf was 1.11 between ABP 501 and adalimumab (USA), and 1.04 between ABP 501 and adalimumab (EU). GMR of Cmax was 1.04 between ABP 501 and adalimumab (USA) and 0.96 between ABP 501 and adalimumab (EU). The 90% CIs for the GMRs of AUCinf and Cmax were within the prespecified standard PK equivalence criteria of 0.80 to 1.25. Treatment-related adverse events were mild to moderate and were reported for 35.8%, 24.6% and 41.8% of subjects in the ABP 501, adalimumab (USA) and adalimumab (EU) groups; incidence of antidrug antibodies (ADAbs) was similar among the study groups. Conclusions Results of this study demonstrated PK similarity of ABP 501 with adalimumab (USA) and adalimumab (EU) after a single 40-mg subcutaneous injection. No new safety signals with ABP 501 were identified. The safety and tolerability of ABP 501 was similar to the reference products, and similar ADAb rates were observed across the three groups. Trial registration number EudraCT number 2012-000785-37; Results. PMID:27466231

Phase I dose-escalation study of afatinib, an ErbB family blocker, plus docetaxel in patients with advanced cancer.

PubMed

Marshall, John; Shapiro, Geoffrey I; Uttenreuther-Fischer, Martina; Ould-Kaci, Mahmoud; Stopfer, Peter; Gordon, Michael S

2013-02-01

To determine the maximum tolerated dose (MTD), safety and anti-tumor activity of afatinib combined with docetaxel in advanced cancer. The MTD was determined from dose-limiting toxicities in the first cycle. Thirty-one patients received 10, 20 and 30 mg oral afatinib, plus 60 and 75 mg/m(2) intravenous docetaxel (six cohorts; 3-week cycles). The MTD of afatinib was 20 mg/day (days 2-21) with 75 mg/m(2) docetaxel (day 1). Dose-limiting toxicities were grade 3/4 diarrhea (n = 3) and febrile neutropenia (n = 6). Most frequently occurring adverse events were diarrhea, neutropenia and rash. Disease stabilization occurred in 14 patients. Afatinib 20 mg/day plus docetaxel was suboptimal and the study could not yield Phase II dose recommendations. The combination resulted in a manageable safety profile.

Suvorexant: a promising, novel treatment for insomnia

PubMed Central

Lee-Iannotti, Joyce K; Parish, James M

2016-01-01

Suvorexant a novel, orexin receptor antagonist was recently approved by the US Food and Drug Administration for the treatment of sleep onset and sleep maintenance insomnia in August 2014. Multiple animal and human studies support the efficacy, safety, and tolerability of suvorexant for patients of various profiles. Current recommendations advocate for a starting dose of 10 mg and a maximum dose of 20 mg, with cautious use in women, obese patients, and patients taking other CYP3A4 inhibitors. More head-to-head studies comparing suvorexant to other sedative-hypnotic therapies are needed to further delineate which patients will benefit the most from this medication over others. PMID:26955275

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

Pharmacokinetics of Intravenous Finafloxacin in Healthy Volunteers

PubMed Central

Chiesa, Joseph; Lückermann, Mark; Fischer, Carsten; Dalhoff, Axel; Fuhr, Uwe

2017-01-01

ABSTRACT Finafloxacin is a novel fluoroquinolone exhibiting enhanced activity under acidic conditions and a broad-spectrum antibacterial profile. The present study assessed the pharmacokinetic properties and the safety and tolerability of finafloxacin following intravenous infusions. In this mixed-parallel-group, crossover study, healthy male and female volunteers received single ascending doses (18 volunteers, 200 to 1,000 mg) or multiple ascending doses (40 volunteers, 600 to 1,000 mg) of finafloxacin or placebo. Plasma and urine samples were collected by a dense sampling scheme to determine the pharmacokinetics of finafloxacin using a noncompartmental approach. Standard safety and tolerability data were documented. Finafloxacin had a volume of distribution of 90 to 127 liters (range) at steady state and 446 to 550 liters at pseudoequilibrium, indicating the elimination of a large fraction before pseudoequilibrium was reached. Areas under the concentration-time curves and maximum plasma concentrations (geometric means) increased slightly more than proportionally (6.73 to 45.9 μg · h/ml and 2.56 to 20.2 μg/ml, respectively), the terminal elimination half-life increased (10.6 to 17.1 h), and the urinary recovery decreased (44.2% to 31.7%) with increasing finafloxacin doses (single doses of 200 to 1,000 mg). The pharmacokinetic profiles suggested multiphasic elimination by both glomerular filtration and saturable tubular secretion. The values of the parameters were similar for single and multiple administrations. The coefficient of variation for the between-subject variability of exposure ranged from 10% (≤600 mg) to 38% (>600 mg). Adverse events were mild and nonspecific, with no dependence of adverse events on dose or treatment (including placebo) being detected. Despite a relatively high interindividual variability at higher doses, the level of exposure following intravenous administration of finafloxacin appears to be predictable. Individual elimination processes should be evaluated in more detail. Finafloxacin exhibited a favorable safety and tolerability profile. (This study has been registered at ClinicalTrials.gov under registration no. NCT01910883.) PMID:28784673

Comparative Safety and Tolerability of Anti-VEGF therapy in Age-Related Macular Degeneration

PubMed Central

Modi, Yasha S.; Tanchon, Carley; Ehlers, Justis P

2015-01-01

Neovascular age-related macular degeneration (NVAMD) is one of the leading causes of blindness. Over the last decade, the treatment of NVAMD has been revolutionized by the development intravitreal anti-vascular endothelial growth factor (VEGF) therapies. Several anti-VEGF medications are used for the treatment of NVAMD. The safety and tolerability of these medications deserve review given the high prevalence of NVAMD and the significant utilization of these medications. Numerous large randomized clinical trials have not shown any definitive differential safety relative to ocular or systemic safety of these medications. Intravitreal anti-VEGF therapy does appear to impact systemic VEGF levels, but the implications of these changes remain unclear. One unique safety concern relates drug compounding and the potential risks of contamination, specifically for bevacizumab. Continued surveillance for systemic safety concerns, particularly for rare events is merited. Overall these medications are well tolerated and effective in the treatment of NVAMD. PMID:25700714

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

Randomized trial of the anti-FGF23 antibody KRN23 in X-linked hypophosphatemia

PubMed Central

Carpenter, Thomas O.; Imel, Erik A.; Ruppe, Mary D.; Weber, Thomas J.; Klausner, Mark A.; Wooddell, Margaret M.; Kawakami, Tetsuyoshi; Ito, Takahiro; Zhang, Xiaoping; Humphrey, Jeffrey; Insogna, Karl L.; Peacock, Munro

2014-01-01

Background. X-linked hypophosphatemia (XLH) is the most common heritable form of rickets and osteomalacia. XLH-associated mutations in phosphate-regulating endopeptidase (PHEX) result in elevated serum FGF23, decreased renal phosphate reabsorption, and low serum concentrations of phosphate (inorganic phosphorus, Pi) and 1,25-dihydroxyvitamin D [1,25(OH)2D]. KRN23 is a human anti-FGF23 antibody developed as a potential treatment for XLH. Here, we have assessed the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of KRN23 following a single i.v. or s.c. dose of KRN23 in adults with XLH. Methods. Thirty-eight XLH patients were randomized to receive a single dose of KRN23 (0.003–0.3 mg/kg i.v. or 0.1–1 mg/kg s.c.) or placebo. PK, PD, immunogenicity, safety, and tolerability were assessed for up to 50 days. Results. KRN23 significantly increased the maximum renal tubular threshold for phosphate reabsorption (TmP/GFR), serum Pi, and 1,25(OH)2D compared with that of placebo (P < 0.01). The maximum serum Pi concentration occurred later following s.c. dosing (8–15 days) compared with that seen with i.v. dosing (0.5–4 days). The effect duration was dose related and persisted longer in patients who received s.c. administration. Changes from baseline in TmP/GFR, serum Pi, and serum 1,25(OH)2D correlated with serum KRN23 concentrations. The mean t1/2 of KRN23 was 8–12 days after i.v. administration and 13–19 days after s.c. administration. Patients did not exhibit increased nephrocalcinosis or develop hypercalciuria, hypercalcemia, anti-KRN23 antibodies, or elevated serum parathyroid hormone (PTH) or creatinine. Conclusion. KRN23 increased TmP/GFR, serum Pi, and serum 1,25(OH)2D. The positive effect of KR23 on serum Pi and its favorable safety profile suggest utility for KRN23 in XLH patients. Trial registration. Clinicaltrials.gov NCT00830674. Funding. Kyowa Hakko Kirin Pharma, Inc. PMID:24569459

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

Application of adaptive design and decision making to a phase II trial of a phosphodiesterase inhibitor for the treatment of intermittent claudication.

PubMed

Lewis, Roger J; Connor, Jason T; Teerlink, John R; Murphy, James R; Cooper, Leslie T; Hiatt, William R; Brass, Eric P

2011-05-25

Claudication secondary to peripheral artery disease (PAD) is associated with substantial functional impairment. Phosphodiesterase (PDE) inhibitors have been shown to increase walking performance in these patients. K-134 is a selective PDE 3 inhibitor being developed as a potential treatment for claudication. The use of K-134, as with other PDE 3 inhibitors, in patients with PAD raises important safety and tolerability concerns, including the induction of cardiac ischemia, tachycardia, and hypotension. We describe the design, oversight, and implementation of an adaptive, phase II, dose-finding trial evaluating K-134 for the treatment of stable, intermittent claudication. The study design was a double-blind, multi-dose (25 mg, 50 mg, and 100 mg of K-134), randomized trial with both placebo and active comparator arms conducted in the United States and Russia. The primary objective of the study was to compare the highest tolerable dose of K-134 versus placebo using peak walking time after 26 weeks of therapy as the primary outcome. Study visits with intensive safety assessments were included early in the study period to provide data for adaptive decision making. The trial used an adaptive, dose-finding strategy to efficiently identify the highest dose(s) most likely to be safe and well tolerated, based on the side effect profiles observed within the trial, so that less promising doses could be abandoned. Protocol specified criteria for safety and tolerability endpoints were used and modeled prior to the adaptive decision making. The maximum target sample size was 85 subjects in each of the retained treatment arms. When 199 subjects had been randomized and 28-day data were available from 143, the Data Monitoring Committee (DMC) recommended termination of the lowest dose (25 mg) treatment arm. Safety evaluations performed during 14- and 28-day visits which included in-clinic dosing and assessments at peak drug concentrations provided core data for the DMC review. At the time of review, no subject in any of the five treatment arms (placebo, three K-134-containing arms, and cilostazol) had met pre-specified definitions for resting tachycardia or ischemic changes on exercise ECG. If, instead of dropping the 25-mg K-134 treatment arm, all arms had been continued to full enrollment, then approximately 43 additional research subjects would have been required to complete the trial. In this phase II, dose-finding trial of K-134 in the treatment of stable intermittent claudication, no concerning safety signals were seen at interim analysis, allowing the discontinuation of the lowest-dose-containing arm and the retention of the two highest-dose-containing arms. The adaptive design facilitated safe and efficient evaluation of K-134 in this high-risk cardiovascular population. ClinicalTrials.gov: NCT00783081.

A pilot study of omalizumab to facilitate rapid oral desensitization in high-risk peanut allergic patients

PubMed Central

Schneider, Lynda C.; Rachid, Rima; LeBovidge, Jennifer; Blood, Emily; Mittal, Mudita; Umetsu, Dale T.

2015-01-01

Background Peanut allergy is a major public health problem that affects 1% of the population and has no effective therapy. Objective To examine the safety and efficacy of oraldesensitization in peanut allergic children in combination with a brief course of anti-IgE monoclonal antibody (omalizumab, Xolair). Methods We performed oral peanut desensitization in peanut allergic children at high risk for developing significant peanut-induced allergic reactions. Omalizumab was administered prior to and during oral peanut desensitization. Results We enrolled 13 children (median age, 10 years), with a median peanut-specific IgE of 229 kUA/L and a median total serum IgE of 621 kU/L, who failed an initial double-blind placebo controlled food challenge at doses 100 mg peanut flour. After pre-treatment with omalizumab, all subjects tolerated the initial 11 desensitization doses given on the first day, including the maximum dose of 500 mg peanut flour (cumulative dose, 992 mg, equivalent to >2 peanuts), requiring minimal or no rescue therapy. 12 subjects then reached the maximum maintenance dose of 4,000 mg peanut flour/day in a median time of 8 weeks, at which point omalizumab was discontinued. All 12 subjects continued on 4,000 mg peanut flour/day and subsequently tolerated a challenge with 8,000 mg peanut flour (equivalent to about 20 peanuts), or 160 to 400 times the dose tolerated before desensitization. During the study, 6 of the 13 subjects experienced mild or no allergic reactions; 6 subjects had Grade 2, and 2 subjects Grade 3 reactions, all of which responded rapidly to treatment. Conclusions Among children with high-risk peanut allergy, treatment with omalizumab may facilitate rapid oral desensitization, and qualitativelyimprove the desensitization process. PMID:24176117

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.

Absolute bioavailability and safety of a novel rivastigmine nasal spray in healthy elderly individuals.

PubMed

Morgan, Timothy M; Soh, Bob

2017-03-01

To test the feasibility of a novel rivastigmine nasal spray as prospective treatment for dementia. A single dose, crossover absolute bioavailability and safety study was conducted with rivastigmine intravenous solution (1 mg) and nasal spray (3.126 mg) in eight healthy elderly individuals, aged 58-75 years. Absolute bioavailability (F) of the nasal spray was significant at 0.62 (0.15) for F > 0 (P < 0.001, n = 8). The systemic dose absorbed was 2.0 (0.6) mg, time to maximum plasma concentration was 1.1 (0.5) h and maximum plasma concentration was 6.9 (2.0) ng ml -1 . The NAP226-90 to rivastigmine AUC 0-∞ ratio was 0.78 (0.19). The single dose safety was good with two of five mild adverse events related to the nasal spray. Nasal and throat irritation were perceived as mild and transient, and both had resolved at 20 min post-nasal dose. An estimated dose of two or three sprays twice-daily with nasal spray would deliver comparable rivastigmine exposure and efficacy as a 6-9.7 mg day -1 oral dose and a 10 cm 2 transdermal patch, respectively. The rivastigmine nasal spray had superior absolute bioavailability compared to historical values for oral capsule and transdermal patch determined by other researchers. It had rapid onset of action, low NAP226-90 to rivastigmine exposure ratio and a favourable safety and tolerability profile. The ability to achieve adjustable, individual, twice-daily dosing during waking hours has good potential to minimise undesirable cholinergic burden and sleep disturbances whilst delivering an effective dose for the treatment of dementia associated with Alzheimer's and Parkinson's disease. © 2016 The British Pharmacological Society.

Long-term safety and efficacy of dalfampridine for walking impairment in patients with multiple sclerosis: Results of open-label extensions of two Phase 3 clinical trials

PubMed Central

Goodman, Andrew D; Bethoux, Francois; Brown, Theodore R; Schapiro, Randall T; Cohen, Ron; Marinucci, Lawrence N; Henney, Herbert R

2015-01-01

Background: In Phase 3 double-blind trials (MS-F203 and MS-F204), dalfampridine extended release tablets 10 mg twice daily (dalfampridine-ER; prolonged-release fampridine in Europe; fampridine modified or sustained release elsewhere) improved walking speed relative to placebo in patients with multiple sclerosis (MS). Objectives: Evaluation of long-term safety and efficacy of dalfampridine-ER in open-label extensions (MS-F203EXT, MS-F204EXT). Methods: Patients received dalfampridine-ER 10 mg twice daily; and had Timed 25-Foot Walk (T25FW) assessments at 2, 14 and 26 weeks, and then every 6 months. Subjects were categorized as dalfampridine-ER responders or non-responders, based on their treatment response in the double-blind parent trials that assessed T25FW. Results: We had 269 patients enter MS-F203EXT and 154 patients complete it; for a maximum exposure of 5 years. We had 214 patients enter MS-F204EXT and 146 complete it; for a maximum exposure of 3.3 years. No new safety signals emerged and dalfampridine-ER tolerability was consistent with the double-blind phase. Improvements in walking speed were lost after dalfampridine-ER was discontinued in the parent trial, but returned by the 2-week assessment after re-initiation of the drug. Throughout the extensions, mean improvement in walking speed declined, but remained improved, among the double-blind responders as compared with non-responders. Conclusions: The dalfamipridine-ER safety profile was consistent with the parent trials. Although walking speed decreased over time, dalfampridine-ER responders continued to show improved walking speed, which was sustained compared with non-responders. PMID:25583832

Balixafortide plus eribulin in HER2-negative metastatic breast cancer: a phase 1, single-arm, dose-escalation trial.

PubMed

Pernas, Sonia; Martin, Miguel; Kaufman, Peter A; Gil-Martin, Marta; Gomez Pardo, Patricia; Lopez-Tarruella, Sara; Manso, Luis; Ciruelos, Eva; Perez-Fidalgo, Jose Alejandro; Hernando, Cristina; Ademuyiwa, Foluso O; Weilbaecher, Katherine; Mayer, Ingrid; Pluard, Timothy J; Martinez Garcia, Maria; Vahdat, Linda; Perez-Garcia, Jose; Wach, Achim; Barker, Debra; Fung, Samson; Romagnoli, Barbara; Cortes, Javier

2018-04-26

The C-X-C chemokine receptor type 4 (CXCR4)-stromal cell-derived factor-1α (SDF-1α) axis regulates function and trafficking of immune cells and the tumour microenvironment. CXCR4 antagonists have been shown to enhance the activity of different anticancer treatments in preclinical models. We assessed the safety, tolerability, pharmacokinetics, and preliminary phase 1 activity of the CXCR4 antagonist, balixafortide, in combination with eribulin chemotherapy in patients with heavily pretreated, relapsed metastatic breast cancer. This single-arm, dose-escalation, phase 1 trial enrolled patients at 11 sites in Spain and the USA. Eligible patients were women aged 18 years or older who had histologically confirmed HER2-negative metastatic breast cancer, evidence of tumour cell CXCR4 expression, an Eastern Cooperative Oncology Group performance status of 0 or 1, and who had previously received between one and three chemotherapy regimens for metastatic breast cancer, and at least one endocrine therapy if they had hormone receptor-positive disease, unless they were considered unsuitable for endocrine therapy. A standard 3+3 dose-escalation design was used, followed by an expanded cohort at the established maximum tolerated dose or highest dose if no dose-limiting toxicity was observed for the combination. After a treatment-related fatal adverse event in the first cohort who received 21-day cycles of treatment with eribulin and balixafortide, a protocol amendment modified the study design to be done in two parts. Patients enrolled to part 1 received an initial 28-day run-in cycle, with some cohorts receiving de-escalated doses of eribulin plus balixafortide to assess the safety and pharmacokinetics of the combination. The evaluation of part 1 did not confirm any dose-limiting toxicities or eribulin-balixafortide interactions, and therefore part 2 started enrolling patients to receive eribulin at the originally planned dose of 1·4 mg/m 2 on days 2 and 9 of a 21-day cycle and balixafortide from a starting dose of 2 mg/kg with dose increments of 0·5 or 1 mg/kg on days 1-3 and 8-10 of the 21-day cycle. Both drugs were administered as intravenous infusions. All patients were to receive treatment until disease progression or unacceptable toxicity. The primary endpoints were dose-limiting toxicities and adverse events, and the establishment of a maximum tolerated dose or recommended phase 2 dose, and pharmacokinetic parameters. Safety analysis was done in all patients who received at least one dose of study treatment. Analysis of antitumour activity was done in all patients who received at least one full cycle of study treatment. The trial is registered at ClinicalTrials.gov, number NCT01837095, and is closed to accrual. Between Jan 28, 2014, and Oct 4, 2016, 56 patients were enrolled into the trial. No dose-limiting toxicities were confirmed and the maximum tolerated dose was not reached. The highest dose was established as eribulin 1·4 mg/m 2 on days 2 and 9, and balixafortide 5·5 mg/kg on days 1-3 and 8-10 of the 21-day cycle. Objective responses (all partial responses) were observed in 16 (30%; 95% CI 18-44) of 54 patients who were evaluable for antitumour activity. The most common treatment-emergent adverse events of any grade were fatigue (44 [79%] of 56 patients), neutropenia (32 [57%]), infusion-related reactions (27 [48%]), alopecia (26 [46%]), constipation (26 [46%]), and nausea (25 [45%]). Serious adverse events occurred in 21 (38%) of 56 patients, including febrile neutropenia in five (9%) of 56 patients, neutrophil count decrease in two (4%) patients, constipation in two (4%) patients, pneumonia in two (4%) patients, and urinary tract infection in three (5%) patients. Two (4%) of 56 patients died while receiving study treatment; one from septic shock and one from pneumonia. The safety and tolerability of balixafortide plus eribulin seems to be similar to that of eribulin or balixafortide monotherapy, and the preliminary activity of the combination seems promising in patients with HER-negative metastatic breast cancer. The results suggest that balixafortide plus eribulin has potential to provide a new therapeutic option in heavily pretreated patients with metastatic breast cancer and warrants further investigation in randomised trials. Polyphor. Copyright © 2018 Elsevier Ltd. All rights reserved.

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).

Nutritional and Safety Outcomes from an Open-Label Micronutrient Intervention for Pediatric Bipolar Spectrum Disorders

PubMed Central

Gracious, Barbara; Arnold, L. Eugene; Failla, Mark; Chitchumroonchokchai, Chureeporn; Habash, Diane; Fristad, Mary A.

2013-01-01

Abstract Objective The purpose of this study was to report the safety, tolerability, and serum micronutrient concentrations and their correlations with mood changes from an 8 week pilot feasibility study of a 36 ingredient multinutrient supplement, EMPowerplus (EMP+), for pediatric bipolar spectrum disorders (BPSD). Methods Ten children ages 6–12 received EMP+ escalating from one to four capsules t.i.d., with four children increased to the maximum suggested dose, five capsules t.i.d. Outcome measures were micronutrient concentrations in serum and red blood cells, vital signs, body mass index (BMI), dietary intake (Food Frequency Questionnaire and 24 hour dietary recall interview), and mood and global functioning ratings. Results Seven children (70%) completed the study. Three (30%) terminated early for tolerability and compliance issues. Adverse effects were mild and transient, and chiefly consisted of initial insomnia or gastrointestinal (GI) upset. No differences occurred in BMI (p=0.310) or waist–hip ratio (WHR; p=0.674) pre- to postsupplementation. Four of the tested serum vitamin concentrations increased from pre- to postsupplementation: vitamin A-retinol, vitamin B6, vitamin E-α-tocopherol; and folate (all p<0.05). The increase in serum 25-OH vitamin D approached significance (p=0.063). No differences were found in dietary intake pre- to postsupplementation, suggesting that blood nutrient level increases were caused by EMP+. Conclusions In this open prospective study, short-term use of EMP+ in children with BPSD appeared safe and well-tolerated, with a side effect profile preferable to first-line psychotropic drugs for pediatric bipolar spectrum disorders. A double-blind, randomized clinical trial is feasible, appears safe, and is warranted by open-label clinical outcomes and plausible mechanisms of action, combined with documentation of increased serum concentrations of specific micronutrients. PMID:24138009

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

Efficacy and safety of disodium ascorbyl phytostanol phosphates in men with moderate dyslipidemia

PubMed Central

Trip, Mieke D.; Pritchard, P. Haydn; Tam, Patrick; Lukic, Tatjana; de Sain-van der Velden, Monique G.; de Barse, Martina; Kastelein, John J. P.

2008-01-01

Objective This study investigated the efficacy, safety, tolerability, and pharmacokinetics of a novel cholesterol absorption inhibitor, FM-VP4, comprising disodium ascorbyl sitostanol phosphate (DASP) and disodium ascorbyl campestanol phosphate (DACP). Methods In phase 1, 30 men received a single dose of 100, 200, 400, 800, 1,600, or 2,000 mg FM-VP4 or placebo. In phase 2, 100 men were treated with 100, 200, 400, or 800 mg/day of FM-VP4 or placebo for 4 weeks. Results The drug was well tolerated at each single or multiple dose level. After 4 weeks of treatment, low-density lipoprotein cholesterol (LDL-C) levels changed by 2.7% in the placebo group and by 2.9%, −4.2%, and −4.6% in the 100, 200, and 800 mg/day groups, respectively, which was not statistically significant. However, 400 mg/day of FM-VP4 significantly decreased LDL-C by 6.5% (p=0.02). Phase 1 showed that DACP and DASP were absorbed into plasma with a median tmax of 12 h for both components, and clearance was slow with a mean t1/2λ of 57 h. During 4 weeks of treatment, steady state was reached by approximately 8 days. Conclusion This study demonstrated that up to 800 mg/day of FM-VP4 is safe and well tolerated for at least 4 weeks. Furthermore, the higher doses significantly reduced LDL-C by 7% compared with baseline or by 10% compared with placebo, with the maximum effect reached at 400 mg/day. PMID:18320185

Phase I study of single-agent ribociclib in Japanese patients with advanced solid tumors.

PubMed

Doi, Toshihiko; Hewes, Becker; Kakizume, Tomoyuki; Tajima, Takeshi; Ishikawa, Norifumi; Yamada, Yasuhide

2018-01-01

The cyclin D-CDK4/6-INK4-Rb pathway is frequently dysregulated in cancers. Ribociclib, an orally available, selective CDK4/6 inhibitor, showed preliminary clinical activity in a phase I study in the USA and Europe for patients with solid tumors and lymphomas. The present study aimed to determine the single-agent maximum tolerated dose (MTD) and recommended dose for expansion (RDE) in Japanese patients with advanced solid tumors. Ribociclib safety, tolerability, pharmacokinetic profile, and preliminary antitumor activity were also assessed. Japanese patients with solid tumors that had progressed on prior therapies received escalating doses of single-agent ribociclib on a 3-weeks-on/1-week-off schedule. Treatment continued until the development of toxicity or disease progression. A dose escalation was planned for patients with esophageal cancer. In the dose-escalation phase, 4 patients received 400 mg ribociclib and 13 patients received 600 mg ribociclib. Four patients experienced dose-limiting toxicities, 3 of whom were in the 600 mg group. The RDE was declared to be 600 mg, and the MTD was not determined. The most frequent adverse events were hematologic and gastrointestinal. Four patients achieved stable disease at the 600 mg dose; no patients achieved complete or partial response. All patients discontinued the study, the majority due to disease progression. No patients discontinued due to adverse events. Dose escalation was not pursued due to lack of observed efficacy in esophageal cancer. At the RDE of 600 mg/d on a 3-weeks-on/1-week-off schedule, ribociclib showed acceptable safety and tolerability profiles in Japanese patients with advanced solid tumors. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

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.

Safety, pharmacokinetics, and pharmacodynamic properties of oral DEBIO1143 (AT-406) in patients with advanced cancer: results of a first-in-man study.

PubMed

Hurwitz, Herbert I; Smith, David C; Pitot, Henry C; Brill, Jeffrey M; Chugh, Rashmi; Rouits, Elisabeth; Rubin, Joseph; Strickler, John; Vuagniaux, Gregoire; Sorensen, J Mel; Zanna, Claudio

2015-04-01

To assess safety/tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of DEBIO1143, an antagonist of inhibitor apoptosis proteins. This first-in-man study in patients with advanced cancer used an accelerated dose titration design. DEBIO1143 was given orally once daily on days 1-5 every 2 or 3 weeks until disease progressed or patients dropped out. The starting dose of 5 mg was escalated by 100% in single patients until related grade 2 toxicity occurred. This triggered expansion to cohorts of three and subsequently six patients and reduction in dose increments to 50%. Maximum tolerated dose (MTD) was exceeded when any two patients within the same cohort experienced dose-limiting toxicity (DLT). On days 1 and 5, PK and PD samples were taken. Thirty-one patients received doses from 5 to 900 mg. Only one DLT was reported at 180 mg. No MTD was found. Most common adverse drug reactions were fatigue (26%), nausea (23%), and vomiting (13%). Average t max and T 1/2 was about 1 and 6 h, respectively. Exposure increased proportionally with doses from 80 to 900 mg, without accumulation over 5 days. Plasma CCL2 increased at 3-6 h postdose and epithelial apoptosis marker M30 on day 5; cIAP-1 levels in PBMCs decreased at all doses >80 mg. Five patients (17%) had stable disease as the best treatment response. DEBIO1143 was well tolerated at doses up to 900 mg and elicited PD effects at doses greater 80 mg. Limited antitumor activity may suggest development rather as adjunct treatment.

Incorporating patient-preference evidence into regulatory decision making.

PubMed

Ho, Martin P; Gonzalez, Juan Marcos; Lerner, Herbert P; Neuland, Carolyn Y; Whang, Joyce M; McMurry-Heath, Michelle; Hauber, A Brett; Irony, Telba

2015-10-01

Patients have a unique role in deciding what treatments should be available for them and regulatory agencies should take their preferences into account when making treatment approval decisions. This is the first study designed to obtain quantitative patient-preference evidence to inform regulatory approval decisions by the Food and Drug Administration Center for Devices and Radiological Health. Five-hundred and forty United States adults with body mass index (BMI) ≥ 30 kg/m(2) evaluated tradeoffs among effectiveness, safety, and other attributes of weight-loss devices in a scientific survey. Discrete-choice experiments were used to quantify the importance of safety, effectiveness, and other attributes of weight-loss devices to obese respondents. A tool based on these measures is being used to inform benefit-risk assessments for premarket approval of medical devices. Respondent choices yielded preference scores indicating their relative value for attributes of weight-loss devices in this study. We developed a tool to estimate the minimum weight loss acceptable by a patient to receive a device with a given risk profile and the maximum mortality risk tolerable in exchange for a given weight loss. For example, to accept a device with 0.01 % mortality risk, a risk tolerant patient will require about 10 % total body weight loss lasting 5 years. Patient preference evidence was used make regulatory decision making more patient-centered. In addition, we captured the heterogeneity of patient preferences allowing market approval of effective devices for risk tolerant patients. CDRH is using the study tool to define minimum clinical effectiveness to evaluate new weight-loss devices. The methods presented can be applied to a wide variety of medical products. This study supports the ongoing development of a guidance document on incorporating patient preferences into medical-device premarket approval decisions.

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

PubMed

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

2017-06-06

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

Safety and Efficacy in Advanced Solid Tumors of a Targeted Nanocomplex Carrying the p53 Gene Used in Combination with Docetaxel: A Phase 1b Study

PubMed Central

Pirollo, Kathleen F; Nemunaitis, John; Leung, Po Ki; Nunan, Robert; Adams, Jana; Chang, Esther H

2016-01-01

Loss of p53 suppressor function, through mutations or inactivation of the p53 pathway, occurs in most human cancers. SGT-53 is a liposomal nanocomplex designed for systemic, tumor-targeting delivery of the wt p53 gene. In this nanodelivery system, an anti-transferrin receptor single-chain antibody fragment serves as the targeting moiety. In an initial phase 1 trial in patients with advanced solid tumors, SGT-53 demonstrated tumor-specific targeting, was shown to be well tolerated, and was associated with an antitumor effect in several patients. Our preclinical studies have also demonstrated enhanced antitumor activity with the combination of SGT-53 and docetaxel. Thus, this dose-escalation trial was undertaken to assess the combination of SGT-53 and docetaxel for safety and potential efficacy in 14 advanced cancer patients. Results reveal that the combination of SGT-53 (maximum dose, 3.6 mg DNA/infusion) and docetaxel (75 mg/m2/infusion) was well tolerated. Moreover, clinical activity involving 12 evaluable patients was observed. Three of these patients achieved RECIST-verified partial responses with tumor reductions of −47%, −51%, and −79%. Two others had stable disease with significant shrinkage (−25% and −16%). These results support phase 2 testing of SGT-53 in combination with docetaxel. PMID:27357628

Phase I study of FOLFIRI plus pimasertib as second-line treatment for KRAS-mutated metastatic colorectal cancer

PubMed Central

Macarulla, T; Cervantes, A; Tabernero, J; Roselló, S; Van Cutsem, E; Tejpar, S; Prenen, H; Martinelli, E; Troiani, T; Laffranchi, B; Jego, V; von Richter, O; Ciardiello, F

2015-01-01

Background: The mitogen-activated protein kinase (MAPK) pathway has been implicated in the molecular pathogenesis of human cancers, including metastatic colorectal cancer (mCRC). This provides a rationale for the development of MAPK-targeted agents such as pimasertib. Methods: Patients with KRAS mutant mCRC were treated in the second-line setting with FOLFIRI (5-fluorouracil/folinic acid/irinotecan) plus pimasertib. The primary objective of the safety run-in phase was to determine the maximum-tolerated dose (MTD) and the recommended phase II dose of pimasertib combined with FOLFIRI. Results: Sixteen patients were enrolled in the trial. Ten and six patients were treated daily with 45 and 60 mg of pimasertib plus FOLFIRI, respectively. The MTD was considered to be 45 mg per day. The most common treatment-emergent adverse events were diarrhoea, nausea, vomiting, asthenia and skin/rash event. Of the 15 patients in the efficacy analysis group, two patients had partial response, nine patients had stable disease, three patients had progressive disease as their best overall response and one patient could not be evaluated. Conclusions: Dose escalation of pimasertib in combination with FOLFIRI was limited by toxicity. At the MTD of 45 mg per day, pimasertib was adequately tolerated in patients with mCRC and no unexpected or new safety signals or concerns were identified. PMID:25989270

Phase I study of icotinib, an EGFR tyrosine kinase inhibitor combined with IMRT in nasopharyngeal carcinoma.

PubMed

Hu, Wei; Wang, Wei; Yang, Peinong; Zhou, Chao; Yang, Weifang; Wu, Bo; Lu, Hongsheng; Yang, Haihua

2015-01-01

Epidermal growth factor receptor (EGFR) is a new target for nasopharyngeal carcinoma (NPC) therapy. This prospective phase I study sought to determine the safety and recommended phase II dose of icotinib, a novel highly selective oral EGFR tyrosine kinase inhibitor, in combination with intensity-modulated radiotherapy (IMRT) in patients with NPC. Eligible patients with NPC received escalating doses of icotinib during IMRT. We treated six patients at a particular dose level until the maximum tolerated dose (MTD) was determined. The starting dose was 125 mg, once-daily and the dose was escalated to another level 125 mg, twice- and thrice- daily, until dose-limiting toxicity (DLT) occurred in two or more patients at a dose level. Expression and mutation analysis of EGFR were performed in all cases. A total of twelve patients were enrolled. Three patients experienced DLT (250 mg/day cohort) and MTD was 125 mg/day. Mucositis toxicity appears to be the major DLT. While EGFR expression in tumor tissue was detected in 75% (9/12) patients, EGFR mutation was detected in 16.67% (1/6) patients in 125 mg/day cohort, and 50% (3/6) in 250 mg/day cohort. The combination of icotinib (125 mg/day) and IMRT in patients with locally NPC had an acceptable safety profile and was well tolerated.

Cadmium accumulation and tolerance of Macleaya cordata: a newly potential plant for sustainable phytoremediation in Cd-contaminated soil.

PubMed

Nie, Jian; Liu, Yunguo; Zeng, Guangming; Zheng, Bohong; Tan, Xiaofei; Liu, Huan; Xie, Jieli; Gan, Chao; Liu, Wei

2016-05-01

Heavy metal pollution is a major concern of the public due to their threats to the safety of food chains. A 60-day pot experiment was conducted using Macleaya cordata as plant material to investigate the phytoremediation potential and anti-oxidative responses of M. cordata under different Cd stress. Significant growth inhibition phenomenon and toxic symptoms were not detected in the experiment. The high biomass of the plant provided high accumulation capacity for Cd with an average dry weight of 3.6 g. The maximum extraction amount of Cd was 393 μg·plant(-1), suggesting that this species had potential for phytoremediation of Cd-contaminated soil. A slight increase of chlorophyll (CHL) content was observed in Cd10 treatment. The plant was confirmed to have relatively high tolerance to the Cd stress on the basis of tolerance indexes (TI), relative water content, and CHLa/CHLb ratio. M. cordata could maintain high level of superoxide dismutase (SOD) activity under Cd stress, indicating strong tolerance capacity for reactive oxygen species (ROS) in plant cells. Catalase (CAT) activity show a certain range of decline in the experiment compare to the control. And peroxidase (POD) activity in leaves changed irregularly when compared to the control. The malondialdehyde (MDA) content increased as Cd concentration elevated compared to the control. In addition, as an inedible crop with relatively high economic value, M. cordata have shown the advantage of high biomass and high tolerance under Cd stress, which can provide a new plant resource for sustainable phytoremediation.

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...

Some physiological aspects of artificial gravity. [gravitational effects on human orthostatic tolerance and physical fitness

NASA Technical Reports Server (NTRS)

Cramer, D. B.; Graybiel, A.

1973-01-01

The effects of increasing artificial gravity exposure on four aspects of physiological fitness are examined in four young men who, prior to exposure, were deconditioned with bed rest and water immersion. The four aspects of physiological fitness are orthostatic tolerance, exercise tolerance, forearm endurance, and maximum strength. Orthostatic tolerance was sharply reduced by deconditioning and was substantially improved by walking in simulated lunar gravity (1/6 g) for 2.5 hours daily for 7 days or by walking in 1/2 g and 1 g for 1 hour daily for 3 days. Exercise tolerance was also sharply reduced by deconditioning but did not significantly improve with increasing g-exposure. Walking in 1 g for 1 hour daily for 3 days raised exercise tolerance only a little above the low produced by deconditioning. Forearm endurance and maximum strength were relatively unaffected by deconditioning and subsequent g-exposure.

Association of hormonal responses and performance of student pilots during acceleration training on the human centrifuge

NASA Astrophysics Data System (ADS)

Wirth, D.; Rohleder, N.; Welsch, H.

2005-08-01

Prediction of student pilots' +Gz tolerance by stress hormone levels would be a useful tool in aviation medicine. The aim of the present study was to analyze the relationship between neuroendocrine parameters with performance during acceleration training on the human centrifuge (HC).We investigated 21 student pilots during self-controlled acceleration training on the HC. Adrenocorticotropic hormone (ACTH), cortisol, epinephrine, and norepinephrine were measured after individual training sessions and at rest. Performance was defined by several characteristics including maximum tolerated acceleration. ACTH and cortisol, were significantly higher 20 minutes after acceleration training compared to the resting condition. Subjects tolerated a maximal acceleration of +6.69 Gz. HPA hormone levels and responses were associated with maximum tolerated acceleration +Gz. These findings support the expectation that acceleration- induced increases in stress hormones may enable the organism to tolerate a higher acceleration and could therefore be used as predictors for acceleration tolerance.

Systematic review of safety and tolerability of a complex micronutrient formula used in mental health.

PubMed

Simpson, J Steven A; Crawford, Susan G; Goldstein, Estelle T; Field, Catherine; Burgess, Ellen; Kaplan, Bonnie J

2011-04-18

Theoretically, consumption of complex, multinutrient formulations of vitamins and minerals should be safe, as most preparations contain primarily the nutrients that have been in the human diet for millennia, and at safe levels as defined by the Dietary Reference Intakes. However, the safety profile of commercial formulae may differ from foods because of the amounts and combinations of nutrients they contain. As these complex formulae are being studied and used clinically with increasing frequency, there is a need for direct evaluation of safety and tolerability. All known safety and tolerability data collected on one complex nutrient formula was compiled and evaluated. Data were assembled from all the known published and unpublished studies for the complex formula with the largest amount of published research in mental health. Biological safety data from 144 children and adults were available from six sources: there were no occurrences of clinically meaningful negative outcomes/effects or abnormal blood tests that could be attributed to toxicity. Adverse event (AE) information from 157 children and adults was available from six studies employing the current version of this formula, and only minor, transitory reports of headache and nausea emerged. Only one of the studies permitted a direct comparison between micronutrient treatment and medication: none of the 88 pediatric and adult participants had any clinically meaningful abnormal laboratory values, but tolerability data in the group treated with micronutrients revealed significantly fewer AEs and less weight gain. This compilation of safety and tolerability data is reassuring with respect to the broad spectrum approach that employs complex nutrient formulae as a primary treatment.

Plant Distribution Data Show Broader Climatic Limits than Expert-Based Climatic Tolerance Estimates

PubMed Central

Curtis, Caroline A.; Bradley, Bethany A.

2016-01-01

Background Although increasingly sophisticated environmental measures are being applied to species distributions models, the focus remains on using climatic data to provide estimates of habitat suitability. Climatic tolerance estimates based on expert knowledge are available for a wide range of plants via the USDA PLANTS database. We aim to test how climatic tolerance inferred from plant distribution records relates to tolerance estimated by experts. Further, we use this information to identify circumstances when species distributions are more likely to approximate climatic tolerance. Methods We compiled expert knowledge estimates of minimum and maximum precipitation and minimum temperature tolerance for over 1800 conservation plant species from the ‘plant characteristics’ information in the USDA PLANTS database. We derived climatic tolerance from distribution data downloaded from the Global Biodiversity and Information Facility (GBIF) and corresponding climate from WorldClim. We compared expert-derived climatic tolerance to empirical estimates to find the difference between their inferred climate niches (ΔCN), and tested whether ΔCN was influenced by growth form or range size. Results Climate niches calculated from distribution data were significantly broader than expert-based tolerance estimates (Mann-Whitney p values << 0.001). The average plant could tolerate 24 mm lower minimum precipitation, 14 mm higher maximum precipitation, and 7° C lower minimum temperatures based on distribution data relative to expert-based tolerance estimates. Species with larger ranges had greater ΔCN for minimum precipitation and minimum temperature. For maximum precipitation and minimum temperature, forbs and grasses tended to have larger ΔCN while grasses and trees had larger ΔCN for minimum precipitation. Conclusion Our results show that distribution data are consistently broader than USDA PLANTS experts’ knowledge and likely provide more robust estimates of climatic tolerance, especially for widespread forbs and grasses. These findings suggest that widely available expert-based climatic tolerance estimates underrepresent species’ fundamental niche and likely fail to capture the realized niche. PMID:27870859

Switching from rivaroxaban to warfarin: an open label pharmacodynamic study in healthy subjects

PubMed Central

Moore, Kenneth Todd; Byra, William; Vaidyanathan, Seema; Natarajan, Jaya; Ariyawansa, Jay; Salih, Hiba; Turner, Kenneth C

2015-01-01

Aims The primary objective was to explore the pharmacodynamic changes during transition from rivaroxaban to warfarin in healthy subjects. Safety, tolerability and pharmacokinetics were assessed as secondary objectives. Methods An open label, non-randomized, sequential two period study. In treatment period 1 (TP1), subjects received rivaroxaban 20 mg once daily (5 days), followed by co-administration with a warfarin loading dose regimen of 5 or 10 mg (for the 10 mg regimen, the dose could be uptitrated to attain target international normalized ratio [INR] ≥2.0) once daily (2–4 days). When trough INR values ≥2.0 were attained, rivaroxaban was discontinued and warfarin treatment continued as monotherapy (INR 2.0–3.0). During treatment period 2, subjects received the same warfarin regimen as in TP1, but without rivaroxaban. Results During co-administration, maximum INR and prothrombin time (PT) values were higher than with rivaroxaban or warfarin monotherapy. The mean maximum effect (Emax) for INR after co-administration was 2.79–4.15 (mean PT Emax 41.0–62.7 s), compared with 1.41–1.74 (mean PT Emax 20.1–25.2 s) for warfarin alone. However, rivaroxaban had the smallest effect on INR at trough rivaroxaban concentrations. Neither rivaroxaban nor warfarin significantly affected maximum plasma concentrations of the other drug. Conclusions The combined pharmacodynamic effects during co-administration of rivaroxaban and warfarin were greater than additive, but the pharmacokinetics of both drugs were unaffected. Co-administration was well tolerated. When transitioning from rivaroxaban to warfarin, INR monitoring during co-administration should be performed at the trough rivaroxaban concentration to minimize the effect of rivaroxaban on INR. PMID:25475601

First-in-man-proof of concept study with molidustat: a novel selective oral HIF-prolyl hydroxylase inhibitor for the treatment of renal anaemia.

PubMed

Böttcher, M; Lentini, S; Arens, E R; Kaiser, A; van der Mey, D; Thuss, U; Kubitza, D; Wensing, G

2018-07-01

Insufficient erythropoietin (EPO) synthesis is a relevant cause of renal anaemia in patients with chronic kidney disease. Molidustat, a selective hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor, increases endogenous EPO levels dose dependently in preclinical models. We examined the pharmacokinetics, safety, tolerability and effect on EPO levels of single oral doses of molidustat in healthy male volunteers. This was a single-centre, randomized, single-blind, placebo-controlled, group-comparison, dose-escalation study. Molidustat was administered at doses of 5, 12.5, 25, 37.5 or 50 mg as a polyethylene glycol-based solution. In total, 45 volunteers received molidustat and 14 received placebo. Molidustat was absorbed rapidly, and the mean maximum plasma concentration and area under the concentration-time curve increased dose dependently. The mean terminal half-life was 4.64-10.40 h. A significant increase in endogenous EPO was observed following single oral doses of molidustat of 12.5 mg and above. Geometric mean peak EPO levels were 14.8 IU l -1 (90% confidence interval 13.0, 16.9) for volunteers who received placebo and 39.8 IU l -1 (90% confidence interval: 29.4, 53.8) for those who received molidustat 50 mg. The time course of EPO levels resembled the normal diurnal variation in EPO. Maximum EPO levels were observed approximately 12 h postdose and returned to baseline after approximately 24-48 h. All doses of molidustat were well tolerated and there were no significant changes in vital signs or laboratory safety parameters. Oral administration of molidustat to healthy volunteers elicited a dose-dependent increase in endogenous EPO. These results support the ongoing development of molidustat as a potential new treatment for patients with renal anaemia. © 2018 The British Pharmacological Society.

Combined use of transcranial magnetic stimulation and metal electrode implants: a theoretical assessment of safety considerations

NASA Astrophysics Data System (ADS)

Golestanirad, Laleh; Rouhani, Hossein; Elahi, Behzad; Shahim, Kamal; Chen, Robert; Mosig, Juan R.; Pollo, Claudio; Graham, Simon J.

2012-12-01

This paper provides a theoretical assessment of the safety considerations encountered in the simultaneous use of transcranial magnetic stimulation (TMS) and neurological interventions involving implanted metallic electrodes, such as electrocorticography. Metal implants are subject to magnetic forces due to fast alternating magnetic fields produced by the TMS coil. The question of whether the mechanical movement of the implants leads to irreversible damage of brain tissue is addressed by an electromagnetic simulation which quantifies the magnitude of imposed magnetic forces. The assessment is followed by a careful mechanical analysis determining the maximum tolerable force which does not cause irreversible tissue damage. Results of this investigation provide useful information on the range of TMS stimulator output powers which can be safely used in patients having metallic implants. It is shown that conventional TMS applications can be considered safe when applied on patients with typical electrode implants as the induced stress in the brain tissue remains well below the limit of tissue damage.

A High Capacity Polymeric Micelle of Paclitaxel: Implication of High Dose Drug Therapy to Safety and In Vivo Anti-Cancer Activity

PubMed Central

He, Zhijian; Wan, Xiaomeng; Schulz, Anita; Bludau, Herdis; Dobrovolskaia, Marina A.; Stern, Stephan T.; Montgomery, Stephanie A.; Yuan, Hong; Li, Zibo; Alakhova, Daria; Sokolsky, Marina; Darr, David B.; Perou, Charles M.; Jordan, Rainer; Luxenhofer, Robert; Kabanov, Alexander V.

2016-01-01

The poor solubility of paclitaxel (PTX), the commercially most successful anticancer drug, has long been hampering the development of suitable formulations. Here, we present translational evaluation of a nanoformulation of PTX, which is characterized by a facile preparation, extraordinary high drug loading of 50 % wt. and PTX solubility of up to 45 g/L, excellent shelf stability and controllable, sub-100 nm size. We observe favorable in vitro and in vivo safety profiles and a higher maximum tolerated dose compared to clinically approved formulations. Pharmacokinetic analysis reveals that the higher dose administered leads to a higher exposure of the tumor to PTX. As a result, we observed improved therapeutic outcome in orthotopic tumor models including particularly faithful and aggressive “T11” mouse claudin-low breast cancer orthotopic, syngeneic transplants. The promising preclinical data on the presented PTX nanoformulation showcase the need to investigate new excipients and is a robust basis to translate into clinical trials. PMID:27315213

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.

40 CFR 180.505 - Emamectin; tolerances for residues.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 25 2012-07-01 2012-07-01 false Emamectin; tolerances for residues... § 180.505 Emamectin; tolerances for residues. (a) General. (1) Tolerances are established for combined residues of emamectin (a mixture of a minimum of 90% 4′-epi-methylamino-4′-deoxyavermectin B1a and maximum...

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.

First-in-human phase 1 study of the BTK inhibitor GDC-0853 in relapsed or refractory B-cell NHL and CLL.

PubMed

Byrd, John C; Smith, Stephen; Wagner-Johnston, Nina; Sharman, Jeff; Chen, Andy I; Advani, Ranjana; Augustson, Bradley; Marlton, Paula; Renee Commerford, S; Okrah, Kwame; Liu, Lichuan; Murray, Elaine; Penuel, Elicia; Ward, Ashley F; Flinn, Ian W

2018-02-27

GDC-0853 is a selective, reversible, and non-covalent inhibitor of Bruton's tyrosine kinase (BTK) that does not require interaction with the Cys481 residue for activity. In this first-in-human phase 1 study we evaluated safety, tolerability, pharmacokinetics, and activity of GDC-0853 in patients with relapsed or refractory non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukemia (CLL). Twenty-four patients, enrolled into 3 cohorts, including 6 patients who were positive for the C481S mutation, received GDC-0853 at 100, 200, or 400 mg once daily, orally. There were no dose limiting toxicities. GDC-0853 was well tolerated and the maximum tolerated dose (MTD) was not reached due to premature study closure. Common adverse events (AEs) in ≥ 15% of patients regardless of causality included fatigue (37%), nausea (33%), diarrhea (29%), thrombocytopenia (25%), headache (20%), and abdominal pain, cough, and dizziness (16%, each). Nine serious AEs were reported in 5 patients of whom 2 had fatal outcomes (confirmed H1N1 influenza and influenza pneumonia). A third death was due to progressive disease. Eight of 24 patients responded to GDC-0853: 1 complete response, 4 partial responses, and 3 partial responses with lymphocytosis, including 1 patient with the C481S mutation. Two additional C481S mutation patients had a decrease in size of target tumors (-23% and -44%). These data demonstrate GDC-0853 was generally well-tolerated with antitumor activity.

Safety studies on intravenous administration of oncolytic recombinant vesicular stomatitis virus in purpose-bred beagle dogs.

PubMed

LeBlanc, Amy K; Naik, Shruthi; Galyon, Gina D; Jenks, Nathan; Steele, Mike; Peng, Kah-Whye; Federspiel, Mark J; Donnell, Robert; Russell, Stephen J

2013-12-01

VSV-IFNβ-NIS is a novel recombinant oncolytic vesicular stomatitis virus (VSV) with documented efficacy and safety in preclinical murine models of cancer. To facilitate clinical translation of this promising oncolytic therapy in patients with disseminated cancer, we are utilizing a comparative oncology approach to gather data describing the safety and efficacy of systemic VSV-IFNβ-NIS administration in dogs with naturally occurring cancer. In support of this, we executed a dose-escalation study in purpose-bred dogs to determine the maximum tolerated dose (MTD) of systemic VSV-hIFNβ-NIS, characterize the adverse event profile, and describe routes and duration of viral shedding in healthy, immune-competent dogs. The data indicate that an intravenous dose of 10(10) TCID50 is well tolerated in dogs. Expected adverse events were mild to moderate fever, self-limiting nausea and vomiting, lymphopenia, and oral mucosal lesions. Unexpected adverse events included prolongation of partial thromboplastin time, development of bacterial urinary tract infection, and scrotal dermatitis, and in one dog receiving 10(11) TCID50 (10 × the MTD), the development of severe hepatotoxicity and symptoms of shock leading to euthanasia. Viral shedding data indicate that detectable viral genome in blood diminishes rapidly with anti-VSV neutralizing antibodies detectable in blood as early as day 5 postintravenous virus administration. While low levels of viral genome copies were detectable in plasma, urine, and buccal swabs of dogs treated at the MTD, no infectious virus was detectable in plasma, urine, or buccal swabs at any of the doses tested. These studies confirm that VSV can be safely administered systemically in dogs, justifying the use of oncolytic VSV as a novel therapy for the treatment of canine cancer.

Efficacy and safety of extended- versus immediate-release pramipexole in Japanese patients with advanced and L-dopa-undertreated Parkinson disease: a double-blind, randomized trial.

PubMed

Mizuno, Yoshikuni; Yamamoto, Mitsutoshi; Kuno, Sadako; Hasegawa, Kazuko; Hattori, Nobutaka; Kagimura, Tatsuro; Sarashina, Akiko; Rascol, Olivier; Schapira, Anthony H V; Barone, Paolo; Hauser, Robert A; Poewe, Werner

2012-01-01

To compare the efficacy, safety, tolerability, and trough plasma levels of pramipexole extended-release (ER) and pramipexole immediate-release (IR), and to assess the effects of overnight switching from an IR to an ER formulation, in L-dopa-treated patients with Parkinson disease (PD). After a 1- to 4-week screening/enrollment, 112 patients who had exhibited L-dopa-related problems or were receiving suboptimal L-dopa dosage were randomized in double-blind, double-dummy, 1:1 fashion to pramipexole ER once daily or pramipexole IR 2 to 3 times daily for 12 weeks, both titrated to a maximum daily dose of 4.5 mg. Successful completers of double-blind treatment were switched to open-label pramipexole ER, beginning with a 4-week dose-adjustment phase. Among the double-blind treatment patients (n = 56 in each group), Unified Parkinson's Disease Rating Scale Parts II+III total scores decreased significantly from baseline and to a similar degree with pramipexole ER and IR formulations. In each group, 47 double-blind patients (83.9%) reported adverse events (AEs), requiring withdrawal of 3 ER patients (5.4%) and 2 IR patients (3.6%). Trough plasma levels at steady state (at the same doses and dose-normalized concentrations) were also similar with both formulations. Among open-label treatment patients (n = 53 from IR to ER), 83% were successfully switched (no worsening of PD symptoms) to pramipexole ER. In L-dopa-treated patients, pramipexole ER and pramipexole IR demonstrated similar efficacy, safety, tolerability, and trough plasma levels. Patients can be safely switched overnight from pramipexole IR to pramipexole ER with no impact on efficacy.

Combined autophagy and HDAC inhibition: a phase I safety, tolerability, pharmacokinetic, and pharmacodynamic analysis of hydroxychloroquine in combination with the HDAC inhibitor vorinostat in patients with advanced solid tumors.

PubMed

Mahalingam, Devalingam; Mita, Monica; Sarantopoulos, John; Wood, Leslie; Amaravadi, Ravi K; Davis, Lisa E; Mita, Alain C; Curiel, Tyler J; Espitia, Claudia M; Nawrocki, Steffan T; Giles, Francis J; Carew, Jennifer S

2014-08-01

We previously reported that inhibition of autophagy significantly augmented the anticancer activity of the histone deacetylase (HDAC) inhibitor vorinostat (VOR) through a cathepsin D-mediated mechanism. We thus conducted a first-in-human study to investigate the safety, preliminary efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of the combination of the autophagy inhibitor hydroxychloroquine (HCQ) and VOR in patients with advanced solid tumors. Of 27 patients treated in the study, 24 were considered fully evaluable for study assessments and toxicity. Patients were treated orally with escalating doses of HCQ daily (QD) (d 2 to 21 of a 21-d cycle) in combination with 400 mg VOR QD (d one to 21). Treatment-related adverse events (AE) included grade 1 to 2 nausea, diarrhea, fatigue, weight loss, anemia, and elevated creatinine. Grade 3 fatigue and/or myelosuppression were observed in a minority of patients. Fatigue and gastrointestinal AE were dose-limiting toxicities. Six-hundred milligrams HCQ and 400 mg VOR was established as the maximum tolerated dose and recommended phase II regimen. One patient with renal cell carcinoma had a confirmed durable partial response and 2 patients with colorectal cancer had prolonged stable disease. The addition of HCQ did not significantly impact the PK profile of VOR. Treatment-related increases in the expression of CDKN1A and CTSD were more pronounced in tumor biopsies than peripheral blood mononuclear cells. Based on the safety and preliminary efficacy of this combination, additional clinical studies are currently being planned to further investigate autophagy inhibition as a new approach to increase the efficacy of HDAC inhibitors.

Single- and multiple-dose pharmacokinetics, pharmacodynamics, and safety of apixaban in healthy Chinese subjects

PubMed Central

Cui, Yimin; Song, Yan; Wang, Jessie; Yu, Zhigang; Schuster, Alan; Barrett, Yu Chen; Frost, Charles

2013-01-01

Background The pharmacokinetics (PK), pharmacodynamics (PD), and safety of apixaban were assessed in healthy Chinese subjects in this randomized, placebo-controlled, double-blind, single-sequence, single- and multiple-dose study. Subjects and methods Eighteen subjects 18–45 years of age were randomly assigned (2:1 ratio) to receive apixaban or matched placebo. Subjects received a single 10 mg dose of apixaban or placebo on day 1, followed by 10 mg apixaban or placebo twice daily for 6 days (days 4–9). The PK and PD of apixaban were assessed by collecting plasma samples for 72 hours following the dose on day 1 and the morning dose on day 9, and measuring apixaban concentration and anti-Xa activity. Safety was assessed via physical examinations, vital sign measurements, electrocardiograms, and clinical laboratory evaluations. Results PK analysis showed similar characteristics of apixaban after single and multiple doses, including a median time to maximum concentration of ~3 hours, mean elimination half-life of ~11 hours, and renal clearance of ~1.2 L/hour. The accumulation index was 1.7, consistent with twice-daily dosing and the observed elimination half-life. Single-dose data predict multiple-dose PK, therefore apixaban PK are time-independent. The relationship between anti-Xa activity and plasma apixaban concentrations appears to be linear. Apixaban was safe and well tolerated, with no bleeding-related adverse events reported. Conclusion Apixaban was safe and well tolerated in healthy Chinese subjects. Apixaban PK and PD were predictable and consistent with findings from previous studies in Asian and non-Asian subjects. The administration of apixaban does not require any dose modification based on race. PMID:24353445

Safety and pharmacokinetic profiles of phosphorodiamidate morpholino oligomers with activity against ebola virus and marburg virus: results of two single-ascending-dose studies.

PubMed

Heald, Alison E; Iversen, Patrick L; Saoud, Jay B; Sazani, Peter; Charleston, Jay S; Axtelle, Tim; Wong, Michael; Smith, William B; Vutikullird, Apinya; Kaye, Edward

2014-11-01

Two identical single-ascending-dose studies evaluated the safety and pharmacokinetics (PK) of AVI-6002 and AVI-6003, two experimental combinations of phosphorodiamidate morpholino oligomers with positive charges (PMOplus) that target viral mRNA encoding Ebola virus and Marburg virus proteins, respectively. Both AVI-6002 and AVI-6003 were found to suppress disease in virus-infected nonhuman primates in previous studies. AVI-6002 (a combination of AVI-7537 and AVI-7539) or AVI-6003 (a combination of AVI-7287 and AVI-7288) were administered as sequential intravenous (i.v.) infusions of a 1:1 fixed dose ratio of the two subcomponents. In each study, 30 healthy male and female subjects between 18 and 50 years of age were enrolled in six-dose escalation cohorts of five subjects each and received a single i.v. infusion of active study drug (0.005, 0.05, 0.5, 1.5, 3, and 4.5 mg/kg per component) or placebo in a 4:1 ratio. Both AVI-6002 and AVI-6003 were safe and well tolerated at the doses studied. A maximum tolerated dose was not observed in either study. The four chemically similar PMOplus components exhibited generally similar PK profiles. The mean peak plasma concentration and area under the concentration-time curve values of the four components exhibited dose-proportional PK. The estimated plasma half-life of all four components was 2 to 5 h. The safety of the two combinations and the PK of the four components were similar, regardless of the target RNA sequence. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Safety, pharmacokinetics and efficacy findings in an open-label, single-arm study of weekly paclitaxel plus lapatinib as first-line therapy for Japanese women with HER2-positive metastatic breast cancer.

