Enhancement of nootropic effect of duloxetine and bupropion by caffeine in mice.

PubMed

Kale, Pravin Popatrao; Addepalli, Veeranjaneyulu

2015-01-01

The existing evidence suggests an association between depression and memory impairment. The objective of present study was to assess the effect of low dose caffeine with duloxetine and bupropion on memory. Mice were divided randomly into seven groups. Intra-peritoneal treatment of normal saline (10 ml/kg), caffeine (10 mg/kg), duloxetine (10 mg/kg), bupropion alone (10 mg/kg), caffeine + duloxetine (5 mg/kg, each), caffeine + bupropion (5 mg/kg, each), and bupropion + duloxetine (5 mg/kg, each) were given to groups I-VII, respectively. Elevated plus maze was used to evaluate transfer latency (TL) and Morris water maze was used to estimate the time spent in target quadrant. Caffeine with duloxetine treated group was better than other combination treated groups in terms of a significant decrease in TL and increase in the time spent in target quadrant recorded. Combining lower dose of caffeine with duloxetine may enhance cognitive benefits than respective monotherapies.

Enhancement of nootropic effect of duloxetine and bupropion by caffeine in mice

PubMed Central

Kale, Pravin Popatrao; Addepalli, Veeranjaneyulu

2015-01-01

Objective: The existing evidence suggests an association between depression and memory impairment. The objective of present study was to assess the effect of low dose caffeine with duloxetine and bupropion on memory. Materials and Methods: Mice were divided randomly into seven groups. Intra-peritoneal treatment of normal saline (10 ml/kg), caffeine (10 mg/kg), duloxetine (10 mg/kg), bupropion alone (10 mg/kg), caffeine + duloxetine (5 mg/kg, each), caffeine + bupropion (5 mg/kg, each), and bupropion + duloxetine (5 mg/kg, each) were given to groups I-VII, respectively. Elevated plus maze was used to evaluate transfer latency (TL) and Morris water maze was used to estimate the time spent in target quadrant. Results: Caffeine with duloxetine treated group was better than other combination treated groups in terms of a significant decrease in TL and increase in the time spent in target quadrant recorded. Conclusion: Combining lower dose of caffeine with duloxetine may enhance cognitive benefits than respective monotherapies. PMID:25878382

Antidepressant behavioral effects of duloxetine and fluoxetine in the rat forced swimming test.

PubMed

Ciulla, Leandro; Menezes, Honório Sampaio; Bueno, Bárbara Beatriz Moreira; Schuh, Alexandre; Alves, Rafael José Vargas; Abegg, Milena Pacheco

2007-01-01

To compare the effects of the antidepressant drugs duloxetine and fluoxetine on depressive behaviors in rodents. Eighteen male Wistar rats were given systemic injections of duloxetine, fluoxetine, or saline prior to a Forced Swimming Test (FST). Immobility and number of stops were measured. Rats given injections of fluoxetine displayed significantly less immobility (p = 0.02) and fewer stops than the control group (p = 0.003). Duloxetine significantly reduced the number of stops (p = 0.003), but did not effect immobility (p = 0.48). Duloxetine and fluoxetine reduced depressive behaviors in the Forced FST. However, our findings suggest that fluoxetine is more effective than duloxetine.

Cost-utility analysis of duloxetine in osteoarthritis: a US private payer perspective.

PubMed

Wielage, Ronald C; Bansal, Megha; Andrews, J Scott; Klein, Robert W; Happich, Michael

2013-06-01

Duloxetine has recently been approved in the USA for chronic musculoskeletal pain, including osteoarthritis and chronic low back pain. The cost effectiveness of duloxetine in osteoarthritis has not previously been assessed. Duloxetine is targeted as post first-line (after acetaminophen) treatment of moderate to severe pain. The objective of this study was to estimate the cost effectiveness of duloxetine in the treatment of osteoarthritis from a US private payer perspective compared with other post first-line oral treatments, including nonsteroidal anti-inflammatory drugs (NSAIDs), and both strong and weak opioids. A cost-utility analysis was performed using a discrete-state, time-dependent semi-Markov model based on the National Institute for Health and Clinical Excellence (NICE) model documented in its 2008 osteoarthritis guidelines. The model was extended for opioids by adding titration, discontinuation and additional adverse events (AEs). A life-long time horizon was adopted to capture the full consequences of NSAID-induced AEs. Fourteen health states comprised the structure of the model: treatment without persistent AE, six during-AE states, six post-AE states and death. Treatment-specific utilities were calculated using the transfer-to-utility method and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total scores from a meta-analysis of osteoarthritis clinical trials of 12 weeks and longer. Costs for 2011 were estimated using Red Book, The Agency for Healthcare Research and Quality's Healthcare Cost and Utilization Project database, the literature and, sparingly, expert opinion. One-way and probabilistic sensitivity analyses were undertaken, as well as subgroup analyses of patients over 65 years old and a population at greater risk of NSAID-related AEs. In the base case the model estimated naproxen to be the lowest total-cost treatment, tapentadol the highest cost, and duloxetine the most effective after considering AEs. Duloxetine

Duloxetine in the treatment of elderly people with major depressive disorder.

PubMed

Del Casale, Antonio; Girardi, Paolo; Brugnoli, Roberto; Sani, Gabriele; Di Pietro, Simone; Brugnoli, Chiara; Caccia, Federica; Angeletti, Gloria; Serata, Daniele; Rapinesi, Chiara; Tatarelli, Roberto; Kotzalidis, Giorgio D

2012-01-01

The elderly population is more frequently subjected to depressive mood compared to the general population and show peculiarities affecting responsiveness; furthermore, aged people need also special care. Duloxetine is a relatively new antidepressant that proved to be effective in adult depression, but has received little attention in elderly population heretofore. To review the evidence of duloxetine in late-life major depressive disorder (MDD). A systematic review of studies focusing on the use of duloxetine in MDD in the elderly has been carried out through the principal specialized databases, including PubMed, PsycLIT, and Embase. Only a handful of papers were specifically dedicated to this issue. Duloxetine was found to be effective and safe in old-age MDD, to be better than placebo on many clinical measures in all studies, and to better differentiate from placebo with respect to selective serotonin reuptake inhibitors. Compared to placebo, its side-effect profile is slightly unfavorable and its drop-out rate is slightly higher. Furthermore, when pain is present in old-age MDD, duloxetine is able to reduce it. The efficacy and safety of duloxetine in old-age depression are similar to those encountered in adult MDD. There is a relative lack of comparative studies other than with placebo. The special needs of elderly patients with MDD must be addressed with close patient contact to avoid the perils of inappropriate dosing.

[Treatment of Persistent Somatoform Pain Disorder by Floating Needle Therapy and Duloxetine].