PubMed

Inoue, Kenichi; Kuroi, Katsumasa; Shimizu, Satoru; Rai, Yoshiaki; Aogi, Kenjiro; Masuda, Norikazu; Nakayama, Takahiro; Iwata, Hiroji; Nishimura, Yuichiro; Armour, Alison; Sasaki, Yasutsuna

2015-12-01

Lapatinib is the human epidermal growth factor receptor 2 (HER2) targeting agent approved globally for HER2-positive metastatic breast cancer (MBC). The efficacy, safety and pharmacokinetics (PK) of lapatinib combined with paclitaxel (L+P) were investigated in this study, to establish clear evidence regarding the combination in Japanese patients. In this two-part, single-arm, open-label study, the tolerability of L+P as first-line treatment in Japanese patients with HER2-positive MBC was evaluated in six patients in the first part, and the safety, efficacy and PK were evaluated in a further six patients (making a total of twelve patients) in the second part. Eligible women were enrolled and received lapatinib 1500 mg once daily and paclitaxel 80 mg/m(2) weekly for at least 6 cycles. The only dose-limiting toxicity reported was Grade 3 diarrhea in one patient. The systemic exposure to maximum plasma concentration and area under the plasma concentration curve (AUC) for lapatinib, as well as the AUC of paclitaxel, were increased when combined. The most common adverse events (AEs) related to the study treatment were alopecia, diarrhea and decreased hemoglobin. The majority of drug-related AEs were Grade 1 or 2. The median overall survival was 35.6 months (95 % confidence interval 23.9, not reached). The response rate and clinical benefit rate were both 83 % (95 % confidence interval 51.6, 97.9). The L+P treatment was well tolerated in Japanese patients with HER2-positive MBC. Although the PK profiles of lapatinib and paclitaxel influenced each other, the magnitudes were not greatly different from those in non-Japanese patients.

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.

A phase 1 trial of ABT-510 concurrent with standard chemoradiation for patients with newly diagnosed glioblastoma.

PubMed

Nabors, Louis B; Fiveash, John B; Markert, James M; Kekan, Manasi S; Gillespie, George Y; Huang, Zhi; Johnson, Martin J; Meleth, Sreelatha; Kuo, Huichien; Gladson, Candece L; Fathallah-Shaykh, Hassan M

2010-03-01

To determine the maximum tolerated dose of ABT-510, a thrombospondin-1 mimetic drug with antiangiogenic properties, when used concurrently with temozolomide and radiotherapy in patients with newly diagnosed glioblastoma. Phase 1 dose-escalation clinical trial. Comprehensive Cancer Center, University of Alabama at Birmingham. Patients A total of 23 patients with newly diagnosed, histologically verified glioblastoma enrolled between April 2005 and January 2007. Four cohorts of 3 patients each received subcutaneous ABT-510 injection at doses of 20, 50, 100, or 200 mg/d. The maximum cohort was expanded to 14 patients to obtain additional safety and gene expression data. The treatment plan included 10 weeks of induction phase (temozolomide and radiotherapy with ABT-510 for 6 weeks plus ABT-510 monotherapy for 4 weeks) followed by a maintenance phase of ABT-510 and monthly temozolomide. Patients were monitored with brain magnetic resonance imaging and laboratory testing for dose-limiting toxicities, defined as grades 3 or 4 nonhematological toxicities and grade 4 hematological toxicities. Therapy was discontinued if 14 maintenance cycles were completed, disease progression occurred, or if the patient requested withdrawal. Disease progression, survival statistics, and gene expression arrays were analyzed. There were no grade 3 or 4 dose-limiting toxicity events that appeared related to ABT-510 for the dose range of 20 to 200 mg/d. A maximum tolerated dose was not defined. Most adverse events were mild, and injection-site reactions. The median time to tumor progression was 45.9 weeks, and the median overall survival time was 64.4 weeks. Gene expression analysis using TaqMan low-density arrays identified angiogenic genes that were differentially expressed in the brains of controls compared with patients with newly diagnosed glioblastoma, and identified FGF-1 and TIE-1 as being downregulated in patients who had better clinical outcomes. ABT-510, at subcutaneous doses up to 200 mg/d, is tolerated well with concurrent temozolomide and radiotherapy in patients with newly diagnosed glioblastoma, and low-density arrays provide a useful method of exploring gene expression profiles.

Lacosamide cardiac safety: a thorough QT/QTc trial in healthy volunteers.

PubMed

Kropeit, D; Johnson, M; Cawello, W; Rudd, G D; Horstmann, R

2015-11-01

To determine whether lacosamide prolongs the corrected QT interval (QTc). In this randomized, double-blind, positive- and placebo-controlled, parallel-design trial, healthy volunteers were randomized to lacosamide 400 mg/day (maximum-recommended daily dose, 6 days), lacosamide 800 mg/day (supratherapeutic dose, 6 days), placebo (6 days), or moxifloxacin 400 mg/day (3 days). Variables included maximum time-matched change from baseline in QT interval individually corrected for heart rate ([HR] QTcI), other ECG parameters, pharmacokinetics (PK), and safety/tolerability. The QTcI mean maximum difference from placebo was -4.3 ms and -6.3 ms for lacosamide 400 and 800 mg/day; upper limits of the 2-sided 90% confidence interval were below the 10 ms non-inferiority margin (-0.5 and -2.5 ms, respectively). Placebo-corrected QTcI for moxifloxacin was +10.4 ms (lower 90% confidence bound >0 [6.6 ms]), which established assay sensitivity for this trial. As lacosamide did not increase QTcI, the trial is considered a negative QTc trial. There was no dose-related or clinically relevant effect on QRS duration. HR increased from baseline by ~5 bpm with lacosamide 800 mg/day versus placebo. Placebo-subtracted mean increases in PR interval at tmax were 7.3 ms (400 mg/day) and 11.9 ms (800 mg/day). There were no findings of second-degree or higher atrioventricular block. Adverse events (AEs) were dose related and most commonly involved the nervous and gastrointestinal systems. Lacosamide (≤ 800 mg/day) did not prolong the QTc interval. Lacosamide caused a small, dose-related increase in mean PR interval that was not associated with AEs. Cardiac, overall safety, and PK profiles for lacosamide in healthy volunteers were consistent with those observed in patients with partial-onset seizures. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Safety, Tolerability and Pharmacokinetics of Single Doses of Oxytocin Administered via an Inhaled Route in Healthy Females: Randomized, Single-blind, Phase 1 Study.

PubMed

Fernando, Disala; Siederer, Sarah; Singh, Sunita; Schneider, Ian; Gupta, Ashutosh; Powell, Marcy; Richards, Duncan; McIntosh, Michelle P; Lambert, Peter; Fowles, Susan

2017-08-01

The utility of intramuscular (IM) oxytocin for the prevention of postpartum hemorrhage in resource-poor settings is limited by the requirement for temperature-controlled storage and skilled staff to administer the injection. We evaluated the safety, tolerability and pharmacokinetics (PK) of a heat-stable, inhaled (IH) oxytocin formulation. This phase 1, randomized, single-center, single-blind, dose-escalation, fixed-sequence study (NCT02542813) was conducted in healthy, premenopausal, non-pregnant, non-lactating women aged 18-45years. Subjects initially received IM oxytocin 10 international units (IU) on day 1, IH placebo on day 2, and IH oxytocin 50μg on day 3. Subjects were then randomized 4:1 using validated GSK internal software to IH placebo or ascending doses of IH oxytocin (200, 400, 600μg). PK was assessed by comparing systemic exposure (maximum observed plasma concentration, area under the concentration-time curve, and plasma concentrations at 10 and 30min post dose) for IH versus IM oxytocin. Adverse events (AEs), spirometry, laboratory tests, vital signs, electrocardiograms, physical examinations, and cardiac telemetry were assessed. Subjects were recruited between September 14, 2015 and October 12, 2015. Of the 16 subjects randomized following initial dosing, 15 (IH placebo n=3; IH oxytocin n=12) completed the study. IH (all doses) and IM oxytocin PK profiles were comparable in shape. However, systemic exposure with IH oxytocin 400μg most closely matched IM oxytocin 10IU. Systemic exposure was approximately dose proportional for IH oxytocin. No serious AEs were reported. No clinically significant findings were observed for any safety parameters. These data suggest that similar oxytocin systemic exposure can be achieved with IM and IH administration routes, and no safety concerns were identified with either route. The inhalation route may offer the opportunity to increase access to oxytocin for women giving birth in resource-poor settings. Copyright © 2017. Published by Elsevier B.V.

A randomised, single-blind, single-dose, three-arm, parallel-group study in healthy subjects to demonstrate pharmacokinetic equivalence of ABP 501 and adalimumab.

PubMed

Kaur, Primal; Chow, Vincent; Zhang, Nan; Moxness, Michael; Kaliyaperumal, Arunan; Markus, Richard

2017-03-01

To demonstrate pharmacokinetic (PK) similarity of biosimilar candidate ABP 501 relative to adalimumab reference product from the USA and European Union (EU) and evaluate safety, tolerability and immunogenicity of ABP 501. Randomised, single-blind, single-dose, three-arm, parallel-group study; healthy subjects were randomised to receive ABP 501 (n=67), adalimumab (USA) (n=69) or adalimumab (EU) (n=67) 40 mg subcutaneously. Primary end points were area under the serum concentration-time curve from time 0 extrapolated to infinity (AUC inf ) and the maximum observed concentration (C max ). Secondary end points included safety and immunogenicity. AUC inf and C max were similar across the three groups. Geometrical mean ratio (GMR) of AUC inf was 1.11 between ABP 501 and adalimumab (USA), and 1.04 between ABP 501 and adalimumab (EU). GMR of C max was 1.04 between ABP 501 and adalimumab (USA) and 0.96 between ABP 501 and adalimumab (EU). The 90% CIs for the GMRs of AUC inf and C max were within the prespecified standard PK equivalence criteria of 0.80 to 1.25. Treatment-related adverse events were mild to moderate and were reported for 35.8%, 24.6% and 41.8% of subjects in the ABP 501, adalimumab (USA) and adalimumab (EU) groups; incidence of antidrug antibodies (ADAbs) was similar among the study groups. Results of this study demonstrated PK similarity of ABP 501 with adalimumab (USA) and adalimumab (EU) after a single 40-mg subcutaneous injection. No new safety signals with ABP 501 were identified. The safety and tolerability of ABP 501 was similar to the reference products, and similar ADAb rates were observed across the three groups. EudraCT number 2012-000785-37; Results. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

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...

40 CFR 180.422 - Tralomethrin; tolerances for residues.

Code of Federal Regulations, 2010 CFR

2010-07-01

...-handling establishments, including food service, manufacturing, and processing establishments, such as... shall be limited to a maximum of 0.06 percent active ingredient. Contamination of food and food-contact...) PESTICIDE PROGRAMS TOLERANCES AND EXEMPTIONS FOR PESTICIDE CHEMICAL RESIDUES IN FOOD Specific Tolerances...

Systematic review of safety and tolerability of a complex micronutrient formula used in mental health

PubMed Central

2011-01-01

Background Theoretically, consumption of complex, multinutrient formulations of vitamins and minerals should be safe, as most preparations contain primarily the nutrients that have been in the human diet for millennia, and at safe levels as defined by the Dietary Reference Intakes. However, the safety profile of commercial formulae may differ from foods because of the amounts and combinations of nutrients they contain. As these complex formulae are being studied and used clinically with increasing frequency, there is a need for direct evaluation of safety and tolerability. Methods All known safety and tolerability data collected on one complex nutrient formula was compiled and evaluated. Results Data were assembled from all the known published and unpublished studies for the complex formula with the largest amount of published research in mental health. Biological safety data from 144 children and adults were available from six sources: there were no occurrences of clinically meaningful negative outcomes/effects or abnormal blood tests that could be attributed to toxicity. Adverse event (AE) information from 157 children and adults was available from six studies employing the current version of this formula, and only minor, transitory reports of headache and nausea emerged. Only one of the studies permitted a direct comparison between micronutrient treatment and medication: none of the 88 pediatric and adult participants had any clinically meaningful abnormal laboratory values, but tolerability data in the group treated with micronutrients revealed significantly fewer AEs and less weight gain. Conclusions This compilation of safety and tolerability data is reassuring with respect to the broad spectrum approach that employs complex nutrient formulae as a primary treatment. PMID:21501484

A retrospective analysis of chemotherapy switch suggests improved outcome in surgically removed, biologically aggressive canine haemangiosarcoma.

PubMed

Finotello, R; Henriques, J; Sabattini, S; Stefanello, D; Felisberto, R; Pizzoni, S; Ferrari, R; Marconato, L

2017-06-01

Haemangiosarcoma (HSA) has an aggressive biological behaviour and carries a poor prognosis, with less than 10% of treated dogs surviving longer than 1 year. In this retrospective study a varied metronomic chemotherapy (MC) regimen preceded by adjuvant doxorubicin-based maximum-tolerated dose chemotherapy (MTDC) was compared with MTDC, in terms of efficacy [time to metastasis, (TTM) and survival time (ST)] and safety in dogs with biologically aggressive HSA. Dogs were eligible if they had no metastasis after MTDC and received either no further chemotherapy or MC maintenance. Twelve dogs received MTDC, and 10 received MC thereafter. Median TTM and ST were significantly longer for dogs receiving MTDC-MC (not reached versus 150 days, P = 0.028; and not reached versus 168 days, P = 0.030, respectively). Treatment was well tolerated. MTDC followed by MC is safe and suggests improved TTM and ST in dogs with surgically removed, biologically aggressive HSA that are treated in the microscopic setting. © 2016 John Wiley & Sons Ltd.

Heavy metals in rice samples on the Torbat-Heidarieh market, Iran.

PubMed

Roya, Amiri Qandashtani; Ali, Mohamadi Sani

2017-03-01

Levels of the heavy metals arsenic (As), cadmium (Cd) and lead (Pb) were determined in rice samples imported from India and Pakistan and marketed in Torbat-Heidarieh, Iran. To assess the safety of dietary intake of these metals by rice, the estimated weekly intake (EWI) was calculated and compared with the provisional tolerable weekly intake (PTWI). The results indicated that mean values for Pb and cadmium in imported rice were considerably higher than the safe limit as set by FAO/WHO. EWI for cadmium and As among the consumed types of imported rice was lower than the PTWI. The results also revealed that the weekly intake of Pb was higher than the maximum weekly intake recommended by WHO/FAO.

High-temperature responses of North American cacti

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

Smith, S.D.; Didden-Zopfy, B.; Nobel, P.S.

1984-04-01

High-temperature tolerances of 14 species of North American cacti were investigated. A reduction in the proportion of chlorenchyma cells taking up a vital stain (neutral red) and reduced nocturnal acid accumulation were used as indicators of high-temperature damage. All species tolerated relatively high tissue temperatures, the mean maximum tolerance being 64/sup 0/C, with an absolute maximum of 69/sup 0/ for two species of ferocactus. Such tissue tolerances to high temperature may be unsurpassed in vascular plants. Morphological features can affect tissue temperatures. Specifically, thin-stemmed species such as the cylindropuntias attain lower maximum temperatures under identical microclimatic conditions than do moremore » massive species; they also tend to be less tolerant of high-temperature stress. Stem diameter changes of three species of columnar ceriod cacti along a Sonoran Desert latitudinal transect were previously attributed to adaptation to progressively colder temperatures northward. Such changes can also be interpreted as a morphological adaptation to high temperatures, particularly in the southern Sonoran Desert. Interspecific differences in high-temperature tolerance may account for distributional differences among other species. Acclimation of high-temperature tolerances in response to increasing day/night air temperatures was observed in all 14 species, especially at higher growh temperatures. From 40/sup 0/ day/30/sup 0/ night to 50/sup 0//40/sup 0/, the tolerable tissue temperatures increased an average of 6/sup 0/. Half-times for the acclimation shifts were 1-3d. Although cacti attain extremely high tissue temperatures in desert habitats, tolerance of high temperatures and pronounced acclimation potential allow them to occur in some of the hottest habitats in North America.« less

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.

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...

Safety assessment of a novel active ingredient, acetyl aspartic acid, according to the EU Cosmetics Regulation and the Scientific Committee on Consumer Safety guidelines.

PubMed

Daly, P; Moran, G

2015-10-01

Acetyl aspartic acid (A-A-A) was proposed as a new novel active ingredient for use in cosmetics. The safety of A-A-A was assessed by following an in-house-developed 'New Ingredient Testing Strategy', which was designed in accordance with the Scientific Committee on Consumer Safety (SCCS) notes of guidance and the requirements of Annex I of the EU Cosmetics Regulation. The aim of the project was to determine whether A-A-A was safe for use in cosmetics and to determine a maximum permitted safe level in the formulations. A literature review was conducted, consulting over 40 different information sources. This highlighted a number of gaps which required testing data. A-A-A was tested for phototoxicity according to OECD test guideline 432, skin irritation according to OECD test guideline 439 and eye irritation according to OECD test guideline 437. Dermal absorption of A-A-A was measured according to OECD test guideline 428 and was used to calculate the margin of safety (MoS). Finally, A-A-A was tested in a human repeat insult patch test (HRIPT) and a 14-day in-use tolerance study. A-A-A was non-phototoxic and was non-irritating to skin and eyes in in vitro testing. Dermal absorption was calculated to be 5%. The MoS for A-A-A was 351, at a level of 5%, for all cosmetic product types, indicating no systemic safety toxicity concern. A-A-A at 5% under occlusive patch on a panel of 50 adult volunteers induced no skin irritation or allergic reaction in the HRIPT study. Finally, repeated application of A-A-A to the periocular area, twice per day for 14 days, in 21 female volunteers, demonstrated that 1% A-A-A was well tolerated following dermatological and ophthalmological assessment in a cosmetic formulation. A-A-A was assessed as safe by the cosmetic safety assessor for use in cosmetics at a level of 5% in all cosmetic product types, in line with the requirements of the EU Cosmetics Regulation and in accordance with the SCCS notes of guidance. © 2015 Society of Cosmetic Scientists and the Société Française de Cosmétologie.

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

PubMed

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

2000-04-01

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

A randomised, double-blind, placebo-controlled phase 1 study of the safety, tolerability and pharmacodynamics of volixibat in overweight and obese but otherwise healthy adults: implications for treatment of non-alcoholic steatohepatitis.

PubMed

Palmer, Melissa; Jennings, Lee; Silberg, Debra G; Bliss, Caleb; Martin, Patrick

2018-03-16

Accumulation of toxic free cholesterol in hepatocytes may cause hepatic inflammation and fibrosis. Volixibat inhibits bile acid reuptake via the apical sodium bile acid transporter located on the luminal surface of the ileum. The resulting increase in bile acid synthesis from cholesterol could be beneficial in patients with non-alcoholic steatohepatitis. This adaptive dose-finding study investigated the safety, tolerability, pharmacodynamics, and pharmacokinetics of volixibat. Overweight and obese adults were randomised 3:1 to double-blind volixibat or placebo, respectively, for 12 days. Volixibat was initiated at a once-daily dose of 20 mg, 40 mg or 80 mg. Based on the assessment of predefined safety events, volixibat dosing was either escalated or reduced. Other dose regimens (titrations and twice-daily dosing) were also evaluated. Assessments included safety, tolerability, stool hardness, faecal bile acid (FBA) excretion, and serum levels of 7α-hydroxy-4-cholesten-3-one (C4) and lipids. All 84 randomised participants (volixibat, 63; placebo, 21) completed the study, with no serious adverse events at doses of up to 80 mg per day (maximum assessed dose). The median number of daily bowel evacuations increased from 1 (range 0-4) to 2 (0-8) during volixibat treatment, and stool was looser with volixibat than placebo. Volixibat was minimally absorbed; serum levels were rarely quantifiable at any dose or sampling time point, thereby precluding pharmacokinetic analyses. Mean daily FBA excretion was 930.61 μmol (standard deviation [SD] 468.965) with volixibat and 224.75 μmol (195.403) with placebo; effects were maximal at volixibat doses ≥20 mg/day. Mean serum C4 concentrations at day 12 were 98.767 ng/mL (standard deviation, 61.5841) with volixibat and 16.497 ng/mL (12.9150) with placebo. Total and low-density lipoprotein cholesterol levels decreased in the volixibat group, with median changes of - 0.70 mmol/L (range - 2.8 to 0.4) and - 0.6990 mmol/L (- 3.341 to 0.570), respectively. This study indicates that maximal inhibition of bile acid reabsorption, as assessed by FBA excretion, occurs at volixibat doses of ≥20 mg/day in obese and overweight adults, without appreciable change in gastrointestinal tolerability. These findings guided dose selection for an ongoing phase 2 study in patients with non-alcoholic steatohepatitis. ClinicalTrials.gov identifier: NCT02287779 (registration first received 6 November 2014).

Heat shock protein expression enhances heat tolerance of reptile embryos

PubMed Central

Gao, Jing; Zhang, Wen; Dang, Wei; Mou, Yi; Gao, Yuan; Sun, Bao-Jun; Du, Wei-Guo

2014-01-01

The role of heat shock proteins (HSPs) in heat tolerance has been demonstrated in cultured cells and animal tissues, but rarely in whole organisms because of methodological difficulties associated with gene manipulation. By comparing HSP70 expression patterns among representative species of reptiles and birds, and by determining the effect of HSP70 overexpression on embryonic development and hatchling traits, we have identified the role of HSP70 in the heat tolerance of amniote embryos. Consistent with their thermal environment, and high incubation temperatures and heat tolerance, the embryos of birds have higher onset and maximum temperatures for induced HSP70 than do reptiles, and turtles have higher onset and maximum temperatures than do lizards. Interestingly, the trade-off between benefits and costs of HSP70 overexpression occurred between life-history stages: when turtle embryos developed at extreme high temperatures, HSP70 overexpression generated benefits by enhancing embryo heat tolerance and hatching success, but subsequently imposed costs by decreasing heat tolerance of surviving hatchlings. Taken together, the correlative and causal links between HSP70 and heat tolerance provide, to our knowledge, the first unequivocal evidence that HSP70 promotes thermal tolerance of embryos in oviparous amniotes. PMID:25080340

Safety and Tolerability of Methylphenidate in Preschool Children with ADHD

ERIC Educational Resources Information Center

Wigal, Tim; Greenhill, Laurence; Chuang, Shirley; McGough, James; Vitiello, Benedetto; Skrobala, Anne; Swanson, James; Wigal, Sharon; Abikoff, Howard; Kollins, Scott; McCracken, James; Riddle, Mark; Posner, Kelly; Ghuman, Jaswinder; Davies, Mark; Thorp, Ben; Stehli, Annamarie

2006-01-01

Objective: To report on the safety and tolerability of methylphenidate (MPH) 3- to 5-year-old children with attention-deficit/hyperactivity disorder (ADHD) during 1 year of treatment. Method: Exactly 183 children (3-5 years old) entered a treatment study of MPH, consisting of a 1-week open-label lead-in (n = 183); a 5-week placebo-controlled,…

Bioterrorism Preparedness for Infectious Disease (BTPID) Proposal

DTIC Science & Technology

2007-01-01

approximately $210,000/ year x 5 years. (Pending) Safety, Tolerability and Immunogenicity of ACAM3000 Modified Vaccinia Ankara (MVA) Small Pox ...Hospital. • (Pending) Safety, Tolerability and Immunogenicity of ACAM3000 Modified Vaccinia Ankara (MVA) Small Pox Vaccine in HIV-Seropositive...choosing optimal pox virus derived vectors as vaccines in terms of reducing clinical reactogenicity and inducing dendritic cell (DC) aturation. 2006 Elsevier

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.

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).

Long-acting atypical injectable antipsychotics in the treatment of schizophrenia: safety and tolerability review.

PubMed

Cañas, Fernando; Möller, Hans-Jürgen

2010-09-01

Although atypical antipsychotics have beneficial efficacy and tolerance, non-adherence and partial adherence remain in patients treated for schizophrenia. Long-acting injectable or depot atypical antipsychotics offer better medication adherence and tolerability advantages. Currently, two drugs are available for the treatment of schizophrenia, risperidone long-acting injectable (RLAI) and olanzapine pamoate (OP). Short- and long-term safety and tolerability data on RLAI and OP from January 2006 through September 2009 were reviewed by performing Medline and PubMed searches, reviewing abstracts and poster presentations, and viewing available material from the FDA and European Medicines Agency. RLAI and OP show good short- and long-term safety when treating patients with schizophrenia, with uncommon discontinuation due to adverse effects. RLAI and OP data show rare problems with injection site reactions and patients exposed to injectable treatments prefer to continue injections. Infrequent but serious post-injection delirium sedation syndrome occurred after 1% of OP injections. Weight gain was generally higher among patients treated with OP versus RLAI. Healthcare providers, patients and family members should be made aware of the safety and benefits of long-acting injectable atypical antipsychotics in order to diminish the unnecessary restrictions of these therapies for patients with schizophrenia.

Thermal tolerance and climate warming sensitivity in tropical snails.

PubMed

Marshall, David J; Rezende, Enrico L; Baharuddin, Nursalwa; Choi, Francis; Helmuth, Brian

2015-12-01

Tropical ectotherms are predicted to be especially vulnerable to climate change because their thermal tolerance limits generally lie close to current maximum air temperatures. This prediction derives primarily from studies on insects and lizards and remains untested for other taxa with contrasting ecologies. We studied the HCT (heat coma temperatures) and ULT (upper lethal temperatures) of 40 species of tropical eulittoral snails (Littorinidae and Neritidae) inhabiting exposed rocky shores and shaded mangrove forests in Oceania, Africa, Asia and North America. We also estimated extremes in animal body temperature at each site using a simple heat budget model and historical (20 years) air temperature and solar radiation data. Phylogenetic analyses suggest that HCT and ULT exhibit limited adaptive variation across habitats (mangroves vs. rocky shores) or geographic locations despite their contrasting thermal regimes. Instead, the elevated heat tolerance of these species (HCT = 44.5 ± 1.8°C and ULT = 52.1 ± 2.2°C) seems to reflect the extreme temperature variability of intertidal systems. Sensitivity to climate warming, which was quantified as the difference between HCT or ULT and maximum body temperature, differed greatly between snails from sunny (rocky shore; Thermal Safety Margin, TSM = -14.8 ± 3.3°C and -6.2 ± 4.4°C for HCT and ULT, respectively) and shaded (mangrove) habitats (TSM = 5.1 ± 3.6°C and 12.5 ± 3.6°C). Negative TSMs in rocky shore animals suggest that mortality is likely ameliorated during extreme climatic events by behavioral thermoregulation. Given the low variability in heat tolerance across species, habitat and geographic location account for most of the variation in TSM and may adequately predict the vulnerability to climate change. These findings caution against generalizations on the impact of global warming across ectothermic taxa and highlight how the consideration of nonmodel animals, ecological transitions, and behavioral responses may alter predictions of studies that ignore these biological details.

Comparative pharmacokinetics/pharmacodynamics of clopidogrel besylate and clopidogrel bisulfate in healthy Korean subjects.

PubMed

Kim, Bo-Hyung; Kim, Jung-Ryul; Lim, Kyoung Soo; Shin, Hyun-Suk; Yoon, Seo Hyun; Cho, Joo-Youn; Jang, In-Jin; Shin, Sang-Goo; Yu, Kyung-Sang

2012-12-01

Clopidogrel selectively inhibits platelet aggregation. Clopidogrel bisulfate (Plavix(®)) was first developed for atherothrombosis prevention and is commonly prescribed for this indication. A new clopidogrel formulation, clopidogrel besylate (KOVIX(®)), has recently been developed. This study was designed to compare the multiple-dose pharmacokinetics/pharmacodynamics and tolerability of clopidogrel besylate with those of clopidogrel bisulfate in 40 healthy male subjects. This was an open-label, randomized-sequence, multiple-dose, two-period, two-treatment crossover study. The subjects were randomly assigned to a sequence group that received two treatments: clopidogrel besylate 75 mg followed by clopidogrel bisulfate 75 mg, or vice versa. The subjects received a 300-mg loading dose on day 1 followed by 75 mg daily for the next 4 days. Serial blood samples were collected to determine the concentrations of clopidogrel and its carboxylic acid metabolite, SR26334. Platelet aggregation and bleeding times were measured. Tolerability was evaluated throughout the study. The clopidogrel plasma concentration-time profiles of the formulations were similar. The measured pharmacokinetic parameters did not differ significantly between the clopidogrel besylate and clopidogrel bisulfate groups. The geometric mean ratios of the clopidogrel besylate group to the clopidogrel bisulfate group with respect to the maximum plasma concentration (C(max)) and the area under the concentration-time curve (AUC) from time zero to the time of last measurable concentration (AUC(last)) were 0.96 (90 % confidence interval [CI] 0.82, 1.12) and 0.95 (0.81, 1.11), respectively. Moreover, the pharmacokinetic parameters of SR26334 did not differ significantly between the two treatment groups. Furthermore, the areas under the platelet aggregation inhibition-time curves (AUIC) and the maximum inhibitory effects (I(max)) did not differ significantly between the two groups. The geometric mean ratios (clopidogrel besylate to clopidogrel bisulfate) were 1.01 (90 % CI 0.95, 1.08) for the I(max) and 0.98 (0.89, 1.07) for the AUIC. Both formulations were well tolerated and exhibited comparable safety profiles. This study demonstrated that the pharmacokinetic/pharmacodynamic profiles of clopidogrel besylate were not significantly different from those of clopidogrel bisulfate. Both formulations were well tolerated in healthy subjects.

Phase I study of topical epigallocatechin-3-gallate (EGCG) in patients with breast cancer receiving adjuvant radiotherapy.

PubMed

Zhao, Hanxi; Zhu, Wanqi; Jia, Li; Sun, Xiaorong; Chen, Guanxuan; Zhao, Xianguang; Li, Xiaolin; Meng, Xiangjiao; Kong, Lingling; Xing, Ligang; Yu, Jinming

2016-01-01

The purpose of this study was to investigate the safety, tolerability and preliminary effectiveness of topical epigallocatechin-3-gallate (EGCG) for radiation dermatitis in patients with breast cancer receiving adjuvant radiotherapy. Patients with breast cancer who received radiotherapy to the chest wall after mastectomy were enrolled. EGCG solution was sprayed to the radiation field from the initiation of Grade 1 radiation dermatitis until 2 weeks after completion of radiotherapy. EGCG concentration escalated from 40 to 660 μmol l(-1) in 7 levels with 3-6 patients in each level. EGCG toxicity was graded using the NCI (National Cancer Institute Common Terminology Criteria for Adverse Events) v. 3.0. Any adverse event >Grade 1 attributed to EGCG was considered dose-limiting toxicity. The maximum tolerated dose was defined as the dose level that induced dose-limiting toxicity in more than one-third of patients at a given cohort. Radiation dermatitis was recorded weekly by the Radiation Therapy Oncology Group scoring and patient-reported symptoms. From March 2012 to August 2013, 24 patients were enrolled. Acute skin redness was observed in 1 patient and considered to be associated with the EGCG treatment at 140 μmol l(-1) level. Three more patients were enrolled at this level and did not experience toxicity to EGCG. The dose escalation stopped at 660 μmol l(-1). No other reported acute toxicity was associated with EGCG. Grade 2 radiation dermatitis was observed in eight patients during or after radiotherapy, but all decreased to Grade 1 after EGCG treatments. Patient-reported symptom scores were significantly decreased at 2 weeks after the end of radiotherapy in pain, burning, itching and tenderness, p < 0.05. The topical administration of EGCG was well tolerated and the maximum tolerated dose was not found. EGCG may be effective in treating radiation dermatitis with preliminary investigation. EGCG solution seemed to be feasible for treating radiation dermatitis in patients with breast cancer after mastectomy. It should be tested as a way to reduce radiation-induced normal tissue toxicity and complications in future years.

An Integrated Fault Tolerant Robotic Controller System for High Reliability and Safety

NASA Technical Reports Server (NTRS)

Marzwell, Neville I.; Tso, Kam S.; Hecht, Myron

1994-01-01

This paper describes the concepts and features of a fault-tolerant intelligent robotic control system being developed for applications that require high dependability (reliability, availability, and safety). The system consists of two major elements: a fault-tolerant controller and an operator workstation. The fault-tolerant controller uses a strategy which allows for detection and recovery of hardware, operating system, and application software failures.The fault-tolerant controller can be used by itself in a wide variety of applications in industry, process control, and communications. The controller in combination with the operator workstation can be applied to robotic applications such as spaceborne extravehicular activities, hazardous materials handling, inspection and maintenance of high value items (e.g., space vehicles, reactor internals, or aircraft), medicine, and other tasks where a robot system failure poses a significant risk to life or property.

Water- and wastewater-related disease and infection risks: what is an appropriate value for the maximum tolerable additional burden of disease?

PubMed

Mara, Duncan

2011-06-01

The maximum additional burden of water- and wastewater-related disease of 10-6 disability-adjusted life year (DALY) loss per person per year (pppy), used in the WHO Drinking-water Quality Guidelines and the WHO Guidelines for Wastewater Use in Agriculture, is based on US EPA'S acceptance of a 70-year lifetime waterborne cancer risk of 10(-5) per person, equivalent to an annual risk of 1.4x10(-7) per person which is four orders of magnitude lower than the actual all-cancer incidence in the USA in 2009 of 1.8x10(-3) pppy. A maximum additional burden of 10(-4) DALY loss pppy would reduce this risk to a more cost-effective, but still low, risk of 1.4x10(-5) pppy. It would increase the DALY loss pppy in low- and middle-income countries due to diarrhoeal diseases from the current level of 0.0119 pppy to 0.0120 pppy, and that due to ascariasis from 0.0026 pppy to 0.0027 pppy, but neither increase is of public-health significance. It is therefore recommended that the maximum additional burden of disease from these activities be increased to a DALY loss of 10(-4) pppy as this provides an adequate margin of public-health safety in relation to waterborne-cancer deaths, diarrhoeal disease and ascariasis in all countries.

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.

Effectiveness and gastrointestinal tolerability during conversion and titration with once-daily OROS® hydromorphone extended release in opioid-tolerant patients with chronic low back pain

PubMed Central

Hale, Martin E; Nalamachu, Srinivas R; Khan, Arif; Kutch, Michael

2013-01-01

Purpose To describe the efficacy and safety of hydromorphone extended-release tablets (OROS hydromorphone ER) during dose conversion and titration. Patients and methods A total of 459 opioid-tolerant adults with chronic moderate to severe low back pain participated in an open-label, 2- to 4-week conversion/titration phase of a double-blind, placebo-controlled, randomized withdrawal trial, conducted at 70 centers in the United States. Patients were converted to once-daily OROS hydromorphone ER at 75% of the equianalgesic dose of their prior total daily opioid dose (5:1 conversion ratio), and titrated as frequently as every 3 days to a maximum dose of 64 mg/day. The primary outcome measure was change in pain intensity numeric rating scale; additional assessments included the Patient Global Assessment and the Roland–Morris Disability Questionnaire scores. Safety assessments were performed at each visit and consisted of recording and monitoring all adverse events (AEs) and serious AEs. Results Mean (standard deviation) final daily dose of OROS hydromorphone ER was 37.5 (17.8) mg. Mean (standard error of the mean [SEM]) numeric rating scale scores decreased from 6.6 (0.1) at screening to 4.3 (0.1) at the final titration visit (mean [SEM] change, −2.3 [0.1], representing a 34.8% reduction). Mean (SEM) change in Patient Global Assessment was −0.6 (0.1), and mean change (SEM) in the Roland–Morris Disability Questionnaire was −2.8 (0.3). Patients achieving a stable dose showed greater improvement than patients who discontinued during titration for each of these measures (P < 0.001). Almost 80% of patients achieving a stable dose (213/268) had a ≥30% reduction in pain. Commonly reported AEs were constipation (15.4%), nausea (11.9%), somnolence (8.7%), headache (7.8%), and vomiting (6.5%); 13.0% discontinued from the study due to AEs. Conclusion The majority of opioid-tolerant patients with chronic low back pain were successfully converted to effective doses of OROS hydromorphone ER within 2 to 4 weeks. PMID:23658495

Clinical Pharmacokinetics and Safety of ALZ-801, a Novel Prodrug of Tramiprosate in Development for the Treatment of Alzheimer's Disease.

PubMed

Hey, John A; Yu, Jeremy Y; Versavel, Mark; Abushakra, Susan; Kocis, Petr; Power, Aidan; Kaplan, Paul L; Amedio, John; Tolar, Martin

2018-03-01

ALZ-801 is an orally available, valine-conjugated prodrug of tramiprosate. Tramiprosate, the active agent, is a small-molecule β-amyloid (Aβ) anti-oligomer and aggregation inhibitor that was evaluated extensively in preclinical and clinical investigations for the treatment of Alzheimer's disease (AD). Tramiprosate has been found to inhibit β-amyloid oligomer formation by a multi-ligand enveloping mechanism of action that stabilizes Aβ42 monomers, resulting in the inhibition of formation of oligomers and subsequent aggregation. Although promising as an AD treatment, tramiprosate exhibited two limiting deficiencies: high intersubject pharmacokinetic (PK) variability likely due to extensive gastrointestinal metabolism, and mild-to-moderate incidence of nausea and vomiting. To address these, we developed an optimized prodrug, ALZ-801, which retains the favorable efficacy attributes of tramiprosate while improving oral PK variability and gastrointestinal tolerability. In this study, we summarize the phase I bridging program to evaluate the safety, tolerability and PK for ALZ-801 after single and multiple rising dose administration in healthy volunteers. Randomized, placebo-controlled, phase I studies in 127 healthy male and female adult and elderly volunteers included [1] a single ascending dose (SAD) study; [2] a 14-day multiple ascending dose (MAD) study; and [3] a single-dose tablet food-effect study. This program was conducted with both a loose-filled capsule and an immediate-release tablet formulation, under both fasted and fed conditions. Safety and tolerability were assessed, and plasma and urine were collected for liquid chromatography-mass spectrometry (LC-MS) determination and non-compartmental PK analysis. In addition, we defined the target dose of ALZ-801 that delivers a steady-state plasma area under the curve (AUC) exposure of tramiprosate equivalent to that studied in the tramiprosate phase III study. ALZ-801 was well tolerated and there were no severe or serious adverse events (AEs) or laboratory findings. The most common AEs were transient mild nausea and some instances of vomiting, which were not dose-related and showed development of tolerance after continued use. ALZ-801 produced dose-dependent maximum plasma concentration (C max ) and AUC exposures of tramiprosate, which were equivalent to that after oral tramiprosate, but with a substantially reduced intersubject variability and a longer elimination half-life. Administration of ALZ-801 with food markedly reduced the incidence of gastrointestinal symptoms compared with the fasted state, without affecting plasma tramiprosate exposure. An immediate-release tablet formulation of ALZ-801 displayed plasma exposure and low variability similar to the loose-filled capsule. ALZ-801 also showed excellent dose-proportionality without accumulation or decrease in plasma exposure of tramiprosate over 14 days. Based on these data, 265 mg of ALZ-801 twice daily was found to achieve a steady-state AUC exposure of tramiprosate equivalent to 150 mg twice daily of oral tramiprosate in the previous phase III trials. ALZ-801, when administered in capsule and tablet forms, showed excellent oral safety and tolerability in healthy adults and elderly volunteers, with significantly improved PK characteristics over oral tramiprosate. A clinical dose of ALZ-801 (265 mg twice daily) was established that achieves the AUC exposure of 150 mg of tramiprosate twice daily, which showed positive cognitive and functional improvements in apolipoprotein E4/4 homozygous AD patients. These bridging data support the phase III development of ALZ-801in patients with AD.

Phase I Study of Anti-GM2 Ganglioside Monoclonal Antibody BIW-8962 as Monotherapy in Patients with Previously Treated Multiple Myeloma.

PubMed

Baz, Rachid C; Zonder, Jeffrey A; Gasparetto, Cristina; Reu, Frederic J; Strout, Vincent

2016-01-01

BIW-8962 is a monoclonal antibody to GM2 ganglioside that shows preclinical activity towards multiple myeloma (MM) cell lines and in animal models bearing MM xenografts. The objective of this study was to determine the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, potential immunogenicity, and preliminary clinical efficacy of BIW-8962 in patients with heavily pretreated MM. Patients ( n  = 23) received escalating doses of BIW-8962 (0.03-3 mg/kg) intravenously every 2 weeks in phase Ia. The highest anticipated dose (10 mg/kg) was not tested and the study was discontinued without proceeding to phases Ib and II. The MTD of BIW-8962 was not established and BIW-8962 was relatively well tolerated. No pattern of consistent toxicity could be inferred from treatment-related AEs grade ≥3 and only two dose-limiting toxicities were recorded (atrial thrombosis + cardiomyopathy and chest pain, respectively). In the efficacy evaluable population ( n  = 22), no patient had a response (complete or partial) and 16 (72.7%) had a best response of stable disease, which was generally not durable. BIW-8962 did not show evidence of clinical activity. The study was therefore stopped and further development of BIW-8962 in MM was halted. This work was funded by Kyowa Kirin Pharmaceutical Development, Inc. ClinicalTrials.gov identifier, NCT00775502.

Pharmacokinetics and safety of the selective progesterone receptor modulator vilaprisan in healthy postmenopausal women
.

PubMed

Schultze-Mosgau, Marcus-Hillert; Schuett, Barbara; Hafner, Frank-Thorsten; Zollmann, Frank; Kaiser, Andreas; Hoechel, Joachim; Rohde, Beate

2017-01-01

Vilaprisan is a novel, potent, and highly selective progesterone receptor modulator, which might offer a promising option for the treatment of uterine fibroids. In this randomized, placebo-controlled, parallel-group phase 1 study, the pharmacokinetics and safety of vilaprisan were investigated in healthy postmenopausal women. Subjects received a single oral dose of vilaprisan (1, 5, 15, or 30 mg) or placebo and - after a wash-out period - daily doses of the same strength over 28 days. Safety assessments included vital signs, ECGs, clinical laboratory tests, and adverse events. Blood samples for pharmacokinetic (PK) profiles were collected over 14 days after single dose (sd) and multiple dose (md; day 28). Vilaprisan was well tolerated. Mild to moderate adverse events occurred with similar frequency at all dose levels. Following single dose, maximum vilaprisan concentrations were observed 1 - 2 hours post-dose. Terminal half-lives ranged from 31 to 38 hours. Maximum concentrations of vilaprisan (Cmax) and exposure to vilaprisan (AUC) increased roughly dose-proportionally from 3.74 µg/L (1 mg) to 68.6 µg/L (30 mg) and 58.5 µg×h/L to 1,590 µg×h/L, respectively. With daily dosing, accumulation consistent with the long terminal half-life was observed (AUC(0-24)md/AUC(0-24)sd ratios: 1.9 to 3.2). The ratio AUC(0-24)md/AUCsd increased with dose from ~ 1 (1 mg) to 1.5 (30 mg). Exposure to vilaprisan increased roughly dose-proportionally in the dose range studied and accumulated after multiple dosing as expected based on t1/2, indicating linear pharmacokinetics of vilaprisan in the expected therapeutic dose range.
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Safety in the Preschool.

ERIC Educational Resources Information Center

Settles, Mimi

Guidelines for safety in the cooperative preschool are outlined, emphasizing control of the physical environment to insure maximum freedom for the children compatible with maximum safety. Building standards are set for stairways, rooms, lavatories, parking lots, harmful supplies, and wading pools. Orientation for safety is discussed in regard to…

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

Long-term tolerability of ethinylestradiol 20 μg/drospirenone 3 mg in a flexible extended regimen: results from a randomised, controlled, multicentre study.

PubMed

Klipping, Christine; Duijkers, Ingrid; Fortier, Michel P; Marr, Joachim; Trummer, Dietmar; Elliesen, Jörg

2012-04-01

This study was designed to assess the long-term safety and tolerability of a new flexible extended regimen of ethinylestradiol (EE) 20 μg/drospirenone (DRSP) 3 mg, which allows management of intracyclic (breakthrough) bleeding [flexible management of intracyclic (breakthrough) bleeding (MIB)], in comparison to conventional 28-day and fixed extended regimens. In this Phase III, multicentre, open-label study, women (aged 18-35 years) were randomised to EE/DRSP in the following regimens: flexible(MIB) (24-120 days' active hormonal intake followed by a 4-day tablet-free interval), conventional 28-day (24 days' active hormonal intake followed by a 4-day hormone-free interval) or fixed extended (120 days' uninterrupted active hormonal intake followed by a 4-day tablet-free interval) during a 1-year comparative phase. Thereafter, women entered a 1-year safety extension phase in which the majority received the flexible(MIB) regimen. Safety/tolerability outcomes were measured over 2 years. A separate analysis of certain safety parameters (endometrial, hormonal, lipid, haemostatic and metabolic variables) was conducted at two of the study centres. Results were analysed in 1067 and 783 women in the comparative and safety extension phases. Overall, 56.3% of women experienced ≥1 adverse event (AE) in the safety extension phase. Serious AEs occurred in 3.0%, 1.4% and 3.3% of women receiving the flexible(MIB), conventional and fixed extended regimens, respectively. No unexpected endometrial, hormonal, lipid, haemostatic or metabolic findings occurred with any of the three regimens. EE/DRSP in a flexible extended regimen with management of intracyclic (breakthrough) bleeding is well-tolerated and, when administered for up to 2 years, has a good safety profile comparable to other estrogen/progestogen oral contraceptives.

Absolute bioavailability and safety of a novel rivastigmine nasal spray in healthy elderly individuals

PubMed Central

Soh, Bob

2016-01-01

Aims To test the feasibility of a novel rivastigmine nasal spray as prospective treatment for dementia. Methods A single dose, crossover absolute bioavailability and safety study was conducted with rivastigmine intravenous solution (1 mg) and nasal spray (3.126 mg) in eight healthy elderly individuals, aged 58–75 years. Results Absolute bioavailability (F) of the nasal spray was significant at 0.62 (0.15) for F > 0 (P < 0.001, n = 8). The systemic dose absorbed was 2.0 (0.6) mg, time to maximum plasma concentration was 1.1 (0.5) h and maximum plasma concentration was 6.9 (2.0) ng ml−1. The NAP226–90 to rivastigmine AUC0–∞ ratio was 0.78 (0.19). The single dose safety was good with two of five mild adverse events related to the nasal spray. Nasal and throat irritation were perceived as mild and transient, and both had resolved at 20 min post‐nasal dose. An estimated dose of two or three sprays twice‐daily with nasal spray would deliver comparable rivastigmine exposure and efficacy as a 6–9.7 mg day–1 oral dose and a 10 cm2 transdermal patch, respectively. Conclusions The rivastigmine nasal spray had superior absolute bioavailability compared to historical values for oral capsule and transdermal patch determined by other researchers. It had rapid onset of action, low NAP226–90 to rivastigmine exposure ratio and a favourable safety and tolerability profile. The ability to achieve adjustable, individual, twice‐daily dosing during waking hours has good potential to minimise undesirable cholinergic burden and sleep disturbances whilst delivering an effective dose for the treatment of dementia associated with Alzheimer's and Parkinson's disease. PMID:27639640

EFFICACY AND SAFETY OF A NEW TOPICAL TESTOSTERONE REPLACEMENT GEL THERAPY FOR THE TREATMENT OF MALE HYPOGONADISM.

PubMed

Cunningham, Glenn; Belkoff, Laurence; Brock, Gerald; Efros, Mitchell; Gittelman, Marc; Carrara, Dario; Neijber, Anders; Ando, Masakazu; Mitchel, Jules

2017-05-01

Testosterone replacement therapy is indicated for male hypogonadism. This study aimed to evaluate the efficacy and safety of testosterone gel 2% (Tgel) over 90 days. This phase 3, open-label, noncomparator study was conducted in adult hypogonadal men (2 consecutive fasting serum testosterone values <300 ng/dL and >86% subjects with symptoms consistent with testosterone deficiency). Subjects applied Tgel 23 mg/day (single pump-actuation using a hands-free cap applicator). The dose was uptitrated to 46 mg/day after 2 weeks if the 4-hour serum total testosterone level was <500 ng/dL. The dose could be further up- or downtitrated to 23, 46, and 69 mg on Days 21, 42, and 63. The primary endpoint included the percentage of subjects with average testosterone concentration (C ave (0-24) ) between 300 and 1,050 ng/dL on Day 90. Safety endpoints were adverse events (AEs), laboratory parameters, and vital signs. Of the 159 who enrolled, 139 men completed the study. Approximately three-quarters (76.1%) of subjects met C ave criteria on Day 90. Most AEs were mild to moderate. There were 5 serious AEs, and 1 (myocardial infarction) was judged as possibly related to Tgel. Confirmed excessive increases in prostate-specific antigen or hematocrit levels were rare. Tgel had a favorable local skin tolerability profile. Overall, 76% of subjects achieved C ave between 300 and 1,050 ng/dL with Tgel. Symptoms of testosterone deficiency improved with few safety concerns. AE = adverse event C ave(0-24) = average testosterone concentration CI = confidence interval C max = maximum concentration IIEF = International Index of Erectile Function MAF = Multidimensional Assessment of Fatigue PK = pharmacokinetic PSA = prostate-specific antigen SAE = serious adverse event SF-12 = Short Form 12 Health Survey Tgel = testosterone gel 2% T max = time to achieve maximum concentration TRT = testosterone replacement therapy.

A pilot study of omalizumab to facilitate rapid oral desensitization in high-risk peanut-allergic patients.

PubMed

Schneider, Lynda C; Rachid, Rima; LeBovidge, Jennifer; Blood, Emily; Mittal, Mudita; Umetsu, Dale T

2013-12-01

Peanut allergy is a major public health problem that affects 1% of the population and has no effective therapy. To examine the safety and efficacy of oral desensitization in peanut-allergic children in combination with a brief course of anti-IgE mAb (omalizumab [Xolair]). We performed oral peanut desensitization in peanut-allergic children at high risk for developing significant peanut-induced allergic reactions. Omalizumab was administered before and during oral peanut desensitization. We enrolled 13 children (median age, 10 years), with a median peanut-specific IgE level of 229 kU(A)/L and a median total serum IgE level of 621 kU/L, who failed an initial double-blind placebo-controlled food challenge at peanut flour doses of 100 mg or less. After pretreatment with omalizumab, all 13 subjects tolerated the initial 11 desensitization doses given on the first day, including the maximum dose of 500 mg peanut flour (cumulative dose, 992 mg, equivalent to >2 peanuts), requiring minimal or no rescue therapy. Twelve subjects then reached the maximum maintenance dose of 4000 mg peanut flour per day in a median time of 8 weeks, at which point omalizumab was discontinued. All 12 subjects continued on 4000 mg peanut flour per day and subsequently tolerated a challenge with 8000 mg peanut flour (equivalent to about 20 peanuts), or 160 to 400 times the dose tolerated before desensitization. During the study, 6 of the 13 subjects experienced mild or no allergic reactions, 5 subjects had grade 2 reactions, and 2 subjects had grade 3 reactions, all of which responded rapidly to treatment. Among children with high-risk peanut allergy, treatment with omalizumab may facilitate rapid oral desensitization and qualitatively improve the desensitization process. Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Heat shock protein expression enhances heat tolerance of reptile embryos.

PubMed

Gao, Jing; Zhang, Wen; Dang, Wei; Mou, Yi; Gao, Yuan; Sun, Bao-Jun; Du, Wei-Guo

2014-09-22

The role of heat shock proteins (HSPs) in heat tolerance has been demonstrated in cultured cells and animal tissues, but rarely in whole organisms because of methodological difficulties associated with gene manipulation. By comparing HSP70 expression patterns among representative species of reptiles and birds, and by determining the effect of HSP70 overexpression on embryonic development and hatchling traits, we have identified the role of HSP70 in the heat tolerance of amniote embryos. Consistent with their thermal environment, and high incubation temperatures and heat tolerance, the embryos of birds have higher onset and maximum temperatures for induced HSP70 than do reptiles, and turtles have higher onset and maximum temperatures than do lizards. Interestingly, the trade-off between benefits and costs of HSP70 overexpression occurred between life-history stages: when turtle embryos developed at extreme high temperatures, HSP70 overexpression generated benefits by enhancing embryo heat tolerance and hatching success, but subsequently imposed costs by decreasing heat tolerance of surviving hatchlings. Taken together, the correlative and causal links between HSP70 and heat tolerance provide, to our knowledge, the first unequivocal evidence that HSP70 promotes thermal tolerance of embryos in oviparous amniotes. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

The Effect of Food or Omeprazole on the Pharmacokinetics of Osimertinib in Patients With Non-Small-Cell Lung Cancer and in Healthy Volunteers.

PubMed

Vishwanathan, Karthick; Dickinson, Paul A; Bui, Khanh; Cassier, Philippe A; Greystoke, Alastair; Lisbon, Eleanor; Moreno, Victor; So, Karen; Thomas, Karen; Weilert, Doris; Yap, Timothy A; Plummer, Ruth

2018-04-01

Two phase 1, open-label studies assessed the impact of food or gastric pH modification (omeprazole) on the exposure and safety/tolerability of osimertinib and its metabolites. The food effect study was an open-label, 2-period crossover study in patients with advanced non-small-cell lung cancer, randomized into 2 treatment sequences: single-dose osimertinib 80 mg in a fed then fasted state or fasted then fed. The gastric pH study was an open-label, 2-period fixed sequence study assessing the effect of omeprazole on osimertinib exposure in healthy male volunteers. In period 1, volunteers received omeprazole 40 mg (days 1-4), then omeprazole 40 mg plus osimertinib 80 mg (day 5). In period 2, volunteers received osimertinib 80 mg alone (single dose). Blood samples were collected at prespecified time points for pharmacokinetic analyses. Safety/tolerability was also assessed. In the food effect study 38 patients were randomized to fed/fasted (n = 18) or fasted/fed (n = 20) sequences with all patients completing treatment. Coadministration with food did not affect osimertinib exposure (geometric least-squares mean ratios [90% confidence intervals]: 106.05% [94.82%, 118.60%] [area under the plasma concentration time curve from zero to 72 hours] and 92.75% [81.40%, 105.68%] [maximum plasma concentration]). In the gastric pH study (n = 68 received treatment, n = 47 completed the study), coadministration with omeprazole did not affect osimertinib exposure (geometric least-squares mean ratios 106.66% [100.26%, 113.46%] [area under the concentration-time curve], 101.65% [94.65%, 109.16%] [peak concentration]). Osimertinib was well tolerated in both studies. Osimertinib may be administered without regard to food. Dose restriction is not required in patients whose gastric pH may be altered by concomitant agents or medical conditions. ClinicalTrials.gov: NCT02224053, NCT02163733. © 2017, The American College of Clinical Pharmacology.

Phase Ia/Ib study of the pan-class I PI3K inhibitor pictilisib (GDC-0941) administered as a single agent in Japanese patients with solid tumors and in combination in Japanese patients with non-squamous non-small cell lung cancer.

PubMed

Yamamoto, Noboru; Fujiwara, Yutaka; Tamura, Kenji; Kondo, Shunsuke; Iwasa, Satoru; Tanabe, Yuko; Horiike, Atsushi; Yanagitani, Noriko; Kitazono, Satoru; Inatani, Michiyasu; Tanaka, Jun; Nishio, Makoto

2017-02-01

Pictilisib (GDC-0941) is an oral class I phosphatidylinositol-3-phosphate kinase inhibitor. This phase Ia/Ib study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of pictilisib in monotherapy or in combination with carboplatin-paclitaxel and bevacizumab (CP + BEV) in Japanese patients with advanced solid tumors or non-squamous non-small cell lung cancer. A standard 3 + 3 dose escalation design was applied. In stage 1, 140, 260, or 340 mg/day of pictilisib was administered once daily to 12 patients with advanced solid tumors. In stage 2, 260 or 340 mg/day of pictilisib was administered in combination with CP + BEV to 7 patients with advanced non-squamous non-small cell lung cancer. In stage 1, 1 of 6 patients in the 340 mg/day cohort exhibited dose limiting toxicity (DLT) of grade 3 maculopapular rash. The maximum plasma concentration and area under the curve of pictilisib were dose-dependent. A reduction in phosphorylated AKT in platelet rich plasma was observed. No patient had an objective anti-tumor response. In stage 2, DLT was observed in 1 of 3 patients in the 260 mg/day cohort (grade 3 febrile neutropenia), and 2 of 4 patients in the 340 mg/day cohort (1 each of grade 3 febrile neutropenia and grade 3 febrile neutropenia/erythema multiforme). Partial responses were observed in 3 out of 7 patients. In conclusion, pictilisib was shown to have good safety and tolerability in Japanese patients with advanced solid tumors. A recommended dose of pictilisib in monotherapy was determined to be 340 mg once daily. For combination with CP + BEV, tolerability up to 260 mg/day was confirmed.

Somapacitan, a once-weekly reversible albumin-binding GH derivative, in children with GH deficiency: A randomized dose-escalation trial.

PubMed

Battelino, Tadej; Rasmussen, Michael Højby; De Schepper, Jean; Zuckerman-Levin, Nehama; Gucev, Zoran; Sävendahl, Lars

2017-10-01

To evaluate the safety, local tolerability, pharmacodynamics and pharmacokinetics of escalating single doses of once-weekly somapacitan, a reversible, albumin-binding GH derivative, vs once-daily GH in children with GH deficiency (GHD). Phase 1, randomized, open-label, active-controlled, dose-escalation trial (NCT01973244). Thirty-two prepubertal GH-treated children with GHD were sequentially randomized 3:1 within each of four cohorts to a single dose of somapacitan (0.02, 0.04, 0.08 and 0.16 mg/kg; n=6 each), or once-daily Norditropin ® SimpleXx ® (0.03 mg/kg; n=2 each) for 7 days. Pharmacokinetic and pharmacodynamic profiles were assessed. Adverse events were all mild, and there were no apparent treatment-dependent patterns in type or frequency. Four mild transient injection site reactions were reported in three of 24 children treated with somapacitan. No antisomapacitan/anti-human growth hormone (hGH) antibodies were detected. Mean serum concentrations of somapacitan increased in a dose-dependent but nonlinear manner: maximum concentration ranged from 21.8 ng/mL (0.02 mg/kg dose) to 458.4 ng/mL (0.16 mg/kg dose). IGF-I and IGFBP-3, and change from baseline in IGF-I standard deviation score (SDS) and IGFBP-3 SDS, increased dose dependently; greatest changes in SDS values were seen for 0.16 mg/kg. IGF-I SDS values were between -2 and +2 SDS, except for peak IGF-I SDS with 0.08 mg/kg somapacitan. Postdosing, IGF-I SDS remained above baseline levels for at least 1 week. Single doses of once-weekly somapacitan (0.02-0.16 mg/kg) were well tolerated in children with GHD, with IGF-I profiles supporting a once-weekly treatment profile. No clinically significant safety/tolerability signals or immunogenicity concerns were identified. © 2017 The Authors. Clinical Endocrinology Published by John Wiley & Sons Ltd.

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 was well tolerated by healthy volunteers.

Pharmacokinetic characteristics of telaprevir in healthy Korean male subjects and comparisons with Japanese.

PubMed

Choi, Yewon; Yoon, Seonghae; Matsumoto, Kyoko; Ohta, Yoshiyasu; Lee, SeungHwan; Yu, Kyung-Sang; Jang, In-Jin

2018-01-01

Telaprevir, a reversible selective inhibitor of viral protease and a potential blocker of viral replication, is indicated for the treatment of hepatitis C virus genotype 1 infection. In this study, the pharmacokinetic profile, safety, and tolerability of telaprevir and the effect of food on telaprevir exposure were evaluated in healthy Korean subjects, and compared with data from a previous study in Japanese male subjects. The single ascending dose study was conducted in 3 dose-based groups (500, 750, and 1,250 mg, six subjects each) in a fasted state. In the multiple dose study, eight subjects in the fed state received 750 mg of telaprevir once on Day 1 and every 8 hours from Day 2 until the morning of Day 6. Serial blood samples for pharmacokinetic analysis were collected for up to 24 hours in the single ascending dose study and for 6 days in the multiple dose study. Individual pharmacokinetic parameters were calculated using a non-compartmental analysis method. Safety and tolerability profiles were evaluated throughout the study. Following multiple administrations of telaprevir, maximum plasma concentrations (C max ), area under the concentration-time curve (AUC 0-8 ), and C trough (concentration at 8 h after drug administration) increased by ~2.41-fold. Compared to fasted state values, mean C max and AUC 0-24 increased by 4.92- and 4.81-fold, respectively, after food intake. The C max and AUC inf of Korean subjects were 26%-34% higher than those of Japanese subjects; however, these differences were not clinically significant. All observed adverse events were mild and there was no discontinuation due to AEs. In conclusion, the telaprevir's pharmacokinetic characteristics were similar in Korean and Japanese subjects. Telaprevir was well tolerated in a single dose of up to 1,250 mg and in multiple doses of 750 mg.