PubMed

Ren, Wan-wen; Zhou, Zhi-ying; Xu, Mi-mi; Long, Sen; Tang, Guang-zheng; Mao, Hong-jing; Chen, Shu-lin

2016-02-01

To evaluate clinical effect and safety of floating needle therapy and duloxetine in treating patients with persistent somatoform pain disorder (PSPD). Totally 108 PSPD patients were randomly assigned to the floating needle treatment group, the duloxetine treatment group, and the placebo treatment group, 36 in each group. Patients in the floating needle treatment group received floating needle therapy and placebo. Those in the duloxetine treatment group received duloxetine and simulated floating needle therapy. Those in the placebo treatment group received the placebo and simulated floating needle therapy. All treatment lasted for six weeks. Efficacy and adverse reactions were evaluated using Simple McGill pain scale (SF-MPQ) and Treatment Emergent Symptom Scale (TESS) before treatment and immediately after treatment, as well as at the end of 1st, 2nd, 4th, and 6th week of treatment, respectively. Hamilton Depression Scale (HAMD, 17 items), Hamilton Anxiety Scale (HAMA) were assessed before treatment and at the end of 1st, 2nd, 4th, and 6th week of treatment, respectively. Patients in the floating needle treatment group and the duloxetine treatment group with the total reducing score rate of SF-MPQ in Pain Rating index (PRI) ≥ 50% after 6 weeks' treatment were involved in the follow-up study. (1) Compared with the same group before treatment, SF-MPQ score, HAMD score and HAMA total scores all decreased in all the three groups at the end of 1st, 2nd, 4th, and 6th week of treatment (P < 0.05, P < 0.01). Besides , each item of SF-MPQ significantly decreased immediately after treatment in the floating needle treatment group (P < 0.01). Compared with the placebo treatment group, SF-MPQ, HAMD, and HAMA total score in the floating needle treatment group significantly decreased after 1, 2, 4, and 6 weeks of treatment (P < 0.05, P < 0.01). SF-MPQ score, HAMD score and HAMA total score in the duloxetine treatment group also significantly decreased after 2, 4, and 6 weeks of

Andexanet alfa to reverse the anticoagulant activity of factor Xa inhibitors: a review of design, development and potential place in therapy.

PubMed

Sartori, Michelangelo; Cosmi, Benilde

2018-04-01

Direct oral anticoagulants are associated with rates of major bleeding which are not negligible, albeit lower than those associated with vitamin K antagonists. No specific reversal agent for factor Xa (FXa) direct inhibitors is currently available for clinical use. A modified activated human FXa decoy protein, andexanet alfa, is being developed that binds FXa direct inhibitors in their active site, thus reversing their anticoagulant effect. The purpose of this article is to review the design, development and clinical trials of andexanet alfa. Andexanet alfa was shown to reverse FXa inhibitors anticoagulant activity both in thrombosis animal models, healthy volunteers and patients with acute major bleeding. Andexanet alfa has been studied in double-blind, placebo-controlled phase II and III studies. A preliminary report of the phase III study showed that an effective hemostasis was obtained after andexanet alfa infusion in the majority of the patients with acute major bleeding associated with FXa inhibitors. Additional studies are ongoing and andexanet alfa is expected to be launched in the market in the near future.

Effects of duloxetine in treatment-refractory men with posttraumatic stress disorder.

PubMed

Walderhaug, E; Kasserman, S; Aikins, D; Vojvoda, D; Nishimura, C; Neumeister, A

2010-03-01

Although there is evidence that selective serotonin reuptake inhibitors provide some benefit in the treatment of post-traumatic stress disorder (PTSD), most meta-analytical reviews have concluded that effect sizes are small and, moreover, that there may be relatively little benefit for some populations (e. g., combat veterans with co-morbid major depression, MDD). This study aimed to evaluate the effectiveness and tolerability of the dual reuptake inhibitor duloxetine in the treatment of PTSD and co-morbid MDD. Twenty-one treatment refractory, male, combat-related patients with PTSD and co-morbid MDD were enrolled in a naturalistic study and twenty completed the trial. Duloxetine was given between 60 and 120 mg daily over 8 weeks. Duloxetine led to a significant improvement of PTSD-characteristic symptoms as well as co-morbid MDD. Duloxetine effectively reduced nightmares, which is important because decreasing nightmares has been associated with improved sleep in PTSD. The results of this naturalistic study suggest that duloxetine is an effective and well-tolerated treatment for patients with PTSD and co-morbid MDD. These initial results need to be extended to the study of women with PTSD.

Duloxetine treatment adherence across mental health and chronic pain conditions

PubMed Central

Able, Stephen L; Cui, Zhanglin; Shen, Wei

2014-01-01

Purpose This study applied a uniform methodology for measuring and comparing duloxetine adherence in the treatment of multiple chronic medical conditions. Materials and methods Study patients 18–64 years of age initiating duloxetine therapy during 2008 were identified from a large managed care database. The study was restricted to patients with continuous health plan eligibility for 12 months pre- and post-duloxetine initiation. Study patients had ≥1 medical claim with an inpatient or outpatient diagnosis of one (and only one) of the following conditions: major depressive disorder (MDD); generalized anxiety disorder (GAD); fibromyalgia, diabetic peripheral neuropathic pain; or chronic musculoskeletal pain, as established in studies in patients with osteoarthritis and chronic lower back pain (CLBP). Patients initiating duloxetine who had two or more of the six studied conditions were not included in this study, thereby avoiding the need to differentiate between primary and secondary diagnoses from the claims records. Adherence rate was defined as the percentage of patients with a 365-day medication possession ratio ≥0.8. Results A total of 20,490 patients initiated duloxetine treatment during 2008 with a diagnosis of one of the studied conditions during the study period. The adherence rate in our sample was 34.6% and was highest among patients with MDD (37.3%) and lowest for patients with CLBP (29.9%). In general, adherence among patients with MDD and GAD was greater than among those with a chronic pain condition. Conclusion Adherence among newly initiated duloxetine patients varied modestly across the medical conditions for which it was used. After adjusting for potential confounders, differences between the mental conditions (MDD and GAD) and the chronic pain conditions (CLBP, osteoarthritis, and diabetic peripheral neuropathic pain) were statistically significant. These results may be useful in the determination of expectations of adherence, and how it may

Two-week administration of the combined serotonin-noradrenaline reuptake inhibitor duloxetine augments functioning of mesolimbic incentive processing circuits.

PubMed

Ossewaarde, Lindsey; Verkes, Robbert J; Hermans, Erno J; Kooijman, Sabine C; Urner, Maren; Tendolkar, Indira; van Wingen, Guido A; Fernández, Guillén

2011-09-15

Anhedonia and lack of motivation are core symptoms of major depressive disorder (MDD). Neuroimaging studies in MDD patients have shown reductions in reward-related activity in terminal regions of the mesolimbic dopamine (DA) system, such as the ventral striatum. Monoamines have been implicated in both mesolimbic incentive processing and the mechanism of action of antidepressant drugs. However, not much is known about antidepressant effects on mesolimbic incentive processing in humans, which might be related to the effects on anhedonia. To investigate the short-term effects of antidepressants on reward-related activity in the ventral striatum, we investigated the effect of the combined serotonin-norepinephrine reuptake inhibitor duloxetine. Healthy volunteers underwent functional magnetic resonance imaging in a randomized, double-blind, placebo-controlled, crossover study. After taking duloxetine (60 mg once a day) or placebo for 14 days, participants completed a monetary incentive delay task that activates the ventral striatum during reward anticipation. Our results (n = 19) show enhanced ventral striatal responses after duloxetine administration compared with placebo. Moreover, this increase in ventral striatal activity was positively correlated with duloxetine plasma levels. This is the first study to demonstrate that antidepressants augment neural activity in mesolimbic DA incentive processing circuits in healthy volunteers. These effects are likely caused by the increase in monoamine neurotransmission in the ventral striatum. Our findings suggest that antidepressants may alleviate anhedonia by stimulating incentive processing. Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Dornase Alfa

MedlinePlus

Dornase alfa is used to reduce the number of lung infections and to improve lung function in patients with ... Dornase alfa comes as a solution to inhale by mouth. It usually is taken one or two times a ...