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 may contribute to alleviating chemotherapy dose limitation due to CIPN and increase the likelihood of success of chemotherapy.

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...

The Safety Zone, 2000.

ERIC Educational Resources Information Center

Fiscus, James W., Ed.; Pollack, Ira, Ed.

2000-01-01

This publication is concerned with how to keep schools safe. The spring 2000 issue "Zero Tolerance: Effective Policy or Display of Administrative Machismo?" (James W. Fiscus) discusses how difficult it is to determine just what zero tolerance means and reminds readers that schools were required to pass zero tolerance rules to remain eligible for…

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.

Effects of Age, Sex, and Race on the Safety and Pharmacokinetics of Single and Multiple Doses of Azilsartan Medoxomil in Healthy Subjects.

PubMed

Harrell, Robert E; Karim, Aziz; Zhang, Wencan; Dudkowski, Caroline

2016-05-01

Azilsartan medoxomil (AZL-M) is an angiotensin II receptor blocker approved to treat hypertension. After oral dosing, AZL-M is quickly hydrolyzed to azilsartan (AZL). The aims of this study were to assess the effects of age, sex, and race on the pharmacokinetics of AZL-M in healthy subjects, as well as safety and tolerability. Sixty-one healthy adults were enrolled in this phase I, single-blind, randomized placebo-controlled study (placebo control was for assessment of safety/tolerability only). Subjects were stratified by age (18-45 vs. 65-85 years), sex, and race (black vs. white) and given oral AZL-M 60 mg (3 × 20 mg capsules) or placebo as a single dose (Day 1) and consecutive daily doses (Days 4-8) (6:2 ratio for AZL-M:placebo per group). Pharmacokinetics were evaluated (AZL-M patients only) on Days 1-3 and 8-9 and safety/tolerability was monitored. Age, sex, and race had no clinically meaningful effect on AZL exposures after single or multiple dosing. Pharmacokinetic parameters remained similar between Days 1 and 8 for each age, sex, and race subgroup. The frequency of adverse events was similar for AZL-M (32%) and placebo (29%). No discontinuations or serious adverse events occurred. Based on these pharmacokinetic and safety/tolerability findings, no AZL-M dose adjustments are required based on age, sex, or race (black/white).

A New Approach to Extreme Value Estimation Applicable to a Wide Variety of Random Variables

NASA Technical Reports Server (NTRS)

Holland, Frederic A., Jr.

1997-01-01

Designing reliable structures requires an estimate of the maximum and minimum values (i.e., strength and load) that may be encountered in service. Yet designs based on very extreme values (to insure safety) can result in extra material usage and hence, uneconomic systems. In aerospace applications, severe over-design cannot be tolerated making it almost mandatory to design closer to the assumed limits of the design random variables. The issue then is predicting extreme values that are practical, i.e. neither too conservative or non-conservative. Obtaining design values by employing safety factors is well known to often result in overly conservative designs and. Safety factor values have historically been selected rather arbitrarily, often lacking a sound rational basis. To answer the question of how safe a design needs to be has lead design theorists to probabilistic and statistical methods. The so-called three-sigma approach is one such method and has been described as the first step in utilizing information about the data dispersion. However, this method is based on the assumption that the random variable is dispersed symmetrically about the mean and is essentially limited to normally distributed random variables. Use of this method can therefore result in unsafe or overly conservative design allowables if the common assumption of normality is incorrect.

Extended‐Release Once‐Daily Formulation of Tofacitinib: Evaluation of Pharmacokinetics Compared With Immediate‐Release Tofacitinib and Impact of Food

PubMed Central

Wang, Rong; Fletcher, Tracey; Alvey, Christine; Kushner, Joseph; Stock, Thomas C.

2016-01-01

Abstract Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. An extended‐release (XR) formulation has been designed to provide a once‐daily (QD) dosing option to patients to achieve comparable pharmacokinetic (PK) parameters to the twice‐daily immediate‐release (IR) formulation. We conducted 2 randomized, open‐label, phase 1 studies in healthy volunteers. Study A characterized single‐dose and steady‐state PK of tofacitinib XR 11 mg QD and intended to demonstrate equivalence of exposure under single‐dose and steady‐state conditions to tofacitinib IR 5 mg twice daily. Study B assessed the effect of a high‐fat meal on the bioavailability of tofacitinib from the XR formulation. Safety and tolerability were monitored in both studies. In study A (N = 24), the XR and IR formulations achieved time to maximum plasma concentration at 4 hours and 0.5 hours postdose, respectively; terminal half‐life was 5.9 hours and 3.2 hours, respectively. Area under plasma concentration‐time curve (AUC) and maximum plasma concentration (Cmax) after single‐ and multiple‐dose administration were equivalent between the XR and IR formulations. In study B (N = 24), no difference in AUC was observed for fed vs fasted conditions. Cmax increased by 27% under the fed state. On repeat administration, negligible accumulation (<20%) of systemic exposures was observed for both formulations. Steady state was achieved within 48 hours of dosing with the XR formulation. Tofacitinib administration as an XR or IR formulation was generally well tolerated in these studies. PMID:26970526

Phase I study of adenovirus p53 administered by bronchoalveolar lavage in patients with bronchioloalveolar cell lung carcinoma: ECOG 6597.

PubMed

Keedy, Vicki; Wang, Wei; Schiller, Joan; Chada, Sunil; Slovis, Bonnie; Coffee, Keith; Worrell, John; Thet, Lyn A; Johnson, David H; Carbone, David P

2008-09-01

This pilot phase I trial evaluated the safety and maximum-tolerated dose of p53 gene transfer using an adenovirus vector (Ad-p53) delivered via bronchoalveolar lavage (BAL) to patients with bronchioloalveolar lung carcinoma (BAC). Patients were initially administered two treatments of Ad-p53 to a single involved lobe, beginning at 2 x 10(9) viral particles (vp) per dose and escalated to a maximum of 2 x 10(12) vp. If a clinical benefit was seen and the treatment was well tolerated, additional doses could be administered to additional lobes. Twenty-five patients were treated at doses between 2 x 10(9) and 2 x 10(12) vp. At 2 x 10(12) vp, one patient experienced grade 4 pulmonary toxicity, and one patient died 25 days after his second cycle; therefore, a cohort of 10 patients was treated at the recommended phase II dose of 5 x 10(11) vp, with no grade 4 toxicity observed. The most frequent toxicities included low-grade fever, hypoxia, and dyspnea. Of the 23 assessable patients, 16 had stable disease as their best response. Subjective improvement in breathing was noted in eight patients. Limited distribution of vector was observed, with transient detection in patient sputum for 1 to 2 days after administration. Ad-p53 can be administered safely by BAL at 5 x 10(11) vp with repeated dosing. Stabilization of disease and symptomatic improvement may warrant further studies of Ad-p53 or other adenoviruses administered by BAL in patients with BAC.

Bioavailability of oxycodone after administration of a new prolonged-release once-daily tablet formulation in healthy subjects, in comparison to an established twice-daily tablet
.

PubMed

Scheidel, Bernhard; Maritz, Martina A; Gschwind, Yves J; Steigerwald, Kerstin; Guth, Volker; Kovacs, Peter; Rey, Helene

2017-11-01

To evaluate and to compare the bioavailability, the influence of food intake on the bioavailability, and the safety and tolerability of a newly-developed oxycodone once-daily (OOD) prolonged-release tablet with an established oxycodone twice-daily (OTD) prolonged-release tablet after single-dose administration under fasting or fed conditions as well as after multiple-dose administration. Three single-center, open-label, randomized, balanced, two-treatment, two-period, two-sequence crossover studies were conducted. In each study, 36 healthy volunteers were randomized to receive 10 mg oxycodone daily as OOD (oxycodone HCL 10-mg PR tablets XL (Develco Pharma Schweiz AG, Pratteln, Switzerland); administration of 1 tablet in the morning) or as OTD (reference formulation: oxygesic 5-mg tablets (Mundipharma GmbH, Limburg an der Lahn, Germany); administration of 1 tablet in the morning and 1 tablet in the evening). Tablets were administered once daily or twice daily under fasting conditions (study 1) or under fed conditions (study 2) as well as after multiple-dose administration (study 3). A sufficient number of blood samples were taken for describing plasma profiles and for calculation of pharmacokinetic parameters. Plasma concentrations of oxycodone were determined by LC-MS/MS. Safety and tolerability were monitored and assessed in all three studies. Plasma profiles of OOD reveal sustained concentrations of oxycodone over the complete dosing interval of 24 hours. In comparison to the OTD reference formulation, the OOD test formulation showed a slightly slower increase of concentrations within the absorption phase and similar plasma concentrations at the maximum and at the end of the dosing interval (24 hours). Extent of bioavailability (AUC), maximum plasma concentrations (C_max), and plasma concentrations at the end of the dosing interval (C_τ,ss,24h) of OOD could be classified as comparable to OTD considering 90% confidence intervals (CIs) and acceptance limits of 80.00 - 125.00%. Bioavailability of OOD was not influenced by concomitant food intake. OOD and OTD were generally well tolerated, a difference between the two products could not be observed. The new 10-mg OOD formulation provides sustained oxycodone plasma concentrations over the dosing interval of 24 hours and is suitable for once-daily administration. Bioavailability of OOD could be classified as comparable to the twice-daily administration of the OTD reference formulation. The new formulation widens and optimizes the range of strong opioid drug products in patient-centered therapy of chronic pain with simplified dosing and better compliance.
.

Rail height effects on safety performance of Midwest Guardrail System.

PubMed

Asadollahi Pajouh, Mojdeh; Julin, Ramen D; Stolle, Cody S; Reid, John D; Faller, Ronald K

2018-02-17

Guardrail heights play a crucial role in the way that errant vehicles interact with roadside barriers. Low rail heights increase the propensity of vehicle rollover and override, whereas excessively tall rails promote underride. Further, rail mounting heights and post embedment depths may be altered by variations in roadside terrain. An increased guardrail height may be desirable to accommodate construction tolerances, soil erosion, frost heave, and future roadway overlays. This study aimed to investigate and identify a maximum safe installation height for the Midwest Guardrail System that would be robust and remain crashworthy before and after pavement overlays. A research investigation was performed to evaluate the safety performance of increased mounting heights for the standard 787-mm (31-in.)-tall Midwest Guardrail System (MGS) through crash testing and computer simulation. Two full-scale crash tests with small passenger cars were performed on the MGS with top-rail mounting heights of 864 and 914 mm (34 and 36 in.). Test results were then used to calibrate computer simulation models. In the first test, a small car impacted the MGS with 864-mm (34-in.) rail height at 102 km/h (63.6 mph) and 25.0° and was successfully redirected. In the second test, another small car impacted the MGS with a 914-mm (36-in.) rail height at 103 km/h (64.1 mph) and 25.6° and was successful. Both system heights satisfied the Manual for Assessing Safety Hardware (MASH) Test Level 3 (TL-3) evaluation criteria. Test results were then used to calibrate computer simulation models. A mounting height of 36 in. was determined to be the maximum guardrail height that would safely contain and redirect small car vehicles. Simulations confirmed that taller guardrail heights (i.e., 37 in.) would likely result in small car underride. In addition, simulation results indicated that passenger vehicle models were successfully contained by the 34- and 36-in.-tall MGS installed on approach slopes as steep as 6:1. A mounting height of 914 mm (36 in.) was determined to be the maximum guardrail height that would safely contain and redirect 1100C vehicles and not allow underride or excessive vehicle snag on support posts. Recommendations were also provided regarding the safety performance of the MGS with increased height.

Switching From Donepezil to Rivastigmine Is Well Tolerated: Results of an Open-Label Safety and Tolerability Study

PubMed Central

Sadowsky, Carl H.; Farlow, Martin R.; Atkinson, Leone; Steadman, Jennifer; Koumaras, Barbara; Chen, Michael; Mirski, Dario

2005-01-01

Background: Transitioning patients between cholinesterase inhibitors was thought to require a washout period to avoid cholinergic toxicity; however, evidence suggests that abrupt discontinuation of donepezil may lead to cognitive decline. We evaluated the safety and tolerability of an immediate switch from donepezil to rivastigmine. Method: This is an analysis of the safety and tolerability data from the first 28 days of an open-label, multicenter, prospective trial, conducted from August 2002 to August 2003, in which patients satisfying NINCDS-ADRDA criteria for probable Alzheimer's disease were administered rivastigmine 1.5 mg b.i.d. within 24 to 36 hours of donepezil discontinuation. Results are compared with adverse event rates from a retrospective analysis of a pivotal, placebo-controlled trial examining patients not previously treated with a cholinesterase inhibitor. Results: Fifty-eight of 61 patients completed the first 28 days, with no suspected drug-related discontinuations during this period. Incidence of overall gastrointestinal adverse events at day 7 was 8.2%, and at day 28 was 11.5%. The corresponding rate for rivastigmine-treated patients in the retrospective analysis of the pivotal trial for day 7 was 3.3%. Conclusion: These study results suggest that transitioning patients from donepezil to rivastigmine without a washout period is safe and well tolerated. PMID:15841194

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.

Thermal adaptation and phosphorus shape thermal performance in an assemblage of rainforest ants.

PubMed

Kaspari, Michael; Clay, Natalie A; Lucas, Jane; Revzen, Shai; Kay, Adam; Yanoviak, Stephen P

2016-04-01

We studied the Thermal Performance Curves (TPCs) of 87 species of rainforest ants and found support for both the Thermal Adaptation and Phosphorus-Tolerance hypotheses. TPCs relate a fitness proxy (here, worker speed) to environmental temperature. Thermal Adaptation posits that thermal generalists (ants with flatter, broader TPCs) are favored in the hotter, more variable tropical canopy compared to the cooler, less variable litter below. As predicted, species nesting in the forest canopy 1) had running speeds less sensitive to temperature; 2) ran over a greater range of temperatures; and 3) ran at lower maximum speeds. Tradeoffs between tolerance and maximum performance are often invoked for constraining the evolution of thermal generalists. There was no evidence that ant species traded off thermal tolerance for maximum speed, however. Phosphorus-Tolerance is a second mechanism for generating ectotherms able to tolerate thermal extremes. It posits that ants active at high temperatures invest in P-rich machinery to buffer their metabolism against thermal extremes. Phosphorus content in ant tissue varied three-fold, and as predicted, temperature sensitivity was lower and thermal range was higher in P-rich species. Combined, we show how the vertical distribution of hot and variable vs. cooler and stable microclimates in a single forest contribute to a diversity of TPCs and suggest that a widely varying P stoichiometry among these ants may drive some of these differences.

Influence of different surfactants on the technological properties and in vivo ocular tolerability of lipid nanoparticles.

PubMed

Leonardi, Antonio; Bucolo, Claudio; Romano, Giovanni Luca; Platania, Chiara Bianca Maria; Drago, Filippo; Puglisi, Giovanni; Pignatello, Rosario

2014-08-15

Addition of one or more surfactant agents is often necessary for the production of nanostructured lipid and polymeric systems. The removal of residual surfactants is a required step for technological and toxicological reasons, especially for peculiar applications, such as the ophthalmic field. This study was planned to assess the technological properties of some surfactants, commonly used for the production of lipid nanoparticles, as well as their ocular safety profile. Stable and small-size solid lipid nanoparticles were obtained using Dynasan(®) 114 as the lipid matrix and all the tested surfactants. However, from a toxicological point of view, the nanocarriers produced using Kolliphor(®) P188 were the most valuable, showing no irritant effect on the ocular surface up to the highest tested surfactant concentration (0.4%, w/v). The SLN produced using Cremophor(®) A25 and Lipoid(®) S100 were tolerated up to a surfactant concentration of 0.2% by weight, while for Tween(®) 80 and Kolliphor(®) HS 15 a maximum concentration of 0.05% can be considered totally not-irritant. Copyright © 2014 Elsevier B.V. All rights reserved.

Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial.

PubMed

Devinsky, Orrin; Marsh, Eric; Friedman, Daniel; Thiele, Elizabeth; Laux, Linda; Sullivan, Joseph; Miller, Ian; Flamini, Robert; Wilfong, Angus; Filloux, Francis; Wong, Matthew; Tilton, Nicole; Bruno, Patricia; Bluvstein, Judith; Hedlund, Julie; Kamens, Rebecca; Maclean, Jane; Nangia, Srishti; Singhal, Nilika Shah; Wilson, Carey A; Patel, Anup; Cilio, Maria Roberta

2016-03-01

Almost a third of patients with epilepsy have a treatment-resistant form, which is associated with severe morbidity and increased mortality. Cannabis-based treatments for epilepsy have generated much interest, but scientific data are scarce. We aimed to establish whether addition of cannabidiol to existing anti-epileptic regimens would be safe, tolerated, and efficacious in children and young adults with treatment-resistant epilepsy. In this open-label trial, patients (aged 1-30 years) with severe, intractable, childhood-onset, treatment-resistant epilepsy, who were receiving stable doses of antiepileptic drugs before study entry, were enrolled in an expanded-access programme at 11 epilepsy centres across the USA. Patients were given oral cannabidiol at 2-5 mg/kg per day, up-titrated until intolerance or to a maximum dose of 25 mg/kg or 50 mg/kg per day (dependent on study site). The primary objective was to establish the safety and tolerability of cannabidiol and the primary efficacy endpoint was median percentage change in the mean monthly frequency of motor seizures at 12 weeks. The efficacy analysis was by modified intention to treat. Comparisons of the percentage change in frequency of motor seizures were done with a Mann-Whitney U test. Between Jan 15, 2014, and Jan 15, 2015, 214 patients were enrolled; 162 (76%) patients who had at least 12 weeks of follow-up after the first dose of cannabidiol were included in the safety and tolerability analysis, and 137 (64%) patients were included in the efficacy analysis. In the safety group, 33 (20%) patients had Dravet syndrome and 31 (19%) patients had Lennox-Gastaut syndrome. The remaining patients had intractable epilepsies of different causes and type. Adverse events were reported in 128 (79%) of the 162 patients within the safety group. Adverse events reported in more than 10% of patients were somnolence (n=41 [25%]), decreased appetite (n=31 [19%]), diarrhoea (n=31 [19%]), fatigue (n=21 [13%]), and convulsion (n=18 [11%]). Five (3%) patients discontinued treatment because of an adverse event. Serious adverse events were reported in 48 (30%) patients, including one death-a sudden unexpected death in epilepsy regarded as unrelated to study drug. 20 (12%) patients had severe adverse events possibly related to cannabidiol use, the most common of which was status epilepticus (n=9 [6%]). The median monthly frequency of motor seizures was 30.0 (IQR 11.0-96.0) at baseline and 15.8 (5.6-57.6) over the 12 week treatment period. The median reduction in monthly motor seizures was 36.5% (IQR 0-64.7). Our findings suggest that cannabidiol might reduce seizure frequency and might have an adequate safety profile in children and young adults with highly treatment-resistant epilepsy. Randomised controlled trials are warranted to characterise the safety profile and true efficacy of this compound. GW Pharmaceuticals, Epilepsy Therapy Project of the Epilepsy Foundation, Finding A Cure for Epilepsy and Seizures. Copyright © 2016 Elsevier Ltd. All rights reserved.

Human Tolerance to Rapidly Applied Accelerations: A Summary of the Literature

NASA Technical Reports Server (NTRS)

Eiband, A. Martin

1959-01-01

The literature is surveyed to determine human tolerance to rapidly applied accelerations. Pertinent human and animal experiments applicable to space flight and to crash impact forces are analyzed and discussed. These data are compared and presented on the basis of a trapezoidal pulse. The effects of body restraint and of acceleration direction, onset rate, and plateau duration on the maximum tolerable and survivable rapidly applied accelerations are shown. Results of the survey indicate that adequate torso and extremity restraint is the primary variable in tolerance to rapidly applied accelerations. The harness, or restraint system, must be arranged to transmit the major portion of the accelerating force directly to the pelvic structure and not via the vertebral column. When the conditions of adequate restraint have been met, then the other variables, direction, magnitude, and onset rate of rapidly applied accelerations, govern maximum tolerance and injury limits. The results also indicate that adequately stressed aft-faced passenger seats offer maximum complete body support with minimum objectionable harnessing. Such a seat, whether designed for 20-, 30-, or 40-G dynamic loading, would include lap strap, chest (axillary) strap, and winged-back seat to increase headward and lateral G protection, full-height integral head rest, arm rests (load-bearing) with recessed hand-holds and provisions to prevent arms from slipping either laterally or beyond the seat back, and leg support to keep the legs from being wedged under the seat. For crew members and others whose duties require forward-facing seats, maximum complete body support requires lap, shoulder, and thigh straps, lap-belt tie-down strap, and full-height seat back with integral head support.

Subthalamic Nucleus Deep Brain Stimulation in Early Stage Parkinson’s Disease

PubMed Central

Charles, David; Konrad, Peter E.; Neimat, Joseph S.; Molinari, Anna L.; Tramontana, Michael G.; Finder, Stuart G.; Gill, Chandler E.; Bliton, Mark J.; Kao, Chris C.; Phibbs, Fenna T.; Hedera, Peter; Salomon, Ronald M.; Cannard, Kevin R.; Wang, Lily; Song, Yanna; Davis, Thomas L.

2014-01-01

Background Deep brain stimulation (DBS) is an effective and approved therapy for advanced Parkinson’s disease (PD), and a recent study suggests efficacy in mid-stage disease. This manuscript reports the results of a pilot trial investigating preliminary safety and tolerability of DBS in early PD. Methods Thirty subjects with idiopathic PD (Hoehn & Yahr Stage II off medication), age 50–75, on medication ≥ 6 months but < 4 years, and without motor fluctuations or dyskinesias were randomized to optimal drug therapy (ODT) (n=15) or DBS+ODT (n=15). Co-primary endpoints were the time to reach a 4-point worsening from baseline in the UPDRS-III off therapy and the change in levodopa equivalent daily dose from baseline to 24 months. Results As hypothesized, the mean UPDRS total and part III scores were not significantly different on or off therapy at 24 months. The DBS+ODT group took less medication at all time points, and this reached maximum difference at 18 months. With a few exceptions, differences in neuropsychological functioning were not significant. Two subjects in the DBS+ODT group suffered serious adverse events; remaining adverse events were mild or transient. Conclusions This study demonstrates that subjects with early stage PD will enroll in and complete trials testing invasive therapies and provides preliminary evidence that DBS is well tolerated in early PD. The results of this trial provide the data necessary to design a large, phase III, double-blind, multicenter trial investigating the safety and efficacy of DBS in early PD. PMID:24768120

Intranasal oxytocin in the treatment of autism spectrum disorders: a review of literature and early safety and efficacy data in youth.

PubMed

Anagnostou, Evdokia; Soorya, Latha; Brian, Jessica; Dupuis, Annie; Mankad, Deepali; Smile, Sharon; Jacob, Suma

2014-09-11

There is a paucity of treatments targeting core symptom domains in Autism Spectrum Disorder (ASD). Several animal models and research in typically developing volunteers suggests that manipulation of the oxytocin system may have therapeutic potential for the treatment of social deficits. We review the literature for oxytocin and ASD and report on early dosing, safety and efficacy data of multi-dose oxytocin on aspects of social cognition/function, as well as repetitive behaviors and co-occurring anxiety within ASD. Fifteen children and adolescents with verbal IQs≥70 were diagnosed with ASD using the ADOS and the ADI-R. They participated in a modified maximum tolerated dose study of intranasal oxytocin (Syntocinon). Data were modeled using repeated measures regression analysis controlling for week, dose, age, and sex. Among 4 doses tested, the highest dose evaluated, 0.4 IU/kg/dose, was found to be well tolerated. No serious or severe adverse events were reported and adverse events reported/observed were mild to moderate. Over 12 weeks of treatment, several measures of social cognition/function, repetitive behaviors and anxiety showed sensitivity to change with some measures suggesting maintenance of effect 3 months past discontinuation of intranasal oxytocin. This pilot study suggests that daily administration of intranasal oxytocin at 0.4 IU/kg/dose in children and adolescents with ASD is safe and has therapeutic potential. Larger studies are warranted. This article is part of a Special Issue entitled Oxytocin and Social Behav. Copyright © 2014 Elsevier B.V. All rights reserved.

Efficacy and safety of alirocumab in reducing lipids and cardiovascular events.

PubMed

Robinson, Jennifer G; Farnier, Michel; Krempf, Michel; Bergeron, Jean; Luc, Gérald; Averna, Maurizio; Stroes, Erik S; Langslet, Gisle; Raal, Frederick J; El Shahawy, Mahfouz; Koren, Michael J; Lepor, Norman E; Lorenzato, Christelle; Pordy, Robert; Chaudhari, Umesh; Kastelein, John J P

2015-04-16

Alirocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9), has been shown to reduce low-density lipoprotein (LDL) cholesterol levels in patients who are receiving statin therapy. Larger and longer-term studies are needed to establish safety and efficacy. We conducted a randomized trial involving 2341 patients at high risk for cardiovascular events who had LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or more and were receiving treatment with statins at the maximum tolerated dose (the highest dose associated with an acceptable side-effect profile), with or without other lipid-lowering therapy. Patients were randomly assigned in a 2:1 ratio to receive alirocumab (150 mg) or placebo as a 1-ml subcutaneous injection every 2 weeks for 78 weeks. The primary efficacy end point was the percentage change in calculated LDL cholesterol level from baseline to week 24. At week 24, the difference between the alirocumab and placebo groups in the mean percentage change from baseline in calculated LDL cholesterol level was -62 percentage points (P<0.001); the treatment effect remained consistent over a period of 78 weeks. The alirocumab group, as compared with the placebo group, had higher rates of injection-site reactions (5.9% vs. 4.2%), myalgia (5.4% vs. 2.9%), neurocognitive events (1.2% vs. 0.5%), and ophthalmologic events (2.9% vs. 1.9%). In a post hoc analysis, the rate of major adverse cardiovascular events (death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization) was lower with alirocumab than with placebo (1.7% vs. 3.3%; hazard ratio, 0.52; 95% confidence interval, 0.31 to 0.90; nominal P=0.02). Over a period of 78 weeks, alirocumab, when added to statin therapy at the maximum tolerated dose, significantly reduced LDL cholesterol levels. In a post hoc analysis, there was evidence of a reduction in the rate of cardiovascular events with alirocumab. (Funded by Sanofi and Regeneron Pharmaceuticals; ODYSSEY LONG TERM ClinicalTrials.gov number, NCT01507831.).

Sequential behavior and its inherent tolerance to memory faults.

NASA Technical Reports Server (NTRS)

Meyer, J. F.

1972-01-01

Representation of a memory fault of a sequential machine M by a function mu on the states of M and the result of the fault by an appropriately determined machine M(mu). Given some sequential behavior B, its inherent tolerance to memory faults can then be measured in terms of the minimum memory redundancy required to realize B with a state-assigned machine having fault tolerance type tau and fault tolerance level t. A behavior having maximum inherent tolerance is exhibited, and it is shown that behaviors of the same size can have different inherent tolerance.

Results from a phase 1 study of nusinersen (ISIS-SMN(Rx)) in children with spinal muscular atrophy.

PubMed

Chiriboga, Claudia A; Swoboda, Kathryn J; Darras, Basil T; Iannaccone, Susan T; Montes, Jacqueline; De Vivo, Darryl C; Norris, Daniel A; Bennett, C Frank; Bishop, Kathie M

2016-03-08

To examine safety, tolerability, pharmacokinetics, and preliminary clinical efficacy of intrathecal nusinersen (previously ISIS-SMNRx), an antisense oligonucleotide designed to alter splicing of SMN2 mRNA, in patients with childhood spinal muscular atrophy (SMA). Nusinersen was delivered by intrathecal injection to medically stable patients with type 2 and type 3 SMA aged 2-14 years in an open-label phase 1 study and its long-term extension. Four ascending single-dose levels (1, 3, 6, and 9 mg) were examined in cohorts of 6-10 participants. Participants were monitored for safety and tolerability, and CSF and plasma pharmacokinetics were measured. Exploratory efficacy endpoints included the Hammersmith Functional Motor Scale Expanded (HFMSE) and Pediatric Quality of Life Inventory. A total of 28 participants enrolled in the study (n = 6 in first 3 dose cohorts; n = 10 in the 9-mg cohort). Intrathecal nusinersen was well-tolerated with no safety/tolerability concerns identified. Plasma and CSF drug levels were dose-dependent, consistent with preclinical data. Extended pharmacokinetics indicated a prolonged CSF drug half-life of 4-6 months after initial clearance. A significant increase in HFMSE scores was observed at the 9-mg dose at 3 months postdose (3.1 points; p = 0.016), which was further increased 9-14 months postdose (5.8 points; p = 0.008) during the extension study. Results from this study support continued development of nusinersen for treatment of SMA. This study provides Class IV evidence that in children with SMA, intrathecal nusinersen is not associated with safety or tolerability concerns. © 2016 American Academy of Neurology.

[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.

Structural Design Methodology Based on Concepts of Uncertainty

NASA Technical Reports Server (NTRS)

Lin, K. Y.; Du, Jiaji; Rusk, David

2000-01-01

In this report, an approach to damage-tolerant aircraft structural design is proposed based on the concept of an equivalent "Level of Safety" that incorporates past service experience in the design of new structures. The discrete "Level of Safety" for a single inspection event is defined as the compliment of the probability that a single flaw size larger than the critical flaw size for residual strength of the structure exists, and that the flaw will not be detected. The cumulative "Level of Safety" for the entire structure is the product of the discrete "Level of Safety" values for each flaw of each damage type present at each location in the structure. Based on the definition of "Level of Safety", a design procedure was identified and demonstrated on a composite sandwich panel for various damage types, with results showing the sensitivity of the structural sizing parameters to the relative safety of the design. The "Level of Safety" approach has broad potential application to damage-tolerant aircraft structural design with uncertainty.

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.

Safety and tolerability of new-generation anti-obesity medications: a narrative review.

PubMed

Patel, Dhiren K; Stanford, Fatima Cody

2018-03-01

The prevalence of obesity and associated comorbidities is rising. Despite their weight-loss efficacy, new generation anti-obesity medications are only prescribed to a minority of adults with obesity, possibly, which in part may be due to safety concerns. This review presents detailed safety profiles for orlistat, phentermine/topiramate, lorcaserin, naltrexone/bupropion and liraglutide 3.0 mg, and discusses the associated risk-benefit profiles. Two anti-obesity medications presented safety issues that warranted further discussion; phentermine/topiramate (fetal toxicity) and liraglutide 3.0 mg (risk of gallstone disease and mild, acute pancreatitis), whereas the adverse events associated with orlistat, lorcaserin, and naltrexone/bupropion were mostly transient tolerability issues. The difficulties surrounding the objective determination of risk-benefit for anti-obesity medications is discussed. The need for more long-term data, thorough patient assessment, individualization of pharmacological interventions and adherence to stopping rules to maximize risk-benefit are highlighted. Overall, the majority of new generation anti-obesity medications present encouraging tolerability profiles; however, in some cases a lack of long-term clinical trials confounds the accurate determination of risk-benefit.

Pesticide Tolerances

EPA Pesticide Factsheets

EPA regulates pesticides used to protect crops and sets limits on the amount of pesticide remaining in or on foods in the U.S. The limits on pesticides on foods are called tolerances in the U.S. (maximum residue limits (MRLs) in many other countries).

Genetic variance of tolerance and the toxicant threshold model.

PubMed

Tanaka, Yoshinari; Mano, Hiroyuki; Tatsuta, Haruki

2012-04-01

A statistical genetics method is presented for estimating the genetic variance (heritability) of tolerance to pollutants on the basis of a standard acute toxicity test conducted on several isofemale lines of cladoceran species. To analyze the genetic variance of tolerance in the case when the response is measured as a few discrete states (quantal endpoints), the authors attempted to apply the threshold character model in quantitative genetics to the threshold model separately developed in ecotoxicology. The integrated threshold model (toxicant threshold model) assumes that the response of a particular individual occurs at a threshold toxicant concentration and that the individual tolerance characterized by the individual's threshold value is determined by genetic and environmental factors. As a case study, the heritability of tolerance to p-nonylphenol in the cladoceran species Daphnia galeata was estimated by using the maximum likelihood method and nested analysis of variance (ANOVA). Broad-sense heritability was estimated to be 0.199 ± 0.112 by the maximum likelihood method and 0.184 ± 0.089 by ANOVA; both results implied that the species examined had the potential to acquire tolerance to this substance by evolutionary change. Copyright © 2012 SETAC.

Safety and Efficacy of Memantine in Children with Autism: Randomized, Placebo-Controlled Study and Open-Label Extension.

PubMed

Aman, Michael G; Findling, Robert L; Hardan, Antonio Y; Hendren, Robert L; Melmed, Raun D; Kehinde-Nelson, Ola; Hsu, Hai-An; Trugman, Joel M; Palmer, Robert H; Graham, Stephen M; Gage, Allyson T; Perhach, James L; Katz, Ephraim

2017-06-01

Abnormal glutamatergic neurotransmission is implicated in the pathophysiology of autism spectrum disorder (ASD). In this study, the safety, tolerability, and efficacy of the glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist memantine (once-daily extended-release [ER]) were investigated in children with autism in a randomized, placebo-controlled, 12 week trial and a 48 week open-label extension. A total of 121 children 6-12 years of age with Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR)-defined autistic disorder were randomized (1:1) to placebo or memantine ER for 12 weeks; 104 children entered the subsequent extension trial. Maximum memantine doses were determined by body weight and ranged from 3 to 15 mg/day. There was one serious adverse event (SAE) (affective disorder, with memantine) in the 12 week study and one SAE (lobar pneumonia) in the 48 week extension; both were deemed unrelated to treatment. Other AEs were considered mild or moderate and most were deemed not related to treatment. No clinically significant changes occurred in clinical laboratory values, vital signs, or electrocardiogram (ECG). There was no significant between-group difference on the primary efficacy outcome of caregiver/parent ratings on the Social Responsiveness Scale (SRS), although an improvement over baseline at Week 12 was observed in both groups. A trend for improvement at the end of the 48 week extension was observed. No improvements in the active group were observed on any of the secondary end-points, with one communication measure showing significant worsening with memantine compared with placebo (p = 0.02) after 12 weeks. This trial did not demonstrate clinical efficacy of memantine ER in autism; however, the tolerability and safety data were reassuring. Our results could inform future trial design in this population and may facilitate the investigation of memantine ER for other clinical applications.

The SKATE study: an open-label community-based study of levetiracetam as add-on therapy for adults with uncontrolled partial epilepsy.

PubMed

Steinhoff, Bernhard J; Somerville, Ernest R; Van Paesschen, Wim; Ryvlin, Philippe; Schelstraete, Isabelle

2007-08-01

The Safety of Keppra as Adjunctive Therapy in Epilepsy (SKATE) study aimed to evaluate the safety and efficacy of levetiracetam (Keppra, LEV) as add-on therapy for refractory partial seizures in clinical practice. This Phase IV, 16-week, open-label study recruited patients > or =16-year old with treatment-resistant partial seizures. LEV (1000 mg/day) was added to a stable concomitant antiepileptic drug regimen. LEV dosage was adjusted based on seizure control and tolerability to a maximum of 3000 mg/day. 1541 patients (intent-to-treat population) were recruited including 1346 (87.3%) who completed the study and 77.0% who declared further continuing on LEV after the trial. Overall, 50.5% of patients reported at least one adverse event that was considered related to LEV treatment. The most frequently reported drug-related adverse events were mild-to-moderate somnolence, fatigue, dizziness and headache. Serious adverse events considered related to LEV occurred in 1.0% of patients. 7.5% of patients reported adverse events as the most important reason for study drug discontinuation. The median reduction from baseline in the frequency of all seizures was 50.2%; 15.8% of patients were seizure free; 50.1% had seizure frequency reduction of > or =50%. At the end of the study, 60.4% of patients were considered by the investigator to show marked or moderate improvement. There was a significant improvement in health-related quality of life as assessed with the QOLIE-10-P (total score increasing from 55.6 to 61.6; p<0.001). This community-based study suggests that LEV is well tolerated and effective as add-on therapy for refractory partial seizures in adults. These data provide supportive evidence for the safety and efficacy of LEV demonstrated in the pivotal Phase III placebo-controlled studies.

Safety and Efficacy of Memantine in Children with Autism: Randomized, Placebo-Controlled Study and Open-Label Extension

PubMed Central

Findling, Robert L.; Hardan, Antonio Y.; Hendren, Robert L.; Melmed, Raun D.; Kehinde-Nelson, Ola; Hsu, Hai-An; Trugman, Joel M.; Palmer, Robert H.; Graham, Stephen M.; Gage, Allyson T.; Perhach, James L.; Katz, Ephraim

2017-01-01

Abstract Objective: Abnormal glutamatergic neurotransmission is implicated in the pathophysiology of autism spectrum disorder (ASD). In this study, the safety, tolerability, and efficacy of the glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist memantine (once-daily extended-release [ER]) were investigated in children with autism in a randomized, placebo-controlled, 12 week trial and a 48 week open-label extension. Methods: A total of 121 children 6–12 years of age with Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR)-defined autistic disorder were randomized (1:1) to placebo or memantine ER for 12 weeks; 104 children entered the subsequent extension trial. Maximum memantine doses were determined by body weight and ranged from 3 to 15 mg/day. Results: There was one serious adverse event (SAE) (affective disorder, with memantine) in the 12 week study and one SAE (lobar pneumonia) in the 48 week extension; both were deemed unrelated to treatment. Other AEs were considered mild or moderate and most were deemed not related to treatment. No clinically significant changes occurred in clinical laboratory values, vital signs, or electrocardiogram (ECG). There was no significant between-group difference on the primary efficacy outcome of caregiver/parent ratings on the Social Responsiveness Scale (SRS), although an improvement over baseline at Week 12 was observed in both groups. A trend for improvement at the end of the 48 week extension was observed. No improvements in the active group were observed on any of the secondary end-points, with one communication measure showing significant worsening with memantine compared with placebo (p = 0.02) after 12 weeks. Conclusions: This trial did not demonstrate clinical efficacy of memantine ER in autism; however, the tolerability and safety data were reassuring. Our results could inform future trial design in this population and may facilitate the investigation of memantine ER for other clinical applications. PMID:26978327

Safety, pharmacokinetics, and antitumor activity of AMG 386, a selective angiopoietin inhibitor, in adult patients with advanced solid tumors.

PubMed

Herbst, Roy S; Hong, David; Chap, Linnea; Kurzrock, Razelle; Jackson, Edward; Silverman, Jeffrey M; Rasmussen, Erik; Sun, Yu-Nien; Zhong, Don; Hwang, Yuying C; Evelhoch, Jeffrey L; Oliner, Jonathan D; Le, Ngocdiep; Rosen, Lee S

2009-07-20

PURPOSE AMG 386 is an investigational peptide-Fc fusion protein (ie, peptibody) that inhibits angiogenesis by preventing the interaction of angiopoietin-1 and angiopoietin-2 with their receptor, Tie2. This first-in-human study evaluated the safety, pharmacokinetics (PK), pharmacodynamics, and antitumor activity of AMG 386 in adults with advanced solid tumors. PATIENTS AND METHODS Patients in sequential cohorts received weekly intravenous AMG 386 doses of 0.3, 1, 3, 10, or 30 mg/kg. Results Thirty-two patients were enrolled on the study and received AMG 386. One occurrence of dose-limiting toxicity was seen at 30 mg/kg: respiratory arrest, which likely was caused by tumor burden that was possibly related to AMG 386. The most common toxicities were fatigue and peripheral edema. Proteinuria (n = 11) was observed without clinical sequelae. Only four patients (12%) experienced treatment-related toxicities greater than grade 1. A maximum-tolerated dose was not reached. PK was dose-linear and the mean terminal-phase elimination half-life values ranged from 3.1 to 6.3 days. Serum AMG 386 levels appeared to reach steady-state after four weekly doses, and there was minimal accumulation. No anti-AMG 386 neutralizing antibodies were detected. Reductions in volume transfer constant (K(trans); measured by dynamic contrast-enhanced magnetic resonance imaging) were observed in 10 patients (13 lesions) 48 hours to 8 weeks after treatment. One patient with refractory ovarian cancer achieved a confirmed partial response (ie, 32.5% reduction by Response Evaluation Criteria in Solid Tumors) and withdrew from the study with a partial response after 156 weeks of treatment; four patients experienced stable disease for at least 16 weeks. CONCLUSION Weekly AMG 386 appeared well tolerated, and its safety profile appeared distinct from that of vascular endothelial growth factor-axis inhibitors. AMG 386 also appeared to impact tumor vascularity and showed antitumor activity in this patient population.

An investigation of the safety and pharmacokinetics of the novel TRPV1 antagonist XEN-D0501 in healthy subjects

PubMed Central

Round, Patrick; Priestley, Anthony; Robinson, Jan

2011-01-01

AIMS XEN-D0501, a novel TRPV1 antagonist, is being developed to treat overactive bladder. This study investigated the safety and pharmacokinetics of repeat-dose XEN-D0501 in healthy subjects. METHODS The study was conducted in two parts. Part 1 was a double-blind, randomized, placebo-controlled, two-way crossover study in three cohorts of 12 young male subjects. Each subject received XEN-D0501 and placebo (in random order) twice daily for 13 days, with a final single dose on day 14. Doses of 1, 2.5 and 5 mg XEN-D0501 were investigated. Part 2 was an open-label, randomized, two-way crossover study in male and female subjects (45 to 65 years). Subjects received single doses of 5 mg XEN-D0501 under fasted and fed conditions in random order. Blood sampling and safety assessments were conducted throughout the study. RESULTS XEN-D0501 was rapidly absorbed (tmax generally 0.5–4 h post dose). XEN-D0501 exposure increased less than proportionally to dose over the range studied and exhibited minimal accumulation with twice daily dosing. Food had no clinically relevant effects on the pharmacokinetics of XEN-D0501. There were no severe or serious adverse events and all doses were well tolerated. A dose-related increase in body temperature was seen with XEN-D0501 which attenuated over time. Differences from placebo in mean maximum core body temperatures were 0.22°C, 0.5°C and 0.74°C following 1 mg, 2.5 mg and 5 mg twice daily XEN-D0501. The observed increase in body temperature was not considered to be of clinical concern. CONCLUSIONS XEN-D0501 appeared safe and well tolerated at doses up to 5 mg twice daily for 14 days in healthy subjects. PMID:21676011

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

PubMed Central

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

2012-01-01

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

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

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

PubMed

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

2015-02-01

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

Nonclinical Safety Assessment of SYN-004: An Oral β-lactamase for the Protection of the Gut Microbiome From Disruption by Biliary-Excreted, Intravenously Administered Antibiotics.

PubMed

Kokai-Kun, John F; Bristol, J Andrew; Setser, John; Schlosser, Michael

2016-05-01

SYN-004 is a first in class, recombinant β-lactamase that degrades β-lactam antibiotics and has been formulated to be administered orally to patients receiving intravenous β-lactam antibiotics including cephalosporins. SYN-004 is intended to degrade unmetabolized antibiotics excreted into the intestines and thus has the potential to protect the gut microbiome from disruption by these antibiotics. Protection of the gut microbiome is expected to protect against opportunistic enteric infections such as Clostridium difficile infection as well as antibiotic-associated diarrhea. In order to demonstrate that oral SYN-004 is safe for human clinical trials, 2 Good Laboratory Practice-compliant toxicity studies were conducted in Beagle dogs. In both studies, SYN-004 was administered orally 3 times per day up to the maximum tolerated dose of the formulation. In the first study, doses of SYN-004 administered over 28 days were safe and well tolerated in dogs with the no-observed-adverse-effect level at the high dose of 57 mg/kg/day. Systemic absorption of SYN-004 was minimal and sporadic and showed no accumulation during the study. In the second study, doses up to 57 mg/kg/day were administered to dogs in combination with an intravenous dose of ceftriaxone (300 mg/kg) given once per day for 14 days. Coadministration of oral SYN-004 with intravenous ceftriaxone was safe and well tolerated, with SYN-004 having no noticeable effect on the plasma pharmacokinetics of ceftriaxone. These preclinical studies demonstrate that SYN-004 is well tolerated and, when coadministered with ceftriaxone, does not interfere with its systemic pharmacokinetics. These data supported advancing SYN-004 into human clinical trials. © The Author(s) 2015.

Thermal Tolerance of the Coffee Berry Borer Hypothenemus hampei: Predictions of Climate Change Impact on a Tropical Insect Pest

PubMed Central

Jaramillo, Juliana; Chabi-Olaye, Adenirin; Kamonjo, Charles; Jaramillo, Alvaro; Vega, Fernando E.; Poehling, Hans-Michael; Borgemeister, Christian

2009-01-01

Coffee is predicted to be severely affected by climate change. We determined the thermal tolerance of the coffee berry borer , Hypothenemus hampei, the most devastating pest of coffee worldwide, and make inferences on the possible effects of climate change using climatic data from Colombia, Kenya, Tanzania, and Ethiopia. For this, the effect of eight temperature regimes (15, 20, 23, 25, 27, 30, 33 and 35°C) on the bionomics of H. hampei was studied. Successful egg to adult development occurred between 20–30°C. Using linear regression and a modified Logan model, the lower and upper thresholds for development were estimated at 14.9 and 32°C, respectively. In Kenya and Colombia, the number of pest generations per year was considerably and positively correlated with the warming tolerance. Analysing 32 years of climatic data from Jimma (Ethiopia) revealed that before 1984 it was too cold for H. hampei to complete even one generation per year, but thereafter, because of rising temperatures in the area, 1–2 generations per year/coffee season could be completed. Calculated data on warming tolerance and thermal safety margins of H. hampei for the three East African locations showed considerably high variability compared to the Colombian site. The model indicates that for every 1°C rise in thermal optimum (Topt.), the maximum intrinsic rate of increase (r max) will increase by an average of 8.5%. The effects of climate change on the further range of H. hampei distribution and possible adaption strategies are discussed. Abstracts in Spanish and French are provided as supplementary material Abstract S1 and Abstract S2. PMID:19649255

(90)Y-labelled anti-CD22 epratuzumab tetraxetan in adults with refractory or relapsed CD22-positive B-cell acute lymphoblastic leukaemia: a phase 1 dose-escalation study.

PubMed

Chevallier, Patrice; Eugene, Thomas; Robillard, Nelly; Isnard, Françoise; Nicolini, Franck; Escoffre-Barbe, Martine; Huguet, Françoise; Hunault, Mathilde; Marcais, Antoine; Gaschet, Joelle; Cherel, Michel; Guillaume, Thierry; Delaunay, Jacques; Peterlin, Pierre; Eveillard, Marion; Thomas, Xavier; Ifrah, Norbert; Lapusan, Simona; Bodet-Milin, Caroline; Barbet, Jacques; Faivre-Chauvet, Alain; Ferrer, Ludovic; Bene, Marie C; Le Houerou, Claire; Goldenberg, David M; Wegener, William A; Kraeber-Bodéré, Françoise

2015-03-01

Prognosis of patients with relapsed or refractory acute lymphoblastic leukaemia is poor and new treatments are needed. We aimed to assess the feasibility, tolerability, dosimetry, and efficacy of yttrium-90-labelled anti-CD22 epratuzumab tetraxetan ((90)Y-DOTA-epratuzumab) radioimmunotherapy in refractory or relapsed CD22-positive B-cell acute lymphoblastic leukaemia in a standard 3 + 3 phase 1 study. Adults (≥18 years) with relapsed or refractory B-cell acute lymphoblastic leukaemia (with CD22 expression on at least 70% of blast cells) were enrolled at six centres in France. Patients received one cycle of (90)Y-DOTA-epratuzumab on days 1 and 8 (give or take 2 days) successively at one of four dose levels: 2·5 mCi/m(2) (92·5 MBq/m(2); level 1), 5·0 mCi/m(2) (185 MBq/m(2); level 2), 7·5 mCi/m(2) (277·5 MBq/m(2); level 3), and 10·0 mCi/m(2) (370 MBq/m(2); level 4). The primary objective was to identify the maximum tolerated dose of (90)Y-DOTA-epratuzumab. We assessed safety during infusions and regularly after radioimmunotherapy over a 6-month period. Analyses included only patients who received radioimmunotherapy. The trial is closed to inclusion and is registered at ClinicalTrials.gov, NCT01354457. Between Aug 25, 2011, and June 11, 2014, 17 patients (median age 62 years; range 27-77) were treated (five at level 1, three at level 2, three at level 3, and six at level 4). Radioimmunotherapy infusion was overall well tolerated. One dose-limiting toxic effect (aplasia lasting 8 weeks) occurred at level 4, but the maximum tolerated dose was not reached. The most common grade 3-4 adverse events were pancytopenia (one patient at level 2, one at level 3, and six at level 4) and infections (three at level 1, one at level 2, and five at level 4). (90)Y-DOTA-epratuzumab radioimmunotherapy is well tolerated. We recommend the dose of 2 × 10·0 mCi/m(2) 1 week apart per cycle for phase 2 studies. Immunomedics and Direction de la Recherche Clinique of Nantes. Copyright © 2015 Elsevier Ltd. All rights reserved.

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.

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

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 tolerated, with no adverse events. • Overall, human fibrinogen concentrate demonstrated a good safety profile. • This data adds to the safety information available to date on this hemostatic agent.« less

Long-term tolerability of ethinylestradiol 20 µg/drospirenone 3 mg in a flexible extended regimen: results from a randomised, controlled, multicentre study

PubMed Central

Klipping, Christine; Duijkers, Ingrid; Fortier, Michel P; Marr, Joachim; Trummer, Dietmar; Elliesen, Jörg

2012-01-01

Background This study was designed to assess the long-term safety and tolerability of a new flexible extended regimen of ethinylestradiol (EE) 20 μg/drospirenone (DRSP) 3 mg, which allows management of intracyclic (breakthrough) bleeding [flexible management of intracyclic (breakthrough) bleeding (MIB)], in comparison to conventional 28-day and fixed extended regimens. Study design In this Phase III, multicentre, open-label study, women (aged 18–35 years) were randomised to EE/DRSP in the following regimens: flexibleMIB (24–120 days' active hormonal intake followed by a 4-day tablet-free interval), conventional 28-day (24 days' active hormonal intake followed by a 4-day hormone-free interval) or fixed extended (120 days' uninterrupted active hormonal intake followed by a 4-day tablet-free interval) during a 1-year comparative phase. Thereafter, women entered a 1-year safety extension phase in which the majority received the flexibleMIB regimen. Safety/tolerability outcomes were measured over 2 years. A separate analysis of certain safety parameters (endometrial, hormonal, lipid, haemostatic and metabolic variables) was conducted at two of the study centres. Results Results were analysed in 1067 and 783 women in the comparative and safety extension phases. Overall, 56.3% of women experienced ≥1 adverse event (AE) in the safety extension phase. Serious AEs occurred in 3.0%, 1.4% and 3.3% of women receiving the flexibleMIB, conventional and fixed extended regimens, respectively. No unexpected endometrial, hormonal, lipid, haemostatic or metabolic findings occurred with any of the three regimens. Conclusions EE/DRSP in a flexible extended regimen with management of intracyclic (breakthrough) bleeding is well-tolerated and, when administered for up to 2 years, has a good safety profile comparable to other estrogen/progestogen oral contraceptives. PMID:22454004

New risk metrics and mathematical tools for risk analysis: Current and future challenges

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

Skandamis, Panagiotis N., E-mail: pskan@aua.gr; Andritsos, Nikolaos, E-mail: pskan@aua.gr; Psomas, Antonios, E-mail: pskan@aua.gr

The current status of the food safety supply world wide, has led Food and Agriculture Organization (FAO) and World Health Organization (WHO) to establishing Risk Analysis as the single framework for building food safety control programs. A series of guidelines and reports that detail out the various steps in Risk Analysis, namely Risk Management, Risk Assessment and Risk Communication is available. The Risk Analysis approach enables integration between operational food management systems, such as Hazard Analysis Critical Control Points, public health and governmental decisions. To do that, a series of new Risk Metrics has been established as follows: i) themore » Appropriate Level of Protection (ALOP), which indicates the maximum numbers of illnesses in a population per annum, defined by quantitative risk assessments, and used to establish; ii) Food Safety Objective (FSO), which sets the maximum frequency and/or concentration of a hazard in a food at the time of consumption that provides or contributes to the ALOP. Given that ALOP is rather a metric of the public health tolerable burden (it addresses the total ‘failure’ that may be handled at a national level), it is difficult to be interpreted into control measures applied at the manufacturing level. Thus, a series of specific objectives and criteria for performance of individual processes and products have been established, all of them assisting in the achievement of FSO and hence, ALOP. In order to achieve FSO, tools quantifying the effect of processes and intrinsic properties of foods on survival and growth of pathogens are essential. In this context, predictive microbiology and risk assessment have offered an important assistance to Food Safety Management. Predictive modelling is the basis of exposure assessment and the development of stochastic and kinetic models, which are also available in the form of Web-based applications, e.g., COMBASE and Microbial Responses Viewer), or introduced into user-friendly softwares, (e.g., Seafood Spoilage Predictor) have evolved the use of information systems in the food safety management. Such tools are updateable with new food-pathogen specific models containing cardinal parameters and multiple dependent variables, including plate counts, concentration of metabolic products, or even expression levels of certain genes. Then, these tools may further serve as decision-support tools which may assist in product logistics, based on their scientifically-based and “momentary” expressed spoilage and safety level.« less

New risk metrics and mathematical tools for risk analysis: Current and future challenges

NASA Astrophysics Data System (ADS)

Skandamis, Panagiotis N.; Andritsos, Nikolaos; Psomas, Antonios; Paramythiotis, Spyridon

2015-01-01

The current status of the food safety supply world wide, has led Food and Agriculture Organization (FAO) and World Health Organization (WHO) to establishing Risk Analysis as the single framework for building food safety control programs. A series of guidelines and reports that detail out the various steps in Risk Analysis, namely Risk Management, Risk Assessment and Risk Communication is available. The Risk Analysis approach enables integration between operational food management systems, such as Hazard Analysis Critical Control Points, public health and governmental decisions. To do that, a series of new Risk Metrics has been established as follows: i) the Appropriate Level of Protection (ALOP), which indicates the maximum numbers of illnesses in a population per annum, defined by quantitative risk assessments, and used to establish; ii) Food Safety Objective (FSO), which sets the maximum frequency and/or concentration of a hazard in a food at the time of consumption that provides or contributes to the ALOP. Given that ALOP is rather a metric of the public health tolerable burden (it addresses the total `failure' that may be handled at a national level), it is difficult to be interpreted into control measures applied at the manufacturing level. Thus, a series of specific objectives and criteria for performance of individual processes and products have been established, all of them assisting in the achievement of FSO and hence, ALOP. In order to achieve FSO, tools quantifying the effect of processes and intrinsic properties of foods on survival and growth of pathogens are essential. In this context, predictive microbiology and risk assessment have offered an important assistance to Food Safety Management. Predictive modelling is the basis of exposure assessment and the development of stochastic and kinetic models, which are also available in the form of Web-based applications, e.g., COMBASE and Microbial Responses Viewer), or introduced into user-friendly softwares, (e.g., Seafood Spoilage Predictor) have evolved the use of information systems in the food safety management. Such tools are updateable with new food-pathogen specific models containing cardinal parameters and multiple dependent variables, including plate counts, concentration of metabolic products, or even expression levels of certain genes. Then, these tools may further serve as decision-support tools which may assist in product logistics, based on their scientifically-based and "momentary" expressed spoilage and safety level.

Defect Tolerant Semiconductors for Solar Energy Conversion.

PubMed

Zakutayev, Andriy; Caskey, Christopher M; Fioretti, Angela N; Ginley, David S; Vidal, Julien; Stevanovic, Vladan; Tea, Eric; Lany, Stephan

2014-04-03

Defect tolerance is the tendency of a semiconductor to keep its properties despite the presence of crystallographic defects. Scientific understanding of the origin of defect tolerance is currently missing. Here we show that semiconductors with antibonding states at the top of the valence band are likely to be tolerant to defects. Theoretical calculations demonstrate that Cu3N with antibonding valence band maximum has shallow intrinsic defects and no surface states, in contrast to GaN with bonding valence band maximum. Experimental measurements indicate shallow native donors and acceptors in Cu3N thin films, leading to 10(16)-10(17) cm(-3) doping with either electrons or holes depending on the growth conditions. The experimentally measured bipolar doping and the solar-matched optical absorption onset (1.4 eV) make Cu3N a promising candidate absorber for photovoltaic and photoelectrochemical solar cells, despite the calculated indirect fundamental band gap (1.0 eV). These conclusions can be extended to other materials with antibonding character of the valence band, defining a class of defect-tolerant semiconductors for solar energy conversion applications.

Temperature-stress resistance and tolerance along a latitudinal cline in North American Arabidopsis lyrata.

PubMed

Wos, Guillaume; Willi, Yvonne

2015-01-01

The study of latitudinal gradients can yield important insights into adaptation to temperature stress. Two strategies are available: resistance by limiting damage, or tolerance by reducing the fitness consequences of damage. Here we studied latitudinal variation in resistance and tolerance to frost and heat and tested the prediction of a trade-off between the two strategies and their costliness. We raised plants of replicate maternal seed families from eight populations of North American Arabidopsis lyrata collected along a latitudinal gradient in climate chambers and exposed them repeatedly to either frost or heat stress, while a set of control plants grew under standard conditions. When control plants reached maximum rosette size, leaf samples were exposed to frost and heat stress, and electrolyte leakage (PEL) was measured and treated as an estimate of resistance. Difference in maximum rosette size between stressed and control plants was used as an estimate of tolerance. Northern populations were more frost resistant, and less heat resistant and less heat tolerant, but-unexpectedly-they were also less frost tolerant. Negative genetic correlations between resistance and tolerance to the same and different thermal stress were generally not significant, indicating only weak trade-offs. However, tolerance to frost was consistently accompanied by small size under control conditions, which may explain the non-adaptive latitudinal pattern for frost tolerance. Our results suggest that adaptation to frost and heat is not constrained by trade-offs between them. But the cost of frost tolerance in terms of plant size reduction may be important for the limits of species distributions and climate niches.

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…

Safety, pharmacokinetics, and antitumour activity of trastuzumab deruxtecan (DS-8201), a HER2-targeting antibody-drug conjugate, in patients with advanced breast and gastric or gastro-oesophageal tumours: a phase 1 dose-escalation study.