Early effects of duloxetine on emotion recognition in healthy volunteers

PubMed Central

Bamford, Susan; Penton-Voak, Ian; Pinkney, Verity; Baldwin, David S; Munafò, Marcus R; Garner, Matthew

2015-01-01

The serotonin-noradrenaline reuptake inhibitor (SNRI) duloxetine is an effective treatment for major depression and generalised anxiety disorder. Neuropsychological models of antidepressant drug action suggest therapeutic effects might be mediated by the early correction of maladaptive biases in emotion processing, including the recognition of emotional expressions. Sub-chronic administration of duloxetine (for two weeks) produces adaptive changes in neural circuitry implicated in emotion processing; however, its effects on emotional expression recognition are unknown. Forty healthy participants were randomised to receive either 14 days of duloxetine (60 mg/day, titrated from 30 mg after three days) or matched placebo (with sham titration) in a double-blind, between-groups, repeated-measures design. On day 0 and day 14 participants completed a computerised emotional expression recognition task that measured sensitivity to the six primary emotions. Thirty-eight participants (19 per group) completed their course of tablets and were included in the analysis. Results provide evidence that duloxetine, compared to placebo, may reduce the accurate recognition of sadness. Drug effects were driven by changes in participants’ ability to correctly detect subtle expressions of sadness, with greater change observed in the placebo relative to the duloxetine group. These effects occurred in the absence of changes in mood. Our preliminary findings require replication, but complement recent evidence that sadness recognition is a therapeutic target in major depression, and a mechanism through which SNRIs could resolve negative biases in emotion processing to achieve therapeutic effects. PMID:25759400

Duloxetine, an antidepressant with analgesic properties – a preliminary analysis

PubMed Central

Onuţu, Adela Hilda

2015-01-01

Serotonin and norepinephrine reuptake inhibitors are second-line antidepressants largely used because of their good tolerance and their reduced side effects. Two of these drugs, duloxetine and venlafaxine, are used also in chronic pain management. In this review we present recent data regarding duloxetine’s effects on the central nervous system, linked to acute pain management, and their efficiency in reducing postoperative chronic pain. The drug’s efficacy results from its modulating effect on the descending inhibitory pain pathways and the inhibition of the nociceptive input. There are already several studies in favor of the analgesic properties of duloxetine. However, further and larger randomized studies are necessary in order to clarify duloxetine efficiency in acute postoperative settings, and thereafter on persistent chronic postoperative pain. PMID:28913467

Urinary retention during combined treatment of postpsychotic depression with duloxetine and olanzapine.

PubMed

Englisch, Susanne; Fritzinger, Michael; Zink, Mathias

2008-01-01

Duloxetine, a dual-reuptake inhibitor of serotonin and norepinephrine, has been approved for the treatment of major depressive episodes and for female stress urinary incontinence. At present, only sparse experiences are available regarding antidepressive treatment in patients with a psychotic lifetime diagnose, whereas this group of patients often suffer from major depressive episodes. Here, we describe the first case of a male patient with postpsychotic depression who developed the severe side effect of urinary retention during antidepressive treatment with duloxetine combined with olanzapine. After remission of his psychotic episode, the patient presented with depressed mood, psychomotor inhibition, sleep disturbance, and suicidal ideas. Without changing the antipsychotic therapy, we implemented duloxetine (60 mg/d) and the patient significantly improved. However, he increasingly suffered from obstructive voiding difficulties and complained about a weak urinary stream and incomplete voiding leading to unacceptable dribbling. The urinary retention disappeared completely within 1 week after discontinuation of duloxetine. We switched to venlafaxine (150 mg/d) and were able to keep the depression in remission. This case report demonstrates for the first time the onset of urinary retention in postpsychotic depression and during combined treatment with duloxetine and olanzapine. We therefore suggest increased attention on voiding function in particular if several pharmacological agents are combined.

Duloxetine in the treatment of Major Depressive Disorder: a comparison of efficacy in patients with and without melancholic features.

PubMed

Mallinckrodt, Craig H; Watkin, John G; Liu, Chaofeng; Wohlreich, Madelaine M; Raskin, Joel

2005-01-04

The most prominent feature of melancholic depression is a near-total loss of the capacity to derive pleasure from activities or other positive stimuli. Additional symptoms can include psychomotor disturbances, anorexia, excessive guilt, and early awakening from sleep. Melancholic patients may exhibit treatment responses and outcomes that differ from those of non-melancholic patients. Pooled data from double-blind, placebo-controlled studies were utilized to compare the efficacy of duloxetine in depressed patients with and without melancholic features. Efficacy data were pooled from 8 double-blind, placebo-controlled clinical trials of duloxetine. The presence of melancholic features (DSM-IV criteria) was determined using results from the Mini International Neuropsychiatric Interview (MINI). Patients (aged >or= 18 years) meeting DSM-IV criteria for major depressive disorder (MDD) received duloxetine (40-120 mg/d; melancholic, N = 759; non-melancholic, N = 379) or placebo (melancholic, N = 519; non-melancholic, N = 256) for up to 9 weeks. Efficacy measures included the 17-item Hamilton Rating Scale for Depression (HAMD17) total score, HAMD17 subscales (Maier, anxiety, retardation, sleep), the Clinical Global Impression of Severity (CGI-S) and Patient Global Impression of Improvement (PGI-I) scales, and Visual Analog Scales (VAS) for pain. In data from all 8 studies, duloxetine's advantage over placebo did not differ significantly between melancholic and non-melancholic patients (treatment-by-melancholic status interactions were not statistically significant). Duloxetine demonstrated significantly greater improvement in depressive symptom severity, compared with placebo, within both melancholic and non-melancholic cohorts (p duloxetine-treated male and female melancholic patients. In the two studies that

Sebelipase alfa: first global approval.

PubMed

Shirley, Matt

2015-11-01

Sebelipase alfa (Kanuma™) is a recombinant human lysosomal acid lipase (LAL) developed by Synageva BioPharma Corp. (now Alexion Pharmaceuticals, Inc.) for long-term enzyme replacement therapy in patients with LAL deficiency. The agent, administered by intravenous infusion once weekly or once every other week, acts to replace the deficient enzyme activity in patients with LAL deficiency, reducing lysosomal lipid accumulation, and thereby improving disease-related abnormalities such as dyslipidaemia and liver abnormalities. Sebelipase alfa received its first global approval, in the EU, in August 2015 for long-term enzyme replacement therapy in patients of all ages with LAL deficiency. Regulatory submissions have also been filed in the USA, Mexico and Japan for use in this indication. This article summarizes the milestones in the development of sebelipase alfa leading to this first approval for the treatment of LAL deficiency.

Efficacy of Duloxetine for the Treatment of Generalized Anxiety Disorder: Implications for Primary Care Physicians

PubMed Central

Koponen, Hannu; Allgulander, Christer; Erickson, Janelle; Dunayevich, Eduardo; Pritchett, Yili; Detke, Michael J.; Ball, Susan G.; Russell, James M.