PubMed

Doi, Toshihiko; Shitara, Kohei; Naito, Yoichi; Shimomura, Akihiko; Fujiwara, Yasuhiro; Yonemori, Kan; Shimizu, Chikako; Shimoi, Tatsunori; Kuboki, Yasutoshi; Matsubara, Nobuaki; Kitano, Atsuko; Jikoh, Takahiro; Lee, Caleb; Fujisaki, Yoshihiko; Ogitani, Yusuke; Yver, Antoine; Tamura, Kenji

2017-11-01

Antibody-drug conjugates have emerged as a powerful strategy in cancer therapy and combine the ability of monoclonal antibodies to specifically target tumour cells with the highly potent killing activity of drugs with payloads too toxic for systemic administration. Trastuzumab deruxtecan (also known as DS-8201) is an antibody-drug conjugate comprised of a humanised antibody against HER2, a novel enzyme-cleavable linker, and a topoisomerase I inhibitor payload. We assessed its safety and tolerability in patients with advanced breast and gastric or gastro-oesophageal tumours. This was an open-label, dose-escalation phase 1 trial done at two study sites in Japan. Eligible patients were at least 20 years old with breast or gastric or gastro-oesophageal carcinomas refractory to standard therapy regardless of HER2 status. Participants received initial intravenous doses of trastuzumab deruxtecan from 0·8 to 8·0 mg/kg and dose-limiting toxicities were assessed over a 21-day cycle; thereafter, dose reductions were implemented as needed and patients were treated once every 3 weeks until they had unacceptable toxic effects or their disease progressed. Primary endpoints included identification of safety and the maximum tolerated dose or recommended phase 2 dosing and were analysed in all participants who received at least one dose of study drug. The dose-escalation study is the first part of a two-part study with the second dose-expansion part ongoing and enrolling patients as of July 8, 2017, in Japan and the USA. This trial is registered at ClinicalTrials.gov, number NCT02564900. Between Aug 28, 2015, and Aug 26, 2016, 24 patients were enrolled and received trastuzumab deruxtecan (n=3 for each of 0·8, 1·6, 3·2, and 8·0 mg/kg doses; n=6 for each of 5·4 and 6·4 mg/kg). Up to the study cutoff date of Feb 1, 2017, no dose-limiting toxic effects, substantial cardiovascular toxic effects, or deaths occurred. One patient was removed from the activity analysis because they had insufficient target lesions for analysis. The most common grade 3 adverse events were decreased lymphocyte (n=3) and decreased neutrophil count (n=2); and grade 4 anaemia was reported by one patient. Three serious adverse events-febrile neutropenia, intestinal perforation, and cholangitis-were reported by one patient each. Overall, in 23 evaluable patients, including six patients with low HER2-expressing tumours, ten patients achieved an objective response (43%, 95% CI 23·2-65·5). Disease control was achieved in 21 (91%; 95% CI 72·0-98·9) of 23 patients. Median follow-up time was 6·7 months (IQR 4·4-10·2), with nine (90%) of ten responses seen at doses of 5·4 mg/kg or greater. The maximum tolerated dose of trastuzumab deruxtecan was not reached. In this small, heavily pretreated study population, trastuzumab deruxtecan showed antitumour activity, even in low HER2-expressing tumours. Based on safety and activity, the most likely recommended phase 2 dosing is 5·4 or 6·4 mg/kg. Daiichi Sankyo Co, Ltd. Copyright © 2017 Elsevier Ltd. All rights reserved.

Riociguat for the treatment of chronic thromboembolic pulmonary hypertension: a long-term extension study (CHEST-2).

PubMed

Simonneau, Gérald; D'Armini, Andrea M; Ghofrani, Hossein-Ardeschir; Grimminger, Friedrich; Hoeper, Marius M; Jansa, Pavel; Kim, Nick H; Wang, Chen; Wilkins, Martin R; Fritsch, Arno; Davie, Neil; Colorado, Pablo; Mayer, Eckhard

2015-05-01

Riociguat is a soluble guanylate cyclase stimulator approved for the treatment of inoperable and persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH). In the 16-week CHEST-1 study, riociguat showed a favourable benefit-risk profile and improved several clinically relevant end-points in patients with CTEPH. The CHEST-2 open-label extension evaluated the long-term safety and efficacy of riociguat. Eligible patients from CHEST-1 received riociguat individually adjusted up to a maximum dose of 2.5 mg three times daily. The primary objective was the safety and tolerability of riociguat; exploratory efficacy end-points included 6-min walking distance (6MWD) and World Health Organization (WHO) functional class (FC). Overall, 237 patients entered CHEST-2 and 211 (89%) were ongoing at this interim analysis (March 2013). The safety profile of riociguat in CHEST-2 was similar to CHEST-1, with no new safety signals. Improvements in 6MWD and WHO FC observed in CHEST-1 persisted for up to 1 year in CHEST-2. In the observed population at 1 year, mean±sd 6MWD had changed by +51±62 m (n=172) versus CHEST-1 baseline (n=237), and WHO FC had improved/stabilised/worsened in 47/50/3% of patients (n=176) versus CHEST-1 baseline (n=236). Long-term riociguat had a favourable benefit-risk profile and apparently showed sustained benefits in exercise and functional capacity for up to 1 year. Copyright ©ERS 2015.

78 FR 76191 - Operational Tests and Inspections for Compliance With Maximum Authorized Train Speeds and Other...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-12-16

... Tests and Inspections for Compliance With Maximum Authorized Train Speeds and Other Speed Restrictions... safety advisory; Operational tests and inspections for compliance with maximum authorized train speeds and other speed restrictions. SUMMARY: FRA is issuing Safety Advisory 2013-08 to stress to railroads...

Intervarietal variations in various oxidative stress markers and antioxidant potential of finger millet (Eleusine coracana) subjected to drought stress.

PubMed

Bartwal, Arti; Pande, Anjali; Sharma, Priyadarshini; Arora, Sandeep

2016-07-01

Drought is a major form of abiotic stress leading to lower crop productivity. Experiment was carried out for selecting the most tolerant genotype among six different genotypes of finger millet under drought stress. Seeds of six finger millet genotypes were sown in pots and grown for 35 days. After this period, drought was induced by withholding watering for stressed plants while control plants were watered regularly for comparison. Among all six different varieties of finger millet screened (PR202, PES400, PRM6107, VL283, VL328 and VL149) under varying intensities of drought stress,PRM6107 and PR202 showed highest stress tolerance by limiting excessive accumulation of reactive oxygen species (ROS) through activation of ROS scavenging antioxidative enzymes. A 200% increase in ascorbate content was recorded in PRM6107 and PR202, while in other varieties limited increase in ascorbate content was observed. Maximum decrease in chlorophyll content was observed in VL328 (83%) while least drop was observed in VL149 (65%). Relative water content indicated that PR202 was able to retain maximum water content under stress, as it recorded least drop in relative water content (55%), contributing to its better survival under stress. In conclusion finger millet genotypes PRM6107 and PR202 possessed maximum drought tolerance potential and thus may be used for allele mining of drought tolerant genes, which can further be employed for the development of more drought stress tolerant staple crops using biotechnological approach.

Evaluating the efficacies of Maximum Tolerated Dose and metronomic chemotherapies: A mathematical approach

NASA Astrophysics Data System (ADS)

Guiraldello, Rafael T.; Martins, Marcelo L.; Mancera, Paulo F. A.

2016-08-01

We present a mathematical model based on partial differential equations that is applied to understand tumor development and its response to chemotherapy. Our primary aim is to evaluate comparatively the efficacies of two chemotherapeutic protocols, Maximum Tolerated Dose (MTD) and metronomic, as well as two methods of drug delivery. Concerning therapeutic outcomes, the metronomic protocol proves more effective in prolonging the patient's life than MTD. Moreover, a uniform drug delivery method combined with the metronomic protocol is the most efficient strategy to reduce tumor density.

30 CFR 57.5039 - Maximum permissible concentration.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Maximum permissible concentration. 57.5039 Section 57.5039 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND NONMETAL MINE SAFETY AND HEALTH SAFETY AND HEALTH STANDARDS-UNDERGROUND METAL AND NONMETAL MINES Air Quality, Radiation, Physical Agents, and Diesel...

30 CFR 57.5039 - Maximum permissible concentration.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Maximum permissible concentration. 57.5039 Section 57.5039 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND NONMETAL MINE SAFETY AND HEALTH SAFETY AND HEALTH STANDARDS-UNDERGROUND METAL AND NONMETAL MINES Air Quality, Radiation, Physical Agents, and Diesel...

30 CFR 57.5039 - Maximum permissible concentration.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Maximum permissible concentration. 57.5039 Section 57.5039 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND NONMETAL MINE SAFETY AND HEALTH SAFETY AND HEALTH STANDARDS-UNDERGROUND METAL AND NONMETAL MINES Air Quality, Radiation, Physical Agents, and Diesel...

30 CFR 57.5039 - Maximum permissible concentration.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Maximum permissible concentration. 57.5039 Section 57.5039 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND NONMETAL MINE SAFETY AND HEALTH SAFETY AND HEALTH STANDARDS-UNDERGROUND METAL AND NONMETAL MINES Air Quality, Radiation, Physical Agents, and Diesel...

30 CFR 57.5039 - Maximum permissible concentration.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Maximum permissible concentration. 57.5039 Section 57.5039 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND NONMETAL MINE SAFETY AND HEALTH SAFETY AND HEALTH STANDARDS-UNDERGROUND METAL AND NONMETAL MINES Air Quality, Radiation, Physical Agents, and Diesel...

24 CFR 232.565 - Maximum loan amount.

Code of Federal Regulations, 2014 CFR

2014-04-01

... Fire Safety Equipment Eligible Security Instruments § 232.565 Maximum loan amount. The principal amount of the loan shall not exceed the lower of the Commissioner's estimate of the cost of the fire safety... Secretary of Health and Human Services and the Commissioner to enhance the fire safety of the project, and...

24 CFR 232.565 - Maximum loan amount.

Code of Federal Regulations, 2013 CFR

2013-04-01

... Fire Safety Equipment Eligible Security Instruments § 232.565 Maximum loan amount. The principal amount of the loan shall not exceed the lower of the Commissioner's estimate of the cost of the fire safety... Secretary of Health and Human Services and the Commissioner to enhance the fire safety of the project, and...

24 CFR 232.565 - Maximum loan amount.

Code of Federal Regulations, 2012 CFR

2012-04-01

... Fire Safety Equipment Eligible Security Instruments § 232.565 Maximum loan amount. The principal amount of the loan shall not exceed the lower of the Commissioner's estimate of the cost of the fire safety... Secretary of Health and Human Services and the Commissioner to enhance the fire safety of the project, and...

More grain per drop of water: Screening rice genotype for physiological parameters of drought tolerance

NASA Astrophysics Data System (ADS)

Massanelli, J.; Meadows-McDonnell, M.; Konzelman, C.; Moon, J. B.; Kumar, A.; Thomas, J.; Pereira, A.; Naithani, K. J.

2016-12-01

Meeting agricultural water demands is becoming progressively difficult due to population growth and changes in climate. Breeding stress-resilient crops is a viable solution, as information about genetic variation and their role in stress tolerance is becoming available due to advancement in technology. In this study we screened eight diverse rice genotypes for photosynthetic capacity under greenhouse conditions. These include the Asian rice (Oryza sativa) genotypes, drought sensitive Nipponbare, and a transgenic line overexpressing the HYR gene in Nipponbare; six genotypes (Vandana, Bengal, Nagina-22, Glaberrima, Kaybonnet, Ai Chueh Ta Pai Ku) and an African rice O. glaberrima, all selected for varying levels of drought tolerance. We collected CO2 and light response curve data under well-watered and simulated drought conditions in greenhouse. From these curves we estimated photosynthesis model parameters, such as the maximum carboxylation rate (Vcmax), the maximum electron transport rate (Jmax), the maximum gross photosynthesis rate, daytime respiration (Rd), and quantum yield (f). Our results suggest that O. glaberrima and Nipponbare were the most sensitive to drought because Vcmax and Pgmax declined under drought conditions; other drought tolerant genotypes did not show significant changes in these model parameters. Our integrated approach, combining genetic information and photosynthesis modeling, shows promise to quantify drought response parameters and improve crop yield under drought stress conditions.

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

PubMed

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

2012-11-01

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

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.

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.

Chronic migraine headache prevention with noninvasive vagus nerve stimulation: The EVENT study.

PubMed

Silberstein, Stephen D; Calhoun, Anne H; Lipton, Richard B; Grosberg, Brian M; Cady, Roger K; Dorlas, Stefanie; Simmons, Kristy A; Mullin, Chris; Liebler, Eric J; Goadsby, Peter J; Saper, Joel R

2016-08-02

To evaluate the feasibility, safety, and tolerability of noninvasive vagus nerve stimulation (nVNS) for the prevention of chronic migraine (CM) attacks. In this first prospective, multicenter, double-blind, sham-controlled pilot study of nVNS in CM prophylaxis, adults with CM (≥15 headache d/mo) entered the baseline phase (1 month) and were subsequently randomized to nVNS or sham treatment (2 months) before receiving open-label nVNS treatment (6 months). The primary endpoints were safety and tolerability. Efficacy endpoints in the intent-to-treat population included change in the number of headache days per 28 days and acute medication use. Fifty-nine participants (mean age, 39.2 years; mean headache frequency, 21.5 d/mo) were enrolled. During the randomized phase, tolerability was similar for nVNS (n = 30) and sham treatment (n = 29). Most adverse events were mild/moderate and transient. Mean changes in the number of headache days were -1.4 (nVNS) and -0.2 (sham) (Δ = 1.2; p = 0.56). Twenty-seven participants completed the open-label phase. For the 15 completers initially assigned to nVNS, the mean change from baseline in headache days after 8 months of treatment was -7.9 (95% confidence interval -11.9 to -3.8; p < 0.01). Therapy with nVNS was well-tolerated with no safety issues. Persistent prophylactic use may reduce the number of headache days in CM; larger sham-controlled studies are needed. NCT01667250. This study provides Class II evidence that for patients with CM, nVNS is safe, is well-tolerated, and did not significantly change the number of headache days. This pilot study lacked the precision to exclude important safety issues or benefits of nVNS. © 2016 American Academy of Neurology.

Seasonal and geographical variation in heat tolerance and evaporative cooling capacity in a passerine bird.

PubMed

Noakes, Matthew J; Wolf, Blair O; McKechnie, Andrew E

2016-03-01

Intraspecific variation in avian thermoregulatory responses to heat stress has received little attention, despite increasing evidence that endothermic animals show considerable physiological variation among populations. We investigated seasonal (summer versus winter) variation in heat tolerance and evaporative cooling in an Afrotropical ploceid passerine, the white-browed sparrow-weaver (Plocepasser mahali; ∼ 47 g) at three sites along a climatic gradient with more than 10 °C variation in mid-summer maximum air temperature (Ta). We measured resting metabolic rate (RMR) and total evaporative water loss (TEWL) using open flow-through respirometry, and core body temperature (Tb) using passive integrated transponder tags. Sparrow-weavers were exposed to a ramped profile of progressively higher Ta between 30 and 52 °C to elicit maximum evaporative cooling capacity (N=10 per site per season); the maximum Ta birds tolerated before the onset of severe hyperthermia (Tb ≈ 44 °C) was considered to be their hyperthermia threshold Ta (Ta,HT). Our data reveal significant seasonal acclimatisation of heat tolerance, with a desert population of sparrow-weavers reaching significantly higher Ta in summer (49.5 ± 1.4 °C, i.e. higher Ta,HT) than in winter (46.8 ± 0.9 °C), reflecting enhanced evaporative cooling during summer. Moreover, desert sparrow-weavers had significantly higher heat tolerance and evaporative cooling capacity during summer compared with populations from more mesic sites (Ta,HT=47.3 ± 1.5 and 47.6 ± 1.3 °C). A better understanding of the contributions of local adaptation versus phenotypic plasticity to intraspecific variation in avian heat tolerance and evaporative cooling capacity is needed for modelling species' responses to changing climates. © 2016. Published by The Company of Biologists Ltd.

Safety and activity of the anti-CD79B antibody-drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase 1 study.

PubMed

Palanca-Wessels, Maria Corinna A; Czuczman, Myron; Salles, Gilles; Assouline, Sarit; Sehn, Laurie H; Flinn, Ian; Patel, Manish R; Sangha, Randeep; Hagenbeek, Anton; Advani, Ranjana; Tilly, Herve; Casasnovas, Olivier; Press, Oliver W; Yalamanchili, Sreeni; Kahn, Robert; Dere, Randall C; Lu, Dan; Jones, Surai; Jones, Cheryl; Chu, Yu-Waye; Morschhauser, Franck

2015-06-01

Patients with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL) have an unfavourable prognosis with few treatment options. Polatuzumab vedotin is an antibody-drug conjugate containing an anti-CD79B monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E. We aimed to assess the safety and clinical activity of polatuzumab vedotin in relapsed or refractory B-cell NHL and chronic lymphocytic leukaemia (CLL). In this phase 1, multicentre, open-label study, we enrolled patients with documented NHL or CLL expected to express CD79B (confirmation of CD79B expression was not required) and for whom no suitable therapy of curative intent or higher priority existed from 13 centres. The primary endpoints of the study were to assess safety and tolerability, determine the maximum tolerated dose, and identify the recommended phase 2 dose of polatuzumab vedotin as a single agent and in combination with rituximab. A 3 + 3 dose-escalation design was used in which we treated patients with polatuzumab vedotin (0·1-2·4 mg/kg every 21 days) in separate dose-escalation cohorts for NHL and CLL. After determination of the recommended phase 2 dose, we enrolled patients with relapsed or refractory diffuse large B-cell lymphoma and relapsed or refractory indolent NHL into indication-specific cohorts. We also enrolled patients with relapsed or refractory NHL into an additional cohort to assess the feasibility of the combination of polatuzumab vedotin and rituximab 375 mg/m(2). Patients who received any dose of polatuzumab vedotin were available for safety analyses. This study is registered with ClinicalTrials.gov, number NCT01290549. Between March 21, 2011, and Nov 30, 2012, we enrolled 95 patients (34 to the NHL dose-escalation cohort, 18 to the CLL dose-escalation cohort, 34 with NHL to the expansion cohort at the recommended phase 2 dose, and nine with NHL to the rituximab combination cohort; no expansion cohort of CLL was started due to lack of activity in the dose-escalation cohort). The recommended phase 2 dose in NHL was 2·4 mg/kg as a single agent and in combination with rituximab; the maximum tolerated dose in CLL was 1·0 mg/kg as a result of dose-limiting toxic effects reported in two of five patients given 1·8 mg/kg. Grade 3-4 adverse events were reported in 26 (58%) of 45 patients with NHL treated at the single-agent recommended phase 2 dose, and the most common grade 3-4 adverse events were neutropenia (18 [40%] of 45), anaemia (five [11%]), and peripheral sensory neuropathy (four [9%]). Serious adverse events were reported in 17 (38%) of 45 patients, and included diarrhoea (two patients), lung infection (two patients), disease progression (two patients), and lung disorder (two patients). Seven (77%) of nine patients in the rituximab combination cohort had a grade 3-4 adverse event, with neutropenia (five [56%]), anaemia (two [22%]), and febrile neutropenia (two [22%]) reported in more than one patient. 11 (12%) of 95 patients died during the study: eight with relapsed or refractory diffuse large B-cell lymphoma (due to progressive disease in four patients, infections in three patients [two treatment related], and treatment-related worsening ascites in one patient) and three with relapsed or refractory CLL (due to progressive disease, pulmonary infection, and pneumonia; none thought to be treatment-related). At the recommended phase 2 dose, objective responses were noted in 23 of 42 activity-evaluable patients with NHL given single-agent polatuzumab vedotin (14 of 25 with diffuse large B-cell lymphoma, seven of 15 with indolent NHL, and two with mantle-cell lymphoma) and seven of nine patients treated with polatuzumab vedotin combined with rituximab. No objective responses were observed in patients with CLL. Polatuzumab vedotin has an acceptable safety and tolerability profile in patients with NHL but not in those with CLL. Its clinical activity should be further assessed in NHL. Genentech. Copyright © 2015 Elsevier Ltd. 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 in pre-clinical research provide encouraging evidence that deliberately inducing tolerance through hematopoietic chimerism might eventually make it from dream to reality. PMID:29312303

Rapid change in the thermal tolerance of a tropical lizard.

PubMed

Leal, Manuel; Gunderson, Alex R

2012-12-01

The predominant view is that the thermal physiology of tropical ectotherms, including lizards, is not labile over ecological timescales. We used the recent introduction (∼35 years ago) of the Puerto Rican lizard Anolis cristatellus to Miami, Florida, to test this thermal rigidity hypothesis. We measured lower (critical thermal minimum [CT(min)]) and upper (critical thermal maximum [CT(max)]) thermal tolerances and found that the introduced population tolerates significantly colder temperatures (by ∼3°C) than does the Puerto Rican source population; however, CT(max) did not differ. These results mirror the thermal regimes experienced by each population: Miami reaches colder ambient temperatures than Puerto Rico, but maximum ambient temperatures are similar. The differences in CT(min) were observed even though lizards from both sites experienced nearly identical conditions for 49 days before CT(min) measurement. Our results demonstrate that changes in thermal tolerance occurred relatively rapidly (∼35 generations), which strongly suggests that the thermal physiology of tropical lizards is more labile than previously proposed.

Balancing efficacy against safety in sublingual immunotherapy with inhalant allergens: what is the best approach?

PubMed

Caminati, Marco; Dama, Annarita; Schiappoli, Michele; Senna, Gianenrico

2013-10-01

Over the last 20 years, studies and clinical trials have demonstrated efficacy, safety and cost-effectiveness of sublingual immunotherapy (SLIT) for respiratory allergic diseases. Nevertheless, it seems to be mostly used as a second-line therapeutic option, and adherence to treatment is not always optimal. Selective literature research was done in Medline and PubMed, including guidelines, position papers and Cochrane meta-analyses concerning SLIT in adult patients. The most recent reviews confirm SLIT as viable and efficacious treatment especially for allergic rhinitis, even if the optimal dosage, duration, schedule are not clearly established for most of the products. Despite an optimal safety profile, tolerability and patient-reported outcomes concerning SLIT have received poor attention until now. Recently, new tools have been specifically developed in order to investigate these aspects. Regular assessment of tolerability profile and SLIT-related patient-reported outcomes will allow balancing efficacy with tolerability and all the other patient-related variables that may affect treatment effectiveness beyond its efficacy.

An increased rectal maximum tolerable volume and long anal canal are associated with poor short-term response to biofeedback therapy for patients with anismus with decreased bowel frequency and normal colonic transit time.

PubMed

Rhee, P L; Choi, M S; Kim, Y H; Son, H J; Kim, J J; Koh, K C; Paik, S W; Rhee, J C; Choi, K W

2000-10-01

Biofeedback is an effective therapy for a majority of patients with anismus. However, a significant proportion of patients still failed to respond to biofeedback, and little has been known about the factors that predict response to biofeedback. We evaluated the factors associated with poor response to biofeedback. Biofeedback therapy was offered to 45 patients with anismus with decreased bowel frequency (less than three times per week) and normal colonic transit time. Any differences in demographics, symptoms, and parameters of anorectal physiologic tests were sought between responders (in whom bowel frequency increased up to three times or more per week after biofeedback) and nonresponders (in whom bowel frequency remained less than three times per week). Thirty-one patients (68.9 percent) responded to biofeedback and 14 patients (31.1 percent) did not. Anal canal length was longer in nonresponders than in responders (4.53 +/- 0.5 vs. 4.08 +/- 0.56 cm; P = 0.02), and rectal maximum tolerable volume was larger in nonresponders than in responders. (361 +/- 87 vs. 302 +/- 69 ml; P = 0.02). Anal canal length and rectal maximum tolerable volume showed significant differences between responders and nonresponders on multivariate analysis (P = 0.027 and P = 0.034, respectively). This study showed that a long anal canal and increased rectal maximum tolerable volume are associated with poor short-term response to biofeedback for patients with anismus with decreased bowel frequency and normal colonic transit time.

Phase I Trial of Anti-CS1 Monoclonal Antibody Elotuzumab in Combination With Bortezomib in the Treatment of Relapsed/Refractory Multiple Myeloma

PubMed Central

Jakubowiak, Andrzej J.; Benson, Don M.; Bensinger, William; Siegel, David S.D.; Zimmerman, Todd M.; Mohrbacher, Ann; Richardson, Paul G.; Afar, Daniel E.H.; Singhal, Anil K.; Anderson, Kenneth C.

2012-01-01

Purpose To evaluate the maximum-tolerated dose (MTD), safety, and efficacy of elotuzumab in combination with bortezomib in patients with relapsed or relapsed and refractory multiple myeloma (MM). Patients and Methods Elotuzumab (2.5, 5.0, 10, or 20 mg/kg intravenously [IV]) and bortezomib (1.3 mg/m2 IV) were administered on days 1 and 11 and days 1, 4, 8, and 11, respectively, in 21-day cycles by using a 3 + 3 dose-escalation design. Patients with stable disease or better after four cycles could continue treatment until disease progression or unexpected toxicity. Responses were assessed during each cycle by using European Group for Blood and Marrow Transplantation (EBMT) criteria. Results Twenty-eight patients with a median of two prior therapies were enrolled; three patients each received 2.5, 5.0, and 10 mg/kg of elotuzumab and 19 received 20 mg/kg (six during dose escalation and 13 during an expansion phase). No dose-limiting toxicities were observed during cycle 1 of the dose-escalation phase, and the MTD was not reached up to the maximum planned dose of 20 mg/kg. The most frequent grade 3 to 4 adverse events (AEs) were lymphopenia (25%) and fatigue (14%). Two elotuzumab-related serious AEs of chest pain and gastroenteritis occurred in one patient. An objective response (a partial response or better) was observed in 13 (48%) of 27 evaluable patients and in two (67%) of three patients refractory to bortezomib. Median time to progression was 9.46 months. Conclusion The combination of elotuzumab and bortezomib was generally well-tolerated and showed encouraging activity in patients with relapsed/refractory MM. PMID:22291084

Extended-Release Once-Daily Formulation of Tofacitinib: Evaluation of Pharmacokinetics Compared With Immediate-Release Tofacitinib and Impact of Food.

PubMed

Lamba, Manisha; Wang, Rong; Fletcher, Tracey; Alvey, Christine; Kushner, Joseph; Stock, Thomas C

2016-11-01

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. An extended-release (XR) formulation has been designed to provide a once-daily (QD) dosing option to patients to achieve comparable pharmacokinetic (PK) parameters to the twice-daily immediate-release (IR) formulation. We conducted 2 randomized, open-label, phase 1 studies in healthy volunteers. Study A characterized single-dose and steady-state PK of tofacitinib XR 11 mg QD and intended to demonstrate equivalence of exposure under single-dose and steady-state conditions to tofacitinib IR 5 mg twice daily. Study B assessed the effect of a high-fat meal on the bioavailability of tofacitinib from the XR formulation. Safety and tolerability were monitored in both studies. In study A (N = 24), the XR and IR formulations achieved time to maximum plasma concentration at 4 hours and 0.5 hours postdose, respectively; terminal half-life was 5.9 hours and 3.2 hours, respectively. Area under plasma concentration-time curve (AUC) and maximum plasma concentration (C max ) after single- and multiple-dose administration were equivalent between the XR and IR formulations. In study B (N = 24), no difference in AUC was observed for fed vs fasted conditions. C max increased by 27% under the fed state. On repeat administration, negligible accumulation (<20%) of systemic exposures was observed for both formulations. Steady state was achieved within 48 hours of dosing with the XR formulation. Tofacitinib administration as an XR or IR formulation was generally well tolerated in these studies. © 2016, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Phase 1 dose-finding study of rebastinib (DCC-2036) in patients with relapsed chronic myeloid leukemia and acute myeloid leukemia

PubMed Central

Cortes, Jorge; Talpaz, Moshe; Smith, Hedy P.; Snyder, David S.; Khoury, Jean; Bhalla, Kapil N.; Pinilla-Ibarz, Javier; Larson, Richard; Mitchell, David; Wise, Scott C.; Rutkoski, Thomas J.; Smith, Bryan D.; Flynn, Daniel L.; Kantarjian, Hagop M.; Rosen, Oliver; Van Etten, Richard A.

2017-01-01

A vailable tyrosine kinase inhibitors for chronic myeloid leukemia bind in an adenosine 5′-triphosphate-binding pocket and are affected by evolving mutations that confer resistance. Rebastinib was identified as a switch control inhibitor of BCR-ABL1 and FLT3 and may be active against resistant mutations. A Phase 1, first-in-human, single-agent study investigated rebastinib in relapsed or refractory chronic or acute myeloid leukemia. The primary objectives were to investigate the safety of rebastinib and establish the maximum tolerated dose and recommended Phase 2 dose. Fifty-seven patients received treatment with rebastinib. Sixteen patients were treated using powder-in-capsule preparations at doses from 57 mg to 1200 mg daily, and 41 received tablet preparations at doses of 100 mg to 400 mg daily. Dose-limiting toxicities were dysarthria, muscle weakness, and peripheral neuropathy. The maximum tolerated dose was 150 mg tablets administered twice daily. Rebastinib was rapidly absorbed. Bioavailability was 3- to 4-fold greater with formulated tablets compared to unformulated capsules. Eight complete hematologic responses were achieved in 40 evaluable chronic myeloid leukemia patients, 4 of which had a T315I mutation. None of the 5 patients with acute myeloid leukemia responded. Pharmacodynamic analysis showed inhibition of phosphorylation of substrates of BCR-ABL1 or FLT3 by rebastinib. Although clinical activity was observed, clinical benefit was insufficient to justify continued development in chronic or acute myeloid leukemia. Pharmacodynamic analyses suggest that other kinases inhibited by rebastinib, such as TIE2, may be more relevant targets for the clinical development of rebastinib (clinicaltrials.gov Identifier:00827138). PMID:27927766

Phase 1 dose-finding study of rebastinib (DCC-2036) in patients with relapsed chronic myeloid leukemia and acute myeloid leukemia.

PubMed

Cortes, Jorge; Talpaz, Moshe; Smith, Hedy P; Snyder, David S; Khoury, Jean; Bhalla, Kapil N; Pinilla-Ibarz, Javier; Larson, Richard; Mitchell, David; Wise, Scott C; Rutkoski, Thomas J; Smith, Bryan D; Flynn, Daniel L; Kantarjian, Hagop M; Rosen, Oliver; Van Etten, Richard A

2017-03-01

A vailable tyrosine kinase inhibitors for chronic myeloid leukemia bind in an adenosine 5'-triphosphate-binding pocket and are affected by evolving mutations that confer resistance. Rebastinib was identified as a switch control inhibitor of BCR-ABL1 and FLT3 and may be active against resistant mutations. A Phase 1, first-in-human, single-agent study investigated rebastinib in relapsed or refractory chronic or acute myeloid leukemia. The primary objectives were to investigate the safety of rebastinib and establish the maximum tolerated dose and recommended Phase 2 dose. Fifty-seven patients received treatment with rebastinib. Sixteen patients were treated using powder-in-capsule preparations at doses from 57 mg to 1200 mg daily, and 41 received tablet preparations at doses of 100 mg to 400 mg daily. Dose-limiting toxicities were dysarthria, muscle weakness, and peripheral neuropathy. The maximum tolerated dose was 150 mg tablets administered twice daily. Rebastinib was rapidly absorbed. Bioavailability was 3- to 4-fold greater with formulated tablets compared to unformulated capsules. Eight complete hematologic responses were achieved in 40 evaluable chronic myeloid leukemia patients, 4 of which had a T315I mutation. None of the 5 patients with acute myeloid leukemia responded. Pharmacodynamic analysis showed inhibition of phosphorylation of substrates of BCR-ABL1 or FLT3 by rebastinib. Although clinical activity was observed, clinical benefit was insufficient to justify continued development in chronic or acute myeloid leukemia. Pharmacodynamic analyses suggest that other kinases inhibited by rebastinib, such as TIE2, may be more relevant targets for the clinical development of rebastinib ( clinicaltrials.gov Identifier:00827138 ). Copyright© Ferrata Storti Foundation.

Deferasirox for the treatment of iron overload after allogeneic hematopoietic cell transplantation: multicenter phase I study (KSGCT1302).

PubMed

Tachibana, Takayoshi; Kanda, Junya; Machida, Shinichiro; Saito, Takeshi; Tanaka, Masatsugu; Najima, Yuho; Koyama, Satoshi; Miyazaki, Takuya; Yamamoto, Eri; Takeuchi, Masahiro; Morita, Satoshi; Kanda, Yoshinobu; Kanamori, Heiwa; Okamoto, Shinichiro

2018-05-01

The aim of this study was to assess the safety and optimal dose of deferasirox for the treatment of iron overload after allogeneic hematopoietic cell transplantation (HCT). The primary endpoint was the maximum tolerated dose of deferasirox that was determined by the intrapatient dose escalation methods. A total of 16 patients with post-HCT iron overload were enrolled in the study. After excluding one case of early relapse, 15 remained evaluable. Their median age was 42 years (range 22-68). Median time from HCT to deferasirox administration was 9 months (range 6-84). Deferasirox was started at a dose of 5 mg/kg, and the dose was increased to 7.5 and 10 mg/kg every 4 weeks unless there were no grade ≥ 2 of adverse events. Achievement rates of planned medication were 80% in 5 mg/kg (12 of 15), 73% in 7.5 mg/kg (11 of 15), and 60% in 10 mg/kg (9 of 15), respectively. The reasons for discontinuation of the drug were grade 2 of adverse events (n = 4), late relapse (n = 1), and self-cessation (n = 1). None of the patients developed grade ≥ 3 of adverse events or exacerbation of GVHD. Among 11 evaluable cases, mean value of ferritin decreased from 1560 ng/ml pre-treatment to 1285 ng/ml post-treatment. These data suggested that 10 mg/kg of deferasirox may be maximum tolerated dose when given after HCT. Our dose escalating method of deferasirox is useful to identify the optimal dosage of the drug in each patient. UMIN000011251.

Phase I study of cediranib in combination with cisplatin plus fluoropyrimidine (S-1 or capecitabine) in Japanese patients with previously untreated advanced gastric cancer.

PubMed

Satoh, Taroh; Yamada, Yasuhide; Muro, Kei; Hayashi, Hidetoshi; Shimada, Yasuhiro; Takahari, Daisuke; Taku, Keisei; Nakajima, Takako Eguchi; Shi, Xiaojin; Brown, Kathryn H; Boku, Narikazu

2012-02-01

The primary objective of this Phase I study was to assess the safety and tolerability of the vascular endothelial growth factor signalling inhibitor cediranib in combination with cisplatin plus an oral fluoropyrimidine, in Japanese patients with previously untreated advanced gastric cancer. Patients received continuous, once-daily oral doses of cediranib 20 mg in combination with either cisplatin (60 mg/m(2) iv day 1) plus S-1 (40-60 mg bid, days 1-21) every 5 weeks for a maximum of eight cycles [Arm A]; or cisplatin (80 mg/m(2) iv, day 1) plus capecitabine (1,000 mg/m(2) bid, days 1-14) every 3 weeks for a maximum of six cycles [Arm B]. In both arms, the assessment period for dose-limiting toxicities (DLTs) was the first 21 days of cycle 1. Fourteen patients (Arm A, n = 6; Arm B, n = 8) were enrolled and received at least one dose of cediranib. One patient in each arm experienced a DLT (Arm A; decreased appetite, grade 3; Arm B, decreased appetite, fatigue and hyponatraemia, all grade 3). Overall, the most common adverse events were decreased appetite, fatigue and nausea (all n = 13 [92.9%]). Preliminary efficacy evaluation showed one confirmed (Arm A) and three unconfirmed (Arm A, n = 1; Arm B, n = 2) partial responses that were ongoing at data cut-off. Cediranib 20 mg/day in combination with cisplatin and S-1 or capecitabine was tolerable, with no new toxicities identified, and showed preliminary evidence of antitumour activity.

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.

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 first. However, alongside with safety, efficacy should also be considered on a patient-tailored basis. PMID:28721057

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.

The linear sizes tolerances and fits system modernization

NASA Astrophysics Data System (ADS)

Glukhov, V. I.; Grinevich, V. A.; Shalay, V. V.

2018-04-01

The study is carried out on the urgent topic for technical products quality providing in the tolerancing process of the component parts. The aim of the paper is to develop alternatives for improving the system linear sizes tolerances and dimensional fits in the international standard ISO 286-1. The tasks of the work are, firstly, to classify as linear sizes the elements additionally linear coordinating sizes that determine the detail elements location and, secondly, to justify the basic deviation of the tolerance interval for the element's linear size. The geometrical modeling method of real details elements, the analytical and experimental methods are used in the research. It is shown that the linear coordinates are the dimensional basis of the elements linear sizes. To standardize the accuracy of linear coordinating sizes in all accuracy classes, it is sufficient to select in the standardized tolerance system only one tolerance interval with symmetrical deviations: Js for internal dimensional elements (holes) and js for external elements (shafts). The main deviation of this coordinating tolerance is the average zero deviation, which coincides with the nominal value of the coordinating size. Other intervals of the tolerance system are remained for normalizing the accuracy of the elements linear sizes with a fundamental change in the basic deviation of all tolerance intervals is the maximum deviation corresponding to the limit of the element material: EI is the lower tolerance for the of the internal elements (holes) sizes and es is the upper tolerance deviation for the outer elements (shafts) sizes. It is the sizes of the material maximum that are involved in the of the dimensional elements mating of the shafts and holes and determine the fits type.

Safety of Abiraterone Acetate in Castration-resistant Prostate Cancer Patients With Concomitant Cardiovascular Risk Factors.

PubMed

Procopio, Giuseppe; Grassi, Paolo; Testa, Isabella; Verzoni, Elena; Torri, Valter; Salvioni, Roberto; Valdagni, Riccardo; de Braud, Filippo

2015-10-01

The aim of this study was to evaluate the safety profile of abiraterone acetate (AA) in metastatic castration-resistant prostate cancer (mCRPC) men with cardiovascular comorbidity, as little conclusive safety data are available in this patient subset. A retrospective analysis of mCRPC patients with controlled cardiovascular comorbidities, receiving AA 1000 mg administered orally once daily and prednisone 5 mg twice daily, between April 2011 and July 2012, was performed. All clinical and instrumental variables and toxicity data were analyzed by descriptive statistics: mean, standard deviation, minimum and maximum values for continuous variables, and absolute and relative frequencies for categorical variables. A total of 51 mCRPC patients were evaluated. Metastatic sites included the bone (74%), lungs, and liver (26%). All patients were previously treated with at least 2 lines of hormone and 1 docetaxel-based chemotherapy. Preexisting cardiac risk factors included hypertension (41%), cardiac ischemia (12%), arrhythmias (6%), dislipidemia (18%), and hyperglycemia (30%). No grade 3-4 adverse events were observed. Grade 1-2 adverse events included fluid retention (18%), asthenia (15%), and hypertension (16%). Median progression-free survival was 5.1 months (95% confidence interval, 0.5-12). Prostate specific antigen assessment revealed a good overall disease control rate (64%). AA appears to be safe and well tolerated even in patients with cardiovascular comorbidities or with increased risk factors for cardiovascular diseases.

Randomized, Evaluator-Blinded Study Comparing Safety and Effect of Two Hyaluronic Acid Gels for Lips Enhancement.

PubMed

Hilton, Said; Sattler, Gerhard; Berg, Anna-Karin; Samuelson, Ulf; Wong, Cindy

2018-02-01

Hyaluronic acid (HA) fillers may differ in terms of gel characteristics and ease of use and it is of interest whether this might affect safety and duration of effect. To compare the long-term safety and effect of 2 HA fillers produced by 2 different technologies for lip enhancement. Subjects with very thin to moderately thick lips were randomized and treated with HA-RK (N = 31) or HA-JV (N = 29) to improve lip fullness by ≥ 1 grade on a 5-point scale, using a maximum of 3 mL of product. A smaller volume of HA-RK compared with HA-JV was required to improve lip fullness by ≥ 1 grade (mean: 1.54 mL vs 1.94 mL, p < .001). Despite the smaller volume, lip fullness and global aesthetic improvement were comparably sustained in both groups. At 6 months, 60.0% versus 57.7% of subjects (HA-RK vs HA-JV) had improved lip fullness. At 12 months, 71.4% versus 76.0% had aesthetic improvement (blinded evaluations) and 85.7% versus 86.2% felt more attractive. Both products were well tolerated. Both products achieved durable improvement in lip fullness and aesthetic appearance. A significantly smaller amount of HA-RK was required compared with HA-JV to achieve optimal treatment effect.

Randomized, Evaluator-Blinded Study Comparing Safety and Effect of Two Hyaluronic Acid Gels for Lips Enhancement

PubMed Central

Sattler, Gerhard; Berg, Anna-Karin; Samuelson, Ulf; Wong, Cindy

2018-01-01

BACKGROUND Hyaluronic acid (HA) fillers may differ in terms of gel characteristics and ease of use and it is of interest whether this might affect safety and duration of effect. OBJECTIVE To compare the long-term safety and effect of 2 HA fillers produced by 2 different technologies for lip enhancement. MATERIALS AND METHODS Subjects with very thin to moderately thick lips were randomized and treated with HA-RK (N = 31) or HA-JV (N = 29) to improve lip fullness by ≥ 1 grade on a 5-point scale, using a maximum of 3 mL of product. RESULTS A smaller volume of HA-RK compared with HA-JV was required to improve lip fullness by ≥ 1 grade (mean: 1.54 mL vs 1.94 mL, p < .001). Despite the smaller volume, lip fullness and global aesthetic improvement were comparably sustained in both groups. At 6 months, 60.0% versus 57.7% of subjects (HA-RK vs HA-JV) had improved lip fullness. At 12 months, 71.4% versus 76.0% had aesthetic improvement (blinded evaluations) and 85.7% versus 86.2% felt more attractive. Both products were well tolerated. CONCLUSION Both products achieved durable improvement in lip fullness and aesthetic appearance. A significantly smaller amount of HA-RK was required compared with HA-JV to achieve optimal treatment effect. PMID:29059146

Phase I study of carboplatin combined with pemetrexed for elderly patients with advanced non-squamous non-small cell lung cancer.

PubMed

Takeoka, Hiroaki; Yamada, Kazuhiko; Azuma, Koichi; Zaizen, Yoshiaki; Yamashita, Fumie; Yoshida, Tsukasa; Naito, Yoshiko; Okayama, Yusuke; Miyamoto, Maki; Hoshino, Tomoaki

2014-05-01

The primary objective of this study was to evaluate the safety and tolerability of carboplatin plus pemetrexed for elderly patients (≥75 years) with chemotherapy-naïve advanced non-squamous non-small cell lung cancer. Patients received escalated doses of carboplatin at an area under the concentration-time curve of 4 (Level 1) or 5 (Level 2) plus pemetrexed (500 mg/m(2)) every 3 weeks for a maximum of six cycles. Dose escalation was decided according to whether dose-limiting toxicity occurred in the first cycle of chemotherapy. A total of 20 patients (6 at Level 1, 14 at Level 2) were enrolled. No dose-limiting toxicities were observed in patients at Level 1 or the first six patients at Level 2, and therefore the combination of carboplatin at an area under the concentration-time curve of 5 plus pemetrexed at 500 mg/m(2) was considered to be the recommended dose. Among a total of 14 patients in Level 2, only 1 patient experienced dose-limiting toxicity: Grade 3 febrile neutropenia and urticaria. The major toxicities were neutropenia, thrombocytopenia and anemia. Liver dysfunction, fatigue and anorexia were also common, but generally manageable. Six patients showed partial responses, giving the overall response rate of 30%. The median progression-free survival period was 4.8 months (95% confidence interval 2.9-6.7 months). The combination of carboplatin at an area under the concentration-time curve of 5 plus pemetrexed at 500 mg/m(2) was determined as the recommended dose in chemotherapy-naïve elderly patients (≥75 years) with advanced non-squamous non-small cell lung cancer, in view of overall safety and tolerability.

Contraceptive efficacy and safety of estradiol valerate/dienogest in a healthy female population: a multicenter, open-label, uncontrolled Phase III study.

PubMed

Yu, Qi; Huang, Zirong; Ren, Mulan; Chang, Qing; Zhang, Zhongqi; Parke, Susanne

2018-01-01

To investigate the efficacy and safety of a combined oral contraceptive containing estradiol valerate and dienogest (EV/DNG) in healthy Asian women. In this multicenter Phase III study, women received oral EV/DNG in a 28-day regimen for 13 cycles. The primary efficacy endpoint was the number of unintended pregnancies, measured by the Pearl Index (PI); secondary efficacy endpoints included bleeding pattern and cycle control parameters. Adverse events were monitored during the study and overall satisfaction with treatment was determined on completion of the study. A total of 954 Asian women (97.7% of subjects assigned to study medication; mean age 33.4 years) were treated. Five pregnancies were reported during EV/DNG treatment over 796.34 relevant woman-years of exposure, giving an unadjusted PI of 0.63 and a cumulative failure rate of 0.0049; 3 pregnancies during EV/DNG treatment over 760.35 relevant woman-years of exposure gave an adjusted PI of 0.39. The bleeding pattern improved during the reporting periods within the study. The proportion of women who experienced withdrawal bleeding decreased with treatment (84.9% of women during Cycle 1 vs 79.3% in Cycle 13), and the mean length of withdrawal bleeding decreased with treatment (4.2 vs 3.4 days). The number and maximum length of intracyclic bleeding/spotting episodes also decreased with EV/DNG. EV/DNG was well tolerated, and 92% of women included in the study were very satisfied or somewhat satisfied with EV/DNG. EV/DNG showed high contraceptive efficacy, was well tolerated in Asian women, and may be effectively used in this population. ClinicalTrials.gov identifier: NCT01638910.

Reduced Sodium Transport With Nasal Administration of the Prostasin Inhibitor Camostat in Subjects With Cystic Fibrosis

PubMed Central

Reeves, Ginger; Hathorne, Heather; Solomon, G. Martin; Abbi, Smita; Renard, Didier; Lock, Ruth; Zhou, Ping; Danahay, Henry; Clancy, John P.; Waltz, David A.

2013-01-01

Background: Prostasin, a trypsin-like serine protease, is a channel-activating protease and major regulator of epithelial sodium channel-mediated sodium absorption. Its direct inhibition by camostat represents a potential approach to inhibiting sodium transport in cystic fibrosis (CF). Methods: To determine whether a topical formulation of camostat represents an efficacious and tolerable approach to reducing Na+ transport in the CF airway, we conducted a two-part randomized, double-blind, placebo-controlled, crossover, ascending single-dose study to evaluate the pharmacodynamics, safety, and pharmacokinetics of camostat administered through a nasal spray pump in subjects with CF. Nasal potential difference (PD) was measured before and after treatment, and safety and pharmacokinetics were assessed by a standardized approach. Results: In part 1, nine subjects were enrolled, and six completed crossover dosing at the maximally tolerated dose. The change in maximal (most polarizing) basal PD 2 h following administration of camostat was +13.1 mV (1.6-mg dose group) compared with −8.6 mV following placebo (P < .005). Intrasubject change in Ringer and amiloride-sensitive PDs exhibited similar and consistent responses. Bayesian analysis in an additional six subjects in part 2 estimated a dose of 18 μg/mL to provide 50% of the maximum effect. There was no significant change in chloride transport or total nasal symptom score, nasal examination rating, and laboratory parameters. Conclusions: This study establishes the proof of concept that a reduction in sodium transport in the human CF airway can be achieved through inhibition of prostasin activity, identifying a potential therapeutic target in the disease. Trial registration: ClinicalTrials.gov; No.: NCT00506792; URL: www.clinicaltrials.gov PMID:23412700

Efficacy and safety of two new formulations of artificial tears in subjects with dry eye disease: a 3-month, multicenter, active-controlled, randomized trial

PubMed Central

Simmons, Peter A; Liu, Haixia; Carlisle-Wilcox, Cindy; Vehige, Joseph G

2015-01-01

Purpose To evaluate and compare the efficacy and safety of two investigational artificial tear formulations (CHO-1 and CHO-2) containing carmellose sodium, hyaluronic acid at different concentrations, and osmoprotectants, with a standard carmellose sodium-containing formulation (Refresh Tears [RT]) in the treatment of dry eye disease. Subjects and methods In this 3-month, double-masked, multicenter study, subjects (n=305) were randomized 1:1:1 to receive CHO-1, CHO-2, or RT, used as needed but at least twice daily. The primary endpoint was change in ocular surface disease index (OSDI) score from baseline to day 90. Other key outcomes included symptoms evaluated on a visual analog scale, corneal and conjunctival staining, and adverse events. Results OSDI scores and dry eye symptoms showed a rapid and sustained reduction from baseline in each group. Both CHO-1 and CHO-2 met the primary efficacy endpoint of noninferiority to RT in day 90 OSDI score change from baseline. OSDI ocular symptoms subscale improved more with CHO-1 than CHO-2 (P=0.048). In subjects with clinically relevant baseline ocular surface staining (>14 total score of a maximum of 55), day 90 improvements were greater with CHO-1 and CHO-2 than RT (P≤0.044). Day 90 improvements in OSDI ocular symptoms subscale scores were also greater with CHO-1 than RT (P<0.007) in subjects with clinically relevant ocular staining. All treatments were well tolerated. Conclusion Both combination artificial tear formulations were efficacious and well tolerated in subjects with dry eye. CHO-1 demonstrated the best performance in improving ocular symptoms and reducing ocular staining in this heterogeneous study population. PMID:25931807

A phase IIa study of HA-irinotecan, formulation of hyaluronic acid and irinotecan targeting CD44 in extensive-stage small cell lung cancer.

PubMed

Alamgeer, Muhammad; Neil Watkins, D; Banakh, Ilia; Kumar, Beena; Gough, Daniel J; Markman, Ben; Ganju, Vinod

2018-04-01

Preclinical studies in small cell lung cancer (SCLC) have shown that hyaluronic acid (HA) can be effectively used to deliver chemotherapy and selectively decrease CD44 expressing (stem cell-like) tumour cells. The current study aimed to replicate these findings and obtain data on safety and activity of HA-irinotecan (HA-IR). Eligible patients with extensive stage SCLC were consented. A safety cohort (n = 5) was treated with HA-IR and Carboplatin (C). Subsequently, the patients were randomised 1:1 to receive experimental (HA-IR + C) or standard (IR + C) treatment, to a maximum of 6 cycles. The second line patients were added to the study and treated with open label HA-IR + C. Tumour response was measured after every 2 cycles. Baseline tumour specimens were stained for CD44s and CD44v6 expression. Circulating tumour cells (CTCs) were enumerated before each treatment cycle. Out of 39 patients screened, 34 were evaluable for the study. The median age was 66 (range 39-83). The overall response rates were 69% and 75% for experimental and standard arms respectively. Median progression free survival was 42 and 28 weeks, respectively (p = 0.892). The treatments were well tolerated. The incidence of grade III/IV diarrhea was more common in the standard arm, while anaemia was more common in the experimental arm. IHC analysis suggested that the patients with CD44s positive tumours may gain survival benefit from HA-IR. HA-IR is well tolerated and active in ES-SCLC. The effect of HA-IR on CD44s + cancer stem-like cells provide an early hint towards a potential novel target.

Efficacy and safety of sorafenib in combination with gemcitabine in patients with advanced hepatocellular carcinoma: a multicenter, open-label, single-arm phase II study.

PubMed

Srimuninnimit, Vichien; Sriuranpong, Virote; Suwanvecho, Suthida

2014-09-01

Currently, the only standard systemic treatment for advanced hepatocellular carcinoma is sorafenib monotherapy. The study was conducted to assess the efficacy and safety of the novel combination of sorafenib and gemcitabine in the treatment of advanced hepatocellular carcinoma. Between March 2008 and October 2010, patients with advanced pathologically proven hepatocellular carcinoma who had not received previous systemic therapy and had Child-Pugh liver function class A or B received sorafenib plus gemcitabine. Treatment included 4-week cycle of gemcitabine (1000 mg/m(2) days 1, 8, 15) to the maximum of six cycles together with sorafenib (400 mg twice daily). Patient continued sorafenib until disease progression or withdrawal from other reasons. The primary end point is progression-free survival. Forty-five patients were enrolled in this study. The median progression-free survival was 3.7 months (95% CI 3.5-3.8). The overall response rate was 4% with no complete responses and the disease control rate was 66%. The median overall survival (OS) was 11.6 months (95% CI 7.4-15.9). The median time to progression was 3.6 months (95% CI 3.4-3.7). The most frequently reported grade 3/4 treatment-related adverse events included thrombocytopenia 33%, neutropenia 16% and hand-foot skin reaction 13%. The study regimen was well tolerated. The combination of sorafenib and gemcitabine in advanced hepatocellular carcinoma is generally well tolerated and has modest clinical efficacy. The median OS is up to 1 year. However, well-designed randomized controlled trials with a sorafenib alone comparator arm are needed to confirm this finding. © 2014 Wiley Publishing Asia Pty Ltd.

Clinical efficacy and safety of 20% glycolic peel, 15% lactic peel, and topical 20% vitamin C in constitutional type of periorbital melanosis: a comparative study.

PubMed

Dayal, Surabhi; Sahu, Priyadarshini; Jain, Vijay Kumar; Khetri, Sneh

2016-12-01

Periorbital Melanosis (POM) is a very common esthetic condition, yet there is no definite treatment modality. Topical therapy is the mainstay of treatment which includes chemical peels, vitamin C, and other depigmenting agents. To compare clinical efficacy, safety, and tolerability of 20% glycolic acid peels, 15% lactic acid peels, and topical 20% vitamin C in treatment of constitutional type of POM in Indian patients. Ninety patients of constitutional POM were enrolled for 12 weeks. The patients were distributed into three groups. One-third of patients underwent 3-weekly GA peel, another one-third underwent 3-weekly lactic peel, and rest applied vitamin C daily. Clinical improvement was assessed objectively using POM grading. Patient's and physicians global assessment along with patient's global tolerance was also evaluated. More than 50% improvement in POM was observed in 73.34% of patients on GA peel, 56.67% on lactic peel, and 26.67% on vitamin C. On comparing improvement with respect to duration of therapy, GA peel was significantly more effective than lactic peel from 12 weeks onward, while it was more effective than vitamin C from 6 weeks onward. Lactic peel was more effective than vitamin C from 6 weeks onward. Physician and patient global assessment was excellent with glycolic peel followed by lactic peel and vitamin C. The incidence of adverse effect was maximum with GA peel followed by lactic peel and vitamin C. Glycolic peel was best among the three modalities, although it was associated with increased rate of side effects. © 2016 Wiley Periodicals, Inc.

Multicenter, Phase I, Dose-Escalation Trial of Lenalidomide Plus Bortezomib for Relapsed and Relapsed/Refractory Multiple Myeloma

PubMed Central

Richardson, Paul G.; Weller, Edie; Jagannath, Sundar; Avigan, David E.; Alsina, Melissa; Schlossman, Robert L.; Mazumder, Amitabha; Munshi, Nikhil C.; Ghobrial, Irene M.; Doss, Deborah; Warren, Diane L.; Lunde, Laura E.; McKenney, Mary; Delaney, Carol; Mitsiades, Constantine S.; Hideshima, Teru; Dalton, William; Knight, Robert; Esseltine, Dixie-Lee; Anderson, Kenneth C.

2009-01-01

Purpose Lenalidomide and bortezomib are active in relapsed and relapsed/refractory multiple myeloma (MM). In preclinical studies, lenalidomide sensitized MM cells to bortezomib and dexamethasone. This phase I, dose-escalation study (ie, NCT00153933) evaluated safety and determined the maximum-tolerated dose (MTD) of lenalidomide plus bortezomib in patients with relapsed or with relapsed and refractory MM. Patients and Methods Patients received lenalidomide 5, 10, or 15 mg/d on days 1 through 14 and received bortezomib 1.0 or 1.3 mg/m2 on days 1, 4, 8, and 11 of 21-day cycles. Dexamethasone (20mg or 40 mg on days 1, 2, 4, 5, 8, 9, 11, and 12) was added for progressive disease after two cycles. Primary end points were safety and MTD determination. Results Thirty-eight patients were enrolled across six dose cohorts. The MTD was lenalidomide 15 mg/d plus bortezomib 1.0 mg/m2. Dose-limiting toxicities (n = 1 for each) were grade 3 hyponatremia and herpes zoster reactivation and grade 4 neutropenia. The most common treatment-related, grades 3 to 4 toxicities included reversible neutropenia, thrombocytopenia, anemia, and leukopenia. Among 36 response-evaluable patients, 61% (90% CI, 46% to 75%) achieved minimal response or better. Among 18 patients who had dexamethasone added, 83% (90% CI, 62% to 95%) achieved stable disease or better. Median overall survival was 37 months. Conclusion Lenalidomide plus bortezomib was well tolerated and showed promising activity with durable responses in patients with relapsed and relapsed/refractory MM, including patients previously treated with lenalidomide, bortezomib, and/or thalidomide. The combination of lenalidomide, bortezomib, and dexamethasone is being investigated in a phase II study in this setting and in newly diagnosed MM. PMID:19786667

Safety and efficacy of neratinib in combination with capecitabine in patients with metastatic human epidermal growth factor receptor 2-positive breast cancer.

PubMed

Saura, Cristina; Garcia-Saenz, Jose A; Xu, Binghe; Harb, Wael; Moroose, Rebecca; Pluard, Timothy; Cortés, Javier; Kiger, Corinne; Germa, Caroline; Wang, Kongming; Martin, Miguel; Baselga, José; Kim, Sung-Bae

2014-11-10

Neratinib is a potent irreversible pan-tyrosine kinase inhibitor with antitumor activity and acceptable tolerability in patients with human epidermal growth factor receptor 2 (HER2) -positive breast cancer. A multinational, open-label, phase I/II trial was conducted to determine the maximum-tolerated dose (MTD) of neratinib plus capecitabine in patients with solid tumors (part one) and to evaluate the safety and efficacy of neratinib plus capecitabine in patients with HER2-positive metastatic breast cancer (part two). Part one was a 3 + 3 dose-escalation study in which patients with advanced solid tumors received oral neratinib once per day continuously plus capecitabine twice per day on days 1 to 14 of a 21-day cycle at predefined dose levels. In part two, patients with trastuzumab-pretreated HER2-positive metastatic breast cancer received neratinib plus capecitabine at the MTD. The primary end point in part two was objective response rate (ORR). In part one (n = 33), the combination of neratinib 240 mg per day plus capecitabine 1,500 mg/m(2) per day was defined as the MTD, which was further evaluated in part 2 (n = 72). The most common drug-related adverse events were diarrhea (88%) and palmar-plantar erythrodysesthesia syndrome (48%). In part two, the ORR was 64% (n = 39 of 61) in patients with no prior lapatinib exposure and 57% (n = 4 of 7) in patients previously treated with lapatinib. Median progression-free survival was 40.3 and 35.9 weeks, respectively. Neratinib in combination with capecitabine had a manageable toxicity profile and showed promising antitumor activity in patients with HER2-positive metastatic breast cancer pretreated with trastuzumab and lapatinib. © 2014 by American Society of Clinical Oncology.

Combined treatment with pemetrexed and vinflunine in patients with metastatic urothelial cell carcinoma after prior platinum-containing chemotherapy - results of an exploratory phase I study.

PubMed

Pappot, H; von der Maase, H; Ullén, A; Agerbæk, M

2017-10-28

Vinflunine is to date the only registered agent for second-line treatment of metastatic urothelial cell carcinoma (UCC) in Europe. However, the effect is modest. Pemetrexed has demonstrated some single-agent activity in this disease entity. In order to improve treatment possibilities for UCC patients, a phase I trial (VINTREX) was undertaken to assess the safety of vinflunine and pemetrexed in metastatic UCC patients. A dose escalation design was planned to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of a vinflunine/pemetrexed combination. Pemetrexed was added to vinflunine dosed at 280 mg/m2 on day 1 of a 21-day cycle. Three levels of pemetrexed were planned starting at 400 mg/m2. Four patients were enrolled with a mean age of 66 years and with a mean number of prior GC-cycles of 6,8. Two DLT's were observed at the lowest dose-level in cohort 1. One patient experienced grade 4 thrombocytopenia and a second demonstrated hepatobiliary toxicity grade 3 with an increase in alanine aminotransaminase. Most common grade 3 and 4 adverse events were anemia, thrombocytopenia and neutropenia. Three out of four patients received 3 cycles of pemetrexed and vinflunine, all had progressive disease. Based on these observations and due to protocol design, the study was interrupted at dose level 1 for safety reasons. The combined therapy of vinflunine (Javlor®, Pierre Fabre Pharma) and pemetrexed (Alimta®, Eli Lilly) is poorly tolerated in metastatic UCC patients. The combination cannot be recommended for further investigations in metastatic UCC.

A phase 1 study of the heat shock protein 90 inhibitor retaspimycin hydrochloride (IPI-504) in patients with gastrointestinal stromal tumors or soft tissue sarcomas

PubMed Central

Wagner, Andrew J.; Chugh, Rashmi; Rosen, Lee S.; Morgan, Jeffrey A.; George, Suzanne; Gordon, Michael; Dunbar, Joi; Normant, Emmanuel; Grayzel, David; Demetri, George D.

2015-01-01

Purpose Heat shock protein 90 (Hsp90) is required for the proper folding, function, and stability of various client proteins, two of which (KIT and PDGFRα) are critical in the pathogenesis and progression of gastrointestinal stromal tumors (GIST). This phase 1 study investigated the safety and maximum tolerated dose (MTD) of retaspimycin hydrochloride (IPI-504), a novel potent and selective Hsp90 inhibitor, in patients with metastatic and/or unresectable GIST or other soft-tissue sarcomas (STS). Experimental Design IPI-504 was administered intravenously at doses ranging from 90 to 500 mg/m2 twice weekly for 2 weeks on/1 week off. Safety, pharmacokinetic, and pharmacodynamic profiles were determined. Response was assessed by Response Evaluation Criteria for Solid Tumors (RECIST) 1.0 and optionally via 18-fluorodeoxyglucose positron emission tomography (18-FDG-PET) imaging. Results Fifty-four patients received IPI-504; 37 with GIST and 17 with other STS. The MTD was 400 mg/m2 twice weekly for 2 weeks on/1 week off. Common related adverse events were fatigue (59%), headache (44%), and nausea (43%). Exposure to IPI-504, 17-AAG, and 17-AG increased with IPI-504 dose. Stable disease (SD) was observed in 70% (26/37) of patients with GIST and 59% (10/17) of patients with STS. There was one confirmed partial response (PR) in a patient with GIST and one PR in a patient with liposarcoma. Metabolic partial responses occurred in 11/29 (38%) of GIST patients. Conclusions In this study of advanced GIST or other STS, IPI-504 was generally well-tolerated with some evidence of anti-tumor activity, serving as a clinical proof-of-concept that HSP90 inhibition remains a promising strategy. PMID:24045182

Pharmacokinetics and tolerability of human mouse chimeric anti-CD22 monoclonal antibody in Chinese patients with CD22-positive non-Hodgkin lymphoma.

PubMed

Li, Su; Zhang, Dongsheng; Sun, Jian; Li, Zhinming; Deng, Liting; Zou, Benyan; Zhan, Jing; Jiang, Wenqi

2012-01-01

The safety and pharmacokinetics assessment of antibodies targeting CD22 (e.g., epratuzumab) have been established in western Caucasian populations, but there are no reports of the effects in Chinese populations. This dose-escalation study examines the safety, pharmacokinetics and biologic effects of multiple doses of anti-CD22 human-murine chimeric monoclonal antibody SM03 in 21 Chinese patients with CD22-positive non-Hodgkin lymphoma. Most of drug-related adverse events (AEs) were mild and reversible. Two patients experienced serious AEs (hemorrhage); one patient had grade 4 neutropenia; one patient had asymptomatic grade III prolongation of activated partial thromboplastin time (APTT). Major AEs included fever (71%), prolongation of APTT (42.8%), leukocytopenia (44.4%), alanine transaminase elevation (28.6%), elevated serum creatinine (23.8%) and injection site skin redness (14.3%). Circulating B cells transiently decreased without significant effects on T cells or immunoglobulin levels. Pharmacokinetic data revealed that mean maximum observed SM03 concentration and mean AUC from time zero to infinity increased in a dose-dependent manner up to 360 mg/m (2) SM03. Mean clearance was similar at doses ≤ 360 mg/m (2) and decreased significantly at dose 480 mg/m (2), supporting saturation of B-cell binding at 360 mg/m (2). Across all dose levels and histologies, one patient achieved partial response at 480 mg/m (2) dose; 14 patients had stable disease as best response and four patients progressed. Overall, SM03 was tolerated at doses ranging from 60-480 mg/m (2) and had potential efficacy in Chinese patients with follicular lymphoma.

Safety and pharmacokinetics of novel selective vascular endothelial growth factor receptor-2 inhibitor YN968D1 in patients with advanced malignancies

PubMed Central

2010-01-01

Background YN968D1 (Apatinib) selectively inhibits phosphorylation of VEGFR-2 and tumor angiogenesis in mice model. The study was conducted to determine the maximum tolerated dose (MTD), safety profile, pharmacokinetic variables, and antitumor activity in advanced solid malignancies. Methods This dose-escalation study was conducted according to the Chinese State Food and Drug Administration (SFDA) recommendations in patients with advanced solid tumors to determine the MTD for orally administered apatinib. Doses of continuously administered apatinib were escalated from 250 mg. Treatment continued after dose-escalation phase until withdrawal of consent, intolerable toxicities, disease progression or death. Results Forty-six patients were enrolled. Hypertension and hand-foot syndrome were the two dose-limiting toxicities noted at dose level of 1000 mg. MTD was determined to be 850 mg once daily. Pharmacokinetic analysis showed early absorption with a half-life of 9 hours. The mean half-life was constant over all dose groups. Steady-state conditions analysis suggested no accumulation during 56 days of once-daily administration. The most frequently observed drug-related adverse events were hypertension (69.5%, 29 grade 1-2 and 3 grade 3-4), proteinuria (47.8%, 16 grade 1-2 and 6 grade 3-4), and hand-foot syndrome (45.6%, 15 grade 1-2 and 6 grade 3-4). Among the thirty-seven evaluable patients, PR was noted in seven patients (18.9%), SD 24 (64.9%), with a disease control rate of 83.8% at 8 weeks. Conclusions The recommended dose of 750 mg once daily was well tolerated. Encouraging antitumor activity across a broad range of malignancies warrants further evaluation in selected populations. Trial registration ClinicalTrials.gov unique identifier: NCT00633490 PMID:20923544

Immunogenicity, efficacy and safety of Nuwiq® (human-cl rhFVIII) in previously untreated patients with severe haemophilia A-Interim results from the NuProtect Study.

PubMed

Liesner, R J; Abashidze, M; Aleinikova, O; Altisent, C; Belletrutti, M J; Borel-Derlon, A; Carcao, M; Chambost, H; Chan, A K C; Dubey, L; Ducore, J; Fouzia, N A; Gattens, M; Gruel, Y; Guillet, B; Kavardakova, N; El Khorassani, M; Klukowska, A; Lambert, T; Lohade, S; Sigaud, M; Turea, V; Wu, J K M; Vdovin, V; Pavlova, A; Jansen, M; Belyanskaya, L; Walter, O; Knaub, S; Neufeld, E J

2018-03-01

Nuwiq ® (Human-cl rhFVIII) is a fourth generation recombinant FVIII, produced in a human cell line, without chemical modification or protein fusion. No inhibitors developed in studies with Nuwiq ® in 201 previously treated patients with haemophilia A (HA). The immunogenicity, efficacy and safety of Nuwiq ® in previously untreated patients (PUPs) with severe HA are being assessed in the ongoing NuProtect study. The study, conducted across 38 centres worldwide, is evaluating 110 true PUPs of all ages and ethnicities enrolled for study up to 100 exposure days (EDs) or 5 years maximum. The primary objective is to assess the immunogenicity of Nuwiq ® (inhibitor activity ≥0.6 BU) using the Nijmegen-modified Bethesda assay at a central laboratory. Data for 66 PUPs with ≥20 EDs from a preplanned interim analysis were analysed. High-titre (HT) inhibitors developed in 8 of 66 patients after a median of 11.5 EDs (range 6-24). Five patients developed low-titre inhibitors (4 transient). The cumulative incidence (95% confidence interval) was 12.8% (4.5%, 21.2%) for HT inhibitors and 20.8% (10.7%, 31.0%) for all inhibitors. During inhibitor-free periods, median annualized bleeding rates during prophylaxis were 0 for spontaneous bleeds and 2.40 for all bleeds. Efficacy was rated as "excellent" or "good" in treating 91.8% of bleeds. Efficacy of surgical prophylaxis was "excellent" or "good" for 8 (89%) procedures and "moderate" for 1 (11%). No tolerability concerns were evident. These interim data show a cumulative incidence of 12.8% for HT inhibitors and convincing efficacy and tolerability in PUPs treated with Nuwiq ® . © 2017 The Authors. Haemophilia published by John Wiley & Sons Ltd.

Factors affecting response and tolerability to ferumoxytol in nondialysis chronic kidney disease patients.

PubMed

Fishbane, Steven; Bolton, W Kline; Winkelmayer, Wolfgang C; Strauss, William; Li, Zhu; Pereira, Brian J G

2012-09-01

Ferumoxytol is a unique intravenous (i.v.) iron therapy. This report examines factors affecting hemoglobin response to i.v. ferumoxytol, and the relationship between hematologic parameters, concomitant erythropoiesis-stimulating agents (ESA), and adverse events (AEs) in nondialysis CKD patients. A series of post-hoc efficacy and safety analyses were performed using pooled data from two identically designed Phase III studies in 608 nondialysis CKD patients randomized to receive two 510 mg i.v. injections of ferumoxytol within 5 ± 3 days versus oral iron. Ferumoxytol resulted in a significant increase in hemoglobin in the presence and absence of ESA, and across a range of baseline hemoglobin, transferrin saturation, ferritin, and reticulocyte hemoglobin content levels. Adverse event rates with ferumoxytol were similar across quartiles of change in hemoglobin; there were no trends suggesting an increased rate of cardiovascular AEs with higher maximum achieved hemoglobin or faster rate of hemoglobin rise. There was no meaningful difference in the rate of AEs, serious AEs, and cardiovascular AEs between patients receiving or not receiving ESA. These analyses add to the knowledge of predictors of response and safety outcomes associated with i.v. iron therapy in nondialysis CKD patients.

Photodynamic therapy with 3-(1'-hexyloxyethyl) pyropheophorbide-a for early-stage cancer of the larynx: Phase Ib study.

PubMed

Shafirstein, Gal; Rigual, Nestor R; Arshad, Hassan; Cooper, Michele T; Bellnier, David A; Wilding, Gregory; Tan, Wei; Merzianu, Mihai; Henderson, Barbara W

2016-04-01

The purpose of this study was for us to report results regarding the safety of 3-(1'-hexyloxyethyl) pyropheophorbide-a (HPPH) mediated photodynamic therapy (PDT) in early laryngeal disease, and offer preliminary information on treatment responses. A single-institution, phase Ib, open label, noncomparative study of HPPH-PDT in patients with high-risk dysplasia, carcinoma in situ, and T1 squamous cell carcinoma (SCC) of the larynx. The primary outcomes were safety and maximum tolerated dose (MTD), and the secondary outcome was response. Twenty-nine patients and 30 lesions were treated. The most common adverse event (AE) was transient hoarseness of voice. Severe edema, requiring tracheostomy, was the most serious AE, which occurred in 2 patients within several hours of therapy. The MTD was 100 J/cm(2) . Patients with T1 SCC seemed to have good complete response rate (82%) to HPPH-PDT at MTD. HPPH-PDT can be safely used to treat early-stage laryngeal cancer, with potential efficacy. © 2015 The Authors Head & Neck Published by Wiley Periodicals, Inc. Head Neck 38: E377-E383, 2016. © 2015 The Authors Head & Neck Published by Wiley Periodicals, Inc.

Photodynamic therapy with 3‐(1′‐hexyloxyethyl) pyropheophorbide‐a for early‐stage cancer of the larynx: Phase Ib study

PubMed Central

Rigual, Nestor R.; Arshad, Hassan; Cooper, Michele T.; Bellnier, David A.; Wilding, Gregory; Tan, Wei; Merzianu, Mihai; Henderson, Barbara W.

2015-01-01

Abstract Background The purpose of this study was for us to report results regarding the safety of 3‐(1′‐hexyloxyethyl) pyropheophorbide‐a (HPPH) mediated photodynamic therapy (PDT) in early laryngeal disease, and offer preliminary information on treatment responses. Methods A single‐institution, phase Ib, open label, noncomparative study of HPPH‐PDT in patients with high‐risk dysplasia, carcinoma in situ, and T1 squamous cell carcinoma (SCC) of the larynx. The primary outcomes were safety and maximum tolerated dose (MTD), and the secondary outcome was response. Results Twenty‐nine patients and 30 lesions were treated. The most common adverse event (AE) was transient hoarseness of voice. Severe edema, requiring tracheostomy, was the most serious AE, which occurred in 2 patients within several hours of therapy. The MTD was 100 J/cm2. Patients with T1 SCC seemed to have good complete response rate (82%) to HPPH‐PDT at MTD. Conclusion HPPH‐PDT can be safely used to treat early‐stage laryngeal cancer, with potential efficacy. © 2015 The Authors Head & Neck Published by Wiley Periodicals, Inc. Head Neck 38: E377–E383, 2016 PMID:25580824

Changes in quality, liking, and purchase intent of irradiated fresh-cut spinach during storage.

PubMed

Fan, Xuetong; Sokorai, Kimberly J B

2011-08-01

The use of ionizing radiation to enhance microbial safety of fresh spinach at a maximum dose of 4 kGy has been approved by the U.S. Food and Drug Administration (FDA). However, whether spinach can tolerate those high doses of radiation is unclear. Therefore, this study was conducted to investigate the effects of irradiation and storage on quality, liking, and purchase intent of fresh-cut spinach. The oxygen radical absorbance capacity values and total phenolic content were not consistently affected by irradiation. However, the ascorbic acid content of irradiated sample decreased rapidly during storage, resulting in these samples being lower in ascorbic acid content than controls after 7 and 14 d of storage at 4 °C. Sensory evaluation by a 50-member panel revealed that purchase intent and ratings for liking of appearance, aroma, texture, flavor, and overall were not affected by irradiation at doses up to 2 kGy. Therefore, irradiation at doses up to 2 kGy may be used to enhance microbial safety without affecting consumer acceptance or overall antioxidant values of irradiated spinach. Journal of Food Science © 2011 Institute of Food Technologists® No claim to original US government works.

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.

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…

Thermal Tolerance in Anuran Embryos with Different Reproductive Modes: Relationship to Altitude

PubMed Central

Lynch, John D.

2013-01-01

Anurans are ectothermic animals very sensitive to temperature, mainly during the embryonic stage. In addition, environmental temperature decreases with altitude, and the amphibian fauna changes. Therefore, we studied the relationship between the embryonic thermal tolerances of twelve species of anurans and the temperatures of their microhabitat along an altitudinal gradient from 430 m to 2600 m. We hypothesized that there is a strong thermal adjustment of embryos to their microhabitat and, consequently, that temperature could be a limiting factor of altitudinal distribution of the anurans. We also compared the embryonic thermal tolerances according to six postulated reproductive modes of the study species. We found a significant relationship between the maximum and minimum thermal tolerances of the anuran embryos and the maximum and minimum temperatures of their microhabitat and altitudinal distribution. We also found a wide range of embryonic thermal tolerances for aquatic breeding species and a narrower range for terrestrial breeding species. Particularly, embryos of direct development species were the most sensitive to temperature. These results show the strong thermal adjustment of anuran embryos to their microhabitat and elevation and do not reject the hypothesis that temperature can be a limiting factor of their altitudinal distribution. PMID:23766678

Lambda network having 2.sup.m-1 nodes in each of m stages with each node coupled to four other nodes for bidirectional routing of data packets between nodes

DOEpatents

Napolitano, Jr., Leonard M.

1995-01-01

The Lambda network is a single stage, packet-switched interprocessor communication network for a distributed memory, parallel processor computer. Its design arises from the desired network characteristics of minimizing mean and maximum packet transfer time, local routing, expandability, deadlock avoidance, and fault tolerance. The network is based on fixed degree nodes and has mean and maximum packet transfer distances where n is the number of processors. The routing method is detailed, as are methods for expandability, deadlock avoidance, and fault tolerance.

Gyro-based Maximum-Likelihood Thruster Fault Detection and Identification

NASA Technical Reports Server (NTRS)

Wilson, Edward; Lages, Chris; Mah, Robert; Clancy, Daniel (Technical Monitor)

2002-01-01

When building smaller, less expensive spacecraft, there is a need for intelligent fault tolerance vs. increased hardware redundancy. If fault tolerance can be achieved using existing navigation sensors, cost and vehicle complexity can be reduced. A maximum likelihood-based approach to thruster fault detection and identification (FDI) for spacecraft is developed here and applied in simulation to the X-38 space vehicle. The system uses only gyro signals to detect and identify hard, abrupt, single and multiple jet on- and off-failures. Faults are detected within one second and identified within one to five accords,

[Insulin, glucagon and growth hormone responses during glucose, arginine and insulin tolerance tests in children with hyperthyroidism].

PubMed

Kato, T; Matsuura, N; Fujita, H; Fujieda, K; Nohara, Y; Mikami, Y; Abe, K; Fukushima, N

1985-06-20

There are many reports of glucose intolerance in adult patients with hyperthyroidism but few reports of glucose intolerance in hyperthyroid children. In this study, we measured plasma levels of glucose, insulin, glucagon and growth hormone in hyperthyroid children and control subjects by the use of three kinds of tolerance tests: an oral glucose tolerance test, an arginine tolerance test and an insulin tolerance test. In the oral glucose tolerance test, mean fasting glucose levels (79.6 +/- 1.4 mg/dl) rose to maximum levels (157.3 +/- 4.3 mg/dl) at 30 min in hyperthyroid children which were significantly higher than the levels in control subjects (p less than 0.01). The maximum levels of glucose fell slowly and returned to fasting levels at 180 min. In this test, plasma insulin levels increased from basal levels (12.7 +/- 1.9 microU/ml) to maximum levels (120.8 +/- 22.1 microU/ml) at 30 min in the prepubertal age group of hyperthyroidism. On the other hand, in the pubertal age group of hyperthyroidism, maximum levels of insulin were observed at 60 min, but not at 30 min. These maximum levels of insulin of both hyperthyroid age groups were significantly higher than those in the control subjects (p less than 0.05, p less than 0.01 respectively). There was no difference in insulin-glucose ratio at 30 min (delta IRI/delta BG) and insulinogenic index (I.I.) at 0 to 60 min between these two groups of hyperthyroid children and control subjects. However, I.I. at 0 to 120 min and 0 to 180 min decreased significantly in the pubertal age group of hyperthyroidism as compared with those in the control group (p less than 0.05, p less than 0.02 respectively). In the oral glucose tolerance test, plasma glucagon levels decreased from basal levels (74.1 +/- 4.3 pg/ml) to minimum levels (36.4 +/- 4.7 pg/ml) at 90 min in hyperthyroidism, which were significantly lower than those in the controls (p less than 0.05). However, there was no difference in -epsilon delta IRG/epsilon delta BG (cumulative glucagon response/cumulative glucose response) between the subjects with hyperthyroidism and the controls. On the other hand, lower responses of blood glucose, insulin, glucagon and growth hormone to arginine were observed in subjects with hyperthyroidism than in the controls. Moreover in the insulin tolerance test, there was no difference in glucagon and growth hormone response between the subjects with hyperthyroidism and the controls. Thus our conclusions are as follows: A marked increase in blood glucose after oral glucose load was observed in spite of normal insulin-glucose ratio in hyperthyroid children, suggesting the existence of peripheral insulin resistance.(ABSTRACT TRUNCATED AT 400 WORDS)

Etanercept in Alzheimer disease: A randomized, placebo-controlled, double-blind, phase 2 trial.

PubMed

Butchart, Joseph; Brook, Laura; Hopkins, Vivienne; Teeling, Jessica; Püntener, Ursula; Culliford, David; Sharples, Richard; Sharif, Saif; McFarlane, Brady; Raybould, Rachel; Thomas, Rhodri; Passmore, Peter; Perry, V Hugh; Holmes, Clive

2015-05-26

To determine whether the tumor necrosis factor α inhibitor etanercept is well tolerated and obtain preliminary data on its safety in Alzheimer disease dementia. In a double-blind study, patients with mild to moderate Alzheimer disease dementia were randomized (1:1) to subcutaneous etanercept (50 mg) once weekly or identical placebo over a 24-week period. Tolerability and safety of this medication was recorded including secondary outcomes of cognition, global function, behavior, and systemic cytokine levels at baseline, 12 weeks, 24 weeks, and following a 4-week washout period. This trial is registered with EudraCT (2009-013400-31) and ClinicalTrials.gov (NCT01068353). Forty-one participants (mean age 72.4 years; 61% men) were randomized to etanercept (n = 20) or placebo (n = 21). Etanercept was well tolerated; 90% of participants (18/20) completed the study compared with 71% (15/21) in the placebo group. Although infections were more common in the etanercept group, there were no serious adverse events or new safety concerns. While there were some interesting trends that favored etanercept, there were no statistically significant changes in cognition, behavior, or global function. This study showed that subcutaneous etanercept (50 mg/wk) was well tolerated in this small group of patients with Alzheimer disease dementia, but a larger more heterogeneous group needs to be tested before recommending its use for broader groups of patients. This study shows Class I evidence that weekly subcutaneous etanercept is well tolerated in Alzheimer disease dementia. © 2015 American Academy of Neurology.

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.

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.

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...

Restorative Resolution

ERIC Educational Resources Information Center

Zaslaw, Jay

2010-01-01

Over the past decade, many schools have adopted zero-tolerance policies to curtail negative student behavior. Such policies persist although "there is as yet little evidence that the strategies typically associated with zero tolerance contribute to improved student behavior or overall school safety." Suspension and expulsion result in…

Restorative Resolution

ERIC Educational Resources Information Center

Zaslaw, Jay

2010-01-01

Over the past decade, many schools have adopted zero-tolerance policies as a means to curtail negative student behavior. Such policies persist although "there is as yet little evidence that the strategies typically associated with zero tolerance contribute to improved student behavior or overall school safety." School suspension and…

Efficacy, safety, and tolerability of lacosamide in patients with gain-of-function Nav1.7 mutation-related small fiber neuropathy: study protocol of a randomized controlled trial-the LENSS study.

PubMed

de Greef, Bianca T A; Merkies, Ingemar S J; Geerts, Margot; Faber, Catharina G; Hoeijmakers, Janneke G J

2016-06-30

Small fiber neuropathy generally leads to considerable pain and autonomic symptoms. Gain-of-function mutations in the SCN9A- gene, which codes for the Nav1.7 voltage-gated sodium channel, have been reported in small fiber neuropathy, suggesting an underlying genetic basis in a subset of patients. Currently available sodium channel blockers lack selectivity, leading to cardiac and central nervous system side effects. Lacosamide is an anticonvulsant, which blocks Nav1.3, Nav1.7, and Nav1.8, and stabilizes channels in the slow-inactivation state. Since multiple Nav1.7 mutations in small fiber neuropathy showed impaired slow-inactivation, lacosamide might be effective. The Lacosamide-Efficacy-'N'-Safety in Small fiber neuropathy (LENSS) study is a randomized, double-blind, placebo-controlled, crossover trial in patients with SCN9A-associated small fiber neuropathy, with the primary objective to evaluate the efficacy of lacosamide versus placebo. Eligible patients (the aim is to recruit 25) fulfilling the inclusion and exclusion criteria will be randomized to receive lacosamide (200 mg b.i.d.) or placebo during the first double-blinded treatment period (8 weeks), which is preceded by a titration period (3 weeks). The first treatment period will be followed by a tapering period (2 weeks). After a 2-week washout period, patients will crossover to the alternate arm for the second period consisting of an equal titration phase, treatment period, and tapering period. The primary efficacy endpoint will be the proportion of patients demonstrating a 1-point average pain score reduction compared to baseline using the Pain Intensity Numerical Rating Scale. We assume a response rate of approximately 60 % based on the criteria composed by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) group for measurement of pain. Patients withdrawing from the study will be considered non- responders. Secondary outcomes will include changes in maximum pain score, the Small Fiber Neuropathy Symptoms Inventory Questionnaire, sleep quality and the quality of life assessment, patients' global impressions of change, and safety and tolerability measurements. Sensitivity analyses will include assessing the proportion of patients having ≥ 2 points average pain improvement compared to the baseline Pain Intensity Numerical Rating Scale scores. This is the first study that will be evaluating the efficacy, safety, and tolerability of lacosamide versus placebo in patients with SCN9A-associated small fiber neuropathy. The findings may increase the knowledge on lacosamide as a potential treatment option in patients with painful neuropathies, considering the central role of Nav1.7 in pain. ClinicalTrials.gov, NCT01911975 . Registered on 13 July 2013.

Phase I study of orally administered S-1 in combination with epirubicin and oxaliplatin in patients with advanced solid tumors and chemotherapy-naïve advanced or metastatic esophagogastric cancer.

PubMed

Moehler, Markus; Mahlberg, Rolf; Heinemann, Volker; Obermannová, Radka; Kubala, Eugen; Melichar, Bohuslav; Weinmann, Arndt; Scigalla, Paul; Tesařová, Marietta; Janda, Petr; Hédouin-Biville, Fabienne; Mansoor, Wasat

2017-03-01

This phase I study investigated the safety and the maximum tolerated dose (MTD) of the oral fluoropyrimidine S-1 when combined with epirubicin and oxaliplatin (EOS). Patients aged ≥18 years with advanced or metastatic solid tumors were enrolled in a 3 + 3 design with S-1 dose escalation (two planned cohorts) performed according to the occurrence of dose-limiting toxicity (DLT). On day 1 of each 21-day cycle, patients received epirubicin 50 mg/m 2 followed by oxaliplatin 130 mg/m 2 (maximum 8 cycles) and then S-1 [20 mg/m 2 (cohort 1) or 25 mg/m 2 (cohort 2), twice daily]: first dose, evening of day 1; subsequent administration on days 2-14, twice daily; last dose, morning of day 15 (unlimited number of S-1 cycles). After protocol amendment, enrollment in a third cohort was restricted to patients with chemotherapy-naïve advanced or metastatic esophagogastric cancer. DLT was reported for two of the five patients in cohort 2, defining 20 mg/m 2 twice daily as the MTD of S-1 combined with epirubicin and oxaliplatin in heavily pretreated patients. Thirteen patients with chemotherapy-naïve advanced or metastatic esophagogastric cancer were subsequently enrolled and treated at an S-1 dose level of 25 mg/m 2 twice daily; no DLTs were reported; median overall survival was 13.1 months. Of the 11 evaluable patients, three (27 %) had partial responses and seven (64 %) had stable disease. The safety profile was in line with expectations. The promising activity of EOS (S-1 dose level, 25 mg/m 2 twice daily) and acceptable safety profile support further clinical development of this combination for the first-line treatment of patients with advanced or metastatic esophagogastric cancer.

Safety and activity of temsirolimus and bevacizumab in patients with advanced renal cell carcinoma previously treated with tyrosine kinase inhibitors: a phase 2 consortium study.

PubMed

Merchan, Jaime R; Qin, Rui; Pitot, Henry; Picus, Joel; Liu, Glenn; Fitch, Tom; Maples, William J; Flynn, Patrick J; Fruth, Briant F; Erlichman, Charles

2015-03-01

Bevacizumab or temsirolimus regimens have clinical activity in the first-line treatment of advanced renal cell carcinoma (RCC). This phase I/II trial was conducted to determine the safety of combining both agents and its efficacy in RCC patients who progressed on at least one prior anti-VEGF receptor tyrosine kinase inhibitor (RTKI) agent. In the phase I portion, eligible patients were treated with temsirolimus (25 mg IV weekly) and escalating doses of IV bevacizumab (level 1 = 5 mg/kg; level 2 = 10 mg/kg) every other week. The primary endpoint for the phase II portion (RTKI resistant patients) was the 6-month progression-free rate. Secondary endpoints were response rate, toxicity evaluation, and PFS and OS. Maximum tolerated dose was not reached at the maximum dose administered in 12 phase I patients. Forty evaluable patients were treated with the phase II recommended dose (temsirolimus 25 mg IV weekly and bevacizumab 10 mg/kg IV every 2 weeks). The 6-month progression-free rate was 40 % (16/40 pts). Median PFS was 5.9 (4-7.8) months, and median OS was 20.6 (11.5-23.7) months. Partial response, stable disease, and progressive disease were seen in 23, 63, and 14 % of patients, respectively. Most common grade 3-4 AEs included fatigue (17.8 %), hypertriglyceridemia (11.1 %), stomatitis (8.9 %), proteinuria (8.9 %), abdominal pain (6.7 %), and anemia (6.7 %). Baseline levels of serum sFLT-1 and VEGF-A were inversely correlated with PFS and OS, respectively. Temsirolimus and bevacizumab is a feasible combination in patients with advanced RCC previously exposed to oral anti-VEGF agents. The safety and efficacy results warrant further confirmatory studies in this patient population.

14 CFR 27.571 - Fatigue evaluation of flight structure.

Code of Federal Regulations, 2010 CFR

2010-01-01

... § 27.309, except that maneuvering load factors need not exceed the maximum values expected in operation... paragraph (a)(3) of this section. (b) Fatigue tolerance evaluation. It must be shown that the fatigue tolerance of the structure ensures that the probability of catastrophic fatigue failure is extremely remote...

NAFTA Guidance Document on Data Requirements for Tolerances on Imported Commodities in the United States and Canada

EPA Pesticide Factsheets

The purpose of this document is to provide detailed guidance on data requirements that meet the North American Free Trade Agreement standards for the establishment of pesticide import tolerances or maximum residue levels in Canada and the United States.

Comparison of the pharmacokinetics and safety of three formulations of infliximab (CT-P13, EU-approved reference infliximab and the US-licensed reference infliximab) in healthy subjects: a randomized, double-blind, three-arm, parallel-group, single-dose, Phase I study.

PubMed

Park, Won; Lee, Sang Joon; Yun, Jihye; Yoo, Dae Hyun

2015-01-01

To compare the pharmacokinetics (PK), safety and tolerability of biosimilar infliximab (CT-P13 [Remsima(®), Inflectra(®)]) with two formulations of the reference medicinal product (RMP) (Remicade(®)) from either Europe (EU-RMP) or the USA (US-RMP). This was a double-blind, three-arm, parallel-group study (EudraCT number: 2013-003173-10). Healthy subjects received single doses (5 mg/kg) of CT-P13 (n = 71), EU-RMP (n = 71) or US-RMP (n = 71). The primary objective was to compare the PK profiles for the three formulations. Assessments of comparative safety and tolerability were secondary objectives. Baseline demographics were well balanced across the three groups. Primary end points (Cmax, AUClast and AUCinf) were equivalent between all formulations (CT-P13 vs EU-RMP; CT-P13 vs US-RMP; EU-RMP vs US-RMP). All other PK end points supported the high similarity of the three treatments. Tolerability profiles of the formulations were similar. The PK profile of CT-P13 is highly similar to EU-RMP and US-RMP. All three formulations were equally well tolerated.

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.

Pembrolizumab Plus Pegylated Interferon alfa-2b or Ipilimumab for Advanced Melanoma or Renal Cell Carcinoma: Dose-Finding Results from the Phase Ib KEYNOTE-029 Study.

PubMed

Atkins, Michael B; Hodi, F Stephen; Thompson, John A; McDermott, David F; Hwu, Wen-Jen; Lawrence, Donald P; Dawson, Nancy A; Wong, Deborah J; Bhatia, Shailender; James, Marihella; Jain, Lokesh; Robey, Seth; Shu, Xinxin; Homet Moreno, Blanca; Perini, Rodolfo F; Choueiri, Toni K; Ribas, Antoni

2018-04-15

Purpose: Pembrolizumab monotherapy, ipilimumab monotherapy, and pegylated interferon alfa-2b (PEG-IFN) monotherapy are active against melanoma and renal cell carcinoma (RCC). We explored the safety and preliminary antitumor activity of pembrolizumab combined with either ipilimumab or PEG-IFN in patients with advanced melanoma or RCC. Experimental Design: The phase Ib KEYNOTE-029 study (ClinicalTrials.gov, NCT02089685) included independent pembrolizumab plus reduced-dose ipilimumab and pembrolizumab plus PEG-IFN cohorts. Pembrolizumab 2 mg/kg every 3 weeks (Q3W) plus 4 doses of ipilimumab 1 mg/kg Q3W was tolerable if ≤6 of 18 patients experienced a dose-limiting toxicity (DLT). The target DLT rate for pembrolizumab 2 mg/kg Q3W plus PEG-IFN was 30%, with a maximum of 14 patients per dose level. Response was assessed per RECIST v1.1 by central review. Results: The ipilimumab cohort enrolled 22 patients, including 19 evaluable for DLTs. Six patients experienced ≥1 DLT. Grade 3 to 4 treatment-related adverse events occurred in 13 (59%) patients. Responses occurred in 5 of 12 (42%) patients with melanoma and 3 of 10 (30%) patients with RCC. In the PEG-IFN cohort, DLTs occurred in 2 of 14 (14%) patients treated at dose level 1 (PEG-IFN 1 μg/kg/week) and 2 of 3 (67%) patients treated at dose level 2 (PEG-IFN 2 μg/kg/week). Grade 3 to 4 treatment-related adverse events occurred in 10 of 17 (59%) patients. Responses occurred in 1 of 5 (20%) patients with melanoma and 2 of 12 (17%) patients with RCC. Conclusions: Pembrolizumab 2 mg/kg Q3W plus ipilimumab 1 mg/kg Q3W was tolerable and provided promising antitumor activity in patients with advanced melanoma or RCC. The maximum tolerated dose of pembrolizumab plus PEG-IFN had limited antitumor activity in this population. Clin Cancer Res; 24(8); 1805-15. ©2018 AACR . ©2018 American Association for Cancer Research.

Levetiracetam for Treatment of Neonatal Seizures

PubMed Central

Abend, Nicholas S.; Gutierrez-Colina, Ana M.; Monk, Heather M.; Dlugos, Dennis J.; Clancy, Robert R.

2011-01-01

Neonatal seizures are often refractory to treatment with initial antiseizure medications. Consequently, clinicians turn to alternatives such as levetiracetam, despite the lack of published data regarding its safety, tolerability, or efficacy in the neonatal population. We report a retrospectively identified cohort of 23 neonates with electroencephalographically confirmed seizures who received levetiracetam. Levetiracetam was considered effective if administration was associated with a greater than 50% seizure reduction within 24 hours. Levetiracetam was initiated at a mean conceptional age of 41 weeks. The mean initial dose was 16 ± 6 mg/kg and the mean maximum dose was 45 ± 19 mg/kg/day. No respiratory or cardiovascular adverse effects were reported or detected. Levetiracetam was associated with a greater than 50% seizure reduction in 35% (8 of 23), including seizure termination in 7. Further study is warranted to determine optimal levetiracetam dosing in neonates and to compare efficacy with other antiseizure medications. PMID:21233461

Effects of long-term self-massage at the musculotendinous junction on hamstring extensibility, stiffness, stretch tolerance, and structural indices: A randomized controlled trial.

PubMed

Akazawa, Naoki; Okawa, Naomi; Kishi, Masaki; Nakatani, Kiyoshi; Nishikawa, Katsuya; Tokumura, Daichi; Matsui, Yuji; Moriyama, Hideki

2016-09-01

The purpose of this study was to examine the effect of long-term self-massage at the musculotendinous junction on hamstring extensibility, stiffness, stretch tolerance, and structural indices. Single-blind, randomized, controlled trial. Laboratory. Thirty-seven healthy men. The right or left leg of each participant was randomly assigned to the massage group, and the other leg was assigned to the control group. The participants conducted self-massage at the musculotendinous junction for 3 min daily, five times per week, for 12 weeks. Hamstring extensibility, stiffness, stretch tolerance, and structural indices were measured by a blinded examiner prior to the massage intervention and after 6 and 12 weeks of intervention. The maximum hip flexion angle (HFA) and the maximum passive pressure after 6 and 12 weeks of intervention in the massage group were significantly higher than prior to intervention. The visual analog scale (for pain perception) at maximum HFA, the stiffness of the hamstring, and the structural indices did not differ in either group over the 12 week period. Our results suggest that long-term self-massage at the musculotendinous junction increases hamstring extensibility by improving stretch tolerance. However, this intervention does not change hamstring stiffness. University Hospital Medical Information Network registration number UMIN000011233. Copyright © 2016 Elsevier Ltd. All rights reserved.

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

PubMed

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

2015-01-01

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

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.

Phase 1, open-label, dose escalation, safety, and pharmacokinetics study of ME-344 as a single agent in patients with refractory solid tumors.

PubMed

Bendell, Johanna C; Patel, Manish R; Infante, Jeffrey R; Kurkjian, Carla D; Jones, Suzanne F; Pant, Shubham; Burris, Howard A; Moreno, Ofir; Esquibel, Vanessa; Levin, Wendy; Moore, Kathleen N

2015-04-01

The current phase 1, open-label, dose escalation study was conducted to establish the safety, tolerability, pharmacokinetic profile, and preliminary antitumor activity of the novel mitochondrial inhibitor ME-344 in patients with refractory solid tumors. Patients with refractory solid tumors were treated in a 3 + 3 dose escalation design. ME-344 was administered via intravenous infusion on days 1, 8, and 15 of the first 28-day cycle and weekly thereafter. Pharmacokinetics was assessed on days 1 and 15 of the first cycle. A total of 30 patients (median age, 65 years; 67% of whom were female) received ME-344. There were 5 dose-limiting toxicities reported. Four patients developed grade 3 neuropathy (2 patients each at doses of 15 mg/kg and 20 mg/kg) and 1 patient treated at a dose of 10 mg/kg developed a grade 3 acute myocardial infarction (toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.03]). The maximum tolerated dose (MTD) was defined as 10 mg/kg weekly. The most common adverse events were nausea, dizziness, and fatigue. At the MTD of 10 mg/kg, the maximal plasma concentration (Cmax) was 25.8 µg/mL and the area under the concentration curve from time zero to infinity was 25.9 hour*µg/mL. One patient with small cell lung cancer achieved a partial response for ≥ 52 weeks. Four patients had prolonged stable disease (1 patient each with urothelial carcinoma [47 weeks], carcinoid tumor [≥ 40 weeks], cervical leiomyosarcoma [39 weeks], and cervical cancer [≥ 31 weeks]). The once-weekly administration of ME-344 was generally well tolerated in the current study, a first-in-human study; dose-limiting neuropathy was noted, but not at the MTD. Exposures at the 10-mg/kg dose level suggest a sufficient therapeutic index. The preliminary clinical activity as a monotherapy supports the further clinical development of ME-344 in combination with chemotherapy. © 2014 American Cancer Society.

A phase 1 study of the bispecific anti-CD30/CD16A antibody construct AFM13 in patients with relapsed or refractory Hodgkin lymphoma.

PubMed

Rothe, Achim; Sasse, Stephanie; Topp, Max S; Eichenauer, Dennis A; Hummel, Horst; Reiners, Katrin S; Dietlein, Markus; Kuhnert, Georg; Kessler, Joerg; Buerkle, Carolin; Ravic, Miroslav; Knackmuss, Stefan; Marschner, Jens-Peter; Pogge von Strandmann, Elke; Borchmann, Peter; Engert, Andreas

2015-06-25

AFM13 is a bispecific, tetravalent chimeric antibody construct (TandAb) designed for the treatment of CD30-expressing malignancies. AFM13 recruits natural killer (NK) cells via binding to CD16A as immune effector cells. In this phase 1 dose-escalation study, 28 patients with heavily pretreated relapsed or refractory Hodgkin lymphoma received AFM13 at doses of 0.01 to 7 mg/kg body weight. Primary objectives were safety and tolerability. Secondary objectives included pharmacokinetics, antitumor activity, and pharmacodynamics. Adverse events were generally mild to moderate. The maximum tolerated dose was not reached. Pharmacokinetics assessment revealed a half-life of up to 19 hours. Three of 26 evaluable patients achieved partial remission (11.5%) and 13 patients achieved stable disease (50%), with an overall disease control rate of 61.5%. AFM13 was also active in brentuximab vedotin-refractory patients. In 13 patients who received doses of ≥1.5 mg/kg AFM13, the overall response rate was 23% and the disease control rate was 77%. AFM13 treatment resulted in a significant NK-cell activation and a decrease of soluble CD30 in peripheral blood. In conclusion, AFM13 represents a well-tolerated, safe, and active targeted immunotherapy of Hodgkin lymphoma. A phase 2 study is currently planned to optimize the dosing schedule in order to further improve the therapeutic efficacy. This phase 1 study was registered at www.clinicaltrials.gov as #NCT01221571. © 2015 by The American Society of Hematology.

Cisplatin, Gemcitabine, and Lapatinib as Neoadjuvant Therapy for Muscle-Invasive Bladder Cancer.

PubMed

Narayan, Vivek; Mamtani, Ronac; Keefe, Stephen; Guzzo, Thomas; Malkowicz, S Bruce; Vaughn, David J

2016-07-01

We sought to investigate the safety and efficacy of gemcitabine, cisplatin, and lapatinib (GCL) as neoadjuvant therapy in patients with muscle-invasive bladder cancer (MIBC) planned for radical cystectomy. Four cycles of GCL were administered as neoadjuvant therapy for patients with MIBC. Although initially designed as a phase II efficacy study with a primary endpoint of pathologic complete response at the time of radical cystectomy, the dose selected for investigation proved excessively toxic. A total of six patients were enrolled. The initial four patients received gemcitabine 1,000 mg/m(2) intravenously on days 1 and 8 and cisplatin 70 mg/m(2) intravenously on day 1 of each 21-day treatment cycle. Lapatinib was administered as 1,000 mg orally daily starting one week prior to the initiation of cycle 1 of gemcitabine and cisplatin (GC) and continuing until the completion of cycle 4 of GC. These initial doses were poorly tolerated, and the final two enrolled patients received a reduced lapatinib dose of 750 mg orally daily. However, reduction of the lapatinib dose did not result in improved tolerance or drug-delivery, and the trial was terminated early due to excessive toxicity. Grade 3/4 toxicities included diarrhea (33%), nausea/vomiting (33%), and thrombocytopenia (33%). The addition of lapatinib to GC as neoadjuvant therapy for MIBC was limited by excessive treatment-related toxicity. These findings highlight the importance of thorough dose-escalation investigation of combination therapies prior to evaluation in the neoadjuvant setting, as well as the limitations of determination of maximum tolerated dose for novel targeted combination regimens.

A phase 1 study of the bispecific anti-CD30/CD16A antibody construct AFM13 in patients with relapsed or refractory Hodgkin lymphoma

PubMed Central

Rothe, Achim; Sasse, Stephanie; Topp, Max S.; Eichenauer, Dennis A.; Hummel, Horst; Reiners, Katrin S.; Dietlein, Markus; Kuhnert, Georg; Kessler, Joerg; Buerkle, Carolin; Ravic, Miroslav; Knackmuss, Stefan; Marschner, Jens-Peter; Pogge von Strandmann, Elke; Borchmann, Peter

2015-01-01

AFM13 is a bispecific, tetravalent chimeric antibody construct (TandAb) designed for the treatment of CD30-expressing malignancies. AFM13 recruits natural killer (NK) cells via binding to CD16A as immune effector cells. In this phase 1 dose-escalation study, 28 patients with heavily pretreated relapsed or refractory Hodgkin lymphoma received AFM13 at doses of 0.01 to 7 mg/kg body weight. Primary objectives were safety and tolerability. Secondary objectives included pharmacokinetics, antitumor activity, and pharmacodynamics. Adverse events were generally mild to moderate. The maximum tolerated dose was not reached. Pharmacokinetics assessment revealed a half-life of up to 19 hours. Three of 26 evaluable patients achieved partial remission (11.5%) and 13 patients achieved stable disease (50%), with an overall disease control rate of 61.5%. AFM13 was also active in brentuximab vedotin–refractory patients. In 13 patients who received doses of ≥1.5 mg/kg AFM13, the overall response rate was 23% and the disease control rate was 77%. AFM13 treatment resulted in a significant NK-cell activation and a decrease of soluble CD30 in peripheral blood. In conclusion, AFM13 represents a well-tolerated, safe, and active targeted immunotherapy of Hodgkin lymphoma. A phase 2 study is currently planned to optimize the dosing schedule in order to further improve the therapeutic efficacy. This phase 1 study was registered at www.clinicaltrials.gov as #NCT01221571. PMID:25887777

Transplantation of Reprogrammed Autologous Stem Cells for Chronic Pain and Drug Abuse

DTIC Science & Technology

2016-07-01

from mesenchymal stem cells (MSCs) and to investigate the analgesic and anti- tolerance effects and the safety of CLCs in animal models. We have...had significant analgesic and robust anti-tolerance effects in both cellular and animal models. Our research has led to 5 poster presentations at...reprogramming, Pain management, Tolerance, Drug abuse, Cell cultures, Spinal transplantation of autologous stem cells, Animal behavioral tests 16. SECURITY

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.

Validation of a Preclinical Spinal Safety Model: Effects of Intrathecal Morphine in the Neonatal Rat

PubMed Central

Westin, B. David; Walker, Suellen M.; Deumens, Ronald; Grafe, Marjorie; Yaksh, Tony L.

2010-01-01

Background Preclinical studies demonstrate increased neuroapoptosis after general anesthesia in early life. Neuraxial techniques may minimize potential risks, but there has been no systematic evaluation of spinal analgesic safety in developmental models. We aimed to validate a preclinical model for evaluating dose-dependent efficacy, spinal cord toxicity, and long term function following intrathecal morphine in the neonatal rat. Methods Lumbar intrathecal injections were performed in anesthetized rats aged postnatal day (P)3, 10 and 21. The relationship between injectate volume and segmental spread was assessed post mortem and by in-vivo imaging. To determine the antinociceptive dose, mechanical withdrawal thresholds were measured at baseline and 30 minutes following intrathecal morphine. To evaluate toxicity, doses up to the maximum tolerated were administered, and spinal cord histopathology, apoptosis and glial response were evaluated 1 and 7 days following P3 or P21 injection. Sensory thresholds and gait analysis were evaluated at P35. Results Intrathecal injection can be reliably performed at all postnatal ages and injectate volume influences segmental spread. Intrathecal morphine produced spinally-mediated analgesia at all ages with lower dose requirements in younger pups. High dose intrathecal morphine did not produce signs of spinal cord toxicity or alter long-term function. Conclusions The therapeutic ratio for intrathecal morphine (toxic dose / antinociceptive dose) was at least 300 at P3, and at least 20 at P21 (latter doses limited by side effects). This data provides relative efficacy and safety data for comparison with other analgesic preparations and contributes supporting evidence for the validity of this preclinical neonatal safety model. PMID:20526189

Validation of a preclinical spinal safety model: effects of intrathecal morphine in the neonatal rat.

PubMed

Westin, B David; Walker, Suellen M; Deumens, Ronald; Grafe, Marjorie; Yaksh, Tony L

2010-07-01

Preclinical studies demonstrate increased neuroapoptosis after general anesthesia in early life. Neuraxial techniques may minimize potential risks, but there has been no systematic evaluation of spinal analgesic safety in developmental models. We aimed to validate a preclinical model for evaluating dose-dependent efficacy, spinal cord toxicity, and long-term function after intrathecal morphine in the neonatal rat. Lumbar intrathecal injections were performed in anesthetized rats aged postnatal day (P) 3, 10, and 21. The relationship between injectate volume and segmental spread was assessed postmortem and by in vivo imaging. To determine the antinociceptive dose, mechanical withdrawal thresholds were measured at baseline and 30 min after intrathecal morphine. To evaluate toxicity, doses up to the maximum tolerated were administered, and spinal cord histopathology, apoptosis, and glial response were evaluated 1 and 7 days after P3 or P21 injection. Sensory thresholds and gait analysis were evaluated at P35. Intrathecal injection can be reliably performed at all postnatal ages and injectate volume influences segmental spread. Intrathecal morphine produced spinally mediated analgesia at all ages with lower dose requirements in younger pups. High-dose intrathecal morphine did not produce signs of spinal cord toxicity or alter long-term function. The therapeutic ratio for intrathecal morphine (toxic dose/antinociceptive dose) was at least 300 at P3 and at least 20 at P21 (latter doses limited by side effects). These data provide relative efficacy and safety for comparison with other analgesic preparations and contribute supporting evidence for the validity of this preclinical neonatal safety model.

Intermediate term safety and efficacy of transscleral cyclophotocoagulation after tube shunt failure

PubMed Central

Ness, Peter J.; Khaimi, Mahmoud A.; Feldman, Robert M.; Tabet, Rania; Sarkisian, Steven R.; Skuta, Gregory L.; Chuang, Alice Z.; Mankiewicz, Kimberly A.

2011-01-01

Purpose To determine the efficacy and safety of diode transscleral cyclophotocoagulation (TSCPC) after tube shunt failure. Patients and Methods The patient population consisted of 32 eyes of 31 patients with uncontrolled glaucoma. Each eye had a previously implanted aqueous tube shunt and was currently on maximally tolerated medication. Each eye also underwent TSCPC treatment using the Iridex (Mountain View, CA) diode laser with a maximum of 360 degrees of treatment. All 31 charts were reviewed for data pertaining to demographics, treatment, ocular history, and follow-up clinical examinations. Safety was evaluated by complication data. Efficacy was evaluated in terms of TSCPC treatment parameters (number of laser applications, laser power, application duration, and degrees of ciliary body treated), intraocular pressure (IOP), number of hypotensive medications, and any further treatment required. Results With a mean (SD) follow-up of 17.1 (16.3) (median = 11.7) months from the last treatment, the mean IOP decreased from 28.6 (10.2) mmHg to 16.8 (7.5) mmHg (35% reduction) at 3 months (n = 30, p < 0.0001) and to 14.7 (7.9) mmHg (43% reduction) at 1 year (n = 13, p < 0.0001). Complications included hypotony (n = 4), hyphema (n = 2), failed corneal transplant (n = 1), and loss of light perception (n = 5). Conclusions TSCPC has a significant ocular hypotensive effect on glaucoma refractory to both tube shunt and medical therapy. The safety of this intervention remains unclear in this high risk patient population and warrants further study. PMID:21336148

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.

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.

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.

Dose-ranging phase 1 study of TMC120, a promising vaginal microbicide, in HIV-negative and HIV-positive female volunteers.

PubMed

Jespers, Vicky A; Van Roey, Jens M; Beets, Greet I; Buvé, Anne M

2007-02-01

To evaluate the short-term safety, tolerability, and systemic exposure of a vaginal microbicide gel containing the nonnucleoside reverse transcriptase inhibitor TMC120. Randomized, controlled, double-blind, phase 1 trial of a gel containing 3 different concentrations of TMC120 versus placebo. Of the 48 HIV-negative and 16 HIV-positive women enrolled, 52 women received active product. Participants applied the gel twice daily for 7 days and were assessed on 6 occasions. Colposcopic evaluation was performed before and after first gel application and on day 8. Laboratory safety assessments were carried out on all visits except day 7. Plasma levels of TMC120 were measured on days 1 and 7. All TMC120 concentrations were well tolerated, and there were no apparent differences in safety parameters. Four women (6%) had treatment-emergent mild cervical findings (petechiae in 3 women and erythema in 1 woman) of <5 mm. Plasma levels of TMC120 were quantifiable on day 1 in 7 (13%) participants and on day 7 in 39 (75%) participants using TMC120 gel. The TMC120 vaginal gel was well-tolerated in this short study by HIV-negative and HIV-positive women. The implications of the absorption of TMC120 should be studied further in expanded safety and effectiveness trials.

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...

77 FR 66721 - Metconazole; Pesticide Tolerances

Federal Register 2010, 2011, 2012, 2013, 2014

2012-11-07

... information in support of this action. EPA has sufficient data to assess the hazards of and to make a... tolerance shows that there will be no increase in the maximum reasonably balanced dietary burden for beef cattle, swine, or poultry but a small increase for diary cattle. There is no increase for beef cattle...

76 FR 82152 - Cyhalofop-butyl; Pesticide Tolerances

Federal Register 2010, 2011, 2012, 2013, 2014

2011-12-30

... original long-term studies were approaching a maximum tolerated dose. In addition, there were no positive....regulations.gov , or, if only available in hard copy, at the OPP Regulatory Public Docket in Rm. S-4400, One..., identified by docket ID number EPA-HQ-OPP-2011-0283, by one of the following methods: Federal eRulemaking...

A safety evaluation of pirfenidone for the treatment of idiopathic pulmonary fibrosis.

PubMed

Anderson, Adam; Shifren, Adrian; Nathan, Steven D

2016-07-01

Pirfenidone is a novel oral anti-fibrotic agent approved for the treatment of idiopathic pulmonary fibrosis (IPF). Since IPF is a chronic and progressive disease most commonly encountered in an older population, therapeutic options should be not only effective, but also free from drug interactions and as safe and tolerable as possible. Comprehensive data from randomized controlled trials, meta-analyses, safety studies, and post-marketing data are available to assess the efficacy and safety of pirfenidone in the treatment of IPF. Information on efficacy, adverse events, drug tolerability and discontinuation rates both in clinical trials and real-world clinical experiences are reported. Pirfenidone has an abundance of data supporting its use in mild-to-moderate IPF. Observational evidence suggests a similar efficacy in severe IPF. In clinical trials, observational studies and real-world use, adverse events are frequent, though generally mild and well tolerated, especially with adequate patient education. Preventative strategies, along with timely and appropriate management of adverse events are critical in improving patient compliance, thereby ensuring the benefits of long-term treatment with pirfenidone.

14 CFR 26.41 - Definitions.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 1 2011-01-01 2011-01-01 false Definitions. 26.41 Section 26.41 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT CONTINUED AIRWORTHINESS AND SAFETY IMPROVEMENTS FOR TRANSPORT CATEGORY AIRPLANES Aging Airplane Safety-Damage Tolerance...

14 CFR 26.41 - Definitions.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 14 Aeronautics and Space 1 2014-01-01 2014-01-01 false Definitions. 26.41 Section 26.41 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT CONTINUED AIRWORTHINESS AND SAFETY IMPROVEMENTS FOR TRANSPORT CATEGORY AIRPLANES Aging Airplane Safety-Damage Tolerance...

14 CFR 26.41 - Definitions.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 1 2012-01-01 2012-01-01 false Definitions. 26.41 Section 26.41 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT CONTINUED AIRWORTHINESS AND SAFETY IMPROVEMENTS FOR TRANSPORT CATEGORY AIRPLANES Aging Airplane Safety-Damage Tolerance...

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.

Rationale and design of a randomized controlled trial of allogeneic mesenchymal stem cells in patients with nonischemic cardiomyopathy.

PubMed

Greene, Stephen J; Epstein, Stephen E; Kim, Raymond J; Quyyumi, Arshed A; Cole, Robert T; Anderson, Allen S; Wilcox, Jane E; Skopicki, Hal A; Sikora, Sergey; Verkh, Lev; Tankovich, Nikolai I; Gheorghiade, Mihai; Butler, Javed

2017-04-01

This article describes an ongoing study investigating the safety and efficacy of ischemia-tolerant mesenchymal stem cell (MSC) therapy in patients with nonischemic heart failure and dysfunctional viable myocardium without scarring. This study will follow principles of the previously described mechanistic translational-phase concept whereby the effect of the study agent on laboratory and imaging markers of cardiac structure and function will be tested in a small homogenous cohort with the goal to enhance the understanding of the effect of interventions on cardiac remodeling and performance. This single-blind, placebo-controlled, crossover, multicenter, randomized study will assess the safety, tolerability, and preliminary efficacy of a single intravenous (i.v.) dose of allogeneic ischemia-tolerant MSCs in individuals with heart failure of nonischemic cause, ejection fraction 40% or less, and dysfunctional viable myocardium who have been receiving guideline-directed medical therapy. Eligible patients will have no evidence of baseline replacement scarring on delayed-enhancement cardiac magnetic resonance (CMR). Approximately 20 patients will be randomized in a 1 : 1 ratio to receive an i.v. infusion of ischemia-tolerant MSCs or placebo. At 90 days, the two groups will undergo crossover and received the alternative treatment. The primary endpoint is safety, as evaluated through at least 1-year post-MSC infusion. Additional efficacy endpoints will include measures of cardiac structure and function, as evaluated by serial cine-CMR and transthoracic echocardiography at 90 and 180 days post-initial infusion. This pilot study will explore the safety and effects on cardiac structure and function of i.v. injection of ischemia-tolerant MSCs in a small homogenous cohort of nonischemic heart failure patients with reduced ejection fraction and absent replacement scarring on CMR. This study also represents a prospective mechanistic translational-phase study using baseline and serial CMR imaging in heart failure patients and serves as a potential model for design of future heart failure trials (ClinicalTrials.gov identifier: NCT02467387).

Lambda network having 2{sup m{minus}1} nodes in each of m stages with each node coupled to four other nodes for bidirectional routing of data packets between nodes

DOEpatents

Napolitano, L.M. Jr.

1995-11-28

The Lambda network is a single stage, packet-switched interprocessor communication network for a distributed memory, parallel processor computer. Its design arises from the desired network characteristics of minimizing mean and maximum packet transfer time, local routing, expandability, deadlock avoidance, and fault tolerance. The network is based on fixed degree nodes and has mean and maximum packet transfer distances where n is the number of processors. The routing method is detailed, as are methods for expandability, deadlock avoidance, and fault tolerance. 14 figs.

The provision of clearances accuracy in piston - cylinder mating

NASA Astrophysics Data System (ADS)

Glukhov, V. I.; Shalay, V. V.

2017-08-01

The paper is aimed at increasing the quality of the pumping equipment in oil and gas industry. The main purpose of the study is to stabilize maximum values of productivity and durability of the pumping equipment based on the selective assembly of the cylinder-piston kinematic mating by optimization criterion. It is shown that the minimum clearance in the piston-cylinder mating is formed by maximum material dimensions. It is proved that maximum material dimensions are characterized by their own laws of distribution within the tolerance limits for the diameters of the cylinder internal mirror and the outer cylindrical surface of the piston. At that, their dispersion zones should be divided into size groups with a group tolerance equal to half the tolerance for the minimum clearance. The techniques for measuring the material dimensions - the smallest cylinder diameter and the largest piston diameter according to the envelope condition - are developed for sorting them into size groups. Reliable control of the dimensions precision ensures optimal minimum clearances of the piston-cylinder mating in all the size groups of the pumping equipment, necessary for increasing the equipment productivity and durability during the production, operation and repair processes.

Avian thermoregulation in the heat: evaporative cooling in five Australian passerines reveals within-order biogeographic variation in heat tolerance.

PubMed

McKechnie, Andrew E; Gerson, Alexander R; McWhorter, Todd J; Smith, Eric Krabbe; Talbot, William A; Wolf, Blair O

2017-07-01

Evaporative heat loss pathways vary among avian orders, but the extent to which evaporative cooling capacity and heat tolerance vary within orders remains unclear. We quantified the upper limits to thermoregulation under extremely hot conditions in five Australian passerines: yellow-plumed honeyeater ( Lichenostomus ornatus ; ∼17 g), spiny-cheeked honeyeater ( Acanthagenys rufogularis ; ∼42 g), chestnut-crowned babbler ( Pomatostomus ruficeps ; ∼52 g), grey butcherbird ( Cracticus torquatus ; ∼86 g) and apostlebird ( Struthidea cinerea ; ∼118 g). At air temperatures ( T a ) exceeding body temperature ( T b ), all five species showed increases in T b to maximum values around 44-45°C, accompanied by rapid increases in resting metabolic rate above clearly defined upper critical limits of thermoneutrality and increases in evaporative water loss (EWL) to levels equivalent to 670-860% of baseline rates at thermoneutral T a Maximum cooling capacity, quantified as the fraction of metabolic heat production dissipated evaporatively, ranged from 1.20 to 2.17, consistent with the known range for passerines, and well below the corresponding ranges for columbids and caprimulgids. Heat tolerance limit (HTL, the maximum T a tolerated) scaled positively with body mass, varying from 46°C in yellow-plumed honeyeaters to 52°C in a single apostlebird, but was lower than that of three southern African ploceid passerines investigated previously. We argue this difference is functionally linked to a smaller scope for increases in EWL above baseline levels. Our data reiterate the reliance of passerines in general on respiratory evaporative heat loss via panting, but also reveal substantial within-order variation in heat tolerance and evaporative cooling capacity. © 2017. Published by The Company of Biologists Ltd.

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.

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...

Natalizumab for relapsing remitting multiple sclerosis.