2007-01-01

Objective: This study examined the efficacy and tolerability of duloxetine, a dual reuptake inhibitor of serotonin and norepinephrine, for the treatment of patients with generalized anxiety disorder (GAD). Method: Patients were ≥ 18 years old and recruited from 5 European countries, the United States, and South Africa. The study had a 9-week, multicenter, randomized, double-blind, fixed-dose, placebo-controlled, parallel-group design. A total of 513 patients (mean age = 43.8 years; 67.8% female) with a DSM-IV–defined GAD diagnosis received treatment with duloxetine 60 mg/day (N = 168), duloxetine 120 mg/day (N = 170), or placebo (N = 175). The primary efficacy measure was the Hamilton Rating Scale for Anxiety (HAM-A) total score. Secondary measures included the Sheehan Disability Scale, HAM-A psychic and somatic anxiety factor scores, and HAM-A response, remission, and sustained improvement rates. The study was conducted from July 2004 to September 2005. Results: Both groups of duloxetine-treated patients demonstrated significantly greater improvements in anxiety symptom severity compared with placebo-treated patients as measured by HAM-A total score and HAM-A psychic and somatic anxiety factor scores (p values ranged from ≤ .01 to ≤ .001). Duloxetine-treated patients had greater functional improvements in Sheehan Disability Scale global and specific domain scores (p ≤ .001) than placebo-treated patients. Both duloxetine doses also resulted in significantly greater HAM-A response, remission, and sustained improvement rates compared with placebo (p values ranged from ≤ .01 to ≤ .001). The rate of study discontinuation due to adverse events was 11.3% for duloxetine 60 mg and 15.3% for duloxetine 120 mg versus 2.3% for placebo (p ≤ .001). Conclusion: The results of this study demonstrate that duloxetine 60 mg/day and 120 mg/day were efficacious and well tolerated and thus may provide primary care physicians with a useful pharmacologic intervention for

Adverse events, toxicity and post-mortem data on duloxetine: case reports and literature survey.

PubMed

Vey, Eric L; Kovelman, Inna

2010-05-01

Duloxetine, a dual acting norepinephrine serotonin reuptake inhibitor, is a relatively new pharmacologic agent utilized in the treatment of depression, as well as diabetic neuropathic pain, fibromyalgia, and female stress urinary incontinence. This expanding scope of usage will inevitably lead to its eventual appearance during routine post-mortem toxicologic assays. Currently there is a paucity of post-mortem toxicologic data concerning duloxetine. The current report provides six additional case reports of post-mortem duloxetine levels, along with a review of duloxetine's pharmacokinetics, and the toxicologic manifestations which have been reported in the literature. The post-mortem levels reported, including the highest level recorded to date, are integrated with previously published reports to generate a foundation for a nascent guide to the interpretation of post-mortem duloxetine levels that could be encountered during routine post-mortem toxicologic analyses, and establish a basis upon which the establishment of toxic and lethal thresholds for this compound can be further elucidated with greater clarity. Copyright (c) 2010 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.

Epoetin Alfa Injection

MedlinePlus

Epoetin alfa injection is used to treat anemia (a lower than normal number of red blood cells) in people ... stop working over a period of time). Epoetin alfa injection is also used to treat anemia caused ...

Darbepoetin Alfa Injection

MedlinePlus

Darbepoetin alfa injection is used to treat anemia (a lower than normal number of red blood cells) in people ... stop working over a period of time). Darbepoetin alfa injection is also used to treat anemia caused ...

Typology of patients with fibromyalgia: cluster analysis of duloxetine study patients.

PubMed

Lipkovich, Ilya A; Choy, Ernest H; Van Wambeke, Peter; Deberdt, Walter; Sagman, Doron

2014-12-23

To identify distinct groups of patients with fibromyalgia (FM) with respect to multiple outcome measures. Data from 631 duloxetine-treated women in 4 randomized, placebo-controlled trials were included in a cluster analysis based on outcomes after up to 12 weeks of treatment. Corresponding classification rules were constructed using a classification tree method. Probabilities for transitioning from baseline to Week 12 category were estimated for placebo and duloxetine patients (Ntotal = 1188) using logistic regression. Five clusters were identified, from "worst" (high pain levels and severe mental/physical impairment) to "best" (low pain levels and nearly normal mental/physical function). For patients with moderate overall severity, mental and physical symptoms were less correlated, resulting in 2 distinct clusters based on these 2 symptom domains. Three key variables with threshold values were identified for classification of patients: Brief Pain Inventory (BPI) pain interference overall scores of <3.29 and <7.14, respectively, a Fibromyalgia Impact Questionnaire (FIQ) interference with work score of <2, and an FIQ depression score of ≥5. Patient characteristics and frequencies per baseline category were similar between treatments; >80% of patients were in the 3 worst categories. Duloxetine patients were significantly more likely to improve after 12 weeks than placebo patients. A sustained effect was seen with continued duloxetine treatment. FM patients are heterogeneous and can be classified into distinct subgroups by simple descriptive rules derived from only 3 variables, which may guide individual patient management. Duloxetine showed higher improvement rates than placebo and had a sustained effect beyond 12 weeks.

Conditioned pain modulation predicts duloxetine efficacy in painful diabetic neuropathy.

PubMed

Yarnitsky, David; Granot, Michal; Nahman-Averbuch, Hadas; Khamaisi, Mogher; Granovsky, Yelena

2012-06-01

This study aims to individualize the selection of drugs for neuropathic pain by examining the potential coupling of a given drug's mechanism of action with the patient's pain modulation pattern. The latter is assessed by the conditioned pain modulation (CPM) and temporal summation (TS) protocols. We hypothesized that patients with a malfunctioning pain modulation pattern, such as less efficient CPM, would benefit more from drugs augmenting descending inhibitory pain control than would patients with a normal modulation pattern of efficient CPM. Thirty patients with painful diabetic neuropathy received 1 week of placebo, 1 week of 30 mg/d duloxetine, and 4 weeks of 60 mg/d duloxetine. Pain modulation was assessed psychophysically, both before and at the end of treatment. Patient assessment of drug efficacy, assessed weekly, was the study's primary outcome. Baseline CPM was found to be correlated with duloxetine efficacy (r=0.628, P<.001, efficient CPM is marked negative), such that less efficient CPM predicted efficacious use of duloxetine. Regression analysis (R(2)=0.673; P=.012) showed that drug efficacy was predicted only by CPM (P=.001) and not by pretreatment pain levels, neuropathy severity, depression level, or patient assessment of improvement by placebo. Furthermore, beyond its predictive value, the treatment-induced improvement in CPM was correlated with drug efficacy (r=-0.411, P=.033). However, this improvement occurred only in patients with less efficient CPM (16.8±16.0 to -1.1±15.5, P<.050). No predictive role was found for TS. In conclusion, the coupling of CPM and duloxetine efficacy highlights the importance of pain pathophysiology in the clinical decision-making process. This evaluative approach promotes personalized pain therapy. Copyright © 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Intravenous Epoetin Alfa-epbx versus Epoetin Alfa for Treatment of Anemia in End-Stage Kidney Disease.