PubMed

Pucci, Eugenio; Giuliani, Giorgio; Solari, Alessandra; Simi, Silvana; Minozzi, Silvia; Di Pietrantonj, Carlo; Galea, Ian

2011-10-05

Natalizumab (NTZ) (Tysabri(®)) is a monoclonal antibody that inhibits leukocyte migration across the blood-brain barrier, thus reducing inflammation in central nervous system, and has been approved worldwide for the treatment of relapsing-remitting multiple sclerosis (RRMS). To evaluate the efficacy, tolerability and safety of NTZ in the treatment of patients with RRMS. We searched the Cochrane Multiple Sclerosis Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, 2010, Issue 1), MEDLINE (PubMed) and EMBASE, all up to 19 February 2010, and bibliographies of papers. Handsearching was carried out. Trialists and pharmaceutical companies were contacted. Furthermore, the websites of US Food and Drug Administration (FDA), the European Medicines Evaluation Agency (EMA) and the National Institute for health and Clinical Excellence (NICE) were also checked. All double-blind, randomised, controlled trials analysing more than a single infusion of NTZ (dosage > 3 mg/kg intravenous infusion every 4 weeks), also including its use as add-on treatment, versus placebo or other drugs in patients with RRMS. No restrictions on the basis of duration of treatment or length of follow up. Three reviewers independently selected articles which met the inclusion criteria. Disagreements were solved by discussion. Two reviewers independently extracted the data and assessed the methodological quality of each trial. Missing data was sought by contacting principal authors and Biogen Idec, through Biogen-Dompé Italia. Three studies met the inclusion criteria. These included one placebo-controlled trial (942 patients) and two add-on placebo-controlled trials, i.e. one plus glatiramer acetate (110 patients) and the second plus interferon beta-1a (1171 patients).This review assessed the efficacy, tolerability and safety of NTZ in patients with RRMS. Data was conclusive with respect to efficacy and tolerability, but not safety. As far as efficacy is concerned, the results showed statistically significant evidence in favour of NTZ for all the primary outcomes and for the secondary ones where data was available. NTZ reduced the risk of experiencing at least one new exacerbation at 2 years by about 40% and of experiencing progression at 2 years by about 25% as compared to a control group. MRI parameters showed statistical evidence in favour of participants receiving NTZ. Infusion reactions, anxiety, sinus congestion, lower limb swelling, rigors, vaginitis and menstrual disorders were reported as adverse events (AEs) more frequently after NTZ treatment. In this review NTZ was found to be well tolerated over a follow-up period of two years: the number of patients experiencing at least one AE (including severe and serious AEs) during this period did not differ between NTZ-treated patients and controls. Safety concerns have been raised about Progressive Multifocal Leukoencephalopathy (PML). In the trials included in this review, two cases of PML were encountered: one in a patient who had received 29 doses of NTZ and a second fatal case of PML in another patient after 37 doses of NTZ. Our protocol was insufficient to evaluate PML risk as well as other rare and long-term adverse events such as cancers and other opportunistic infections, which are very important issues in considering the risk/benefit ratio of NTZ. Although one trial did not contribute to efficacy results due to its duration, we found robust evidence in favour of a reduction in relapses and disability at 2 years in RRMS patients treated with NTZ. The drug was well tolerated. There are current significant safety concerns due to reporting of an increasing number of PML cases in patients treated with NTZ. This review was unable to provide an up-to-date systematic assessment of the risk due to the maximum 2 year-duration of the trials included. An independent systematic review of the safety profile of NTZ is warranted. NTZ should be used only by skilled neurologists in MS centres under surveillance programs.All the data in this review came from trials supported by the Pharmaceutical Industry. In agreement with the Cochrane Collaboration policy, this may be considered a potential source of bias.

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.

Guidance, Navigation, and Control System Design in a Mass Reduction Exercise

NASA Technical Reports Server (NTRS)

Crain, Timothy; Begly, Michael; Jackson, Mark; Broome, Joel

2008-01-01

Early Orion GN&C system designs optimized for robustness, simplicity, and utilization of commercially available components. During the System Definition Review (SDR), all subsystems on Orion were asked to re-optimize with component mass and steady state power as primary design metrics. The objective was to create a mass reserve in the Orion point of departure vehicle design prior to beginning the PDR analysis cycle. The Orion GN&C subsystem team transitioned from a philosophy of absolute 2 fault tolerance for crew safety and 1 fault tolerance for mission success to an approach of 1 fault tolerance for crew safety and risk based redundancy to meet probability allocations of loss of mission and loss of crew. This paper will discuss the analyses, rationale, and end results of this activity regarding Orion navigation sensor hardware, control effectors, and trajectory design.

Side effects as influencers of treatment outcome.

PubMed

Sharif, Zafar

2008-01-01

Research relative to the efficacy of a therapeutic agent commands a clinician's greatest interest, but treatment decisions are made based on optimizing efficacy and tolerability/safety considerations. Second-generation atypical antipsychotic drugs are a study in the importance of taking a careful look at the full benefit-risk profile of each drug. The disorders that atypical antipsychotics are approved to treat--schizophrenia, schizoaffective disorder, and bipolar disorder--are associated with an increased rate of certain medical comorbidities compared to the general population. Between-drug differences in efficacy are relatively modest for the atypicals, or between atypicals and conventionals, while differences in safety and tolerability are larger and more clinically relevant. The current article will provide a brief summary of safety-related issues that influence treatment outcome and choice of drug.

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

14 CFR 26.49 - Compliance plan.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 1 2011-01-01 2011-01-01 false Compliance plan. 26.49 Section 26.49 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT CONTINUED AIRWORTHINESS AND SAFETY IMPROVEMENTS FOR TRANSPORT CATEGORY AIRPLANES Aging Airplane Safety-Damage Tolerance...

14 CFR 26.49 - Compliance plan.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 1 2012-01-01 2012-01-01 false Compliance plan. 26.49 Section 26.49 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT CONTINUED AIRWORTHINESS AND SAFETY IMPROVEMENTS FOR TRANSPORT CATEGORY AIRPLANES Aging Airplane Safety-Damage Tolerance...

14 CFR 26.49 - Compliance plan.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Compliance plan. 26.49 Section 26.49 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT CONTINUED AIRWORTHINESS AND SAFETY IMPROVEMENTS FOR TRANSPORT CATEGORY AIRPLANES Aging Airplane Safety-Damage Tolerance...

14 CFR 26.49 - Compliance plan.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 14 Aeronautics and Space 1 2013-01-01 2013-01-01 false Compliance plan. 26.49 Section 26.49 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT CONTINUED AIRWORTHINESS AND SAFETY IMPROVEMENTS FOR TRANSPORT CATEGORY AIRPLANES Aging Airplane Safety-Damage Tolerance...

14 CFR 26.49 - Compliance plan.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 14 Aeronautics and Space 1 2014-01-01 2014-01-01 false Compliance plan. 26.49 Section 26.49 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT CONTINUED AIRWORTHINESS AND SAFETY IMPROVEMENTS FOR TRANSPORT CATEGORY AIRPLANES Aging Airplane Safety-Damage Tolerance...

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

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 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.

Pesticide tolerant and phosphorus solubilizing Pseudomonas sp. strain SGRAJ09 isolated from pesticides treated Achillea clavennae rhizosphere soil.

PubMed

Rajasankar, R; Manju Gayathry, G; Sathiavelu, A; Ramalingam, C; Saravanan, V S

2013-05-01

In this study, an attempt was made to identify an effective phosphate solubilizing bacteria from pesticide polluted field soil. Based on the formation of solubilization halo on Pikovskaya's agar, six isolates were selected and screened for pesticide tolerance and phosphate (P) solubilization ability through liquid assay. The results showed that only one strain (SGRAJ09) obtained from Achillea clavennae was found to tolerate maximum level of the pesticides tested and it was phylogenetically identified as Pseudomonas sp. It possessed a wide range of pesticide tolerance, ranging from 117 μg mL(-1) for alphamethrin to 2,600 μg mL(-1) for endosulfan. The available P concentrations increased with the maximum and double the maximum dose of monocrotophos and imidacloprid, respectively. On subjected to FT-IR and HPLC analysis, the presence of organic acids functional group in the culture broth and the production of gluconic acid as dominant acid aiding the P solubilization were identified. On comparison with control broth, monocrotophos and imidacloprid added culture broth showed quantitatively high organic acids production. In addition to gluconic acid production, citric and acetic acids were also observed in the pesticide amended broth. Furthermore, the Pseudomonas sp. strain SGRAJ09 possessed all the plant growth promoting traits tested. In presence of monocrotophos and imidacloprid, its plant growth promoting activities were lower than that of the pesticides unamended treatment.

Multiple-dose pharmacokinetics and safety of bevirimat, a novel inhibitor of HIV maturation, in healthy volunteers.

PubMed

Martin, David E; Blum, Robert; Doto, Judy; Galbraith, Hal; Ballow, Charles

2007-01-01

Bevirimat [3-O-(3',3'-dimethylsuccinyl)-betulinic acid] is a novel inhibitor of HIV-1 maturation. This study was performed to investigate the pharmacokinetics and safety of bevirimat during repeated dosing in healthy volunteers. The study was a 10-day, randomised, double-blind, placebo-controlled, dose escalation study. A total of 48 healthy male volunteers, aged 19-54 years, took part in the study. Treatment was administered for 10 days in six escalating dose cohorts (n = 8 in each cohort; 6 bevirimat, 2 placebo). The doses of bevirimat given in each successive cohort were 25 mg, 50 mg, 75 mg (with 150 mg loading dose), 100 mg, 150 mg and 200mg. Safety follow-up was performed 28 days after the first dose. PHARMACOKINETIC AND STATISTICAL ANALYSIS: Plasma bevirimat levels were measured from blood samples collected pre-dose on days 1-10 and then at approximately 48-hour intervals until 21 days after dosing started. On days 1 and 10, further blood samples were obtained at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours after dosing. Urine samples were collected in the morning on days 1, 5 and 11 and at the end of the study for the measurement of cortisol and 6beta-hydroxycortisol. The pharmacokinetic parameters of bevirimat were estimated using non-compartmental methods. Dose proportionality of exposure to bevirimat, assessed by the maximum plasma concentration and the area under the plasma concentration-time curve. The mean terminal elimination half-life of bevirimat ranged from 56.3 to 69.5 hours, and the mean clearance ranged from 173.9 to 185.8 mL/hour. Bevirimat showed approximately 4-fold greater accumulation on day 10 compared with day 1, and the degree of accumulation was similar with all doses. Maximum plasma concentrations ranged from 8 to 58 microg/mL at day 10. Testing for dose-proportionality showed that exposure to bevirimat was proportional to the dose, both after a single dose and after repeat dosing for 10 days. Measurement of the urinary 6beta-hydroxycortisol/cortisol ratio indicated that bevirimat did not affect cytochrome P450 3A activity. Repeated dosing with bevirimat for 10 days was well tolerated. There was no increase in adverse events observed for bevirimat compared with placebo, and no serious adverse events occurred. No clinically relevant changes in vital signs, physical examination or clinical laboratory evaluations were observed. Bevirimat shows dose-proportional pharmacokinetics during repeated dosing for 10 days. Its accumulation is approximately 4-fold greater on day 10 compared with day 1. Repeated dosing with bevirimat is well tolerated. These properties make bevirimat potentially suitable for inclusion in highly active antiretroviral therapy regimens.

A lower starting dose of eltrombopag is efficacious in Japanese patients with previously treated chronic immune thrombocytopenia.

PubMed

Tomiyama, Y; Miyakawa, Y; Okamoto, S; Katsutani, S; Kimura, A; Okoshi, Y; Ninomiya, H; Kosugi, H; Nomura, S; Ozaki, K; Ikeda, Y; Hattori, T; Katsura, K; Kanakura, Y

2012-05-01

Eltrombopag is an oral, non-peptide thrombopoietin receptor agonist that has shown efficacy and safety in chronic immune thrombocytopenia (ITP). However, ethnic differences in eltrombopag exposure have been reported: area under the curve exposure to eltrombopag was 87% greater among ITP patients of East Asian descent than among ITP patients of non-East Asian ITP descent. To evaluate the efficacy and safety of eltrombopag by using, in Japanese ITP patients, lower starting (12.5 mg) and maximum (50 mg) doses of eltrombopag than the standard starting (50 mg) and maximum (75 mg) doses approved in the USA and Europe. We examined 23 Japanese patients with previously treated chronic ITP with a platelet count of < 30,000 μL(-1) in a multicenter study comprising a randomized, double-blind, placebo-controlled phase for 6-week evaluation (15 eltrombopag, and eight placebo) and an open-label phase for 6-month evaluation (23 eltrombopag). The response rate (platelet count of ≥ 50,000 μL(-1) ) at week 6 of the 6-week double-blind phase was 60% in eltrombopag-treated patients and 0% in placebo-treated patients. Ten of 23 patients (43.5%) responded for ≥ 75% of predefined assessment visits during the 6-month open-label phase. Notably, 22% (5/23) of patients responded to 12.5 mg of eltrombopag, which was administered within the first 3 weeks of eltrombopag treatment. Bleeding decreased with eltrombopag treatment as compared with baseline. Eltrombopag was generally well tolerated; one patient experienced a transient ischemic attack on day 9. Eltrombopag (12.5-50 mg) is effective for the management of Japanese patients with chronic ITP (NCT00540423). © 2012 International Society on Thrombosis and Haemostasis.

Phase I safety, pharmacokinetic, and pharmacodynamic study of the thrombospondin-1-mimetic angiogenesis inhibitor ABT-510 in patients with advanced cancer.

PubMed

Hoekstra, Ronald; de Vos, Filip Y F L; Eskens, Ferry A L M; Gietema, Jourik A; van der Gaast, Ate; Groen, Harry J M; Knight, Raymond A; Carr, Robert A; Humerickhouse, Rod A; Verweij, Jaap; de Vries, Elisabeth G E

2005-08-01

ABT-510 is an angiogenesis inhibitor derived from thrombospondin-1, a naturally occurring inhibitor of angiogenesis. We investigated ABT-510, which was administered subcutaneously in patients with advanced solid malignancies, to assess safety, pharmacokinetics, and serum markers of angiogenesis. ABT-510 was administered subcutaneously as a continuous infusion (100 mg/24 h) and bolus injections (100, 200, and 260 mg once daily; 50 and 100 mg twice daily) in 28-day cycles. Thirty-nine patients received a total of 144 treatment cycles. Administration by continuous infusion was hampered by the onset of painful skin infiltrates at the injection site. In the bolus injection regimens, the most common toxicities observed were mild injection-site reactions and fatigue. Maximum-tolerated dose was not defined, but 260 mg was defined as the maximum clinically practical dose. ABT-510 pharmacokinetics were linear across the dosage ranges tested, and the potential therapeutic threshold (plasma concentrations > 100 ng/mL > 3 h/d) was achieved with all dose regimens. Median serum basic fibroblast growth factor (bFGF) levels decreased from 14.1 pg/mL (range, 0.5 to 77.7 pg/mL) at baseline to 3.2 pg/mL (range, 0.2 to 29.4 pg/mL) after 56 days of treatment (P = .003). No correlations with time on study or ABT-510 dose or exposure were observed for individual changes in bFGF. Stable disease lasting for six cycles or more was seen in six patients. ABT-510 demonstrated a favorable toxicity profile and linear and time-independent pharmacokinetics with biologically relevant plasma concentrations. The significant number of patients with prolonged stable disease and the convenient method of dosing merit further studies with this angiogenesis inhibitor.

Maximum Oxygen Uptake Determination in Insulin-Dependent Diabetes Mellitus.

ERIC Educational Resources Information Center

Fremion, Amy S.; And Others

1987-01-01

A study of 10 children with insulin-dependent diabetes mellitus performing a maximum-effort cycling test indicated blood glucose levels did not change appreciably during test, while maximal oxygen uptake was substandard for their age groups. Findings suggest patients in fair to poor metabolic control can tolerate stress testing without…

Long-term safety of once-daily, dual-release hydrocortisone in patients with adrenal insufficiency: a phase 3b, open-label, extension study

PubMed Central

Nilsson, Anna G; Bergthorsdottir, Ragnhildur; Burman, Pia; Dahlqvist, Per; Ekman, Bertil; Engström, Britt Edén; Ragnarsson, Oskar; Skrtic, Stanko; Wahlberg, Jeanette; Achenbach, Heinrich; Uddin, Sharif; Marelli, Claudio

2017-01-01

Objective To investigate the long-term safety and tolerability of a once-daily, dual-release hydrocortisone (DR-HC) tablet as oral glucocorticoid replacement therapy in patients with primary adrenal insufficiency (AI). Design Prospective, open-label, multicenter, 5-year extension study of DR-HC conducted at five university clinics in Sweden. Methods Seventy-one adult patients diagnosed with primary AI who were receiving stable glucocorticoid replacement therapy were recruited. Safety and tolerability outcomes included adverse events (AEs), intercurrent illness episodes, laboratory parameters and vital signs. Quality of life (QoL) was evaluated using generic questionnaires. Results Total DR-HC exposure was 328 patient-treatment years. Seventy patients reported 1060 AEs (323 per 100 patient-years); 85% were considered unrelated to DR-HC by the investigator. The most common AEs were nasopharyngitis (70%), fatigue (52%) and gastroenteritis (48%). Of 65 serious AEs reported by 32 patients (20 per 100 patient-years), four were considered to be possibly related to DR-HC: acute AI (n = 2), gastritis (n = 1) and syncope (n = 1). Two deaths were reported (fall from height and subarachnoid hemorrhage), both considered to be unrelated to DR-HC. From baseline to 5 years, intercurrent illness episodes remained relatively stable (mean 2.6–5.4 episodes per patient per year), fasting plasma glucose (0.7 mmol/L; P < 0.0001) and HDL cholesterol (0.2 mmol/L; P < 0.0001) increased and patient-/investigator-assessed tolerability improved. QoL total scores were unchanged but worsening physical functioning was recorded (P = 0.008). Conclusions In the first prospective study evaluating the long-term safety of glucocorticoid replacement therapy in patients with primary AI, DR-HC was well tolerated with no safety concerns observed during 5-year treatment. PMID:28292927

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.

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

Phase I dose-escalation study of copanlisib in combination with gemcitabine or cisplatin plus gemcitabine in patients with advanced cancer.

PubMed

Kim, R D; Alberts, S R; Peña, C; Genvresse, I; Ajavon-Hartmann, A; Xia, C; Kelly, A; Grilley-Olson, J E

2018-02-20

Copanlisib is a pan-class I phosphatidylinositol 3-kinase (PI3K) inhibitor with predominant PI3K-α/δ activity that has demonstrated clinical activity and manageable safety when administered as monotherapy in a phase II study. Combination therapy may overcome compensatory signalling that could occur with PI3K pathway inhibition, resulting in enhanced inhibitory activity, and preclinical studies of copanlisib with gemcitabine have demonstrated potent anti-tumour activity in vivo. A phase I, open-label, dose-escalation study to evaluate the safety, tolerability and recommended phase II dose (RP2D) of copanlisib with gemcitabine or with cisplatin plus gemcitabine (CisGem) in patients with advanced malignancies, including an expansion cohort in patients with biliary tract cancer (BTC) at the RP2D of copanlisib plus CisGem. Copanlisib and gemcitabine were administered on days 1, 8 and 15 of a 28-day cycle; maximum tolerated dose (MTD) and RP2D of copanlisib were determined. Copanlisib plus CisGem was administered on days 1 and 8 of a 21-day cycle; pharmacokinetics and biomarkers were assessed. Fifty patients received treatment as follows: dose-escalation cohorts, n=16; copanlisib plus CisGem cohort, n=14; and BTC expansion cohort, n=20. Copanlisib 0.8 mg kg -1 plus gemcitabine was the MTD and RP2D for both combinations. Common treatment-emergent adverse events included nausea (86%), hyperglycaemia (80%) and decreased platelet count (80%). Copanlisib exposure displayed a dose-proportional increase. No differences were observed upon co-administration of CisGem. Response rates were as follows: copanlisib plus gemcitabine, 6.3% (one partial response in a patient with peritoneal carcinoma); copanlisib plus CisGem, 12% (one complete response and three partial responses all in patients with BTC (response rate 17.4% in patients with BTC)). Mutations were detected in PIK3CA (1 out of 43), KRAS (10 out of 43) and BRAF (2 out of 22), with phosphate and tensin homologue protein loss in 41% (12 out of 29). Copanlisib plus CisGem demonstrated a manageable safety profile, favourable pharmacokinetics, and potentially promising clinical response.

Can chilling tolerance of C4 photosynthesis in Miscanthus be transferred to sugarcane?

USDA-ARS?s Scientific Manuscript database

The goal of this study was to investigate if chilling tolerance of C4 photosynthesis in Miscanthus can be transferred to sugarcane. Net leaf CO2 uptake (Asat) and the maximum operating efficiency of photosystem II ('PSII) were measured in warm conditions (25 °C/20 °C), and then during and following ...

77 FR 8741 - Spirotetramat; Pesticide Tolerances for Emergency Exemptions

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-15

... on onion, dry bulb under section 408(l)(6) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U... pesticide on dry bulb onions. This regulation establishes a maximum permissible level for residues of... degradates, in or on onion, dry bulb at 0.3 parts per million (ppm). This time-limited tolerance expires on...

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.

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

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 consistent with the known anesthetic properties of xenon and with previous safety assessments of 129 Xe MRI in adults. Hyperpolarized 129 Xe is a safe and well-tolerated inhaled contrast agent for pulmonary MR imaging in healthy children and in children with cystic fibrosis who have mild to moderate lung disease.

77 FR 42654 - Trifloxystrobin; Pesticide Tolerance

Federal Register 2010, 2011, 2012, 2013, 2014

2012-07-20

... code 112). Food manufacturing (NAICS code 311). Pesticide manufacturing (NAICS code 32532). This... filing. III. Aggregate Risk Assessment and Determination of Safety Section 408(b)(2)(A)(i) of FFDCA... dose at which adverse effects of concern are identified (the LOAEL). Uncertainty/safety factors are...

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.

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 difference between any study outcome, including the risk of relapse, the risk of discontinuations, and safety outcomes. Aripiprazole once-monthly is similarly efficacious to other LAIs with relatively low rates of discontinuation due to AEs and due to reasons other than AEs than other LAIs.

24 CFR 232.565 - Maximum loan amount.

Code of Federal Regulations, 2011 CFR

2011-04-01

... MORTGAGE INSURANCE FOR NURSING HOMES, INTERMEDIATE CARE FACILITIES, BOARD AND CARE HOMES, AND ASSISTED... Fire Safety Equipment Eligible Security Instruments § 232.565 Maximum loan amount. The principal amount of the loan shall not exceed the lower of the Commissioner's estimate of the cost of the fire safety...

Safety, pharmacokinetics, and preliminary clinical activity of inotuzumab ozogamicin, a novel immunoconjugate for the treatment of B-cell non-Hodgkin's lymphoma: results of a phase I study.

PubMed

Advani, Anjali; Coiffier, Bertrand; Czuczman, Myron S; Dreyling, Martin; Foran, James; Gine, Eva; Gisselbrecht, Christian; Ketterer, Nicolas; Nasta, Sunita; Rohatiner, Ama; Schmidt-Wolf, Ingo G H; Schuler, Martin; Sierra, Jorge; Smith, Mitchell R; Verhoef, Gregor; Winter, Jane N; Boni, Joseph; Vandendries, Erik; Shapiro, Mark; Fayad, Luis

2010-04-20

PURPOSE Inotuzumab ozogamicin (CMC-544) is an antibody-targeted chemotherapy agent composed of a humanized anti-CD22 antibody conjugated to calicheamicin, a potent cytotoxic agent. This was a phase I study to determine the maximum-tolerated dose (MTD), safety, and preliminary efficacy of inotuzumab ozogamicin in an expanded MTD cohort of patients with relapsed or refractory CD22(+) B-cell non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS Inotuzumab ozogamicin was administered intravenously as a single agent once every 3 or 4 weeks at doses ranging from 0.4 to 2.4 mg/m(2). Outcomes included MTD, safety, pharmacokinetics, response, progression-free survival (PFS), and overall survival. Results Seventy-nine patients were enrolled. The MTD was determined to be 1.8 mg/m(2). Common adverse events at the MTD were thrombocytopenia (90%), asthenia (67%), and nausea and neutropenia (51% each). The objective response rate at the end of treatment was 39% for the 79 enrolled patients, 68% for all patients with follicular NHL treated at the MTD, and 15% for all patients with diffuse large B-cell lymphoma treated at the MTD. Median PFS was 317 days (approximately 10.4 months) and 49 days for patients with follicular NHL and diffuse large B-cell lymphoma, respectively. CONCLUSION Inotuzumab ozogamicin has demonstrated efficacy against CD22(+) B-cell NHL, with reversible thrombocytopenia as the main toxicity.

Single- and multiple-dose pharmacokinetics and absolute bioavailability of tedizolid.

PubMed

Flanagan, Shawn; Fang, Edward; Muñoz, Kelly A; Minassian, Sonia L; Prokocimer, Philippe G

2014-09-01

Tedizolid phosphate is a novel antibacterial under investigation for the treatment of gram-positive infections. This study was conducted to assess the pharmacokinetics, safety, and tolerability of intravenous tedizolid phosphate as well as the oral bioavailability of tedizolid phosphate. Double-blind, single-ascending dose, multiple-dose pharmacokinetics study, as well as tolerability and open-label crossover studies. Single center in the United States (Covance Clinical Research Unit, Madison, WI) between September 2009 and January 2010. Ninety healthy volunteers. Single intravenous (IV) doses of tedizolid phosphate 50 mg (lead-in) and 100-400 mg. Single oral and IV dose of tedizolid phosphate 200 mg in crossover fashion. Multiple IV doses of tedizolid phosphate 200 and 300 mg for up to 7 days. A dose-dependent increase was observed in the maximum plasma concentration (1.2-5.1 μg/ml) and the area under the concentration-time curve (17.4-58.7 μg × hr/ml) of tedizolid (the microbiologically active moiety of tedizolid phosphate) after single IV doses of tedizolid phosphate 100-400 mg. Administration of IV tedizolid phosphate 200 mg once/day for 7 days resulted in minimal (28%) tedizolid accumulation. The absolute oral bioavailability of tedizolid after a single 200-mg dose of tedizolid phosphate was 91%; pharmacokinetic parameters of tedizolid were similar with oral and IV administration. Treatment-related adverse events occurred in 41% of subjects. Most adverse events were related to infusion site and became more frequent with multiple dosing. In an additional 3-day tolerability study, IV tedizolid phosphate 200 mg and placebo were similarly tolerated, based on visual infusion phlebitis scores. These results from a population of healthy volunteers support once/day dosing of tedizolid phosphate 200 mg with both the oral and IV formulations, without the need for dose adjustment when switching administration routes. © 2014 Cubist Pharmaceuticals. Pharmacotherapy published by Wiley Periodicals, Inc. on behalf of Pharmacotherapy Publications, Inc.

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.

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…

Poster - Thur Eve - 38: Review of couch parameters using an FMEA.

PubMed

Larouche, R; Doucet, R; Rémy, E; Filion, A; Poirier, L

2012-07-01

To improve patient safety during positioning, we undertook a systematic review of the processes used by our center to obtain couch positions. We used a Failure Mode and Effects Analysis (FMEA) framework and fifteen different possible failures were identified and rated. The three major failures were 1) Loss of planned couch position and bias from the previous day's couch position, 2) DICOM origin or isocenter is different between two plans (imaging or treatment), and 3) Patient shift in opposite direction than intended. The main effect of these failures was to cause an override of couch parameters. Based on these results, we modified our processes, introduced new QA and software checks and developed new tolerance tables so as to improve system robustness and increase our success rate at catching failures before they can affect the patient. It has been a year since we made these modifications. Based on our results, we have reduced the number of overrides at our center from a maximum of 20.5% to a maximum of 6.3%, with an average at 4% of daily treatments. Our results suggest that FMEA is an effective tool in improving treatment quality that could be used in other centers. © 2012 American Association of Physicists in Medicine.

Screening of Trichoderma isolates for their potential of biosorption of nickel and cadmium.

PubMed

Nongmaithem, Nabakishor; Roy, Ayon; Bhattacharya, Prateek Madhab

2016-01-01

Fourteen Trichoderma isolates were evaluated for their tolerance to two heavy metals, nickel and cadmium. Three isolates, MT-4, UBT-18, and IBT-I, showed high levels of nickel tolerance, whereas MT-4, UBT-18, and IBT-II showed better tolerance of cadmium than the other isolates. Under nickel stress, biomass production increased up to a Ni concentration of 60ppm in all strains but then decreased as the concentrations of nickel were further increased. Among the nickel-tolerant isolates, UBT-18 produced significantly higher biomass upon exposure to nickel (up to 150ppm); however, the minimum concentration of nickel required to inhibit 50% of growth (MIC50) was highest in IBT-I. Among the cadmium-tolerant isolates, IBT-II showed both maximum biomass production and a maximum MIC50 value in cadmium stress. As the biomass of the Trichoderma isolates increased, a higher percentage of nickel removal was observed up to a concentration of 40ppm, followed by an increase in residual nickel and a decrease in biomass production at higher nickel concentrations in the medium. The increase in cadmium concentrations resulted in a decrease in biomass production and positively correlated with an increase in residual cadmium in the culture broth. Nickel and cadmium stress also influenced the sensitivity of the Trichoderma isolates to soil fungistasis. Isolates IBT-I and UBT-18 were most tolerant to fungistasis under nickel and cadmium stress, respectively. Copyright © 2016 Sociedade Brasileira de Microbiologia. Published by Elsevier Editora Ltda. All rights reserved.

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

ERIC Educational Resources Information Center

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

2012-01-01

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

PRN 2007-2: Guidance on Small-Scale Field Testing and Low-level Presence in Food of Plant-Incorporated Protectants (PIPs)

EPA Pesticide Factsheets

This notice clarifies how EPA ensures the safety of residues of PIPs possibly present in food or feed and when a tolerance or tolerance exemption would be required for field tests for biotechnology-derived food and feed crop plants containing PIPs.

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...

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...

Clonidine for Attention-Deficit/Hyperactivity Disorder: II. ECG Changes and Adverse Events Analysis

ERIC Educational Resources Information Center

Daviss, W. Burleson; Patel, Nick C.; Robb, Adelaide S.; McDermott, Michael P.; Bukstein, Oscar G.; Pelham, William E., Jr.; Palumbo, Donna; Harris, Peter; Sallee, Floyd R.

2008-01-01

A study to examine the safety and tolerance of clonidine, alone or with methylphenidate as a form of treatment in children with attention-deficit/hyperactivity disorders (ADHD) is conducted. Results conclude that clonidine used alone or in combination with methylphenidate were safe and well tolerated in children with ADHD.

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.

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

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.

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.

CSF1R inhibition with emactuzumab in locally advanced diffuse-type tenosynovial giant cell tumours of the soft tissue: a dose-escalation and dose-expansion phase 1 study.

PubMed

Cassier, Philippe A; Italiano, Antoine; Gomez-Roca, Carlos A; Le Tourneau, Christophe; Toulmonde, Maud; Cannarile, Michael A; Ries, Carola; Brillouet, Anne; Müller, Claudia; Jegg, Anna-Maria; Bröske, Ann-Marie; Dembowski, Markus; Bray-French, Katharine; Freilinger, Christine; Meneses-Lorente, Georgina; Baehner, Monika; Harding, Ross; Ratnayake, Jayantha; Abiraj, Keelara; Gass, Nathalie; Noh, Karen; Christen, Randolph D; Ukarma, Lidia; Bompas, Emmanuelle; Delord, Jean-Pierre; Blay, Jean-Yves; Rüttinger, Dominik

2015-08-01

Diffuse-type tenosynovial giant cell tumour (dt-GCT) of the soft tissue (alternatively known as pigmented villonodular synovitis), an orphan disease with unmet medical need, is characterised by an overexpression of colony-stimulating factor 1 (CSF1), and is usually caused by a chromosomal translocation involving CSF1. CSF1 receptor (CSF1R) activation leads to the recruitment of CSF1R-expressing cells of the mononuclear phagocyte lineage that constitute the tumor mass in dt-GCT. Emactuzumab (RG7155) is a novel monoclonal antibody that inhibits CSF1R activation. We have assessed the safety, tolerability and activity of emactuzumab in patients with Dt-GCT of the soft tissue. In this phase 1, first-in-human dose-escalation and dose-expansion study, eligible patients were aged 18 years or older with dt-GCT of the soft tissue with locally advanced disease or resectable tumours requiring extensive surgery, an Eastern Cooperative Oncology Group performance status of 1 or less, measurable disease according to Response Evaluation Criteria In Solid Tumors version 1.1, and adequate end-organ function. Patients with GCT of the bone were not eligible. Patients received intravenous emactuzumab at 900 mg, 1350 mg, or 2000 mg every 2 weeks in the dose-escalation phase and at the optimal biological dose in a dose-expansion phase. The primary objective was to evaluate the safety and tolerability of emactuzumab, and to determine the maximum tolerated dose or optimal biological dose. All treated patients were included in the analyses. Expansion cohorts are currently ongoing. This study is registered with ClinicalTrials.gov, number NCT01494688. Between July 26, 2012, and Oct 21, 2013, 12 patients were enrolled in the dose-escalation phase. No dose-limiting toxicities were noted in the dose-escalation cohort; on the basis of pharmacokinetic, pharmacodynamic, and safety information, we chose a dose of 1000 mg every 2 week for the dose-expansion cohort, into which 17 patients were enrolled. Owing to different cutoff dates for safety and efficacy readouts, the safety population comprised 25 patients. Common adverse events after emactuzumab treatment were facial oedema (16 [64%] of 25 patients), asthenia (14 [56%]), and pruritus (14 [56%]). Five serious adverse events (periorbital oedema, lupus erythematosus [occurring twice], erythema, and dermohypodermitis all experienced by one [4%] patient each) were reported in five patients. Three of the five serious adverse events-periorbital oedema (one [4%]), lupus erythematosus (one [4%]), and dermohypodermitis (one [4%])-were assessed as grade 3. Two other grade 3 events were reported: mucositis (one [4%]) and fatigue (one [4%]). 24 (86%) of 28 patients achieved an objective response; two (7%) patients achieved a complete response. Further study of dt-GCT is warranted and different possibilities, such as an international collaboration with cooperative groups to assure appropriate recruitment in this rare disease, are currently being assessed. F Hoffmann-La Roche. Copyright © 2015 Elsevier Ltd. All rights reserved.

Characterization of Commercial Li-ion Cells in Pouch Format

NASA Technical Reports Server (NTRS)

Jeevarajan, Judith

2014-01-01

The li-ion pouch design cells exhibit similar behavior under off-nominal conditions as those in metal cans that do not have the internal safety devices. Safety should be well characterized before batteries are designed. Some of the li-ion pouch cell designs studied in this program reacted most violently to overcharge conditions at the medium rates but were tolerant to overcharge at very low rates. Some pouch cell designs have higher tolerance to vacuum exposures than some others. A comparison of the pouch material itself does not show a correlation between this tolerance and the number of layers or composition of the pouch indicating that this is a property of the electrode stack design inside the pouch. Reduced pressure (8 to 10 psi) test environments show that the extent of capacity degradation under reduced pressure environments is much less than that observed under vacuum conditions. Lithium-ion Pouch format cells are not necessarily true polymer cells.

Transcranial magnetic stimulation for the treatment of major depression

PubMed Central

Janicak, Philip G; Dokucu, Mehmet E

2015-01-01

Major depression is often difficult to diagnose accurately. Even when the diagnosis is properly made, standard treatment approaches (eg, psychotherapy, medications, or their combination) are often inadequate to control acute symptoms or maintain initial benefit. Additional obstacles involve safety and tolerability problems, which frequently preclude an adequate course of treatment. This leaves an important gap in our ability to properly manage major depression in a substantial proportion of patients, leaving them vulnerable to ensuing complications (eg, employment-related disability, increased risk of suicide, comorbid medical disorders, and substance abuse). Thus, there is a need for more effective and better tolerated approaches. Transcranial magnetic stimulation is a neuromodulation technique increasingly used to partly fill this therapeutic void. In the context of treating depression, we critically review the development of transcranial magnetic stimulation, focusing on the results of controlled and pragmatic trials for depression, which consider its efficacy, safety, and tolerability. PMID:26170668

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.

78 FR 23497 - Propiconazole; Pesticide Tolerances

Federal Register 2010, 2011, 2012, 2013, 2014

2013-04-19

...). Animal production (NAICS code 112). Food manufacturing (NAICS code 311). Pesticide manufacturing (NAICS.... Aggregate Risk Assessment and Determination of Safety Section 408(b)(2)(A)(i) of FFDCA allows EPA to... dose at which adverse effects of concern are identified (the LOAEL). Uncertainty/safety factors are...

Dienogest in the treatment of endometriosis.

PubMed

Bizzarri, Nicolò; Remorgida, Valentino; Leone Roberti Maggiore, Umberto; Scala, Carolina; Tafi, Emanuela; Ghirardi, Valentina; Salvatore, Stefano; Candiani, Massimo; Venturini, Pier Luigi; Ferrero, Simone

2014-09-01

Dienogest (DNG) is an oral progestin, derivative of 19-nortestosterone, that has recently been introduced for the treatment of endometriosis. This review examines the clinical efficacy, safety and tolerability of DNG in the treatment of endometriosis. The material included in the current manuscript was searched and obtained via Medline, Pubmed and EMBASE, from inception until February 2014. The term 'dienogest' was associated with the following search terms: 'endometriosis', 'pharmacokinetics', 'safety' and 'efficacy'. Several trials demonstrated the clinical efficacy, safety and tolerability of DNG. However the use of DNG is associated with some limitations. So far, no study investigated the potential of contraceptive effect of this treatment and therefore, it should be recommended with other methods of contraception (e.g., barrier methods). A further limitation of the use of DNG as daily therapy in the long term is that the cost of the therapy is higher than other progestins available on the market and combined oral contraceptives. Therefore, future studies should be designed to compare the efficacy and safety of DNG with other progestins.

Temperature tolerance of young-of-the-year cisco, Coregonus artedii

USGS Publications Warehouse

Edsall, Thomas A.; Colby, Peter J.

1970-01-01

Young-of-the-year ciscoes (Coregonus artedii) acclimated to 2, 5, 10, 20 and 25 C and tested for tolerance to high and low temperatures provide the first detailed description of the thermal tolerance of coregonids in North America. The upper ultimate lethal temperature of the young ciscoes was 26 C (6 C higher than the maximum sustained temperature tolerated by adult ciscoes in nature) and the ultimate lower lethal temperature approached 0 C (near that commonly tolerated in nature by adult ciscoes). The temperature of 26 C is slightly higher than the lowest ultimate upper lethal temperature recorded for North American freshwater fishes; however, published information on the depth distributions of fishes in the Great Lakes suggests that some of the other coregonids may be less tolerant of high temperatures than the cisco.

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.

Interspecific variation in thermoregulation among three sympatric bats inhabiting a hot, semi-arid environment.

PubMed

Cory Toussaint, Dawn; McKechnie, Andrew E

2012-12-01

Bats in hot roosts experience some of the most thermally challenging environments of any endotherms, but little is known about how heat tolerance and evaporative cooling capacity vary among species. We investigated thermoregulation in three sympatric species (Nycteris thebaica, Taphozous mauritianus and Sauromys petrophilus) in a hot, semi-arid environment by measuring body temperature (T(b)), metabolic rate and evaporative water loss (EWL) at air temperatures (T(a)) of 10-42 °C. S. petrophilus was highly heterothermic with no clear thermoneutral zone, and exhibited rapid increases in EWL at high T(a) to a maximum of 23.7 ± 7.4 mg g⁻¹ h⁻¹ at T(a) ≈ 42 °C, with a concomitant maximum T(b) of 43.7 ± 1.0 °C. T. mauritianus remained largely normothermic at T(a)s below thermoneutrality and increased EWL to 14.7 ± 1.3 mg g⁻¹ h⁻¹ at T(a) ≈ 42 °C, with a maximum T(b) of 42.9 ± 1.6 °C. In N. thebaica, EWL began increasing at lower T (a) than in either of the other species and reached a maximum of 18.6 ± 2.1 mg g⁻¹ h⁻¹ at T(a) = 39.4 °C, with comparatively high maximum T(b) values of 45.0 ± 0.9 °C. Under the conditions of our study, N. thebaica was considerably less heat tolerant than the other two species. Among seven species of bats for which data on T(b) as well as roost temperatures in comparison to outside T(a) are available, we found limited evidence for a correlation between overall heat tolerance and the extent to which roosts are buffered from high T(a).

Requirements Flowdown for Prognostics and Health Management

NASA Technical Reports Server (NTRS)

Goebel, Kai; Saxena, Abhinav; Roychoudhury, Indranil; Celaya, Jose R.; Saha, Bhaskar; Saha, Sankalita

2012-01-01

Prognostics and Health Management (PHM) principles have considerable promise to change the game of lifecycle cost of engineering systems at high safety levels by providing a reliable estimate of future system states. This estimate is a key for planning and decision making in an operational setting. While technology solutions have made considerable advances, the tie-in into the systems engineering process is lagging behind, which delays fielding of PHM-enabled systems. The derivation of specifications from high level requirements for algorithm performance to ensure quality predictions is not well developed. From an engineering perspective some key parameters driving the requirements for prognostics performance include: (1) maximum allowable Probability of Failure (PoF) of the prognostic system to bound the risk of losing an asset, (2) tolerable limits on proactive maintenance to minimize missed opportunity of asset usage, (3) lead time to specify the amount of advanced warning needed for actionable decisions, and (4) required confidence to specify when prognosis is sufficiently good to be used. This paper takes a systems engineering view towards the requirements specification process and presents a method for the flowdown process. A case study based on an electric Unmanned Aerial Vehicle (e-UAV) scenario demonstrates how top level requirements for performance, cost, and safety flow down to the health management level and specify quantitative requirements for prognostic algorithm performance.

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-blind, placebo-controlled, single-dose, dose-ascending study in elderly male and female subjects at a dose of TRC4186 500 mg followed by TRC4186 1000 mg after a 7-day washout period. The safety and tolerability of TRC4186 were assessed by considering adverse events (AEs), ECG findings, vital signs and laboratory investigation results. TRC4186 was rapidly absorbed, with maximum plasma concentrations (C(max)) attained within 1-4 hours. C(max) and area under the plasma concentration-time curve (AUC) were dose proportional over the range 250-2500 mg for a single dose and 500-2000 mg for multiple doses with twice-daily administration. Steady-state conditions were attained within 6 days at different dose levels. C(max) and AUC were not affected by age, sex, race or type of formulation. The tablet formulation of TRC4186 was bioequivalent with the solution form of the drug under fasting conditions and systemic availability of the tablet formulation was reduced by 40% when administered under fed conditions. Terminal elimination and renal clearance in the elderly male (age 69.1 +/- 6.0 years) were not significantly different compared with younger subjects (age 31 +/- 8.6 years). TRC4186 was safe and well tolerated when administered orally with either a single or multiple doses across the different ages, sexes, races and formulations studied. A dose-proportional increase in plasma TRC4186 concentration was seen, with steady state being achieved within 6 days.

23 CFR 658.17 - Weight.

Code of Federal Regulations, 2012 CFR

2012-04-01

... the bridge formula. (c) The maximum gross weight upon any one axle, including any one axle of a group... following formula, referred to as the Bridge Gross Weight Formula: EC14OC91.012 except that two consecutive... derived from the Bridge Formula, up to a maximum of 80,000 pounds, including all enforcement tolerances...

23 CFR 658.17 - Weight.

Code of Federal Regulations, 2011 CFR

2011-04-01

... the bridge formula. (c) The maximum gross weight upon any one axle, including any one axle of a group... following formula, referred to as the Bridge Gross Weight Formula: EC14OC91.012 except that two consecutive... derived from the Bridge Formula, up to a maximum of 80,000 pounds, including all enforcement tolerances...

An empirical assessment of driver motivation and emotional states in perceived safety margins under varied driving conditions.

PubMed

Zhang, Yu; Kaber, David B

2013-01-01

Motivation models in driving behaviour postulate that driver motives and emotional states dictate risk tolerance under various traffic conditions. The present study used time and driver performance-based payment systems to manipulate motivation and risk-taking behaviour. Ten participants drove to a predefined location in a simulated driving environment. Traffic patterns (density and velocity) were manipulated to cause driver behaviour adjustments due to the need to conform with the social norms of the roadway. The driving environment complexity was investigated as a mediating factor in risk tolerance. Results revealed the performance-based payment system to closely relate to risk-taking behaviour as compared with the time-based payment system. Drivers conformed with social norms associated with specific traffic patterns. Higher roadway complexity led to a more conservative safety margins and speeds. This research contributes to the further development of motivational models of driver behaviour. This study provides empirical justification for two motivation factors in driver risk-taking decisions, including compliance with social norm and emotions triggered by incentives. Environment complexity was identified as a mediating factor in motivational behaviour model. This study also recommended safety margin measures sensitive to changes in driver risk tolerance.

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

Safety of oral tenofovir disoproxil fumarate-based pre-exposure prophylaxis for HIV prevention.

PubMed

Mugwanya, Kenneth K; Baeten, Jared M

2016-01-01

Tenofovir disoproxil fumarate (TDF)-based pre-exposure prophylaxis is a novel HIV prevention strategy for individuals at increased sexual risk for HIV infection. For any biomedical prevention intervention, the bar for tolerating adverse effects in healthy persons is high compared to therapeutic interventions. We provide a concise summary of the clinical safety of TDF-based pre-exposure prophylaxis with focus on TDF-related effects on tolerability, kidney function, bone density, HIV resistance, sexual and reproductive health. The evidence base for this review is derived from a literature search of both randomized and observational studies evaluating efficacy and safety of TDF-based PrEP, TDF alone or in combination with emtricitabine, identified from PUBMED and EMBASE electronic databases, clinicaltrials.gov and major HIV conferences. TDF-based pre-exposure prophylaxis is a potent intervention against HIV acquisition when taken which is generally safe and well tolerated. The risk of the small, non-progressive, and reversible decline in glomerular filtration rate and bone mineral density as well as the potential selection for drug resistance associated with PrEP are outweighed, at the population level and broadly for individuals, by PrEP's substantial reduction in the risk of HIV infection.

Anamorelin hydrochloride for the treatment of cancer-anorexia-cachexia in NSCLC.

PubMed

Zhang, Hongjie; Garcia, Jose M

2015-06-01

Cancer anorexia-cachexia syndrome (CACS) is associated with increased morbidity and mortality. Anamorelin is a novel, orally active ghrelin receptor agonist in clinical development for the treatment of CACS in NSCLC. The aim of this review is to summarize preclinical and clinical studies evaluating anamorelin as a potential promising treatment for CACS in NSCLC. Pharmacodynamics, pharmacokinetics and metabolism, clinical efficacy, safety and tolerability of anamorelin for the treatment of CACS in NSCLC were reviewed. Anamorelin administration may lead to increases in food intake, body weight and lean body mass, and a stimulatory effect on growth hormone secretion in NSCLC patients. Anamorelin is well tolerated with no dose-limiting toxicities identified to date. Targeting ghrelin receptors presents the advantage of potentially addressing multiple mechanisms of CACS simultaneously including appetite, muscle protein balance, adipose tissue metabolism, energy expenditure and inflammation. Clinical data suggest that anamorelin is well tolerated and it effectively increases appetite, body weight and lean mass in patients with advanced NSCLC. Long-term safety remains unknown at this time. The potential synergistic effects of anamorelin with nutritional support or exercise as well as its efficacy/safety in other tumor types are also unknown.

The safety of istradefylline for the treatment of Parkinson's disease.

PubMed

Müller, Thomas

2015-05-01

Antagonism of the A2A receptor improves motor behavior in patients with Parkinson's disease (PD), according to results of clinical studies which confirm findings of previous experimental research. The xanthine derivative, istradefylline , has the longest half-life out of the available A2A receptor antagonists. Istradefylline easily crosses the blood-brain barrier and shows a high affinity to the human A2A receptor. This narrative review aims to discuss the safety and tolerability of istradefylline against the background of the currently available drug portfolio for the treatment of PD patients. Istradefylline was safe and well tolerated in clinical trials, which have focused on l-DOPA-treated PD patients. The future of istradefylline as a complementary drug for modulation of the dopaminergic neurotransmission also relies on its potential to act like an l-DOPA plus dopamine agonist sparing future treatment alternative and to reduce the risk of predominant l-DOPA-related onset of motor complications in addition to its direct ameliorating effect on motor symptoms. Dopamine-substituting drugs may dose-dependently produce systemic side effects, particularly onset of hypotension and nausea by peripheral dopamine receptor stimulation. Istradefylline does not interfere with these peripheral receptors and therefore shows a good safety and tolerability profile.

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.

Efficacy and safety of biologic therapies for systemic lupus erythematosus treatment: systematic review and meta-analysis.

PubMed

Borba, Helena Hiemisch Lobo; Wiens, Astrid; de Souza, Thais Teles; Correr, Cassyano Januário; Pontarolo, Roberto

2014-04-01

The objectives of this study were to evaluate the efficacy, safety, and tolerability of biologic drugs compared with placebo for systemic lupus erythematosus (SLE) treatment. A systematic review evaluating the efficacy and safety of biologic therapies compared with placebo in adult SLE patients treatment was performed. Data from studies performed before September 2013 were collected from several databases (MEDLINE, Cochrane Library, SCIELO, Scopus, and International Pharmaceutical Abstracts). Study eligibility criteria included randomized, double-blind, placebo-controlled trials; regarding treatment with biologic agents in SLE adult patients; and published in English, German, Portuguese, and Spanish. Extracted data were statistically analyzed in a meta-analysis using the Review Manager (RevMan) 5.1 software. Efficacy outcomes included the SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index) score, the SRI (Systemic Lupus Erythematosus Responder Index), normalization of low C3 (<90 mg/dL), anti-double-stranded DNA positive to negative, and no new BILAG (British Isles Lupus Assessment Group index) 1A or 2B flares. Data on safety profile included adverse events, serious and severe adverse events, death, malignancy, infections, and infusion reactions. We also evaluated withdrawals from treatment due to lack of efficacy or adverse events. Thirteen randomized placebo-controlled trials met the criteria for data extraction for systematic review. A meta-analysis regarding the efficacy and safety of belimumab compared with placebo involving four of these trials was undertaken and the remainder contributed to a meta-analysis of the safety of biologic agents. In addition, two trials allowed the performance of a meta-analysis regarding the efficacy and safety of rituximab compared with placebo. Belimumab was more effective than placebo in most evaluated outcomes. No significant differences in the safety and tolerability data were observed between the belimumab and placebo groups. No differences were observed between the rituximab and placebo groups for the efficacy outcomes or safety parameters. Extracted data from the 13 studies were pooled, allowing assessment of the safety of biologic drugs. The meta-analysis revealed a satisfactory safety profile of these agents when used for SLE treatment, as there were no significant differences between the two evaluated groups (biologic agents and placebo) for all outcomes analyzed. Belimumab exhibited a satisfactory profile regarding efficacy, safety, and tolerability. Rituximab showed no superiority over placebo in terms of efficacy, despite its suitable safety profile. Biologic agents exhibited a good safety profile for SLE treatment, indicating that these agents are promising therapies and should be further investigated.

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

Pilot-scale verification of maximum tolerable hydrodynamic stress for mammalian cell culture.

PubMed

Neunstoecklin, Benjamin; Villiger, Thomas K; Lucas, Eric; Stettler, Matthieu; Broly, Hervé; Morbidelli, Massimo; Soos, Miroslav

2016-04-01

Although several scaling bioreactor models of mammalian cell cultures are suggested and described in the literature, they mostly lack a significant validation at pilot or manufacturing scale. The aim of this study is to validate an oscillating hydrodynamic stress loop system developed earlier by our group for the evaluation of the maximum operating range for stirring, based on a maximum tolerable hydrodynamic stress. A 300-L pilot-scale bioreactor for cultivation of a Sp2/0 cell line was used for this purpose. Prior to cultivations, a stress-sensitive particulate system was applied to determine the stress values generated by stirring and sparging. Pilot-scale data, collected from 7- to 28-Pa maximum stress conditions, were compared with data from classical 3-L cultivations and cultivations from the oscillating stress loop system. Results for the growth behavior, analyzed metabolites, productivity, and product quality showed a dependency on the different environmental stress conditions but not on reactor size. Pilot-scale conditions were very similar to those generated in the oscillating stress loop model confirming its predictive capability, including conditions at the edge of failure.

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.

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

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

PubMed Central

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

2016-01-01

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

Combined MTOR and autophagy inhibition

PubMed Central

Rangwala, Reshma; Chang, Yunyoung C; Hu, Janice; Algazy, Kenneth M; Evans, Tracey L; Fecher, Leslie A; Schuchter, Lynn M; Torigian, Drew A; Panosian, Jeffrey T; Troxel, Andrea B; Tan, Kay-See; Heitjan, Daniel F; DeMichele, Angela M; Vaughn, David J; Redlinger, Maryann; Alavi, Abass; Kaiser, Jonathon; Pontiggia, Laura; Davis, Lisa E; O’Dwyer, Peter J; Amaravadi, Ravi K

2014-01-01

The combination of temsirolimus (TEM), an MTOR inhibitor, and hydroxychloroquine (HCQ), an autophagy inhibitor, augments cell death in preclinical models. This phase 1 dose-escalation study evaluated the maximum tolerated dose (MTD), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of HCQ in combination with TEM in cancer patients. In the dose escalation portion, 27 patients with advanced solid malignancies were enrolled, followed by a cohort expansion at the top dose level in 12 patients with metastatic melanoma. The combination of HCQ and TEM was well tolerated, and grade 3 or 4 toxicity was limited to anorexia (7%), fatigue (7%), and nausea (7%). An MTD was not reached for HCQ, and the recommended phase II dose was HCQ 600 mg twice daily in combination with TEM 25 mg weekly. Other common grade 1 or 2 toxicities included fatigue, anorexia, nausea, stomatitis, rash, and weight loss. No responses were observed; however, 14/21 (67%) patients in the dose escalation and 14/19 (74%) patients with melanoma achieved stable disease. The median progression-free survival in 13 melanoma patients treated with HCQ 1200mg/d in combination with TEM was 3.5 mo. Novel 18-fluorodeoxyglucose positron emission tomography (FDG-PET) measurements predicted clinical outcome and provided further evidence that the addition of HCQ to TEM produced metabolic stress on tumors in patients that experienced clinical benefit. Pharmacodynamic evidence of autophagy inhibition was evident in serial PBMC and tumor biopsies only in patients treated with 1200 mg daily HCQ. This study indicates that TEM and HCQ is safe and tolerable, modulates autophagy in patients, and has significant antitumor activity. Further studies combining MTOR and autophagy inhibitors in cancer patients are warranted. PMID:24991838

Combined MTOR and autophagy inhibition: phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma.

PubMed

Rangwala, Reshma; Chang, Yunyoung C; Hu, Janice; Algazy, Kenneth M; Evans, Tracey L; Fecher, Leslie A; Schuchter, Lynn M; Torigian, Drew A; Panosian, Jeffrey T; Troxel, Andrea B; Tan, Kay-See; Heitjan, Daniel F; DeMichele, Angela M; Vaughn, David J; Redlinger, Maryann; Alavi, Abass; Kaiser, Jonathon; Pontiggia, Laura; Davis, Lisa E; O'Dwyer, Peter J; Amaravadi, Ravi K

2014-08-01

The combination of temsirolimus (TEM), an MTOR inhibitor, and hydroxychloroquine (HCQ), an autophagy inhibitor, augments cell death in preclinical models. This phase 1 dose-escalation study evaluated the maximum tolerated dose (MTD), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of HCQ in combination with TEM in cancer patients. In the dose escalation portion, 27 patients with advanced solid malignancies were enrolled, followed by a cohort expansion at the top dose level in 12 patients with metastatic melanoma. The combination of HCQ and TEM was well tolerated, and grade 3 or 4 toxicity was limited to anorexia (7%), fatigue (7%), and nausea (7%). An MTD was not reached for HCQ, and the recommended phase II dose was HCQ 600 mg twice daily in combination with TEM 25 mg weekly. Other common grade 1 or 2 toxicities included fatigue, anorexia, nausea, stomatitis, rash, and weight loss. No responses were observed; however, 14/21 (67%) patients in the dose escalation and 14/19 (74%) patients with melanoma achieved stable disease. The median progression-free survival in 13 melanoma patients treated with HCQ 1200mg/d in combination with TEM was 3.5 mo. Novel 18-fluorodeoxyglucose positron emission tomography (FDG-PET) measurements predicted clinical outcome and provided further evidence that the addition of HCQ to TEM produced metabolic stress on tumors in patients that experienced clinical benefit. Pharmacodynamic evidence of autophagy inhibition was evident in serial PBMC and tumor biopsies only in patients treated with 1200 mg daily HCQ. This study indicates that TEM and HCQ is safe and tolerable, modulates autophagy in patients, and has significant antitumor activity. Further studies combining MTOR and autophagy inhibitors in cancer patients are warranted.

Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma.

PubMed

Rangwala, Reshma; Leone, Robert; Chang, Yunyoung C; Fecher, Leslie A; Schuchter, Lynn M; Kramer, Amy; Tan, Kay-See; Heitjan, Daniel F; Rodgers, Glenda; Gallagher, Maryann; Piao, Shengfu; Troxel, Andrea B; Evans, Tracey L; DeMichele, Angela M; Nathanson, Katherine L; O'Dwyer, Peter J; Kaiser, Jonathon; Pontiggia, Laura; Davis, Lisa E; Amaravadi, Ravi K

2014-08-01

Blocking autophagy with hydroxychloroquine (HCQ) augments cell death associated with alkylating chemotherapy in preclinical models. This phase I study evaluated the maximum tolerated dose (MTD), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of HCQ in combination with dose-intense temozolomide (TMZ) in patients with advanced solid malignancies. Forty patients (73% metastatic melanoma) were treated with oral HCQ 200 to 1200 mg daily with dose-intense oral TMZ 150 mg/m (2) daily for 7/14 d. This combination was well tolerated with no recurrent dose-limiting toxicities observed. An MTD was not reached for HCQ and the recommended phase II dose was HCQ 600 mg twice daily combined with dose-intense TMZ. Common toxicities included grade 2 fatigue (55%), anorexia (28%), nausea (48%), constipation (20%), and diarrhea (20%). Partial responses and stable disease were observed in 3/22 (14%) and 6/22 (27%) patients with metastatic melanoma. In the final dose cohort 2/6 patients with refractory BRAF wild-type melanoma had a near complete response, and prolonged stable disease, respectively. A significant accumulation in autophagic vacuoles (AV) in peripheral blood mononuclear cells was observed in response to combined therapy. Population pharmacokinetics (PK) modeling, individual PK simulations, and PK-pharmacodynamics (PD) analysis identified a threshold HCQ peak concentration that predicts therapy-associated AV accumulation. This study indicates that the combination of high-dose HCQ and dose-intense TMZ is safe and tolerable, and is associated with autophagy modulation in patients. Prolonged stable disease and responses suggest antitumor activity in melanoma patients, warranting further studies of this combination, or combinations of more potent autophagy inhibitors and chemotherapy in melanoma.

Oxcarbazepine in migraine headache: a double-blind, randomized, placebo-controlled study.

PubMed

Silberstein, S; Saper, J; Berenson, F; Somogyi, M; McCague, K; D'Souza, J

2008-02-12

To evaluate the efficacy, safety, and tolerability of oxcarbazepine (1,200 mg/day) vs placebo as prophylactic therapy for patients with migraine headaches. This multicenter, double-blind, randomized, placebo-controlled, parallel-group trial consisted of a 4-week single-blind baseline phase and a 15-week double-blind phase consisting of a 6-week titration period, an 8-week maintenance period, and a 1-week down-titration period, after which patients could enter a 13-week open-label extension phase. During the 6-week titration period, oxcarbazepine was initiated at 150 mg/day and increased by 150 mg/day every 5 days to a maximum tolerated dose of 1,200 mg/day. The primary outcome measure was change from baseline in the number of migraine attacks during the last 28-day period of the double-blind phase. Eighty-five patients were randomized to receive oxcarbazepine and 85 to receive placebo. There was no difference between the oxcarbazepine (-1.30) and placebo groups in mean change in number of migraine attacks from baseline during the last 28 days of double-blind phase (-1.74; p = 0.2274). Adverse events were reported for 68 oxcarbazepine-treated patients (80%) and 55 placebo-treated patients (65%). The majority of adverse events were mild or moderate in severity. The most common adverse events (>or=15% of patients) in the oxcarbazepine-treated group were fatigue (20.0%), dizziness (17.6%), and nausea (16.5%); no adverse event occurred in more than 15% of the placebo-treated patients. Overall, oxcarbazepine was safe and well tolerated; however, oxcarbazepine did not show efficacy in the prophylactic treatment of migraine headaches.

Multicenter phase I trial of the mitogen-activated protein kinase 1/2 inhibitor BAY 86-9766 in patients with advanced cancer.

PubMed

Weekes, Colin D; Von Hoff, Daniel D; Adjei, Alex A; Leffingwell, Diane P; Eckhardt, S Gail; Gore, Lia; Lewis, Karl D; Weiss, Glen J; Ramanathan, Ramesh K; Dy, Grace K; Ma, Wen W; Sheedy, Beth; Iverson, Cory; Miner, Jeffrey N; Shen, Zancong; Yeh, Li-Tain; Dubowy, Ronald L; Jeffers, Michael; Rajagopalan, Prabhu; Clendeninn, Neil J

2013-03-01

To evaluate the safety, pharmacokinetics, and pharmacodynamics of BAY 86-9766, a selective, potent, orally available, small-molecule allosteric inhibitor of mitogen-activated protein kinase 1/2 in patients with advanced solid tumors. BAY 86-9766 was administered orally daily in 28-day courses, with doses escalated to establish the maximum-tolerated dose (MTD). An expanded cohort was evaluated at the MTD. Pharmacokinetic and pharmacodynamic parameters were assessed, with extracellular signal-regulated kinase (ERK) phosphorylation evaluated in paired biopsies from a subset of the expanded MTD cohort. Tumor specimens were evaluated for mutations in select genes. Sixty-nine patients were enrolled, including 20 patients at the MTD. The MTD was 100 mg given once-daily or in two divided doses. BAY 86-9766 was well-tolerated. The most common treatment-related toxicities were acneiform rash and gastrointestinal toxicity. BAY 86-9766 was well-absorbed after oral administration (plasma half-life ~12 hours), and displayed dose proportional pharmacokinetics throughout the tested dose range. Continuous daily dosing resulted in moderate accumulation at most dose levels. BAY 86-9766 suppressed ERK phosphorylation in biopsied tissue and tetradecanoylphorbol acetate-stimulated peripheral blood leukocytes. Of 53 evaluable patients, one patient with colorectal cancer achieved a partial response and 11 patients had stable disease for 4 or more courses. An ocular melanoma specimen harbored a GNAQ-activating mutation and exhibited reduced ERK phosphorylation in response to therapy. This phase I study showed that BAY 86-9766 was well-tolerated, with good oral absorption, dose proportional pharmacokinetics, target inhibition at the MTD, and some evidence of clinical benefit across a range of tumor types. ©2012 AACR.

Examination of Org 26576, an AMPA receptor positive allosteric modulator, in patients diagnosed with major depressive disorder: an exploratory, randomized, double-blind, placebo-controlled trial.

PubMed

Nations, Kari R; Dogterom, Peter; Bursi, Roberta; Schipper, Jacques; Greenwald, Scott; Zraket, David; Gertsik, Lev; Johnstone, Jack; Lee, Allen; Pande, Yogesh; Ruigt, Ge; Ereshefsky, Larry

2012-12-01

Org 26576 acts by modulating ionotropic AMPA-type glutamate receptors to enhance glutamatergic neurotransmission. The aim of this Phase 1b study (N=54) was to explore safety, tolerability, pharmacokinetics, and pharmacodynamics of Org 26576 in depressed patients. Part I (N=24) evaluated the maximum tolerated dose (MTD) and optimal titration schedule in a multiple rising dose paradigm (range 100 mg BID to 600 mg BID); Part II (N=30) utilized a parallel groups design (100 mg BID, 400 mg BID, placebo) to examine all endpoints over a 28-day dosing period. Based on the number of moderate intensity adverse events reported at the 600 mg BID dose level, the MTD established in Part I was 450 mg BID. Symptomatic improvement as measured by the Montgomery-Asberg Depression Rating Scale was numerically greater in the Org 26576 groups than in the placebo group in both study parts. In Part II, the 400 mg BID dose was associated with improvements in executive functioning and speed of processing cognitive tests. Org 26576 was also associated with growth hormone increases and cortisol decreases at the end of treatment but did not influence prolactin or brain-derived neurotrophic factor. The quantitative electroencephalogram index Antidepressant Treatment Response at Week 1 was able to significantly predict symptomatic response at endpoint in the active treatment group, as was early improvement in social acuity. Overall, Org 26576 demonstrated good tolerability and pharmacokinetic properties in depressed patients, and pharmacodynamic endpoints suggested that it may show promise in future well-controlled, adequately powered proof of concept trials.

Nimotuzumab combined with concurrent chemoradiotherapy in Japanese patients with esophageal cancer: A phase I study.

PubMed

Kato, Ken; Ura, Takashi; Koizumi, Wasaburo; Iwasa, Satoru; Katada, Chikatoshi; Azuma, Mizutomo; Ishikura, Satoshi; Nakao, Yoshinori; Onuma, Hiroshi; Muro, Kei

2018-03-01

Nimotuzumab is a humanized anti-epidermal growth factor receptor IgG1 monoclonal antibody. This phase I study assessed the tolerability, safety, efficacy, and pharmacokinetics of nimotuzumab in combination with chemoradiotherapy in Japanese patients with esophageal cancer. Patients with stage II, III, and IV esophageal cancer were enrolled. Patients were planned to receive nimotuzumab (level 1: 200 mg/wk for 25 weeks; or level 2: 400 mg/wk in the chemoradiation period, 400 mg biweekly in an additional chemotherapy period [8 weeks after the chemoradiation period] and a maintenance therapy period [after chemotherapy to 25 weeks]) combined with cisplatin (75 mg/m 2 on day 1) and fluorouracil (1000 mg/m 2 on days 1-4) in the chemoradiation and additional chemotherapy periods. Radiotherapy was given concurrently at 50.4 Gy. A total of 10 patients were enrolled in level 1. Dose-limiting toxicities were observed in 2 patients (grade 3 infection and renal disorder). Maximum-tolerated dose was estimated to be at least 200 mg/wk and the dose was not escalated to level 2. The most common grade ≥3 toxicities were lymphopenia (90%), leukopenia (60%), neutropenia (50%), and febrile neutropenia, decreased appetite, hyponatremia, and radiation esophagitis (30% each). Neither treatment-related death nor grade ≥3 skin toxicity was observed in any patient. Complete response rate was 50%. Progression-free survival was 13.9 months. One- and 3-year survival rates were 75% and 37.5%, respectively. Immunogenicity was not reported in any patient. Nimotuzumab in combination with concurrent chemoradiotherapy was tolerable and effective for Japanese patients with esophageal cancer. © 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

A Study of the Focal Adhesion Kinase Inhibitor GSK2256098 in Patients with Recurrent Glioblastoma with Evaluation of Tumor Penetration of [11C]GSK2256098.

PubMed

Brown, Nicholas F; Williams, Matthew; Arkenau, Hendrik-Tobias; Fleming, Ronald A; Tolson, Jerry; Yan, Li; Zhang, Jianping; Swartz, Lisa; Singh, Rajendra; Auger, Kurt R; Lenox, Laurie; Cox, David; Lewis, Yvonne; Plisson, Christophe; Searle, Graham; Saleem, Azeem; Blagden, Sarah; Mulholland, Paul

2018-05-17

GSK2256098 is a novel oral focal adhesion kinase inhibitor. Preclinical studies demonstrate growth inhibition in glioblastoma cell lines. However, rodent studies indicate limited blood-brain barrier penetration. In this expansion cohort within a phase I study, the safety, tolerability, pharmacokinetics and clinical activity of GSK2256098 were evaluated in patients with recurrent glioblastoma. Biodistribution and kinetics of [11C]GSK2256098 were assessed in a sub-study using positron-emission tomography (PET). Patients were treated with GSK2256098 until disease progression or withdrawal due to adverse events (AEs). Serial pharmacokinetic samples were collected on Day 1. On a single day between Days 9-20, patients received a microdose of intravenous [11C]GSK2256098 and scanned with PET over 90 minutes with parallel PK sample collection. Response was assessed by MRI every six weeks. Thirteen patients were treated in three dose cohorts (1000 mg, 750 mg, 500 mg; all dosed twice-daily). The maximum tolerated dose was 1000 mg twice-daily. Dose-limiting toxicities were related to cerebral edema. Treatment-related AEs (>25%) were diarrhea, fatigue and nausea. Eight patients participated in the PET sub-study, with [11C]GSK2256098 VT estimates of 0.9 in tumor tissue, 0.5 in surrounding T2 enhancing areas, and 0.4 in normal brain,. Best response of stable disease was observed in three patients, including one patient on treatment for 11.3 months. GSK2256098 was tolerable in patients with relapsed glioblastoma. GSK2256098 crossed the blood-brain barrier at low levels into normal brain, but at markedly higher levels into tumor, consistent with tumor-associated blood-brain barrier disruption. Additional clinical trials of GSK2256098 are ongoing.

Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study.

PubMed

Perl, Alexander E; Altman, Jessica K; Cortes, Jorge; Smith, Catherine; Litzow, Mark; Baer, Maria R; Claxton, David; Erba, Harry P; Gill, Stan; Goldberg, Stuart; Jurcic, Joseph G; Larson, Richard A; Liu, Chaofeng; Ritchie, Ellen; Schiller, Gary; Spira, Alexander I; Strickland, Stephen A; Tibes, Raoul; Ustun, Celalettin; Wang, Eunice S; Stuart, Robert; Röllig, Christoph; Neubauer, Andreas; Martinelli, Giovanni; Bahceci, Erkut; Levis, Mark

2017-08-01

Internal tandem duplication mutations in FLT3 are common in acute myeloid leukaemia and are associated with rapid relapse and short overall survival. The clinical benefit of FLT3 inhibitors in patients with acute myeloid leukaemia has been limited by rapid generation of resistance mutations, particularly in codon Asp835 (D835). We aimed to assess the highly selective oral FLT3 inhibitor gilteritinib in patients with relapsed or refractory acute myeloid leukaemia. In this phase 1-2 trial, we enrolled patients aged 18 years or older with acute myeloid leukaemia who either were refractory to induction therapy or had relapsed after achieving remission with previous treatment. Patients were enrolled into one of seven dose-escalation or dose-expansion cohorts assigned to receive once-daily doses of oral gilteritinib (20 mg, 40 mg, 80 mg, 120 mg, 200 mg, 300 mg, or 450 mg). Cohort expansion was based on safety and tolerability, FLT3 inhibition in correlative assays, and antileukaemic activity. Although the presence of an FLT3 mutation was not an inclusion criterion, we required ten or more patients with locally confirmed FLT3 mutations (FLT3 mut+ ) to be enrolled in expansion cohorts at each dose level. On the basis of emerging findings, we further expanded the 120 mg and 200 mg dose cohorts to include FLT3 mut+ patients only. The primary endpoints were the safety, tolerability, and pharmacokinetics of gilteritinib. Safety and tolerability were assessed in the safety analysis set (all patients who received at least one dose of gilteritinib). Responses were assessed in the full analysis set (all patients who received at least one dose of study drug and who had at least one datapoint post-treatment). Pharmacokinetics were assessed in a subset of the safety analysis set for which sufficient data for concentrations of gilteritinib in plasma were available to enable derivation of one or more pharmacokinetic variables. This study is registered with ClinicalTrials.gov, number NCT02014558, and is ongoing. Between Oct 15, 2013, and Aug 27, 2015, 252 adults with relapsed or refractory acute myeloid leukaemia received oral gilteritinib once daily in one of seven dose-escalation (n=23) or dose-expansion (n=229) cohorts. Gilteritinib was well tolerated; the maximum tolerated dose was established as 300 mg/day when two of three patients enrolled in the 450 mg dose-escalation cohort had two dose-limiting toxicities (grade 3 diarrhoea and grade 3 elevated aspartate aminotransferase). The most common grade 3-4 adverse events irrespective of relation to treatment were febrile neutropenia (97 [39%] of 252), anaemia (61 [24%]), thrombocytopenia (33 [13%]), sepsis (28 [11%]), and pneumonia (27 [11%]). Commonly reported treatment-related adverse events were diarrhoea (92 [37%] of 252]), anaemia (86 [34%]), fatigue (83 [33%]), elevated aspartate aminotransferase (65 [26%]), and increased alanine aminotransferase (47 [19%]). Serious adverse events occurring in 5% or more of patients were febrile neutropenia (98 [39%] of 252; five related to treatment), progressive disease (43 [17%]), sepsis (36 [14%]; two related to treatment), pneumonia (27 [11%]), acute renal failure (25 [10%]; five related to treatment), pyrexia (21 [8%]; three related to treatment), bacteraemia (14 [6%]; one related to treatment), and respiratory failure (14 [6%]). 95 people died in the safety analysis set, of which seven deaths were judged possibly or probably related to treatment (pulmonary embolism [200 mg/day], respiratory failure [120 mg/day], haemoptysis [80 mg/day], intracranial haemorrhage [20 mg/day], ventricular fibrillation [120 mg/day], septic shock [80 mg/day], and neutropenia [120 mg/day]). An exposure-related increase in inhibition of FLT3 phosphorylation was noted with increasing concentrations in plasma of gilteritinib. In-vivo inhibition of FLT3 phosphorylation occurred at all dose levels. At least 90% of FLT3 phosphorylation inhibition was seen by day 8 in most patients receiving a daily dose of 80 mg or higher. 100 (40%) of 249 patients in the full analysis set achieved a response, with 19 (8%) achieving complete remission, ten (4%) complete remission with incomplete platelet recovery, 46 (18%) complete remission with incomplete haematological recovery, and 25 (10%) partial remission INTERPRETATION: Gilteritinib had a favourable safety profile and showed consistent FLT3 inhibition in patients with relapsed or refractory acute myeloid leukaemia. These findings confirm that FLT3 is a high-value target for treatment of relapsed or refractory acute myeloid leukaemia; based on activity data, gilteritinib at 120 mg/day is being tested in phase 3 trials. Astellas Pharma, National Cancer Institute (Leukemia Specialized Program of Research Excellence grant), Associazione Italiana Ricerca sul Cancro. Copyright © 2017 Elsevier Ltd. All rights reserved.

Probabilistic modeling approach for evaluating the compliance of ready-to-eat foods with new European Union safety criteria for Listeria monocytogenes.

PubMed

Koutsoumanis, Konstantinos; Angelidis, Apostolos S

2007-08-01

Among the new microbiological criteria that have been incorporated in EU Regulation 2073/2005, of particular interest are those concerning Listeria monocytogenes in ready-to eat (RTE) foods, because for certain food categories, they no longer require zero tolerance but rather specify a maximum allowable concentration of 100 CFU/g or ml. This study presents a probabilistic modeling approach for evaluating the compliance of RTE sliced meat products with the new safety criteria for L. monocytogenes. The approach was based on the combined use of (i) growth/no growth boundary models, (ii) kinetic growth models, (iii) product characteristics data (pH, a(w), shelf life) collected from 160 meat products from the Hellenic retail market, and (iv) storage temperature data recorded from 50 retail stores in Greece. This study shows that probabilistic analysis of the above components using Monte Carlo simulation, which takes into account the variability of factors affecting microbial growth, can lead to a realistic estimation of the behavior of L. monocytogenes throughout the food supply chain, and the quantitative output generated can be further used by food managers as a decision-making tool regarding the design or modification of a product's formulation or its "use-by" date in order to ensure its compliance with the new safety criteria. The study also argues that compliance of RTE foods with the new safety criteria should not be considered a parameter with a discrete and binary outcome because it depends on factors such as product characteristics, storage temperature, and initial contamination level, which display considerable variability even among different packages of the same RTE product. Rather, compliance should be expressed and therefore regulated in a more probabilistic fashion.

Safety, pharmacokinetics, and antitumor response of depatuxizumab mafodotin as monotherapy or in combination with temozolomide in patients with glioblastoma.

PubMed

Gan, Hui K; Reardon, David A; Lassman, Andrew B; Merrell, Ryan; van den Bent, Martin; Butowski, Nicholas; Lwin, Zarnie; Wheeler, Helen; Fichtel, Lisa; Scott, Andrew M; Gomez, Erica J; Fischer, JuDee; Mandich, Helen; Xiong, Hao; Lee, Ho-Jin; Munasinghe, Wijith P; Roberts-Rapp, Lisa A; Ansell, Peter J; Holen, Kyle D; Kumthekar, Priya

2018-05-18

We recently reported an acceptable safety and pharmacokinetic profile of depatuxizumab mafodotin (depatux-m), formerly called ABT-414, plus radiation and temozolomide in newly diagnosed glioblastoma (arm A). The purpose of this study was to evaluate the safety and pharmacokinetics of depatux-m, either in combination with temozolomide in newly diagnosed or recurrent glioblastoma (arm B) or as monotherapy in recurrent glioblastoma (arm C). In this multicenter phase I dose escalation study, patients received depatux-m (0.5-1.5 mg/kg in arm B, 1.25 mg/kg in arm C) every 2 weeks by intravenous infusion. Maximum tolerated dose (MTD), recommended phase II dose (RP2D), and preliminary efficacy were also determined. Thirty-eight patients were enrolled as of March 1, 2016. The most frequent toxicities were ocular, occurring in 35/38 (92%) patients. Keratitis was the most common grade 3 adverse event observed in 6/38 (16%) patients; thrombocytopenia was the most common grade 4 event seen in 5/38 (13%) patients. The MTD was set at 1.5 mg/kg in arm B and was not reached in arm C. RP2D was declared as 1.25 mg/kg for both arms. Depatux-m demonstrated a linear pharmacokinetic profile. In recurrent glioblastoma patients, the progression-free survival (PFS) rate at 6 months was 30.8% and the median overall survival was 10.7 months. Best Response Assessment in Neuro-Oncology responses were 1 complete and 2 partial responses. Depatux-m alone or in combination with temozolomide demonstrated an acceptable safety and pharmacokinetic profile in glioblastoma. Further studies are currently under way to evaluate its efficacy in newly diagnosed (NCT02573324) and recurrent glioblastoma (NCT02343406).

Tolerability and blinding of 4x1 high-definition transcranial direct current stimulation (HD-tDCS) at two and three milliamps.

PubMed

Reckow, Jaclyn; Rahman-Filipiak, Annalise; Garcia, Sarah; Schlaefflin, Stephen; Calhoun, Oliver; DaSilva, Alexandre F; Bikson, Marom; Hampstead, Benjamin M

2018-05-04

Transcranial direct current stimulation (tDCS) is an in-demand form of neuromodulation generally regarded as safe and well tolerated. However, few studies have examined the safety, tolerability, or blinding of High Definition (HD-) tDCS, especially in older adults and at stimulation intensities of 2 milliamps (mA) or greater. We examined the rates of serious adverse events and common side effects to establish safety and tolerability, respectively, in HD-tDCS. Blinding was evaluated using participants' accuracy in correctly stating their condition (i.e., active or sham). The sample included 101 older adults (M age  = 69.69, SD = 8.33; M educ  = 16.27, SD = 2.42) who participated in our double blind randomized controlled studies or in case studies that used HD-tDCS for 20-30 min at 2 mA (n = 66, 31 active) or 3 mA (n = 35, 20 active). Participants completed a standardized side effect questionnaire and were asked whether they received active or sham stimulation at the end of each session. There were no serious adverse events and no participants withdrew, suggesting that HD-tDCS meets basic safety parameters. Tolerability was comparable between active and sham HD-tDCS regardless of intensity (2 mA and 3 mA) in first session (allp > .09). Tingling was the most commonly endorsed item (59% active; 56% sham) followed by burning sensation (51% active; 50% sham), the majority of which were mild in nature. "Severe" ratings were reported in fewer than 4% of sessions. Blinding appeared adequate since there were no significant group differences between individuals correctly stating their stimulation condition (χ2 = 0.689, p = .679). The above tolerability and blinding findings generally persisted when multiple session data (i.e., 186 total sessions) were considered. HD-tDCS appears well-tolerated and safe with effective sham-control in older adults, even at 3 mA. These data support the use of HD-tDCS in randomized controlled trials and clinical translation efforts. Published by Elsevier Inc.

Atomoxetine pharmacokinetics in healthy Chinese subjects and effect of the CYP2D6*10 allele.

PubMed

Cui, Yi M; Teng, Choo H; Pan, Alan X; Yuen, Eunice; Yeo, Kwee P; Zhou, Ying; Zhao, Xia; Long, Amanda J; Bangs, Mark E; Wise, Stephen D

2007-10-01

To characterize atomoxetine pharmacokinetics, explore the effect of the homozygous CYP2D6*10 genotype on atomoxetine pharmacokinetics and evaluate the tolerability of atomoxetine, in healthy Chinese subjects. Twenty-four subjects, all CYP2D6 extensive metabolizers (EM), were randomized to receive atomoxetine (40 mg qd for 3 days, then 80 mg qd for 7 days) or matching placebo (2 : 1 ratio) in a double-blind fashion. Atomoxetine serum concentrations were measured following single (40 mg) and multiple (80 mg) doses. Adverse events, clinical safety laboratory data and vital signs were assessed during the study. Atomoxetine was rapidly absorbed with median time to maximum serum concentrations of approximately 1.5 h after single and multiple doses. Atomoxetine concentrations appeared to decrease monoexponentially with a mean apparent terminal half-life (t(1/2)) of approximately 4 h. The apparent clearance, apparent volume of distribution and t(1/2) following single and multiple doses were similar, suggesting linear pharmacokinetics with respect to time. Homozygous CYP2D6*10 subjects had 50% lower clearances compared with other EM subjects, resulting in twofold higher mean exposures. No clinically significant changes or abnormalities were noted in laboratory data and vital signs. The pharmacokinetics of atomoxetine in healthy Chinese subjects appears comparable to other ethnic populations. Multiple dosing of 80 mg qd atomoxetine was well tolerated in this study.

Repeated dose studies with pure Epigallocatechin-3-gallate demonstrated dose and route dependant hepatotoxicity with associated dyslipidemia.

PubMed

Ramachandran, Balaji; Jayavelu, Subramani; Murhekar, Kanchan; Rajkumar, Thangarajan

2016-01-01

EGCG (Epigallocatechin-3-gallate) is the major active principle catechin found in green tea. Skepticism regarding the safety of consuming EGCG is gaining attention, despite the fact that it is widely being touted for its potential health benefits, including anti-cancer properties. The lack of scientific data on safe dose levels of pure EGCG is of concern, while EGCG has been commonly studied as a component of GTE (Green tea extract) and not as a single active constituent. This study has been carried out to estimate the maximum tolerated non-toxic dose of pure EGCG and to identify the treatment related risk factors. In a fourteen day consecutive treatment, two different administration modalities were compared, offering an improved [i.p (intraperitoneal)] and limited [p.o (oral)] bioavailability. A trend of dose and route dependant hepatotoxicity was observed particularly with i.p treatment and EGCG increased serum lipid profile in parallel to hepatotoxicity. Fourteen day tolerable dose of EGCG was established as 21.1 mg/kg for i.p and 67.8 mg/kg for p.o. We also observed that, EGCG induced effects by both treatment routes are reversible, subsequent to an observation period for further fourteen days after cessation of treatment. It was demonstrated that the severity of EGCG induced toxicity appears to be a function of dose, route of administration and period of treatment.

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

[Study of Flexible Doses of Paliperidone ER in Pacients with Schizophrenia who Have Undergone Inefficient Treatment with other Antipsychotics].

PubMed

Córdoba, Rodrigo; Cano, Juan Fernando; Arango-Dávila, César Augusto; Miranda, Carlos; Holguín, Jorge; Fernández, Darío; Márquez, Miguel; Lupo, Christian; Gargoloff, Pedro; Petracca, Gustavo; Lucchetti, César

2012-06-01

Extended-release (ER) paliperidone is an innovative atypical antipsychotic that allows minimal peak-to-through fluctuations with once-daily dosing. To evaluate effectiveness, safety and tolerability of flexible, once-daily doses of paliperidone ER (3-12 mg/day) in patients with schizophrenia from Argentina and Colombia who had previously failed treatment with other antipsychotic agents. The authors conducted a 6-month, open-label, prospective and multicentric study. Effectiveness was assessed with Positive and Negative Syndrome Scale (PANSS) and Personal and Social Performance scale (PSP). Other measures of effectiveness, safety and tolerability, were also conducted. Paliperidone ER 3-12 mg/day improved Positive and Negative Syndrome Scale (PANSS) total scores (primary endpoint) from baseline to study end (p < 0,001). In the PANSS total score, the mean change from baseline (83, 9 units) to end point (53,7 units) was significant (p < 0,001). Flexible doses of paliperidone ER demonstrated a ≥20% reduction in the PANSS total score (p<0.001) in almost two-thirds of patients. PSP mean change from baseline (52 units) to end point (85 units) was significant (p < 0,001). Secondary effectiveness assessments, as well as safety and tolerability measures, demonstrated favourable results throughout the study. Flexible doses of paliperidone ER over 6 months were effective, safe and well tolerated in patients with schizophrenia from Argentina and Colombia. Copyright © 2012 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.

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.

49 CFR 395.3 - Maximum driving time for property-carrying vehicles.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 49 Transportation 5 2014-10-01 2014-10-01 false Maximum driving time for property-carrying vehicles. 395.3 Section 395.3 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL MOTOR CARRIER SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION FEDERAL MOTOR CARRIER SAFETY REGULATIONS HOURS OF SERVICE OF DRIVERS § 395.3...

49 CFR 395.5 - Maximum driving time for passenger-carrying vehicles.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 49 Transportation 5 2014-10-01 2014-10-01 false Maximum driving time for passenger-carrying vehicles. 395.5 Section 395.5 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL MOTOR CARRIER SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION FEDERAL MOTOR CARRIER SAFETY REGULATIONS HOURS OF SERVICE OF DRIVERS § 395.5...

A verified design of a fault-tolerant clock synchronization circuit: Preliminary investigations

NASA Technical Reports Server (NTRS)

Miner, Paul S.

1992-01-01

Schneider demonstrates that many fault tolerant clock synchronization algorithms can be represented as refinements of a single proven correct paradigm. Shankar provides mechanical proof that Schneider's schema achieves Byzantine fault tolerant clock synchronization provided that 11 constraints are satisfied. Some of the constraints are assumptions about physical properties of the system and cannot be established formally. Proofs are given that the fault tolerant midpoint convergence function satisfies three of the constraints. A hardware design is presented, implementing the fault tolerant midpoint function, which is shown to satisfy the remaining constraints. The synchronization circuit will recover completely from transient faults provided the maximum fault assumption is not violated. The initialization protocol for the circuit also provides a recovery mechanism from total system failure caused by correlated transient faults.

75 FR 24501 - Fatigue Tolerance Evaluation of Metallic Structures; Extension of Comment Period

Federal Register 2010, 2011, 2012, 2013, 2014

2010-05-05

... notice responds to a request from the European Aviation Safety Agency (EASA) to extend the comment period... European Aviation Safety Agency (EASA) addressed the joint interest in this rulemaking objective on the... DEPARTMENT OF TRANSPORTATION Federal Aviation Administration 14 CFR Part 27 [Docket No. FAA-2009...

The Failure of Zero Tolerance

ERIC Educational Resources Information Center

Skiba, Russell J.

2014-01-01

There is no doubt that the safety of children in schools and in communities is paramount. Incidents of school violence in the United States have motivated researchers and practitioners to explore and employ effective methodologies and strategies to promote safety in classrooms and schools. Still, issues of disruptive behavior top the list of…

Flaw tolerance promoted by dissipative deformation mechanisms between material building blocks

NASA Astrophysics Data System (ADS)

Verho, Tuukka; Buehler, Markus J.

2014-09-01

Novel high-performance composite materials often draw inspiration from natural materials such as bone or mollusc shells. A prime feature of such composites is that they are, like their natural counterparts, quasibrittle. They are tolerant to material flaws up to a certain characteristic flaw-tolerant size scale, exhibiting high strength and toughness, but start to behave in a brittle manner when sufficiently large flaws are present. Here, we establish that better flaw tolerance can be achieved by maximizing fracture toughness relative to the maximum elastic energy available in the material, and we demonstrate this concept with simple two-dimensional coarse-grained simulations where the transition from brittle to quasibrittle behaviour is examined.

40 CFR 180.1052 - 2,2,5-trimethyl-3-dichloro-acetyl-1,3-oxazolidine; exemption from the requirement of a tolerance.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 23 2010-07-01 2010-07-01 false 2,2,5-trimethyl-3-dichloro-acetyl-1,3... Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) PESTICIDE PROGRAMS TOLERANCES AND EXEMPTIONS FOR... diisobutylthiocarbamate applied to corn fields before the corn plants emerge from the soil with a maximum of 0.5 pound of...

Isolation of a lead tolerant novel bacterial species, Achromobacter sp. TL-3: assessment of bioflocculant activity.

PubMed

Batta, Neha; Subudhi, Sanjukta; Lal, Banwari; Devi, Arundhuti

2013-11-01

Lead is one of the four heavy metals that has a profound damaging effects on human health. In the recent past there has been an increasing global concern for development of sustainable bioremediation technologies for detoxification of lead contaminant. Present investigation highlights for lead biosorption by a newly isolated novel bacterial species; Achromobacter sp. TL-3 strain, isolated from activated sludge samples contaminated with heavy metals (collected from oil refinery, Assam, North-East India). For isolation of lead tolerant bacteria, sludge samples were enriched into Luria Broth medium supplemented separately with a range of lead nitrate; 250, 500, 750, 1000, 1250 and 1500 ppm respectively. The bacterial consortium that could tolerate 1500 ppm of lead nitrate was selected further for purification of lead tolerant bacterial isolates. Purified lead tolerant bacterial isolates were then eventually inoculated into production medium supplemented with ethanol and glycerol as carbon and energy source to investigate for bioflocculant production. Bioflocculant production was estimated by monitoring the potential of lead tolerant bacterial isolate to flocculate Kaolin clay in presence of 1% CaCl2. Compared to other isolates, TL-3 isolate demonstrated for maximum bioflocculant activity of 95% and thus was identified based on 16S rRNA gene sequence analysis. TL3 isolate revealed maximum homology (98%) with Achromobacter sp. and thus designated as Achromobacter sp. TL-3. Bioflocculant activity of TL-3 isolate was correlated with the change in pH and growth. Achromobacter sp. TL-3 has significant potential for lead biosorption and can be effectively employed for detoxification of lead contaminated waste effluents/waste waters.

Use of botulinum toxin in individuals with neurogenic detrusor overactivity: State of the art review

PubMed Central

Linsenmeyer, Todd A.

2013-01-01

Background Botulinum neurotoxin (BoNT) injection into the bladder wall has been shown to be an effective alternative to anticholinergic (antimuscarinic) medications and more invasive surgery in those with multiple sclerosis and spinal cord injury with neurogenic detrusor overactivity (NDO) and urinary incontinence who are not tolerating anticholinergic medications. In August 2011, Botox® (onabotulinumtoxinA) received Food and Drug Administration (FDA) approval for this use. Clinically, intradetrusor injection of BoNT has been found to decrease urinary incontinence and improve quality of life. Its impact on urodynamic parameters is an increase in the maximum cystometric (bladder) capacity and decrease in the maximum detrusor pressures. The most common side effects are urinary tract infections and urinary retention. There have been rare reports and a black box warning of distant spread of BoNT. BoNT has gained popularity because of its effectiveness and long duration of action, relative ease of administration, easy learning curve, reproducibility of results on repeated administration, and low incidence of complications. Objective To discuss the structure and function, mechanisms of action, clinical and urodynamic studies, injection technique, potential beneficial and adverse effects, and potential areas of research of BoNT. Methods Literature search focused on botulinum toxin in MEDLINE/PubMed. Search terms included botulinum toxin, neurogenic bladder, NDO, botox bladder, botox spinal cord injury, botox, FDA, botox side effects. All papers identified were English language, full-text papers. In addition, English abstracts of non-English papers were noted. The reference list of identified articles was also searched for further papers. Conclusion Botulinum toxin is an alternative treatment for individuals with NDO who fail to tolerate anticholinergic medications. Its popularity has increased because of the literature, which has supported its effectiveness, safety, easy use and learning curve, reproducibility of results on repeated use, and recent FDA approval of Botox® (onabotulinumtoxinA). PMID:23941788

Ceritinib in ALK-Rearranged Non–Small-Cell Lung Cancer

PubMed Central

Shaw, Alice T.; Kim, Dong-Wan; Mehra, Ranee; Tan, Daniel S.W.; Felip, Enriqueta; Chow, Laura Q.M.; Camidge, D. Ross; Vansteenkiste, Johan; Sharma, Sunil; De Pas, Tommaso; Riely, Gregory J.; Solomon, Benjamin J.; Wolf, Juergen; Thomas, Michael; Schuler, Martin; Liu, Geoffrey; Santoro, Armando; Lau, Yvonne Y.; Goldwasser, Meredith; Boral, Anthony L.; Engelman, Jeffrey A.

2014-01-01

BACKGROUND Non–small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase gene (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib, but resistance invariably develops. Ceritinib (LDK378) is a new ALK inhibitor that has shown greater antitumor potency than crizotinib in preclinical studies. METHODS In this phase 1 study, we administered oral ceritinib in doses of 50 to 750 mg once daily to patients with advanced cancers harboring genetic alterations in ALK. In an expansion phase of the study, patients received the maximum tolerated dose. Patients were assessed to determine the safety, pharmacokinetic properties, and antitumor activity of ceritinib. Tumor biopsies were performed before ceritinib treatment to identify resistance mutations in ALK in a group of patients with NSCLC who had had disease progression during treatment with crizotinib. RESULTS A total of 59 patients were enrolled in the dose-escalation phase. The maximum tolerated dose of ceritinib was 750 mg once daily; dose-limiting toxic events included diarrhea, vomiting, dehydration, elevated aminotransferase levels, and hypophosphatemia. This phase was followed by an expansion phase, in which an additional 71 patients were treated, for a total of 130 patients overall. Among 114 patients with NSCLC who received at least 400 mg of ceritinib per day, the overall response rate was 58% (95% confidence interval [CI], 48 to 67). Among 80 patients who had received crizotinib previously, the response rate was 56% (95% CI, 45 to 67). Responses were observed in patients with various resistance mutations in ALK and in patients without detectable mutations. Among patients with NSCLC who received at least 400 mg of ceritinib per day, the median progression-free survival was 7.0 months (95% CI, 5.6 to 9.5). CONCLUSIONS Ceritinib was highly active in patients with advanced, ALK-rearranged NSCLC, including those who had had disease progression during crizotinib treatment, regardless of the presence of resistance mutations in ALK. (Funded by Novartis Pharmaceuticals and others; ClinicalTrials.gov number, NCT01283516.) PMID:24670165

A 2D ion chamber array audit of wedged and asymmetric fields in an inhomogeneous lung phantom.

PubMed

Lye, Jessica; Kenny, John; Lehmann, Joerg; Dunn, Leon; Kron, Tomas; Alves, Andrew; Cole, Andrew; Williams, Ivan

2014-10-01

The Australian Clinical Dosimetry Service (ACDS) has implemented a new method of a nonreference condition Level II type dosimetric audit of radiotherapy services to increase measurement accuracy and patient safety within Australia. The aim of this work is to describe the methodology, tolerances, and outcomes from the new audit. The ACDS Level II audit measures the dose delivered in 2D planes using an ionization chamber based array positioned at multiple depths. Measurements are made in rectilinear homogeneous and inhomogeneous phantoms composed of slabs of solid water and lung. Computer generated computed tomography data sets of the rectilinear phantoms are supplied to the facility prior to audit for planning of a range of cases including reference fields, asymmetric fields, and wedged fields. The audit assesses 3D planning with 6 MV photons with a static (zero degree) gantry. Scoring is performed using local dose differences between the planned and measured dose within 80% of the field width. The overall audit result is determined by the maximum dose difference over all scoring points, cases, and planes. Pass (Optimal Level) is defined as maximum dose difference ≤3.3%, Pass (Action Level) is ≤5.0%, and Fail (Out of Tolerance) is >5.0%. At close of 2013, the ACDS had performed 24 Level II audits. 63% of the audits passed, 33% failed, and the remaining audit was not assessable. Of the 15 audits that passed, 3 were at Pass (Action Level). The high fail rate is largely due to a systemic issue with modeling asymmetric 60° wedges which caused a delivered overdose of 5%-8%. The ACDS has implemented a nonreference condition Level II type audit, based on ion chamber 2D array measurements in an inhomogeneous slab phantom. The powerful diagnostic ability of this audit has allowed the ACDS to rigorously test the treatment planning systems implemented in Australian radiotherapy facilities. Recommendations from audits have led to facilities modifying clinical practice and changing planning protocols.

Phase I/II randomized trial of aerobic exercise in Parkinson disease in a community setting.

PubMed

Uc, Ergun Y; Doerschug, Kevin C; Magnotta, Vincent; Dawson, Jeffrey D; Thomsen, Teri R; Kline, Joel N; Rizzo, Matthew; Newman, Sara R; Mehta, Sonya; Grabowski, Thomas J; Bruss, Joel; Blanchette, Derek R; Anderson, Steven W; Voss, Michelle W; Kramer, Arthur F; Darling, Warren G

2014-07-29

To (1) investigate effects of aerobic walking on motor function, cognition, and quality of life in Parkinson disease (PD), and (2) compare safety, tolerability, and fitness benefits of different forms of exercise intervention: continuous/moderate intensity vs interval/alternating between low and vigorous intensity, and individual/neighborhood vs group/facility setting. Initial design was a 6-month, 2 × 2 randomized trial of different exercise regimens in independently ambulatory patients with PD. All arms were required to exercise 3 times per week, 45 minutes per session. Randomization to group/facility setting was not feasible because of logistical factors. Over the first 2 years, we randomized 43 participants to continuous or interval training. Because preliminary analyses suggested higher musculoskeletal adverse events in the interval group and lack of difference between training methods in improving fitness, the next 17 participants were allocated only to continuous training. Eighty-one percent of 60 participants completed the study with a mean attendance of 83.3% (95% confidence interval: 77.5%-89.0%), exercising at 46.8% (44.0%-49.7%) of their heart rate reserve. There were no serious adverse events. Across all completers, we observed improvements in maximum oxygen consumption, gait speed, Unified Parkinson's Disease Rating Scale sections I and III scores (particularly axial functions and rigidity), fatigue, depression, quality of life (e.g., psychological outlook), and flanker task scores (p < 0.05 to p < 0.001). Increase in maximum oxygen consumption correlated with improvements on the flanker task and quality of life (p < 0.05). Our preliminary study suggests that aerobic walking in a community setting is safe, well tolerated, and improves aerobic fitness, motor function, fatigue, mood, executive control, and quality of life in mild to moderate PD. This study provides Class IV evidence that in patients with PD, an aerobic exercise program improves aerobic fitness, motor function, fatigue, mood, and cognition. © 2014 American Academy of Neurology.

Redistribution, Hyperproliferation, Activation of Natural Killer Cells and CD8 T Cells, and Cytokine Production During First-in-Human Clinical Trial of Recombinant Human Interleukin-15 in Patients With Cancer

PubMed Central

Conlon, Kevin C.; Lugli, Enrico; Welles, Hugh C.; Rosenberg, Steven A.; Fojo, Antonio Tito; Morris, John C.; Fleisher, Thomas A.; Dubois, Sigrid P.; Perera, Liyanage P.; Stewart, Donn M.; Goldman, Carolyn K.; Bryant, Bonita R.; Decker, Jean M.; Chen, Jing; Worthy, Tat'Yana A.; Figg, William D.; Peer, Cody J.; Sneller, Michael C.; Lane, H. Clifford; Yovandich, Jason L.; Creekmore, Stephen P.; Roederer, Mario; Waldmann, Thomas A.

2015-01-01

Purpose Interleukin-15 (IL-15) has significant potential in cancer immunotherapy as an activator of antitumor CD8 T and natural killer (NK) cells. The primary objectives of this trial were to determine safety, adverse event profile, dose-limiting toxicity, and maximum-tolerated dose of recombinant human IL-15 (rhIL-15) administered as a daily intravenous bolus infusion for 12 consecutive days in patients with metastatic malignancy. Patients and Methods We performed a first in-human trial of Escherichia coli–produced rhIL-15. Bolus infusions of 3.0, 1.0, and 0.3 μg/kg per day of IL-15 were administered for 12 consecutive days to patients with metastatic malignant melanoma or metastatic renal cell cancer. Results Flow cytometry of peripheral blood lymphocytes revealed dramatic efflux of NK and memory CD8 T cells from the circulating blood within minutes of IL-15 administration, followed by influx and hyperproliferation yielding 10-fold expansions of NK cells that ultimately returned to baseline. Up to 50-fold increases of serum levels of multiple inflammatory cytokines were observed. Dose-limiting toxicities observed in patients receiving 3.0 and 1.0 μg/kg per day were grade 3 hypotension, thrombocytopenia, and elevations of ALT and AST, resulting in 0.3 μg/kg per day being determined the maximum-tolerated dose. Indications of activity included clearance of lung lesions in two patients. Conclusion IL-15 could be safely administered to patients with metastatic malignancy. IL-15 administration markedly altered homeostasis of lymphocyte subsets in blood, with NK cells and γδ cells most dramatically affected, followed by CD8 memory T cells. To reduce toxicity and increase efficacy, alternative dosing strategies have been initiated, including continuous intravenous infusions and subcutaneous IL-15 administration. PMID:25403209

Randomized double-blind placebo-controlled multicenter evaluation of efficacy and dose finding of midodrine hydrochloride in women with mild to moderate stress urinary incontinence: a phase II study.

PubMed

Weil, E H; Eerdmans, P H; Dijkman, G A; Tamussino, K; Feyereisl, J; Vierhout, M E; Schmidbauer, C; Egarter, C; Kölle, D; Plasman, J E; Heidler, H; Abbühl, B E; Wein, W

1998-01-01

Midodrine is a potent and selective alpha1-receptor agonist and its potential to increase urethral closure pressure could be useful in the treatment of female stress incontinence. The aim of this randomized double-blind placebo-controlled multicenter study was to evaluate the efficacy and safety of midodrine for the treatment of stress urinary incontinence. The primary criterion of efficacy was the maximum urethral closure pressure at rest. Voiding diaries, symptom and incontinence questionnaires and patient/investigator global assessment were also used to evaluate its efficacy. After 4 weeks of treatment no significant changes in MUCP were found. The global assessment by the patient and investigator did indicate that patients on active treatment had a more positive assessment than the placebo group. In conclusion, midodrine did not cause significant improvements in urodynamic parameters, but there were subjective improvements in some of the patients in the treated groups. Furthermore midodrine was well tolerated.

Moving Beyond Maximum Tolerated Dose for Targeted Oncology Drugs: Use of Clinical Utility Index to Optimize Venetoclax Dosage in Multiple Myeloma Patients.

PubMed

Freise, K J; Jones, A K; Verdugo, M E; Menon, R M; Maciag, P C; Salem, A H

2017-12-01

Exposure-response analyses of venetoclax in combination with bortezomib and dexamethasone in previously treated patients with multiple myeloma (MM) were performed on a phase Ib venetoclax dose-ranging study. Logistic regression models were utilized to determine relationships, identify subpopulations with different responses, and optimize the venetoclax dosage that balanced both efficacy and safety. Bortezomib refractory status and number of prior treatments were identified to impact the efficacy response to venetoclax treatment. Higher venetoclax exposures were estimated to increase the probability of achieving a very good partial response (VGPR) or better through venetoclax doses of 1,200 mg. However, the probability of neutropenia (grade ≥3) was estimated to increase at doses >800 mg. Using a clinical utility index, a venetoclax dosage of 800 mg daily was selected to optimally balance the VGPR or better rates and neutropenia rates in MM patients administered 1-3 prior lines of therapy and nonrefractory to bortezomib. © 2017 American Society for Clinical Pharmacology and Therapeutics.

[Copper nanoparticles as modulators of apoptosis and structural changes in some organs].

PubMed

Sizova, E A; Miroshnikov, S A; Poliakova, V S; Lebedev, S V; Glushchenko, N N

2013-01-01

The effect of repeated intramuscular injection into the organism of copper nanoparticles (CNP) with the diameter of 103 nm on the index of cell readiness to apoptosis and the structure of liver, spleen, kidney, as well as sensomotor cerebral cortex, was studied in 78 male Wistar rats. CNP were injected once per week for 12 weeks. The organs were studied using histological, immunohistochemical and morphometric methods. It was found that after the injections, CNP were distributed into organs and tissues of animals causing structural changes that were specific for eaach tissue. Toxicity of CNP in respect to microgliocytes was demonstrated at a dose of 2 mg/kg, hepatotoxicity and nephrotoxicity--at 6 mg/kg. The increase of CNP load on the organism up to toxic threshold (maximum tolerated dose) resulted in the appearance of signs of dystrophy and tissue necrosis. The data obtained suggest the application of an index of cell readiness to apoptosis, as assessed by caspase 3 expression, as a criterion for evaluation of CNP injection safety.

Large-scale purification and acute toxicity of hygromycin B phosphotransferase.

PubMed

Zhuo, Qin; Piao, Jian-Hua; Tian, Yuan; Xu, Jie; Yang, Xiao-Guang

2009-02-01

To provide the acute toxicity data of hygromycin B phosphotransferase (HPT) using recombinant protein purified from E. coli. Recombinant HPT protein was expressed and purified from E. coli. To exclude the potential adverse effect of bacteria protein in recombinant HPT protein, bacterial control plasmid was constructed, and bacteria control protein was extracted and prepared as recombinant HPT protein. One hundred mice, randomly assigned to 5 groups, were administrated 10 g/kg, 5 g/kg, or 1 g/kg body weight of HPT or 5 g/kg body weight of bacterial control protein or phosphate-buffered saline (PBS) respectively by oral gavage. All animals survived with no significant change in body weight gain throughout the study. Macroscopic necropsy examination on day 15 revealed no gross pathological lesions in any of the animals. The maximum tolerated dose (MTD) of HPT was 10 g/kg body weight in mice and could be regarded as nontoxic. HPT protein does not have any safety problems to human health.

77 FR 26703 - Inflation Adjustment of the Aggravated Maximum Civil Monetary Penalty for a Violation of a...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-05-07

.... FRA-2004-17529; Notice No. 9] RIN 2130-AB94 Inflation Adjustment of the Aggravated Maximum Civil Monetary Penalty for a Violation of a Federal Railroad Safety Law or Federal Railroad Administration Safety... rule, pursuant to the Federal Civil Penalties Inflation Adjustment Act of 1990, which increased the...

Resilience of rice (Oryza spp.) pollen germination and tube growth to temperature stress.

PubMed

Coast, Onoriode; Murdoch, Alistair J; Ellis, Richard H; Hay, Fiona R; Jagadish, Krishna S V

2016-01-01

Resilience of rice cropping systems to potential global climate change will partly depend on the temperature tolerance of pollen germination (PG) and tube growth (PTG). Pollen germination of high temperature-susceptible Oryza glaberrima Steud. (cv. CG14) and Oryza sativa L. ssp. indica (cv. IR64) and high temperature-tolerant O. sativa ssp. aus (cv. N22), was assessed on a 5.6-45.4 °C temperature gradient system. Mean maximum PG was 85% at 27 °C with 1488 μm PTG at 25 °C. The hypothesis that in each pollen grain, the minimum temperature requirements (Tn ) and maximum temperature limits (Tx ) for germination operate independently was accepted by comparing multiplicative and subtractive probability models. The maximum temperature limit for PG in 50% of grains (Tx(50) ) was the lowest (29.8 °C) in IR64 compared with CG14 (34.3 °C) and N22 (35.6 °C). Standard deviation (sx ) of Tx was also low in IR64 (2.3 °C) suggesting that the mechanism of IR64's susceptibility to high temperatures may relate to PG. Optimum germination temperatures and thermal times for 1 mm PTG were not linked to tolerating high temperatures at anthesis. However, the parameters Tx(50) and sx in the germination model define new pragmatic criteria for successful and resilient PG, preferable to the more traditional cardinal (maximum and minimum) temperatures. © 2014 John Wiley & Sons Ltd.

Efficacy and Safety of Three Cryotherapy Devices for Wart Treatment: A Randomized, Controlled, Investigator-Blinded, Comparative Study.

PubMed

Walczuk, Imko; Eertmans, Frank; Rossel, Bart; Cegielska, Agnieszka; Stockfleth, Eggert; Antunes, Andre; Adriaens, Els

2018-06-01

Cutaneous warts are common skin lesions, caused by human papillomavirus. For years, liquid nitrogen is the cryogen of choice for wart treatment. Alternatively, several cryogenic devices for home treatment are commercially available. The present trial assessed efficacy and safety of a novel nitrous oxide-based cryogenic device for home use (EndWarts Freeze ® in Europe, Compound W ® Nitro-Freeze in the USA). This investigator-blinded, controlled, randomized study compared the nitrous oxide device (test product) with a dimethylether propane-based product (Wartner ® ; comparator 1). Subjects with common or plantar warts (50/50 ratio) were randomized into two groups (n = 58, test product; n = 40, comparator 1). Sequentially, an extra treatment arm (n = 40) was added to compare with a dimethylether-based product with metal nib (Wortie ® ; comparator 2). Main objective implied comparison of the percentage cured subjects after one to maximum three treatments. Efficacy and safety was evaluated by a blinded investigator. After a maximum of three applications, a significantly (p = 0.001) higher cure rate of 70.7% (Intention-to-Treat analysis) was observed with test product versus 46.2% (comparator 1) and 47.5% (comparator 2). Almost three times more subjects were cured after 1 test product application (29.3%), versus comparator 1 (10.4%) and comparator 2 (12.5%). Reported side effects were transient and typical of cryotherapy. All treatments were well-tolerated. The superior cure rates for the test product versus two comparators can be explained by its design. Combination of nitrous oxide (cooling agent), the specific activation method (holding the liquid coolant in the cap), and skin-conforming polyurethane foam, results in higher cooling efficiency (- 80 °C) and more effective wart freezing. This trial demonstrated that the nitrous oxide device is a safe, user-friendly and effective wart treatment for home use, comparing favourably to dimethylether (propane) devices with higher freezing temperature, regardless of the applicator type. Oystershell Laboratories. Clinicaltrials.gov identifier, NCT03129373.

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.

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.

The relationship between workplace violence, perceptions of safety, and Professional Quality of Life among emergency department staff members in a Level 1 Trauma Centre.

PubMed

Copeland, Darcy; Henry, Melissa

2018-02-02

Emergency department staff members are frequently exposed to workplace violence which may have physical, psychological, and workforce related consequences. The purpose of this study was to examine the relationships between exposure to workplace violence, tolerance to violence, expectations of violence, perceptions of workplace safety, and Professional Quality of Life (compassion satisfaction - CS, burnout - BO, secondary traumatic stress - STS) among emergency department staff members. A cross-sectional design was used to survey all emergency department staff members from a suburban Level 1 Trauma Centre in the western United States. All three dimensions of Professional Quality of Life were associated with exposure to non-physical patient violence including: general threats (CS p = .012, BO p = .001, STS p = .035), name calling (CS p = .041, BO p = .021, STS p = .018), and threats of lawsuit (CS p = .001, BO p = .001, STS p = .02). Tolerance to violence was associated with BO (p = .004) and CS (p = .001); perception of safety was associated with BO (p = .018). Exposure to non-physical workplace violence can significantly impact staff members' compassion satisfaction, burnout and secondary traumatic stress. Greater attention should be paid to the effect of non-physical workplace violence. Additionally, addressing tolerance to violence and perceptions of safety in the workplace may impact Professional Quality of Life. Copyright © 2018 Elsevier Ltd. All rights reserved.

Effect of Surgical Curve Correction on Exercise Tolerance and Physical Capacities in Patients of Severe Spinal Deformity.

PubMed

Patil, Prateek C; Rathod, Ashok K; Borde, Mandar; Singh, Vishwajeet; Singh, Hemant U

2016-12-01

Traditionally, surgical intervention for patients with a spinal deformity has been considered for cosmetic benefits, but surgical intervention can alter the lung physiology or volumes and in turn leads to increase in physical capacity and exercise tolerance. Therefore, we conducted this to determine whether a surgical correction would restore the lung physiology, physical capacity and exercise tolerance in patients with kyphoscoliosis. To evaluate the usage of six-minute walk test scores and modified Borg scores as tools/measures for exercise tolerance in patients with spinal deformity and to study the effects of surgical correction of spinal deformity on exercise tolerance with above parameters as the measures. Thirty patients with spinal deformity, who had undergone surgery for deformity correction, were evaluated. All patients were investigated pre-operatively with x-rays of the spine (anteroposterior and lateral views). Clinical tests like breath holding time (after full inspiration) in number of seconds, modified Borg scores, six-minute walk test scores (heart rate, respiratory rate, maximum distance walked); were recorded as measures of exercise tolerance. The patients were followed up on the first, third, sixth and twelfth month post-operatively and tested clinically for breath holding time, modified Borg scores, six-minute walk test scores (heart rate, respiratory rate, maximum distance walked) and x-rays of the spine (anteroposterior and lateral views). In our study, breath holding time (p-value = 0.001) and modified Borg scores (p-value = 0.012) showed a significant improvement at 12 months post-operatively. We noted similar findings with heart rate, respiratory rate and maximum distance walked after a six-minute walk test. Improvements were noted in all the parameters, especially in the group of patients with greater than 60 degrees of cobb angle. However, the differences between the two groups (pre-operative cobb angle less than 60 degrees and pre-operative cobb angle more than 60 degrees) were not significant. The results were analysed and tested for significance using Student's t-test (paired and unpaired as appropriate) and Wilcoxon signed rank test. Surgical correction in cases of spinal deformity improves the cosmetic appearance and balance in the patients. Favourable results of surgical intervention were found in exercise tolerance with improvements in modified Borg scores, six-minute walk test results and breath holding time. The above parameters appear to be good tools for the assessment of physical capacity and exercise tolerance in patients with spinal deformity.

Safety, Pharmacokinetic, and Efficacy Studies of Oral DB868 in a First Stage Vervet Monkey Model of Human African Trypanosomiasis

PubMed Central

Thuita, John K.; Wolf, Kristina K.; Murilla, Grace A.; Liu, Qiang; Mutuku, James N.; Chen, Yao; Bridges, Arlene S.; Mdachi, Raymond E.; Ismail, Mohamed A.; Ching, Shelley; Boykin, David W.; Hall, James Edwin; Tidwell, Richard R.; Paine, Mary F.; Brun, Reto; Wang, Michael Zhuo

2013-01-01

There are no oral drugs for human African trypanosomiasis (HAT, sleeping sickness). A successful oral drug would have the potential to reduce or eliminate the need for patient hospitalization, thus reducing healthcare costs of HAT. The development of oral medications is a key objective of the Consortium for Parasitic Drug Development (CPDD). In this study, we investigated the safety, pharmacokinetics, and efficacy of a new orally administered CPDD diamidine prodrug, 2,5-bis[5-(N-methoxyamidino)-2-pyridyl]furan (DB868; CPD-007-10), in the vervet monkey model of first stage HAT. DB868 was well tolerated at a dose up to 30 mg/kg/day for 10 days, a cumulative dose of 300 mg/kg. Mean plasma levels of biomarkers indicative of liver injury (alanine aminotransferase, aspartate aminotransferase) were not significantly altered by drug administration. In addition, no kidney-mediated alterations in creatinine and urea concentrations were detected. Pharmacokinetic analysis of plasma confirmed that DB868 was orally available and was converted to the active compound DB829 in both uninfected and infected monkeys. Treatment of infected monkeys with DB868 began 7 days post-infection. In the infected monkeys, DB829 attained a median Cmax (dosing regimen) that was 12-fold (3 mg/kg/day for 7 days), 15-fold (10 mg/kg/day for 7 days), and 31-fold (20 mg/kg/day for 5 days) greater than the IC50 (14 nmol/L) against T. b. rhodesiense STIB900. DB868 cured all infected monkeys, even at the lowest dose tested. In conclusion, oral DB868 cured monkeys with first stage HAT at a cumulative dose 14-fold lower than the maximum tolerated dose and should be considered a lead preclinical candidate in efforts to develop a safe, short course (5–7 days), oral regimen for first stage HAT. PMID:23755309

Safety and efficacy of neratinib in combination with weekly paclitaxel and trastuzumab in women with metastatic HER2‑positive breast cancer: an NSABP Foundation Research Program phase I study.

PubMed

Jankowitz, Rachel C; Abraham, Jame; Tan, Antoinette R; Limentani, Steven A; Tierno, Marni B; Adamson, Laura M; Buyse, Marc; Wolmark, Norman; Jacobs, Samuel A

2013-12-01

Neratinib is an oral, small-molecule inhibitor that irreversibly binds to pan-HER (ErbB) receptor tyrosine kinases. Studies suggest that dual anti-HER therapies utilized in breast cancer patients are more efficacious than single agents in both the metastatic and neoadjuvant settings. In this phase I study, neratinib was combined with trastuzumab and paclitaxel in metastatic HER2-positive patients. Twenty-one patients entered this dose-escalation study to determine the maximum-tolerated dose, safety, and efficacy of neratinib (120 up to 240 mg/day) with trastuzumab (4 mg/kg IV loading dose, then 2 mg/kg IV weekly), and paclitaxel (80 mg/m(2) IV days 1, 8, and 15 of a 28-day cycle) in women with HER2-positive metastatic breast cancer previously treated with anti-HER agent(s) and a taxane. The recommended phase II dose of neratinib with trastuzumab and paclitaxel was 200 mg/day. Common grade 3/4 adverse events were diarrhea (38 %), dehydration (14 %), electrolyte imbalance (19 %), and fatigue (19 %). With mandated primary diarrheal prophylaxis, ≥grade 3 diarrhea was not observed. Objective responses, complete (CR) and partial (PR), occurred in eight patients (38 %), with a clinical benefit of CR + PR+ stable disease (SD) ≥24 weeks in 11 patients (52 %). Median time-to-disease progression was 3.7 months. Dual anti-HER blockade with neratinib and trastuzumab resulted in significant clinical benefit despite prior exposure to trastuzumab, lapatinib, T-DM1, a taxane, and multiple lines of chemotherapy. In selected populations, inhibiting multiple ErbB-family receptors may be more advantageous than single-agent inhibition. Based on favorable tolerance and efficacy, this three-drug combination will be further assessed in a randomized phase II neoadjuvant trial (NSABP FB-7:NCT01008150).

Pharmacokinetics and pharmacodynamics of single and multiple doses of the glucagon receptor antagonist LGD-6972 in healthy subjects and subjects with type 2 diabetes mellitus.

PubMed

Vajda, Eric G; Logan, Douglas; Lasseter, Kenneth; Armas, Danielle; Plotkin, Diane J; Pipkin, J D; Li, Yong-Xi; Zhou, Rong; Klein, David; Wei, Xiaoxiong; Dilzer, Stacy; Zhi, Lin; Marschke, Keith B

2017-01-01

To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple doses of a novel, oral glucagon receptor antagonist, LGD-6972, in healthy subjects and subjects with type 2 diabetes (T2DM). In the single ascending dose study, LGD-6972 (2-480 mg) was administered to healthy subjects (n = 48) and T2DM subjects (n = 8). In the multiple ascending dose study, healthy subjects (n = 12) received a dose of 15 mg LGD-6972 and T2DM subjects (n = 36) received doses of 5, 10 or 15 mg of LGD-6972 daily for 14 days. LGD-6972 had linear plasma pharmacokinetics consistent with once-daily dosing that was comparable in healthy and T2DM subjects. Dose-dependent decreases in fasting plasma glucose were observed in all groups with a maximum of 3.15 mmol/L (56.8 mg/dL) on day 14 in T2DM subjects. LGD-6972 also reduced plasma glucose in the postprandial state. Dose-dependent increases in fasting plasma glucagon were observed, but glucagon levels decreased and insulin levels increased after an oral glucose load in T2DM subjects. LGD-6972 was well tolerated at the doses tested without dose-related or clinically meaningful changes in clinical laboratory parameters. No subject experienced hypoglycaemia. Inhibition of glucagon action by LGD-6972 was associated with decreases in glucose in both healthy and T2DM subjects, the magnitude of which was sufficient to predict improvement in glycaemic control with longer treatment duration in T2DM patients. The safety and pharmacological profile of LGD-6972 after 14 days of dosing supports continued clinical development. © 2016 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

A first-in-human phase I study of SAR125844, a selective MET tyrosine kinase inhibitor, in patients with advanced solid tumours with MET amplification.