PubMed

Fishbane, Steven; Singh, Bhupinder; Kumbhat, Seema; Wisemandle, Wayne A; Martin, Nancy E

2018-06-19

This study was conducted to compare the safety and efficacy of intravenous epoetin alfa-epbx, an epoetin alfa biosimilar, to epoetin alfa in patients on hemodialysis with ESKD and anemia. In this 24-week, multicenter, double-blind comparative efficacy and safety study, 612 patients on hemodialysis with ESKD and anemia who had stable hemoglobin and were receiving stable doses of intravenous epoetin alfa were randomized (1:1) to intravenous epoetin alfa or epoetin alfa-epbx. Dosing was adjusted according to the epoetin alfa prescribing information. The coprimary efficacy end points were the least squares mean difference between the two treatments in mean weekly hemoglobin level and mean weekly epoetin dose per kilogram of body weight during the last 4 weeks of treatment. The least squares mean difference between epoetin alfa-epbx and epoetin alfa in weekly hemoglobin was -0.12 g/dl and the 95% confidence interval (-0.25 to 0.01) was contained within the prespecified equivalence margin (-0.5 to 0.5 g/dl). The least squares mean difference between epoetin alfa-epbx and epoetin alfa in weekly epoetin dose per kilogram of body weight was 0.37 U/kg per week, and the 95% confidence interval (-10.40 to 11.13) was contained within the prespecified equivalence margin (-45 to 45 U/kg per week). Incidences of adverse events (77.1% versus 75.3%), serious adverse events (24.9% versus 27.0%), and deaths ( n =5 versus 6) were similar between the epoetin alfa-epbx and epoetin alfa groups, respectively. Five patients tested positive for anti-recombinant human erythropoietin antibodies at baseline, and two additional patients ( n =1 per group) developed anti-recombinant human erythropoietin antibodies while on study treatment. All patients tested negative for neutralizing antibodies, and no patient in either group experienced an event of pure red cell aplasia. This 24-week, comparative, clinical trial in patients on hemodialysis with ESKD and anemia demonstrated there is no clinically

Neuroprotective effect of duloxetine in a mouse model of diabetic neuropathy: Role of glia suppressing mechanisms.

PubMed

Tawfik, Mona K; Helmy, Seham A; Badran, Dahlia I; Zaitone, Sawsan A

2018-07-15

Painful diabetic neuropathy (PDN) is one of the most frequent complications of diabetes and the current therapies have limited efficacy. This study aimed to study the neuroprotective effect of duloxetine, a serotonin noradrenaline reuptake inhibitor (SNRI), in a mouse model of diabetic neuropathy. Nine weeks after developing of PDN, mice were treated with either saline or duloxetine (15 or 30 mg/kg) for four weeks. The effect of duloxetine was assessed in terms of pain responses, histopathology of sciatic nerve and spinal cord, sciatic nerve growth factor (NGF) gene expression and on the spinal expression of astrocytes (glial fibrillary acidic protein, GFAP) and microglia (CD 11 b). The present results highlighted that duloxetine (30 mg/kg) increased the withdrawal threshold in von-Frey test. In addition, both doses of duloxetine prolonged the licking time and latency to jump in the hot-plate test. Moreover, duloxetine administration downregulated the spinal expression of both CD 11 b and GFAP associated with enhancement in sciatic mRNA expression of NGF. The current results highlighted that duloxetine provided peripheral and central neuroprotective effects in neuropathic pain is, at least in part, related to its downregulation in spinal astrocytes and microglia. Further, this neuroprotective effect was accompanied by upregulation of sciatic expression of NGF. Copyright © 2018 Elsevier Inc. All rights reserved.

Acute and long-term treatment of late-life major depressive disorder: duloxetine versus placebo.

PubMed

Robinson, Michael; Oakes, Tina Myers; Raskin, Joel; Liu, Peng; Shoemaker, Scarlett; Nelson, J Craig

2014-01-01

To compare the efficacy of duloxetine with placebo on depression in elderly patients with major depressive disorder. Multicenter, 24-week (12-week short-term and 12-week continuation), randomized, placebo-controlled, double-blind trial. United States, France, Mexico, Puerto Rico. Age 65 years or more with major depressive disorder diagnosis (one or more previous episode); Mini-Mental State Examination score ≥20; Montgomery-Asberg Depression Rating Scale total score ≥20. Duloxetine 60 or 120 mg/day or placebo; placebo rescue possible. Primary-Maier subscale of the 17-item Hamilton Depression Rating Scale (HAMD-17) at week 12. Secondary-Geriatric Depression Scale, HAMD-17 total score, cognitive measures, Brief Pain Inventory (BPI), Numeric Rating Scales (NRS) for pain, Clinical Global Impression-Severity scale, Patient Global Impression of Improvement in acute phase and acute plus continuation phase of treatment. Compared with placebo, duloxetine did not show significantly greater improvement from baseline on Maier subscale at 12 weeks, but did show significantly greater improvement at weeks 4, 8, 16, and 20. Similar patterns for Geriatric Depression Scale and Clinical Global Impression-Severity scale emerged, with significance also seen at week 24. There was a significant treatment effect for all BPI items and 4 of 6 NRS pain measures in the acute phase, most BPI items and half of the NRS measures in the continuation phase. More duloxetine-treated patients completed the study (63% versus 55%). A significantly higher percentage of duloxetine-treated patients versus placebo discontinued due to adverse event (15.3% versus 5.8%). Although the antidepressant efficacy of duloxetine was not confirmed by the primary outcome, several secondary measures at multiple time points suggested efficacy. Duloxetine had significant and meaningful beneficial effects on pain. Copyright © 2014 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights

Duloxetine Plasma Concentrations and Its Effectiveness in the Treatment of Nonorganic Chronic Pain in the Orofacial Region.

PubMed

Kobayashi, Yuka; Nagashima, Wataru; Tokura, Tatsuya; Yoshida, Keizo; Umemura, Eri; Miyauchi, Tomoya; Arao, Munetaka; Ito, Mikiko; Kimura, Hiroyuki; Kurita, Kenichi; Ozaki, Norio

The purpose of this study was to examine the relationship between the pain-relieving effects of duloxetine and its plasma concentrations in patients with burning mouth syndrome and atypical odontalgia characterized by chronic nonorganic pain in the orofacial region. We administered duloxetine to 77 patients diagnosed as having burning mouth syndrome or atypical odontalgia for 12 weeks. The initial dose of duloxetine was established as 20 mg/d and was increased to 40 mg/d after week 2. We evaluated pain using the visual analog scale and depressive symptoms using the Structured Interview Guide for the Hamilton Depression Rating Scale at weeks 0, 2, 4, 6, 8, 10, and 12 and measured plasma concentrations of duloxetine 12 weeks after the start of its administration. Visual analog scale scores were significantly lower 12 weeks after than at the start of the administration of duloxetine (paired t test, t = 6.65, P < 0.0001). We examined the relationship between the rate of decreases in visual analog scale scores and plasma concentrations of duloxetine. There was no significant linear regression or quadratic regression. Duloxetine significantly relieved pain in patients with chronic nonorganic pain in the orofacial region. However, no relationship was observed between its pain-relieving effects and plasma concentrations.

Predictors of Treatment with Duloxetine or Venlafaxine XR among Adult Patients Treated for Depression in Primary Care Practices in the United Kingdom

PubMed Central

Shi, Nianwen; Durden, Emily; Torres, Amelito; Cao, Zhun; Happich, Michael

2012-01-01

Background. Knowledge about real-world use of duloxetine and venlafaxine XR to treat depression in the UK is limited. Aims. To identify predictors of duloxetine or venlafaxine XR initiation. Method. Adult depressed patients who initiated duloxetine or venlafaxine XR between January 1, 2006 and September 30, 2007 were identified in the UK's General Practice Research Database. Demographic and clinical predictors of treatment initiation with duloxetine and venlafaxine XR were identified using logistic regression. Results. Patients initiating duloxetine (n = 909) were 4 years older than venlafaxine XR recipients (n = 1286). Older age, preexisting unexplained pain, respiratory disease, and pre-period use of anticonvulsants, opioids, and antihyperlipidemics were associated with increased odds of initiating duloxetine compared to venlafaxine XR. Pre-period anxiety disorder was associated with decreased odds of receiving duloxetine. Conclusion. Initial treatment choice with duloxetine versus venlafaxine XR was primarily driven by patient-specific mental and medical health characteristics. General practitioners in the UK favor duloxetine over venlafaxine XR when pain conditions coexist with depression. PMID:22720149

Efficacy and safety of duloxetine in Chinese breast cancer patients with paclitaxel-induced peripheral neuropathy

PubMed Central

Wang, Jiani; Li, Qing; Xu, Binghe; Zhang, Tongtong; Chen, Shanshan; Luo, Yang

2017-01-01

Objective Chemotherapy with paclitaxel is associated with significant neurotoxicity that may offset patients’ quality of life and therapeutic benefits. This prospective, non-randomized control study evaluated the efficacy and safety of an antidepressant drug, duloxetine, at 30 or 60 mg/d, in the treatment of paclitaxel-induced peripheral neuropathy (PIPN) in Chinese breast cancer patients. Methods A total of 102 patients with a median age of 50 (range, 25–60) years, treated in the Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, between November 2014 and January 2017 were finally enrolled. Stratified by baseline characteristics, the patients were classified into two groups, receiving either duloxetine or alternative anti-neurotoxicity drugs. During the course of the paclitaxel regimen, the eligibility criteria included sensory neuropathy, as evaluated by the National Cancer Institute-Common Toxicity Criteria for Adverse Events. The treatment consisted of receiving 30 mg duloxetine (for the first 4 weeks) and 60 mg duloxetine for an additional 8 weeks, or any other anti-neurotoxicity drug daily during the same crossover period. The improvement associated with PIPN from the patient’s perspective were assessed by the Functional Assessment of Cancer Therapy-Taxane (FACT-Tax) Scales, which contained questions scored from 0 to 4 (0, not at all; 4, very much; total score range, 0–44). Results Duloxetine was more effective in decreasing PIPN (odds ratio=5.426; 95% confidence interval, 1.898–15.514; P=0.002). Between duloxetine group and control group, the median (25th–75th percentiles) decreasing difference in the FACT-Tax pain score was 4 (2–6) vs. 1 (0–4) (P=0.005). Conclusions Duloxetine is a promising and safe option with tolerable toxicity at a dose of 60 mg/d for Chinese breast cancer patients with PIPN. Non-neuropathy adverse events were mild and similar in

Interferon Alfa-2b Injection

MedlinePlus

Interferon alfa-2b injection is used to treat a number of conditions.Interferon alfa-2b injection is used alone or in combination ... lymphoma (NHL; a slow-growing blood cancer). Interferon alfa-2b is in a class of medications called ...

Duloxetine for the treatment of painful diabetic peripheral neuropathy in Venezuela: economic evaluation.

PubMed

Carlos, Fernando; Espejel, Luis; Novick, Diego; López, Rubén; Flores, Daniel

2015-09-25

Painful diabetic peripheral neuropathy affects 40-50% of patients with diabetic neuropathy, leading to impaired quality of life and substantial costs. Duloxetine and pregabalin have evidence-based support, and are formally approved for controlling painful diabetic peripheral neuropathy. We used a 12-week decision model for examining painful diabetic peripheral neuropathy first-line therapy with daily doses of duloxetine 60mg or pregabalin 300mg, under the perspective of the Instituto Venezolano de los Seguros Sociales. We gathered model parameters from published literature and expert´s opinion, focusing on the magnitude of pain relief, the presence of adverse events, the possibility of withdrawal owing to intolerable adverse events or due to lack of efficacy, and the quality-adjusted life years expected in each strategy. We analyzed direct medical costs (which are expressed in Bolívares Fuertes, BsF) comprising drug acquisition besides additional care devoted to treatment of adverse events and poor pain relief. We conducted both deterministic and probabilistic sensitivity analyses. Total expected costs per 1000 patients were BsF 1 046 146 (26%) lower with duloxetine than with pregabalin. Most of these savings (91%) corresponds to the difference in the acquisition’s cost of each medication. duloxetine also provided 23 more patients achieving good pain relief and a gain of about two quality-adjusted life years per 1000 treated. Model was robust to plausible changes in main parameters. Duloxetine remained the preferred option in 93.9% of the second-order Monte Carlo simulations. This study suggests duloxetine dominates (i.e., is more effective and lead to gains in quality-adjusted life years), remaining less costly than pregabalin for treatment of painful diabetic peripheral neuropathy.

Dornase alfa for cystic fibrosis.

PubMed

Yang, Connie; Chilvers, Mark; Montgomery, Mark; Nolan, Sarah J

2016-04-04

Dornase alfa is currently used as a mucolytic to treat pulmonary disease (the major cause of morbidity and mortality) in cystic fibrosis. It reduces mucus viscosity in the lungs, promoting improved clearance of secretions. This is an update of a previously published review. To determine whether the use of dornase alfa in cystic fibrosis is associated with improved mortality and morbidity compared to placebo or other medications that improve airway clearance, and to identify any adverse events associated with its use. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic database searches, handsearching relevant journals and abstracts from conferences. Date of the most recent search of the Group's Cystic Fibrosis Register: 30 November 2015.Clinicaltrials.gov was also searched to identify unpublished or ongoing trials. Date of most recent search: 28 November 2015. All randomised and quasi-randomised controlled trials comparing dornase alfa to placebo, standard therapy or other medications that improve airway clearance. Authors independently assessed trials against the inclusion criteria; two authors carried out analysis of methodological quality and data extraction. The searches identified 54 trials, of which 19 (including a total of 2565 participants) met our inclusion criteria. Three additional papers examined the healthcare cost from one of the clinical trials. Fifteen trials compared dornase alfa to placebo or no dornase alfa treatment (2447 participants); two compared daily dornase to hypertonic saline (32 participants); one compared daily dornase alfa with hypertonic saline and alternate day dornase alfa (48 participants); one compared dornase alfa to mannitol and the combination of both drugs (38 participants). Trial duration varied from six days to three years.Compared to placebo, forced expiratory volume at one second improved in the intervention groups, with

An open treatment trial of duloxetine in elderly patients with dysthymic disorder

PubMed Central

Kerner, Nancy; D’Antonio, Kristina; Pelton, Gregory H; Salcedo, Elianny; Ferrar, Jennifer; Roose, Steven P