PubMed

Angevin, Eric; Spitaleri, Gianluca; Rodon, Jordi; Dotti, Katia; Isambert, Nicolas; Salvagni, Stefania; Moreno, Victor; Assadourian, Sylvie; Gomez, Corinne; Harnois, Marzia; Hollebecque, Antoine; Azaro, Analia; Hervieu, Alice; Rihawi, Karim; De Marinis, Filippo

2017-12-01

Dysregulated MET signalling is implicated in oncogenesis. The safety and preliminary efficacy of a highly selective MET kinase inhibitor (SAR125844) was investigated in patients with advanced solid tumours and MET dysregulation. This was a phase I dose-escalation (3 + 3 design [50-740 mg/m 2 ]) and dose-expansion study. In the dose escalation, patients had high total MET (t-MET) expression by immunohistochemistry (IHC) or MET amplification by fluorescence in situ hybridisation. In the dose expansion, patients had MET amplification (including a subset of patients with non-small cell lung cancer [NSCLC]) or phosphorylated-MET (p-MET) expression (IHC). Objectives were determination of maximum tolerated dose (MTD) of once-weekly intravenous SAR125844 based on dose-limiting toxicities; safety and pharmacokinetic profile; preliminary efficacy of SAR125844 MTD in the expansion cohort. In total, 72 patients were enrolled: dose escalation, N = 33; dose expansion, N = 39; 570 mg/m 2 was established as the MTD. Most frequent treatment-emergent adverse events (AEs) were asthenia/fatigue (58.3%), nausea (31.9%), and abdominal pain, constipation, and dyspnea (27.8% for each); 58.3% of patients reported grade 3 AEs (19.4% were treatment related). Of the 29 evaluable patients with MET amplification treated at 570 mg/m 2 , five achieved a partial response, including four of 22 with NSCLC; 17 patients had stable disease. No response was observed in patients with high p-MET solid tumours. There was no correlation between tumour response and t-MET status or MET gene copy number. The MTD of once-weekly SAR125844 was 570 mg/m 2 ; SAR125844 was well tolerated, with significant antitumour activity in patients with MET-amplified NSCLC. NCT01391533. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Multiple Rising Doses of Oral BI 425809, a GlyT1 Inhibitor, in Young and Elderly Healthy Volunteers: A Randomised, Double-Blind, Phase I Study Investigating Safety and Pharmacokinetics.

PubMed

Moschetti, Viktoria; Schlecker, Christina; Wind, Sven; Goetz, Sophia; Schmitt, Holger; Schultz, Armin; Liesenfeld, Karl-Heinz; Wunderlich, Glen; Desch, Michael

2018-05-30

Schizophrenia and Alzheimer's disease are characterised by abnormalities in glutamatergic pathways related to N-methyl-D-aspartate receptor hypofunction. Glycine is an N-methyl-D-aspartate receptor co-agonist; inhibition of glycine transporter 1 may improve N-methyl-D-aspartate receptor function. This phase I, randomised, two-part study evaluated the safety, tolerability and pharmacokinetic profile of BI 425809, a novel glycine transporter 1 inhibitor, in healthy male and female volunteers. Part 1 evaluated BI 425809 10, 25, 50 or 75 mg once daily or 75 mg twice daily in young subjects, and 25 mg or 50 mg once daily in elderly subjects. Each dose group comprised 12 subjects who received BI 425809 (n = 9) or placebo (n = 3) for 14 days (day 1: single dose; days 4-14: multiple dosing). Part 2 compared pharmacokinetic profiles in 12 subjects who received a single dose of BI 425809 25 mg in the morning and evening. Pharmacokinetic profiles were similarly shaped for all dose groups. Median time to maximum plasma concentration was 3.0-4.5 h with steady state being reached between days 6 and 10. Pharmacokinetic parameters demonstrated dose linearity at the predicted therapeutic exposure range of BI 425809 ≤ 25 mg once daily, but increased less than dose proportionally for ≥ 50 mg once daily. All reported adverse events were of mild-to-moderate intensity, 51/84 (61%; part 1) subjects had one or more treatment-related adverse event, no serious adverse events occurred and no dose dependency was observed. Pharmacokinetic properties support both morning and evening dosing. BI 425809 was generally well tolerated at all tested doses. CLINICALTRIALS. NCT02337283.

Safety, Correlative Markers, and Clinical Results of Adjuvant Nivolumab in Combination with Vaccine in Resected High-Risk Metastatic Melanoma

PubMed Central

Gibney, Geoffrey T.; Kudchadkar, Ragini R.; DeConti, Ronald C.; Thebeau, Melissa S.; Czupryn, Maria P.; Tetteh, Leticia; Eysmans, Cabell; Richards, Allison; Schell, Michael J.; Fisher, Kate J.; Horak, Christine E.; Inzunza, H. David; Yu, Bin; Martinez, Alberto J.; Younos, Ibrahim; Weber, Jeffrey S.

2015-01-01

Purpose The anti-programmed death-1 (PD-1) antibody nivolumab (BMS-936558) has clinical activity in patients with metastatic melanoma. Nivolumab plus vaccine was investigated as adjuvant therapy in resected stage IIIC and IV melanoma patients. Experimental Design HLA-A*0201 positive patients with HMB-45, NY-ESO-1, and/or MART-1 positive resected tumors received nivolumab (1 mg/kg, 3 mg/kg, or 10 mg/kg i.v.) with a multi-peptide vaccine (gp100, MART-1, and NY-ESO-1 with Montanide ISA 51 VG) every 2 weeks for 12 doses followed by nivolumab maintenance every 12 weeks for 8 doses. Primary objective was safety and determination of a maximum tolerated dose (MTD). Secondary objectives included relapse-free survival (RFS), overall survival (OS), and immunologic correlative studies. Results Thirty-three patients were enrolled. Median age was 47 years; 55% were male. Two patients had stage IIIC disease; 31 patients had stage IV disease. Median follow-up was 32.1 months. MTD was not reached. Most common related adverse events (>40%) were vaccine injection site reaction, fatigue, rash, pruritus, nausea, and arthralgias. Five related grade 3 adverse events [hypokalemia (1), rash (1), enteritis (1), and colitis (2)] were observed. Ten of 33 patients relapsed. Estimated median RFS was 47.1 months; median OS was not reached. Increases in CTLA-4+/CD4+, CD25+Treg/CD4+, and tetramer specific CD8+ T-cell populations were observed with treatment (P < 0.05). Trends for lower baseline myeloid-derived suppressor cell and CD25+Treg/CD4+ populations were seen in nonrelapsing patients; PD-L1 tumor status was not significantly associated with RFS. Conclusions Nivolumab with vaccine is well tolerated as adjuvant therapy and demonstrates immunologic activity with promising survival in high-risk resected melanoma, justifying further study. PMID:25524312

Safety, correlative markers, and clinical results of adjuvant nivolumab in combination with vaccine in resected high-risk metastatic melanoma.

PubMed

Gibney, Geoffrey T; Kudchadkar, Ragini R; DeConti, Ronald C; Thebeau, Melissa S; Czupryn, Maria P; Tetteh, Leticia; Eysmans, Cabell; Richards, Allison; Schell, Michael J; Fisher, Kate J; Horak, Christine E; Inzunza, H David; Yu, Bin; Martinez, Alberto J; Younos, Ibrahim; Weber, Jeffrey S

2015-02-15

The anti-programmed death-1 (PD-1) antibody nivolumab (BMS-936558) has clinical activity in patients with metastatic melanoma. Nivolumab plus vaccine was investigated as adjuvant therapy in resected stage IIIC and IV melanoma patients. HLA-A*0201 positive patients with HMB-45, NY-ESO-1, and/or MART-1 positive resected tumors received nivolumab (1 mg/kg, 3 mg/kg, or 10 mg/kg i.v.) with a multi-peptide vaccine (gp100, MART-1, and NY-ESO-1 with Montanide ISA 51 VG) every 2 weeks for 12 doses followed by nivolumab maintenance every 12 weeks for 8 doses. Primary objective was safety and determination of a maximum tolerated dose (MTD). Secondary objectives included relapse-free survival (RFS), overall survival (OS), and immunologic correlative studies. Thirty-three patients were enrolled. Median age was 47 years; 55% were male. Two patients had stage IIIC disease; 31 patients had stage IV disease. Median follow-up was 32.1 months. MTD was not reached. Most common related adverse events (>40%) were vaccine injection site reaction, fatigue, rash, pruritus, nausea, and arthralgias. Five related grade 3 adverse events [hypokalemia (1), rash (1), enteritis (1), and colitis (2)] were observed. Ten of 33 patients relapsed. Estimated median RFS was 47.1 months; median OS was not reached. Increases in CTLA-4(+)/CD4(+), CD25(+)Treg/CD4(+), and tetramer specific CD8(+) T-cell populations were observed with treatment (P < 0.05). Trends for lower baseline myeloid-derived suppressor cell and CD25(+)Treg/CD4(+) populations were seen in nonrelapsing patients; PD-L1 tumor status was not significantly associated with RFS. Nivolumab with vaccine is well tolerated as adjuvant therapy and demonstrates immunologic activity with promising survival in high-risk resected melanoma, justifying further study. ©2014 American Association for Cancer Research.

Phase I Study of Inotuzumab Ozogamicin Combined with R-CVP for Relapsed/Refractory CD22+ B-cell Non-Hodgkin Lymphoma.

PubMed

Ogura, Michinori; Tobinai, Kensei; Hatake, Kiyohiko; Davies, Andrew; Crump, Michael; Ananthakrishnan, Revathi; Ishibashi, Taro; Paccagnella, M Luisa; Boni, Joseph; Vandendries, Erik; MacDonald, David

2016-10-01

To evaluate the safety, preliminary efficacy, and pharmacokinetics of inotuzumab ozogamicin, an anti-CD22 antibody conjugated to calicheamicin, in combination with the immunochemotherapeutic regimen, rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP), in patients with relapsed/refractory CD22+ B-cell non-Hodgkin lymphoma (NHL). In part 1 (n = 16), patients received inotuzumab ozogamicin plus R-CVP on a 21-day cycle with escalating doses of cyclophosphamide first then inotuzumab ozogamicin. Part 2 (n = 10) confirmed the safety and tolerability of the maximum tolerated dose (MTD), which required a dose-limiting toxicity rate of <33% in cycle 1 and <33% of patients discontinuing before cycle 3 due to treatment-related adverse events (AEs). Part 3 (n = 22) evaluated the preliminary efficacy of inotuzumab ozogamicin plus R-CVP. The MTD was determined to be standard-dose R-CVP plus inotuzumab ozogamicin 0.8 mg/m 2 The most common treatment-related grade ≥3 AEs in the MTD cohort (n = 38) were hematologic: neutropenia (74%), thrombocytopenia (50%), lymphopenia (42%), and leukopenia (47%). Among the 48 patients treated in the study, 13 discontinued due to AEs, most commonly thrombocytopenia (n = 10). Overall, 13 patients died, including one death due to treatment-related pneumonia secondary to neutropenia. Among patients receiving the MTD (n = 38), the overall response rate (ORR) was 84% (n = 32), including 24% (n = 9) with complete response; the ORR was 100% for patients with indolent lymphoma (n = 27) and 57% for those with aggressive histology lymphoma (n = 21). Inotuzumab ozogamicin at 0.8 mg/m 2 plus full dose R-CVP was associated with manageable toxicities and demonstrated a high rate of response in patients with relapsed/refractory CD22+ B-cell NHL. The study is registered at ClinicalTrials.gov (NCT01055496). Clin Cancer Res; 22(19); 4807-16. ©2016 AACR. ©2016 American Association for Cancer Research.

A phase I dose-escalation study of LY2875358, a bivalent MET antibody, given as monotherapy or in combination with erlotinib or gefitinib in Japanese patients with advanced malignancies.

PubMed

Yoh, Kiyotaka; Doi, Toshihiko; Ohmatsu, Hironobu; Kojima, Takashi; Takahashi, Hideaki; Zenke, Yoshitaka; Wacheck, Volker; Enatsu, Sotaro; Nakamura, Takashi; Turner, Kellie; Uenaka, Kazunori

2016-10-01

Background MET is a tyrosine kinase receptor involved in the regulation of cell proliferation and migration. Reported here are the phase I dose-escalation results for LY2875358, a monoclonal antibody against MET, in Japanese patients with advanced malignancies. Methods The study comprised a 3 + 3 dose-escalation part for LY2875358 monotherapy in patients with advanced malignancies (Part A) followed by an assessment of LY2875358 in combination with erlotinib or gefitinib in patients with non-small cell lung cancer (Part B). LY2875358 was administered once every 2 weeks. The primary objective was to evaluate the safety and tolerability of LY2875358; secondary objectives included evaluation of pharmacokinetics, pharmacodynamics, and antitumor activity. Results Eleven patients received LY2875358 monotherapy at 3 dose levels (700 mg, N = 3; 1400 mg, N = 3; 2000 mg, N = 5) and 6 patients received LY2875358 2000 mg in combination with erlotinib (N = 3) or gefitinib (N = 3). No dose-limiting toxicities or serious adverse events related to LY2875358 were observed. The most frequently reported drug-related adverse events were hypoalbuminemia (2 patients) in Part A and dermatitis acneiform (4 patients) in Part B. LY2875358 area under the curve (AUC) and maximum concentration (Cmax) increased with dose over the dose range of 700 mg to 2000 mg. A best response of stable disease was achieved by 2/11 patients in Part A and 4/6 patients in Part B (disease control rate: 35 %). Conclusions LY2875358 at doses up to 2000 mg demonstrated a favorable safety and tolerability profile as monotherapy or in combination with erlotinib or gefitinib in Japanese patients with advanced malignancies.

Phase I study of nanoparticle albumin-bound paclitaxel, carboplatin and trastuzumab in women with human epidermal growth factor receptor 2-overexpressing breast cancer

PubMed Central

Tezuka, Kenji; Takashima, Tsutomu; Kashiwagi, Shinichiro; Kawajiri, Hidemi; Tokunaga, Shinya; Tei, Seika; Nishimura, Shigehiko; Yamagata, Shigehito; Noda, Satoru; Nishimori, Takeo; Mizuyama, Yoko; Sunami, Takeshi; Ikeda, Katsumi; Ogawa, Yoshinari; Onoda, Naoyoshi; Ishikawa, Tetsuro; Kudoh, Shinzoh; Takada, Minoru; Hirakawa, Kosei

2017-01-01

Although the concurrent use of anthracycline-containing chemotherapy and taxane with trastuzumab are considered the treatment of choice for the primary systemic therapy of human epidermal growth factor receptor 2 (HER2)-overexpressing early breast cancer, non-anthracycline regimens, such as concurrent administration of docetaxel and carboplatin with trastuzumab, exhibited similar efficacies in a previous study. In addition, tri-weekly treatment with nanoparticle albumin-bound paclitaxel (nab-paclitaxel) resulted in significantly higher response rates and a favorable safety profile compared with standard paclitaxel for metastatic breast cancer patients in another phase III study. Based on these results, a phase I study of combination therapy with nab-paclitaxel, carboplatin and trastuzumab was planned, in order to estimate its efficacy and safety for HER2-overexpressing locally advanced breast cancer. The present study was designed to determine the dose-limiting toxicity (DLT), maximum tolerated dose and recommended dose of this combination treatment in women with HER2-overexpressing locally advanced breast cancer. The starting dose of nab-paclitaxel was 220 mg/m2 (level 1), and the dose was escalated to 260 mg/m2 (level 2). Nab-paclitaxel was administered with carboplatin (area under the curve, 6 mg/ml/min) and trastuzumab tri-weekly. A total of 6 patients were enrolled. Although no DLT was observed during the first cycle, 4 patients developed grade 4 thrombocytopenia, 2 had grade 4 neutropenia and 3 exhibited a grade 4 decrease in hemoglobin levels. In the present phase I study, although no patients experienced DLTs, this regimen was associated with severe hematological toxicities and it was not well tolerated. However, considering the high efficacy and lower risk of cardiotoxicity and secondary carcinogenesis with taxane, platinum and trastuzumab combination therapy, further evaluation of another regimen including weekly administration or a more accurate dose setting should be conducted. PMID:28413662

Survival of the probiotic Escherichia coli Nissle 1917 (EcN) in the gastrointestinal tract given in combination with oral mesalamine to healthy volunteers.

PubMed

Joeres-Nguyen-Xuan, Thai Hoa; Boehm, Stephan Karl; Joeres, Lars; Schulze, Juergen; Kruis, Wolfgang

2010-02-01

Mesalamine and the probiotic E. coli Nissle 1917 (EcN) are both effective agents for the treatment of ulcerative colitis. A combined therapy may have more than additive efficacy. However, mesalamine may have antimicrobial effects on EcN. In this prospective, randomized, double-blind, placebo-controlled study, 48 healthy volunteers took EcN in a run-in phase for 17 days (5-50 x 10(9) viable bacteria od). If stool samples became positive for EcN, volunteers received combination treatment with EcN plus either mesalamine (1500 mg twice a day) or placebo for 1 week. Fecal samples were further tested for EcN in 2- to 3-day intervals until a maximum of 48 weeks after treatment. Patient diaries, blood, and urine were checked to assess safety, compliance, and tolerance. During run-in, viable EcN were detected in 45 of the 48 volunteers (94%); 2 volunteers were positive before taking EcN. From days 1 to 7 of combination treatment (n = 40), the number of EcN-positive volunteers varied between 70% and 80% in the mesalamine group and between 85% and 95% in the placebo group. Differences between the groups were not significant (normal approximation: day 3, P > 0.15; day 5, P > 0.25; day 7, P > 0.076). At treatment discontinuation, 16 of 20 volunteers in the mesalamine group and 15 of 20 volunteers in the placebo group were EcN positive, whereas this figure dropped continuously up to week 12 after discontinuation (mesalamine, 7 of 20; placebo, 4 of 20). No differences between the groups were seen with regard to tolerance and safety. The combination of EcN and mesalamine has no significant effect on the survival of EcN in healthy volunteers.

First-in-Human Study of PF-05212384 (PKI-587), a Small-Molecule, Intravenous, Dual Inhibitor of PI3K and mTOR in Patients with Advanced Cancer.

PubMed

Shapiro, Geoffrey I; Bell-McGuinn, Katherine M; Molina, Julian R; Bendell, Johanna; Spicer, James; Kwak, Eunice L; Pandya, Susan S; Millham, Robert; Borzillo, Gary; Pierce, Kristen J; Han, Lixin; Houk, Brett E; Gallo, Jorge D; Alsina, Maria; Braña, Irene; Tabernero, Josep

2015-04-15

To evaluate safety (primary endpoint), tolerability, pharmacokinetics, pharmacodynamic profile, and preliminary activity of the intravenous, pan-class I isoform PI3K/mTOR inhibitor PF-05212384 in patients with advanced solid tumors. Part 1 of this open-label phase I study was designed to estimate the maximum-tolerated dose (MTD) in patients with nonselected solid tumors, using a modified continual reassessment method to guide dose escalation. Objectives of part 2 were MTD confirmation and assessment of preliminary activity in patients with selected tumor types and PI3K pathway dysregulation. Seventy-seven of the 78 enrolled patients received treatment. The MTD for PF-05212384, administered intravenously once weekly, was estimated to be 154 mg. The most common treatment-related adverse events (AE) were mucosal inflammation/stomatitis (58.4%), nausea (42.9%), hyperglycemia (26%), decreased appetite (24.7%), fatigue (24.7%), and vomiting (24.7%). The majority of patients treated at the MTD experienced only grade 1 treatment-related AEs. Grade 3 treatment-related AEs occurred in 23.8% of patients at the MTD. No treatment-related grade 4-5 AEs were reported at any dose level. Antitumor activity was noted in this heavily pretreated patient population, with two partial responses (PR) and an unconfirmed PR. Eight patients had long-lasting stable disease (>6 months). Pharmacokinetic analyses showed a biphasic concentration-time profile for PF-05212384 (half-life, 30-37 hours after multiple dosing). PF-05212384 inhibited downstream effectors of the PI3K pathway in paired tumor biopsies. These findings demonstrate the manageable safety profile and antitumor activity of the PI3K/mTOR inhibitor PF-05212384, supporting further clinical development for patients with advanced solid malignancies. ©2015 American Association for Cancer Research.

Phase 1 study of inotuzumab ozogamicin combined with R-GDP for the treatment of patients with relapsed/refractory CD22+ B-cell non-Hodgkin lymphoma.

PubMed

Sangha, Randeep; Davies, Andrew; Dang, Nam H; Ogura, Michinori; MacDonald, David A; Ananthakrishnan, Revathi; Paccagnella, M Luisa; Vandendries, Erik; Boni, Joseph; Goh, Yeow Tee

2017-01-01

Objective : To evaluate safety, tolerability, and preliminary activity of inotuzumab ozogamicin (InO) plus rituximab, gemcitabine, dexamethasone, and cisplatin (R-GDP) in patients with relapsed/refractory CD22+ B-cell non-Hodgkin lymphoma (NHL). Methods : Patients received InO plus R-GDP (21-day cycle; six-cycle maximum) using up-and-down dose-escalation schema for gemcitabine and cisplatin to define the highest dosage regimen(s) with acceptable toxicity (Part 1; n  = 27). Part 2 ( n  = 10) confirmed safety and tolerability; Part 3 ( n  = 18) evaluated preliminary efficacy. Results: Among 55 patients enrolled, 42% were refractory at baseline (median 2 [range, 1-6] prior therapies); 38% had diffuse large B-cell lymphoma (DLBCL). The highest dosage regimen with acceptable toxicity was InO 0.8 mg/m 2 , rituximab 375 mg/m 2 , cisplatin 50 mg/m 2 , gemcitabine 500 mg/m 2 (day 1 only) and dexamethasone 40 mg (days 1-4); this was confirmed in Part 2, in which three patients had dose-limiting toxicities (grade 4 thrombocytopenia [ n  = 2], febrile neutropenia [ n  = 2]). Most frequent treatment-related adverse events were thrombocytopenia (any grade, 85%; grade ≥3, 75%) and neutropenia (69%; 62%). Overall (objective) response rate (ORR) was 53% (11 complete, 18 partial responses); ORR was 71%, 33%, and 62% in patients with follicular lymphoma ( n  = 14), DLBCL ( n  = 21), and mantle cell lymphoma ( n  = 13), respectively. Conclusions: InO 0.8 mg/m 2 plus R-GDP was associated with manageable toxicity, although gemcitabine and cisplatin doses were lower than in the standard R-GDP regimen due to hematologic toxicity. Evidence of antitumor activity was observed; however, these exploratory data should be interpreted with caution due to the small sample size and short follow-up duration (Clinicaltrials.gov number: NCT01055496).

Phase 1 dose-escalation study of mirvetuximab soravtansine (IMGN853), a folate receptor α-targeting antibody-drug conjugate, in patients with solid tumors.

PubMed

Moore, Kathleen N; Borghaei, Hossein; O'Malley, David M; Jeong, Woondong; Seward, Shelly M; Bauer, Todd M; Perez, Raymond P; Matulonis, Ursula A; Running, Kelli L; Zhang, Xiaoyan; Ponte, Jose F; Ruiz-Soto, Rodrigo; Birrer, Michael J

2017-08-15

Mirvetuximab soravtansine (IMGN853) is an antibody-drug conjugate that selectively targets folate receptor α (FRα). In this phase 1 dose-escalation study, the authors investigated IMGN853 in patients with FRα-positive solid tumors. Patients received IMGN853 on day 1 of a 21-day cycle (once every 3 weeks dosing), with cycles repeated until patients experienced dose-limiting toxicity or progression. Dose escalation commenced in single-patient cohorts for the first 4 planned dose levels and then followed a standard 3 + 3 scheme. The primary objectives were to determine the maximum tolerated dose and the recommended phase 2 dose. Secondary objectives were to determine safety and tolerability, to characterize the pharmacokinetic profile, and to describe preliminary clinical activity. In total, 44 patients received treatment at doses escalating from 0.15 to 7.0 mg/kg. No meaningful drug accumulation was observed with the dosing regimen of once every 3 weeks. The most common treatment-related adverse events were fatigue, blurred vision, and diarrhea, the majority of which were grade 1 or 2. The dose-limiting toxicities observed were grade 3 hypophosphatemia (5.0 mg/kg) and grade 3 punctate keratitis (7.0 mg/kg). Two patients, both of whom were individuals with epithelial ovarian cancer, achieved confirmed tumor responses according to Response Evaluation Criteria in Solid Tumors 1.1, and each was a partial response. IMGN853 demonstrated a manageable safety profile and encouraging preliminary clinical activity, particularly in patients with ovarian cancer. The results establish a recommended phase 2 dosing of 6.0 mg/kg (based on adjusted ideal body weight) once every 3 weeks. Cancer 2017. © 2017 American Cancer Society. Cancer 2017;123:3080-7. © 2017 American Cancer Society. © 2017 American Cancer Society.

Drug-Drug Interaction between the Direct-Acting Antiviral Regimen of Ombitasvir-Paritaprevir-Ritonavir plus Dasabuvir and the HIV Antiretroviral Agent Dolutegravir or Abacavir plus Lamivudine.

PubMed

Khatri, Amit; Trinh, Roger; Zhao, Weihan; Podsadecki, Thomas; Menon, Rajeev

2016-10-01

The direct-acting antiviral regimen of 25 mg ombitasvir-150 mg paritaprevir-100 mg ritonavir once daily (QD) plus 250 mg dasabuvir twice daily (BID) is approved for the treatment of hepatitis C virus genotype 1 infection, including patients coinfected with human immunodeficiency virus. This study was performed to evaluate the pharmacokinetic, safety, and tolerability effects of coadministering the regimen of 3 direct-acting antivirals with two antiretroviral therapies (dolutegravir or abacavir plus lamivudine). Healthy volunteers (n = 24) enrolled in this phase I, single-center, open-label, multiple-dose study received 50 mg dolutegravir QD for 7 days or 300 mg abacavir plus 300 mg lamivudine QD for 4 days, the 3-direct-acting-antiviral regimen for 14 days, followed by the 3-direct-acting-antiviral regimen with dolutegravir or abacavir plus lamivudine for 10 days. Pharmacokinetic parameters were calculated to compare combination therapy with 3-direct-acting-antiviral or antiretroviral therapy alone, and safety/tolerability were assessed throughout the study. Coadministration of the 3-direct-acting-antiviral regimen increased the geometric mean maximum plasma concentration (Cmax) and the area under the curve (AUC) of dolutegravir by 22% (central value ratio [90% confidence intervals], 1.219 [1.153, 1.288]) and 38% (1.380 [1.295, 1.469]), respectively. Abacavir geometric mean Cmax and AUC values decreased by 13% (0.873 [0.777, 0.979]) and 6% (0.943 [0.901, 0.986]), while those for lamivudine decreased by 22% (0.778 [0.719, 0.842]) and 12% (0.876 [0.821, 0.934]). For the 3-direct-acting-antiviral regimen, geometric mean Cmax and AUC during coadministration were within 18% of measurements made during administration of the 3-direct-acting-antiviral regimen alone, although trough concentrations for paritaprevir were 34% (0.664 [0.585, 0.754]) and 27% (0.729 [0.627, 0.847]) lower with dolutegravir and abacavir-lamivudine, respectively. All study treatments were generally well tolerated, with no evidence of increased rates of adverse events during combination administration. These data indicate that the 3-direct-acting-antiviral regimen can be administered with dolutegravir or abacavir plus lamivudine without dose adjustment. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Food safety objective approach for controlling Clostridium botulinum growth and toxin production in commercially sterile foods.

PubMed

Anderson, N M; Larkin, J W; Cole, M B; Skinner, G E; Whiting, R C; Gorris, L G M; Rodriguez, A; Buchanan, R; Stewart, C M; Hanlin, J H; Keener, L; Hall, P A

2011-11-01

As existing technologies are refined and novel microbial inactivation technologies are developed, there is a growing need for a metric that can be used to judge equivalent levels of hazard control stringency to ensure food safety of commercially sterile foods. A food safety objective (FSO) is an output-oriented metric that designates the maximum level of a hazard (e.g., the pathogenic microorganism or toxin) tolerated in a food at the end of the food supply chain at the moment of consumption without specifying by which measures the hazard level is controlled. Using a risk-based approach, when the total outcome of controlling initial levels (H(0)), reducing levels (ΣR), and preventing an increase in levels (ΣI) is less than or equal to the target FSO, the product is considered safe. A cross-disciplinary international consortium of specialists from industry, academia, and government was organized with the objective of developing a document to illustrate the FSO approach for controlling Clostridium botulinum toxin in commercially sterile foods. This article outlines the general principles of an FSO risk management framework for controlling C. botulinum growth and toxin production in commercially sterile foods. Topics include historical approaches to establishing commercial sterility; a perspective on the establishment of an appropriate target FSO; a discussion of control of initial levels, reduction of levels, and prevention of an increase in levels of the hazard; and deterministic and stochastic examples that illustrate the impact that various control measure combinations have on the safety of well-established commercially sterile products and the ways in which variability all levels of control can heavily influence estimates in the FSO risk management framework. This risk-based framework should encourage development of innovative technologies that result in microbial safety levels equivalent to those achieved with traditional processing methods.

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.

Safety of Repeated-Dose Intratympanic Injections with AM-101 in Acute Inner Ear Tinnitus.

PubMed

Staecker, Hinrich; Morelock, Michael; Kramer, Timothy; Chrbolka, Pavel; Ahn, Joong Ho; Meyer, Thomas

2017-09-01

Objective To evaluate the safety and tolerability of repeated intratympanic administration of the gel-formulated NMDA receptor antagonist AM-101 in acute patients with inner ear tinnitus. Study Design Prospective, double-blind, randomized, placebo-controlled study. Setting Sixty-nine secondary and tertiary sites in North America, Europe, and Asia. Subjects and Methods In total, 343 subjects with persistent acute tinnitus after traumatic cochlear injury or otitis media were randomized to receive 3 intratympanic doses of either AM-101 0.87 mg/mL or placebo over 3 to 5 days. They were followed for 84 days. The primary safety end point was the incidence of a clinically meaningful hearing deterioration from baseline to study day 35. Further safety assessments included tympanic membrane closure rates, analysis of adverse events, hematology, blood chemistry, and vital signs. In addition, data were collected on applied anesthetics and injection techniques. Results The treatment was well tolerated, with no intervention-related serious adverse events. The incidence of clinically meaningful hearing deterioration was low, comparable between treatment groups ( P = .82 for the primary safety end point) and not different between treated and untreated ears in unilaterally treated subjects. The rate of treatment and procedure-related adverse events was similar among treatment groups. The tympanic membrane was closed in 92% of subjects within 1 week and in all subjects by study day 84. Blood values and vital signs were inconspicuous. Conclusion Repeated intratympanic injections of AM-101 over a 3- to 5-day period appear to be safe and well tolerated, demonstrating the ability to potentially use this delivery approach over longer time periods.

Safety and patient outcomes with lubiprostone for up to 52 weeks in patients with irritable bowel syndrome with constipation.

PubMed

Chey, W D; Drossman, D A; Johanson, J F; Scott, C; Panas, R M; Ueno, R

2012-03-01

Irritable bowel syndrome with constipation (IBS-C) significantly decreases quality of life and the ability to perform daily living activities. To demonstrate the long-term safety, tolerability and patient outcomes of lubiprostone in patients with IBS-C. This extension study enrolled 522 IBS-C patients who had completed one of two randomised phase 3 studies. All enrolled patients received open-label lubiprostone orally for 36-weeks (8 mcg, twice daily). The primary objective was the assessment of long-term safety and tolerability, monitored via adverse events (AEs), laboratory parameters and vital signs. Additional outcome endpoints included monthly responder rates and patient evaluations of IBS-C symptom severity and impact on quality of life. The evaluable safety population comprised of 520 patients; 476 of which had patient reported outcome data available. The overall safety profile of lubiprostone during this study was similar to that observed in the preceding phase 3 studies. The most common AEs were diarrhoea (11.0%), nausea (11.0%), urinary tract infection (9.0%), sinusitis (9.0%) and abdominal distention (5.8%). Diarrhoea and nausea were the most common treatment-related AEs. No serious AEs were considered treatment-related. Seventeen patients discontinued due to a treatment-related AE, of which diarrhoea and nausea accounted for six (1.2%) and three (0.6%) respectively. For responder rates and patient-evaluated parameters (n = 476), all groups experienced significant improvements from baseline, with initial improvements maintained throughout the study. In patients with irritable bowel syndrome with constipation, lubiprostone 8 mcg twice daily was found to be safe and well tolerated over 9-13 months of treatment. © 2012 Blackwell Publishing Ltd.

Facial nerve stimulation in normal pigs and healthy human volunteers: transitional development of a medical device for the emergency treatment of ischemic stroke.

PubMed

Sanchez, Olivia; García, Andrea; Castro-Prado, Fernando; Perez, Miriam; Lara-Estrada, Rafael; Ramirez-Meza, Martin; Godinez, Montserrat; Coco, Michael L; Azpiroz, Joaquín; Borsody, Mark K; Sacristán, Emilio

2018-02-15

Magnetic stimulation of the facial nerve has been tested in preclinical studies as a new, non-invasive emergency treatment of ischemic stroke that acts by increasing cerebral blood flow (CBF). The objective of the studies reported herein was to identify minimal stimulation parameters that increase CBF in large animals and then test those stimulation parameters in healthy volunteers for safety, tolerability, and effectiveness at increasing CBF. This translational research is necessary preparation for clinical studies in ischemic stroke patients. Initial experiments in anesthetized Yorkshire pigs were undertaken in order to identify the lowest stimulus power and duration that increase CBF. A full 3 × 3 factorial design was used to evaluate magnetic stimulation of the facial nerve at various stimulation powers (1.3, 1.6, and 1.9 Tesla field strength at coil surface) and for various durations (2, 3.5, and 5 min). CBF was measured with contrast MRI perfusion imaging and the internal carotid arteries were assessed with MR angiography. Magnetic facial nerve stimulation with parameters identified in the pig study was then applied to 35 healthy volunteers. Safety was assessed with adverse event reports and by medical examination. Tolerability was defined as each volunteer's ability to withstand at least 2 min of stimulation. Volunteers could determine the maximum power of stimulation they received during a ramp-up period. In pigs, unilateral facial nerve stimulation increased CBF by as much as 77% over pre-stimulation baseline when administered across a range of 1.3-1.9 Tesla power and for 2- to 5-min duration. No clear dose-response relationship could be observed across this range, but lower powers and durations than these were markedly less effective. The effect of a single stimulation lasted 90 min. A second stimulation delivered 100 min after the first stimulation sustained the increased CBF without evidence of tachyphylaxis. In human, bilateral facial nerve stimulation caused only non-serious adverse events that were limited to the 2-min stimulation period. Tolerability was greatly improved by gentle encouragement from the study staff, which enabled most volunteers to tolerate 1.6-1.8 Tesla of stimulation power. CBF measures taken approximately 10 min after stimulation demonstrated on average a 32 ± 6% increase in CBF, with ≥ 25% increases in CBF occurring in 10 of the 31 volunteers who had adequate CBF measurements. The minimal effective stimulation parameters defined by increased CBF, as identified in the pig study, translated into safe, tolerable, and effective stimulation of healthy volunteers. These results support the future development and evaluation of non-invasive facial nerve stimulation for the emergency treatment of ischemic stroke. Trial Registration retrospectively registered with clinicaltrials.gov NRV_P1_01_15 on June 6, 2017.

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 share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

30 CFR 56.19062 - Maximum acceleration and deceleration.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Maximum acceleration and deceleration. 56.19062 Section 56.19062 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND... Hoisting Hoisting Procedures § 56.19062 Maximum acceleration and deceleration. Maximum normal operating...

30 CFR 57.19062 - Maximum acceleration and deceleration.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Maximum acceleration and deceleration. 57.19062 Section 57.19062 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND... Hoisting Hoisting Procedures § 57.19062 Maximum acceleration and deceleration. Maximum normal operating...

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.

An update of safety of clinically used atypical antipsychotics.

PubMed

Orsolini, L; Tomasetti, C; Valchera, A; Vecchiotti, R; Matarazzo, I; Vellante, F; Iasevoli, F; Buonaguro, E F; Fornaro, M; Fiengo, A L C; Martinotti, G; Mazza, M; Perna, G; Carano, A; De Bartolomeis, A; Di Giannantonio, M; De Berardis, D

2016-10-01

The atypical antipsychotic (APs) drugs have become the most widely used agents to treat a variety of psychoses because of their superiority with regard to safety and tolerability profile compared to conventional/'typical' APs. We aimed at providing a synthesis of most current evidence about the safety and tolerability profile of the most clinically used atypical APs so far marketed. Qualitative synthesis followed an electronic search made inquiring of the following databases: MEDLINE, Embase, PsycINFO and the Cochrane Library from inception until January 2016, combining free terms and MESH headings for the topics of psychiatric disorders and all atypical APs as following: ((safety OR adverse events OR side effects) AND (aripiprazole OR asenapine OR quetiapine OR olanzapine OR risperidone OR paliperidone OR ziprasidone OR lurasidone OR clozapine OR amisulpride OR iloperidone)). A critical issue in the treatment with atypical APs is represented by their metabolic side effect profile (e.g. weight gain, lipid and glycaemic imbalance, risk of diabetes mellitus and diabetic ketoacidosis) which may limit their use in particular clinical samples. Electrolyte imbalance, ECG abnormalities and cardiovascular adverse effects may recommend a careful baseline and periodic assessments.

Power Goals for NASA's Exploration Program

NASA Technical Reports Server (NTRS)

Jeevarajan, Judith A.

2009-01-01

Exciting Future Programs ahead for NASA. Power is needed for all Exploration vehicles and for the missions. For long term missions as in Lunar and Mars programs, safe, high energy/ultra high energy batteries are required. Safety is top priority for human-rated missions. Two-fault tolerance to catastrophic failures is required for human-rated safety To meet power safety goals -inherent cell safety may be required; it can lessen complexity of external protective electronics and prevents dependency on hardware that may also have limitations. Inherent cell safety will eliminate the need to carry out screening of all cells (X-rays, vibration, etc.)

Long-term Safety and Efficacy of Tapentadol Extended Release Following up to 2 Years of Treatment in Patients With Moderate to Severe, Chronic Pain: Results of an Open-label Extension Trial.

PubMed

Buynak, Robert; Rappaport, Stephen A; Rod, Kevin; Arsenault, Pierre; Heisig, Fabian; Rauschkolb, Christine; Etropolski, Mila

2015-11-01

Tapentadol extended release (ER) has demonstrated efficacy and safety for the management of moderate to severe, chronic pain in adults. This study evaluated the long-term safety and tolerability of tapentadol ER in patients with chronic osteoarthritis or low back pain. Patients were enrolled in this 1-year, open-label extension study after completing one of two 15-week, placebo-controlled studies of tapentadol ER and oxycodone controlled release (CR) for osteoarthritis knee pain (NCT00421928) or low back pain (NCT00449176), a 7-week crossover study between tapentadol immediate release and tapentadol ER for low back pain (NCT00594516), or a 1-year safety study of tapentadol ER and oxycodone CR for osteoarthritis or low back pain (NCT00361504). After titrating the drug to an optimal dose, patients received tapentadol ER (100-250 mg BID) for up to 1 year (after finishing treatment in the preceding studies); patients who were previously treated with tapentadol ER in the 1-year safety study received tapentadol ER continuously for up to 2 years in total. Of the 1,154 patients in the safety population, 82.7% were aged >65 years and 57.9% were female; 50.1% had mild baseline pain intensity. Mean (SD) pain intensity scores (11-point numerical rating scale) were 3.9 (2.38) at baseline (end of preceding study) and 3.7 (2.42) at end point, indicating that pain relief was maintained during the extension study. Improvements in measures of quality of life (eg, EuroQol-5 Dimension and the 36-item Short Form Health Survey [SF-36]) health status questionnaires) achieved during the preceding studies were maintained during the open-label extension study. Tapentadol ER was associated with a safety and tolerability profile comparable to that observed in the preceding studies. The most common treatment-emergent adverse events (incidence ≥10%; n = 1154) were headache (13.1%), nausea (11.8%), and constipation (11.1%). Similar efficacy and tolerability results were shown for patients who received up to 2 years of tapentadol ER treatment. Pain relief and improvements in quality of life achieved during the preceding studies were maintained throughout this extension study, during which tapentadol ER was well tolerated for the long-term treatment of chronic osteoarthritis or low back pain over up to 2 years of treatment. (ClinicalTrials.gov identifier: NCT00487435.). Copyright © 2015. Published by Elsevier Inc.

An open-label, two-period comparative study on pharmacokinetics and safety of a combined ethinylestradiol/gestodene transdermal contraceptive patch.

PubMed

Zhang, Chao; Li, Haiyan; Xiong, Xin; Zhai, Suodi; Wei, Yudong; Zhang, Shuang; Zhang, Yuanyuan; Xu, Lin; Liu, Li

2017-01-01

We investigated the pharmacokinetics and safety profiles of a newly developed combined ethinylestradiol (EE)/gestodene (GSD) transdermal contraceptive patch after a single-dose administration and compared with the market available tablet formulation in healthy adult subjects. An open-label, two-period comparative study was conducted in 12 healthy women volunteers. A single dose of the study combined EE/GE transdermal contraceptive patch and oral tablet (Milunet ® ) were administered. Blood samples at different time points after dose were collected, and concentrations were analyzed. A reliable, highly sensitive and accurate high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC/MS/MS) assay method was developed in this study to determine the plasma concentrations of EE and GSD. Compared to the tablet, the study patch had a significantly decreased maximum plasma concentration ( C max ), extended time to reach the C max and half-life, as well as increased clearance and apparent volume of distribution. The half-lives of EE and GSD of the patch were 3.3 and 2.2 times, respectively, than the half-life of the tablet. The areas under the plasma concentration-time curve (AUCs) of EE and GSD of the patch were 8.0 and 16.2 times, respectively, than the AUC of the tablet. No severe adverse event was observed during the whole study, and the general safety was acceptable. In conclusion, compared to the oral tablet Milunet, the study contraceptive patch was well tolerated and showed potent drug exposure, significant extended half-life and stable drug concentrations.

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.

Cardiovascular benefits and safety profile of acarbose therapy in prediabetes and established type 2 diabetes

PubMed Central

Hanefeld, Markolf

2007-01-01

Dysglycaemic disease is one of the most important health issues facing the world in the 21st century. Patients with type 2 diabetes and individuals with prediabetes are at risk of developing macrovascular and microvascular complications. Long-term management strategies are therefore required that are effective at controlling dysglycaemia, well tolerated and, ideally, offer additional cardiovascular disease (CVD) risk-reduction benefits. The efficacy, safety and tolerability of the α-glucosidase inhibitor acarbose have been well-established in a wide range of patient populations in both clinical and community trials. In addition, acarbose has been shown to reduce cardiovascular complications in type 2 diabetes and prevent hypertension and CVD in individuals with impaired glucose tolerance (IGT). Acarbose has a very good safety profile and, owing to its straightforward, non-systemic mode of action, avoids most adverse events. The most common side-effects of acarbose are mild-to-moderate gastrointestinal complaints that subside as treatment continues. They can be minimised through the use of an appropriate stepwise dosing regimen and careful choice of diet. Acarbose is therefore a valuable option for the management of type 2 diabetes and, as the only oral antidiabetes agent approved for the treatment of prediabetes, can help to improve clinical management across the dysglycaemic disease continuum. PMID:17697384

Safety of Oral Tenofovir Disoproxil Fumarate-Based Pre-Exposure Prophylaxis for HIV Prevention

PubMed Central

Mugwanya, Kenneth K.; Baeten, Jared M.

2016-01-01

Introduction Tenofovir disoproxil fumarate (TDF)-based pre-exposure prophylaxis is a novel HIV prevention strategy for individuals at increased sexual risk for HIV infection. For any biomedical prevention intervention, the bar for tolerating adverse effects in healthy persons is high compared to therapeutic interventions. Areas covered We provide a concise summary of the clinical safety of TDF-based pre-exposure prophylaxis with focus on TDF-related effects on tolerability and side effects, kidney function, bone density, HIV resistance, sexual and reproductive health. The evidence base for this review is derived from a literature search of both randomized and observational studies evaluating efficacy and safety of TDF-based PrEP, TDF alone or in combination with emtricitabine, identified from PUBMED and EMBASE electronic databases, clinicaltrials.gov and major HIV conferences. Expert opinion TDF-based pre-exposure prophylaxis is a potent intervention against HIV acquisition when taken which is generally safe and well tolerated. The risk of the small, non-progressive, and reversible decline in glomerular filtration rate and bone mineral density as well as the potential selection for drug resistance associated with PrEP are outweighed, at the population level and broadly for individuals, by PrEP’s substantial reduction in the risk of HIV infection. PMID:26634852

Use of asenapine as add-on therapy in the treatment of bipolar disorder: a comprehensive review and case series.

PubMed

Dell'Osso, Bernardo; Cremaschi, Laura; Palazzo, Maria Carlotta; Spagnolin, Gregorio; Cattaneo, Alma; Grancini, Benedetta; Maggi, Matteo; Altamura, Alfredo Carlo

2014-09-01

Several randomized controlled trials (RCTs), conducted in schizophrenic and bipolar patients, have documented the efficacy and tolerability of asenapine as monotherapy both for short- and long-term treatment. However, evidence on its augmentative use is more limited and related to the manic/mixed phase of bipolar disorder (BD). The present article reviews augmentative asenapine efficacy and safety/tolerability in the treatment of BD. It also includes some original cases of bipolar patients treated with add-on asenapine in the short- and long-term. To date, only a single RCT with manic/mixed patients with partial response to mood-stabilizer monotherapy supports the efficacy and safety/tolerability of augmentative asenapine to lithium/valproate, both in acute and long-term treatment. Additionally, two case reports confirm the overall effectiveness of augmentative asenapine to clozapine and valproate. Our case series, consisting of 4 bipolar patients treated with adjunctive asenapine to mood stabilizers and atypical antipsychotics - with treatment duration ranging from 1 to 14 months - provided clinical results that are consistent with literature data. Taken as a whole, available evidence seems to support the efficacy and safety of adjunctive asenapine in bipolar patients, though additional studies with active comparators are requested to confirm the current body of evidence.

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.

Some considerations on the safety evaluation of nonviral microbial pesticides

PubMed Central

Shadduck, J. A.

1983-01-01

The tactics and rationale of maximum challenge safety tests for nonviral microbial pesticides have been reviewed. Maximum challenge tests and a tier approach to data collection for regulatory purposes offer the best opportunities to detect the acute effects of entomopathogenic organisms in mammals. Premature condemnation of promising organisms that are based on incomplete results of maximum challenge tests must be avoided. Further investigations should be conducted on the role of mammalian immune response in resistance to entomopathogenic organisms and on the value of medium- or long-term exposure tests. PMID:6601535

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.

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.

The Effects of Metabolic Work Rate and Ambient Environment on Physiological Tolerance Times While Wearing Explosive and Chemical Personal Protective Equipment

PubMed Central

Costello, Joseph T.; Stewart, Kelly L.; Stewart, Ian B.

2015-01-01

This study evaluated the physiological tolerance times when wearing explosive and chemical (>35 kg) personal protective equipment (PPE) in simulated environmental extremes across a range of differing work intensities. Twelve healthy males undertook nine trials which involved walking on a treadmill at 2.5, 4, and 5.5 km·h−1 in the following environmental conditions, 21, 30, and 37°C wet bulb globe temperature (WBGT). Participants exercised for 60 min or until volitional fatigue, core temperature reached 39°C, or heart rate exceeded 90% of maximum. Tolerance time, core temperature, skin temperature, mean body temperature, heart rate, and body mass loss were measured. Exercise time was reduced in the higher WBGT environments (WBGT37 < WBGT30 < WBGT21; P < 0.05) and work intensities (5.5 < 4 < 2.5 km·h−1; P < 0.001). The majority of trials (85/108; 78.7%) were terminated due to participant's heart rate exceeding 90% of their maximum. A total of eight trials (7.4%) lasted the full duration. Only nine (8.3%) trials were terminated due to volitional fatigue and six (5.6%) due to core temperatures in excess of 39°C. These results demonstrate that physiological tolerance times are influenced by the external environment and workload and that cardiovascular strain is the limiting factor to work tolerance when wearing this heavy multilayered PPE. PMID:25866818

A phase I study with neratinib (HKI-272), an irreversible pan ErbB receptor tyrosine kinase inhibitor, in patients with solid tumors.

PubMed

Wong, Kwok-K; Fracasso, Paula M; Bukowski, Ronald M; Lynch, Thomas J; Munster, Pamela N; Shapiro, Geoffrey I; Jänne, Pasi A; Eder, Joseph P; Naughton, Michael J; Ellis, Matthew J; Jones, Suzanne F; Mekhail, Tarek; Zacharchuk, Charles; Vermette, Jennifer; Abbas, Richat; Quinn, Susan; Powell, Christine; Burris, Howard A

2009-04-01

The dose-limiting toxicities, maximum tolerated dose, pharmacokinetic profile, and preliminary antitumor activity of neratinib (HKI-272), an irreversible pan ErbB inhibitor, were determined in patients with advanced solid tumors. Neratinib was administered orally as a single dose, followed by a 1-week observation period, and then once daily continuously. Planned dose escalation was 40, 80, 120, 180, 240, 320, 400, and 500 mg. For pharmacokinetic analysis, timed blood samples were collected after administration of the single dose and after the first 14 days of continuous daily administration. Dose-limiting toxicity was grade 3 diarrhea, which occurred in one patient treated with 180 mg and in four patients treated with 400 mg neratinib; hence, the maximum tolerated dose was determined to be 320 mg. Other common neratinib-related toxicities included nausea, vomiting, fatigue, and anorexia. Exposure to neratinib was dose dependent, and the pharmacokinetic profile of neratinib supports a once-a-day dosing regimen. Partial response was observed for 8 (32%) of the 25 evaluable patients with breast cancer. Stable disease >or=24 weeks was observed in one evaluable breast cancer patient and 6 (43%) of the 14 evaluable non-small cell lung cancer patients. The maximum tolerated dose of once-daily oral neratinib is 320 mg. The most common neratinib-related toxicity was diarrhea. Antitumor activity was observed in patients with breast cancer who had previous treatment with trastuzumab, anthracyclines, and taxanes, and tumors with a baseline ErbB-2 immunohistochemical staining intensity of 2+ or 3+. The antitumor activity, tolerable toxicity profile, and pharmacokinetic properties of neratinib warrant its further evaluation.

Neurological and psychiatric tolerability of rilpivirine (TMC278) vs. efavirenz in treatment-naïve, HIV-1-infected patients at 48 weeks.

PubMed

Mills, A M; Antinori, A; Clotet, B; Fourie, J; Herrera, G; Hicks, C; Madruga, J V; Vanveggel, S; Stevens, M; Boven, K

2013-08-01

The aim of the study was to compare the neuropsychiatric safety and tolerability of rilpivirine (TMC278) vs. efavirenz in a preplanned pooled analysis of data from the ECHO and THRIVE studies which compared the safety and efficacy of the two drugs in HIV-1 infected treatment naïve adults. ECHO and THRIVE were randomized, double-blind, double-dummy, 96-week, international, phase 3 trials comparing the efficacy, safety and tolerability of rilpivirine 25 mg vs. efavirenz 600 mg once daily in combination with two background nucleoside/tide reverse transcriptase inhibitors. Safety and tolerability analyses were conducted when all patients had received at least 48 weeks of treatment or discontinued earlier. Differences between treatments in the incidence of neurological and psychiatric adverse events (AEs) of interest were assessed in preplanned statistical analyses using Fisher's exact test. At the time of the week 48 analysis, the cumulative incidences in the rilpivirine vs. efavirenz groups of any grade 2-4 treatment-related AEs and of discontinuation because of AEs were 16% vs. 31% (P<0.0001) and 3% vs. 8% (P=0.0005), respectively. The incidence of treatment-related neuropsychiatric AEs was 27% vs. 48%, respectively (P<0.0001). The incidence of treatment-related neurological AEs of interest was 17% vs. 38% (P<0.0001), and that of treatment-related psychiatric AEs of interest was 15% vs. 23% (P=0.0002). Dizziness and abnormal dreams/nightmares occurred significantly less frequently with rilpivirine vs. efavirenz (P<0.01). In both groups, patients with prior neuropsychiatric history tended to report more neuropsychiatric AEs but rates remained lower for rilpivirine than for efavirenz. Rilpivirine was associated with fewer neurological and psychiatric AEs of interest than efavirenz over 48 weeks in treatment-naïve, HIV-1-infected adults. © 2013 British HIV Association.

Critical appraisal of 3-monthly paliperidone depot injections in the treatment of schizophrenia.

PubMed

Carpiniello, Bernardo; Pinna, Federica

2016-01-01

Three-monthly injections of paliperidone palmitate (PP-3M) represent a new and recently introduced long-acting antipsychotic therapeutic option. This review focuses on available data relating to the efficacy and safety of PP-3M and its position in the current therapeutic scenario. An analysis of PubMed, Scopus, and ISI Web of Knowledge databases was conducted, and all available papers on PP-3M, including poster presentations, were selected and considered for the purpose of the present review. to date, three full papers have been published, the first, a Phase 1 randomized, open label study investigating the pharmacokinetics, safety, and tolerability of the drug; the second, a Phase 3 double blind study vs placebo focusing on efficacy and tolerability; and the last relating to the practical use of PP-3M. The five posters identified describe data reported in the above-cited papers. Overall, the pharmacokinetic findings obtained in these studies highlight the feasibility of administering PP-3M on a 3-monthly basis, subsequent to the administration of four 1-monthly injections of PP at doses 3.5 times higher than the stabilized dose of 1-monthly injections of PP (ie, 175, 300, 450, and 525 mgs). The published studies highlight a significantly longer time to relapse compared to placebo, and significantly better results compared to placebo for all secondary end-points (Positive and Negative Syndrome Scale, Clinical Global Impression-Severity Scale, Personal and Social Performance Scale scores), in addition to reasonably good safety and tolerability profiles. PP-3M emerges as a potential candidate for use as a first-line long-acting agent in the maintenance treatment of patients with schizophrenia. Further studies should however be conducted to confirm this expectation. In view of its efficacy, tolerability, and safety, together with the longer timespan between injections, PP-3M currently represents one of the best available options, and may contribute towards addressing the issue of poor adherence, even in early psychosis.

Safety, tolerability, and immunogenicity of the novel antituberculous vaccine RUTI: randomized, placebo-controlled phase II clinical trial in patients with latent tuberculosis infection.

PubMed

Nell, Andre S; D'lom, Eva; Bouic, Patrick; Sabaté, Montserrat; Bosser, Ramon; Picas, Jordi; Amat, Mercè; Churchyard, Gavin; Cardona, Pere-Joan

2014-01-01

To evaluate the safety, tolerability and immunogenicity of three different doses (5, 25 and 50 µg) of the novel antituberculous vaccine RUTI compared to placebo in subjects with latent tuberculosis infection. Double-blind, randomized, placebo-controlled Phase II Clinical Trial (95 patients randomized). Three different RUTI doses and placebo were tested, randomized both in HIV-positive (n = 47) and HIV-negative subjects (n = 48), after completion of one month isoniazid (INH) pre-vaccination. Each subject received two vaccine administrations, 28 Days apart. Five patients withdrew and 90 patients completed the study. Assessment of safety showed no deaths during study. Two subjects had serious adverse events one had a retinal detachment while taking INH and was not randomized and the other had a severe local injection site abscess on each arm and was hospitalized; causality was assessed as very likely and by the end of the study the outcome had resolved. All the patients except 5 (21%) patients of the placebo group (3 HIV+ and 2 HIV-) reported at least one adverse event (AE) during the study. The most frequently occurring AEs among RUTI recipients were (% in HIV+/-): injection site reactions [erythema (91/92), induration (94/92), local nodules (46/25), local pain (66/75), sterile abscess (6/6), swelling (74/83), ulcer (20/11), headache (17/22) and nasopharyngitis (20/5)]. These events were mostly mild and well tolerated. Overall, a polyantigenic response was observed, which differed by HIV- status. The best polyantigenic response was obtained when administrating 25 µg RUTI, especially in HIV-positive subjects which was not increased after the second inoculation. This Phase II clinical trial demonstrates reasonable tolerability of RUTI. The immunogenicity profile of RUTI vaccine in LTBI subjects, even being variable among groups, allows us considering one single injection of one of the highest doses in future trials, preceded by an extended safety clinical phase. ClinicalTrials.gov NCT01136161.

A Phase I study of bizelesin (NSC 615291) in patients with advanced solid tumors.

PubMed

Pitot, Henry C; Reid, Joel M; Sloan, Jeff A; Ames, Matthew M; Adjei, Alex A; Rubin, Joseph; Bagniewski, Pamela G; Atherton, Pamela; Rayson, Daniel; Goldberg, Richard M; Erlichman, Charles

2002-03-01

To evaluate the toxicities, characterize the pharmacokinetics, and determine the maximum-tolerated dose of bizelesin administered once every 4 weeks. Patients with advanced solid tumors received escalating doses of bizelesin as an i.v. push every 4 weeks. Pharmacokinetic studies were performed with the first treatment cycle. Nineteen eligible patients received a total of 54 courses of bizelesin at doses ranging from 0.1 to 1 microg/m(2). Dose-limiting toxicity of neutropenia was seen in 2 of 4 patients treated at the 1 microg/m(2) dose level. Nonhematological toxicity was generally mild with maximum toxicity being

36 CFR 1192.4 - Miscellaneous instructions.

Code of Federal Regulations, 2014 CFR

2014-07-01

... General § 1192.4 Miscellaneous instructions. (a) Dimensional conventions. Dimensions that are not noted as minimum or maximum are absolute. (b) Dimensional tolerances. All dimensions are subject to conventional...

36 CFR 1192.4 - Miscellaneous instructions.

Code of Federal Regulations, 2012 CFR

2012-07-01

... General § 1192.4 Miscellaneous instructions. (a) Dimensional conventions. Dimensions that are not noted as minimum or maximum are absolute. (b) Dimensional tolerances. All dimensions are subject to conventional...

36 CFR 1192.4 - Miscellaneous instructions.

Code of Federal Regulations, 2011 CFR

2011-07-01

... General § 1192.4 Miscellaneous instructions. (a) Dimensional conventions. Dimensions that are not noted as minimum or maximum are absolute. (b) Dimensional tolerances. All dimensions are subject to conventional...

Atomoxetine and Methylphenidate Treatment in Children with ADHD: The Efficacy, Tolerability and Effects on Executive Functions

ERIC Educational Resources Information Center

Yildiz, Ozlem; Sismanlar, Sahika G.; Memik, Nursu Cakin; Karakaya, Isik; Agaoglu, Belma

2011-01-01

The aim of this study was to compare the safety, efficacy, tolerability, and the effects of atomoxetine and OROS-MPH on executive functions in children with ADHD. This study was an open-label study that only included two medication groups. Children were randomized to open-label atomoxetine or OROS-MPH for 12 weeks. Primary efficacy measures were…

Researchers studying alternative to bladder removal for bladder cancer patients | Center for Cancer Research

Cancer.gov

A new phase I clinical trial conducted by researchers at the Center for Cancer Research (CCR) is evaluating the safety and tolerability, or the degree to which any side effects can be tolerated by patients, of a two-drug combination as a potential alternative to bladder removal for bladder cancer patients. The trial targets patients with non-muscle invasive bladder cancer