2014-01-01

Objective: We evaluated the efficacy and side effects of the selective serotonin and norepinephrine reuptake inhibitor antidepressant duloxetine in older adults with dysthymic disorder. Methods: Patients ≥ 60 years old with dysthymic disorder received flexible dose duloxetine 20–120 mg daily in an open-label 12-week trial. The main outcomes were change from baseline to 12 weeks in 24-item Hamilton Depression Rating Scale scores and Treatment Emergent Symptoms Scale scores. Response required ≥ 50% decline in Hamilton Depression Rating Scale scores with a Clinical Global Impression of much improved or better, and remission required final Hamilton Depression Rating Scale ≤ 6. Intent-to-treat analyses were conducted with the last observation carried forward. Results: In 30 patients, the mean age was 70.7 (standard deviation (SD) = 7.6) years and 56.7% were female. In intent-to-treat analyses, there were 16 responders (53.3%) and 10 remitters (33.3%). Of these, 19 patients completed the trial. The mean maximum dose was 76.3 mg (SD = 38.5) in the total sample and 101 mg (SD = 17.9) in completers. In the total sample, the mean final dose was 51 mg (SD = 27.2) and correlated significantly with decline in Hamilton Depression Rating Scale (p < .03); decline in Hamilton Depression Rating Scale correlated significantly with decline in Treatment Emergent Symptoms Scale (p < .001). Daily doses above 60 mg were associated with greater improvement and well tolerated. This result was partly confounded by early dropouts having received low doses. Demographic and medical comorbidities, including cardiac disease and hypertension, were not related to response. Somatic side effects were common prior to duloxetine treatment and improved rather than worsened with duloxetine. There were no serious adverse events. Conclusion: Duloxetine at relatively high doses showed moderate efficacy in elderly patients with dysthymic disorder and was well tolerated in successful completers

An open treatment trial of duloxetine in elderly patients with dysthymic disorder.

PubMed

Kerner, Nancy; D'Antonio, Kristina; Pelton, Gregory H; Salcedo, Elianny; Ferrar, Jennifer; Roose, Steven P; Devanand, Dp

2014-05-08

We evaluated the efficacy and side effects of the selective serotonin and norepinephrine reuptake inhibitor antidepressant duloxetine in older adults with dysthymic disorder. Patients ≥ 60 years old with dysthymic disorder received flexible dose duloxetine 20-120 mg daily in an open-label 12-week trial. The main outcomes were change from baseline to 12 weeks in 24-item Hamilton Depression Rating Scale scores and Treatment Emergent Symptoms Scale scores. Response required ≥ 50% decline in Hamilton Depression Rating Scale scores with a Clinical Global Impression of much improved or better, and remission required final Hamilton Depression Rating Scale ≤ 6. Intent-to-treat analyses were conducted with the last observation carried forward. In 30 patients, the mean age was 70.7 (standard deviation (SD) = 7.6) years and 56.7% were female. In intent-to-treat analyses, there were 16 responders (53.3%) and 10 remitters (33.3%). Of these, 19 patients completed the trial. The mean maximum dose was 76.3 mg (SD = 38.5) in the total sample and 101 mg (SD = 17.9) in completers. In the total sample, the mean final dose was 51 mg (SD = 27.2) and correlated significantly with decline in Hamilton Depression Rating Scale ( p < .03); decline in Hamilton Depression Rating Scale correlated significantly with decline in Treatment Emergent Symptoms Scale ( p < .001). Daily doses above 60 mg were associated with greater improvement and well tolerated. This result was partly confounded by early dropouts having received low doses. Demographic and medical comorbidities, including cardiac disease and hypertension, were not related to response. Somatic side effects were common prior to duloxetine treatment and improved rather than worsened with duloxetine. There were no serious adverse events. Duloxetine at relatively high doses showed moderate efficacy in elderly patients with dysthymic disorder and was well tolerated in successful completers. Reduced somatic symptoms were associated with

Duloxetine Inhibits Effects of MDMA (“Ecstasy") In Vitro and in Humans in a Randomized Placebo-Controlled Laboratory Study

PubMed Central

Nicola, Valentina G.; Vischer, Nerina; Donzelli, Massimiliano; Krähenbühl, Stephan; Grouzmann, Eric; Huwyler, Jörg; Hoener, Marius C.; Liechti, Matthias E.

2012-01-01

This study assessed the effects of the serotonin (5-HT) and norepinephrine (NE) transporter inhibitor duloxetine on the effects of 3,4–methylenedioxy­methamphetamine (MDMA, ecstasy) in vitro and in 16 healthy subjects. The clinical study used a double-blind, randomized, placebo-controlled, four-session, crossover design. In vitro, duloxetine blocked the release of both 5-HT and NE by MDMA or by its metabolite 3,4-methylenedioxyamphetamine from transmitter-loaded human cells expressing the 5-HT or NE transporter. In humans, duloxetine inhibited the effects of MDMA including elevations in circulating NE, increases in blood pressure and heart rate, and the subjective drug effects. Duloxetine inhibited the pharmacodynamic response to MDMA despite an increase in duloxetine-associated elevations in plasma MDMA levels. The findings confirm the important role of MDMA-induced 5-HT and NE release in the psychotropic effects of MDMA. Duloxetine may be useful in the treatment of psychostimulant dependence. Trial Registration Clinicaltrials.gov NCT00990067 PMID:22574166

Assessment of the biopotency of follitropin alfa and lutropin alfa combined in one injection: a comparative trial in Sprague-Dawley rats

PubMed Central

Alper, Michael; Meyer, Randal; Dekkers, Chris; Ezcurra, Diego; Schertz, Joan; Kelly, Eduardo

2008-01-01

Background The current study was designed to determine if follitropin alfa (recombinant human follicle-stimulating hormone; r-hFSH) and lutropin alfa (recombinant human luteinizing hormone; r-hLH) biopotencies were unchanged by reconstituting in sterile water for injection and mixing prior to injection. Methods The biopotencies of r-hFSH and r-hLH were determined following injection of female Sprague-Dawley rats with a mixture of follitropin alfa revised formulation female (RFF) and lutropin alfa (1:1, r-hFSH:r-hLH). Biopotencies of follitropin alfa RFF and lutropin alfa were measured using ovarian weight and ascorbic acid depletion assays, respectively, and compared with a reference standard. Stock mixtures of follitropin alfa RFF and lutropin alfa (1:1) were prepared within 1 h prior to each respective assay's injection and stored at 6 +/- 2°C. Separate low dose (follitropin alfa RFF 1.5 IU/rat, lutropin alfa 2 IU/rat) and high dose (follitropin alfa RFF 3 IU/rat, lutropin alfa 8 IU/rat) treatments were prepared from stock mixtures or individual solutions by diluting with 0.22% bovine serum albumin saline solution and injected within 1 h of preparation. The main outcome measures were ovarian weight and ovarian ascorbic acid depletion. Results FSH bioactivities were similar (p > 0.10) between the individual follitropin alfa RFF test solution (84.2 IU) and follitropin alfa RFF/lutropin alfa (87.6 IU) mixtures prepared within 1 h of injection and stored at 6 +/- 2°C. LH bioactivities were similar (p > 0.10) between lutropin alfa (94.7 IU) test solution and lutropin alfa/follitropin alfa RFF (85.3 IU) mixtures prepared within 1 h of injection and stored at 6 +/- 2°C for not more than 1 h prior to injection. Conclusion Mixing follitropin alfa RFF and lutropin alfa did not alter the bioactivity of either FSH or LH. PMID:18647398

Improvement in multiple dimensions of fatigue in patients with fibromyalgia treated with duloxetine: secondary analysis of a randomized, placebo-controlled trial.

PubMed

Arnold, Lesley M; Wang, Fujun; Ahl, Jonna; Gaynor, Paula J; Wohlreich, Madelaine M

2011-06-13

Fatigue is one of the most disabling symptoms associated with fibromyalgia that greatly impacts quality of life. Fatigue was assessed as a secondary objective in a 2-phase, 24-week study in outpatients with American College of Rheumatology-defined fibromyalgia. Patients were randomized to duloxetine 60-120 mg/d (N = 263) or placebo (N = 267) for the 12-week acute phase. At Week 12, all placebo-treated patients were switched to double-blind treatment with duloxetine for the extension phase. Fatigue was assessed at baseline and every 4 weeks with the Multidimensional Fatigue Inventory (MFI) scales: General Fatigue, Physical Fatigue, Mental Fatigue, Reduced Activity, and Reduced Motivation. Other assessments that may be associated with fatigue included Brief Pain Inventory (BPI) average pain, numerical scales to rate anxiety, depressed mood, bothered by sleep difficulties, and musculoskeletal stiffness. Treatment-emergent fatigue-related events were also assessed. Changes from baseline to Week 12, and from Week 12 to Week 24, were analyzed by mixed-effects model repeated measures analysis. At Week 12, duloxetine versus placebo significantly (all p < .05) reduced ratings on each MFI scale, BPI pain, anxiety, depressed mood, and stiffness. Improvement in ratings of being bothered by sleep difficulties was significant only at Weeks 4 and 8. At Week 24, mean changes in all measures indicated improvement was maintained for patients who received duloxetine for all 24 weeks (n = 176). Placebo-treated patients switched to duloxetine (n = 187) had significant within-group improvement in Physical Fatigue (Weeks 16, 20, and 24); General Fatigue (Weeks 20 and 24); Mental Fatigue (Week 20); and Reduced Activity (Weeks 20 and 24). These patients also experienced significant within-group improvement in BPI pain, anxiety, depressed mood, bothered by sleep difficulties, and stiffness. Overall, the most common (> 5% incidence) fatigue-related treatment-emergent adverse events were

Duloxetine compliance and its association with healthcare costs among patients with diabetic peripheral neuropathic pain.

PubMed

Wu, N; Chen, S; Boulanger, L; Fraser, K; Bledsoe, S L; Zhao, Y

2009-09-01

Duloxetine is approved to treat diabetic peripheral neuropathic pain (DPNP) in the US. The study objective was to examine the predictors of duloxetine compliance, and its association with healthcare costs among DPNP patients. The study used administrative claims databases to identify non-depressed DPNP patients with a duloxetine prescription dispensed between October 1, 2004 and December 31, 2006. Two cohorts of patients were constructed based on compliance to duloxetine therapy over 1-year follow-up with high compliance defined as a medication possession ratio (MPR) > or =0.80. All-cause, diabetes-, and DPNP-related healthcare costs during 1-year follow-up were estimated. Logistic regressions were performed to examine how average daily dose (ADD) of duloxetine and other factors may influence compliance. Multivariate regressions were estimated to examine the association between compliance and healthcare costs. The study included 1,380 commercially insured (mean age 55 years) and 974 patients with employer-sponsored Medicare supplemental insurance (mean age 75 years). In both populations, patients with an ADD >30 mg were more likely to be compliant with the therapy compared with those with an ADD of < or =30 mg (odds ratio ranged 1.79-3.38, all p<0.05). Controlling for differences in demographics, clinical and economic characteristics, commercially insured low duloxetine compliance patients had greater all-cause ($5,334, p<0.05) and diabetes-related healthcare costs ($3,414, p<0.05) than high-compliance patients, with the biggest difference from inpatient costs (all-cause: $7,508; diabetes-related: $3,785, all p<0.05). Similar trends were found in the Medicare supplemental insured population; however, differences in all-cause healthcare costs were not significant. DPNP patients with a higher ADD of duloxetine over a 1-year follow-up period were more compliant with the therapy. Duloxetine patients with high compliance were also associated with lower healthcare costs

Peginterferon Alfa-2b (PEG-Intron)

MedlinePlus

Peginterferon alfa-2b is used alone or in combination with ribavirin (a medication) to treat chronic (long-term) hepatitis ... treated with interferon alpha (medication similar to peginterferon alfa-2b) in the past. Peginterferon alfa-2b is ...

Evidences for amelioration of reserpine-induced fibromyalgia in rat by low dose of gamma irradiation and duloxetine.

PubMed

Shibrya, Eman E; Radwan, Rasha R; Abd El Fattah, Mai A; Shabaan, Esmat A; Kenawy, Sanaa A

2017-05-01

Fibromyalgia is a prevalent disorder characterized by chronic widespread pain and complex symptoms. This study was conducted to investigate the potential therapeutic effect of low-dose irradiation (LDI) alone or in combination with duloxetine on the reserpine-induced fibromyalgia in rats. Fibromyalgia was induced by administration of reserpine (1 mg/kg/s.c) for 3 consecutive days. Duloxetine (30 mg/kg, p.o) was administered 60 min before a forced swimming test (FST), and rats were exposed to a single dose of γ-radiation (0.5 Gy) 1 day before the FST. Reserpine significantly increased immobility time in the FST, decreased the amount of 5-hydroxytryptamine, dopamine, and norepinephrine in cerebral cortex. It also increased malondialdehyde and nitric oxide and reduced glutathione contents in brain tissue. LDI alone or combined with duloxetine completely antagonized reserpine-induced fibromyalgia as assessed by the measured parameters. One of the most significant findings in this study was that the therapeutic effect of duloxetine was more pronounced by its combination with LDI. A possible mechanism of action of LDI and duloxetine responsible for their therapeutic effect was discussed. On the basis of the presented evidences, it could be concluded that LDI alone or combined with duloxetine could be of value in the management of fibromyalgia.

Purification and Characterization of Recombinant Darbepoetin Alfa from Leishmania tarentolae.

PubMed

Kianmehr, Anvarsadat; Mahrooz, Abdolkarim; Oladnabi, Morteza; Safdari, Yaghoub; Ansari, Javad; Veisi, Kamal; Evazalipour, Mehdi; Shahbazmohammadi, Hamid; Omidinia, Eskandar

2016-09-01

Darbepoetin alfa is a biopharmaceutical glycoprotein that stimulates erythropoiesis and is used to treat anemia, which associated with renal failure and cancer chemotherapy. We herein describe the structural characterization of recombinant darbepoetin alfa produced by Leishmania tarentolae T7-TR host. The DNA expression cassette was integrated into the L. tarentolae genome through homologous recombination. Transformed clones were selected by antibiotic resistance, diagnostic PCRs, and protein expression analysis. The structure of recombinant darbepoetin alfa was analyzed by isoelectric focusing, ultraviolet-visible spectrum, and circular dichroism (CD) spectroscopy. Expression analysis showed the presence of a protein band at 40 kDa, and its expression level was 51.2 mg/ml of culture medium. Darbepoetin alfa have 5 isoforms with varying degree of sialylation. The UV absorption and CD spectra were analogous to original drug (Aranesp), which confirmed that the produced protein was darbepoetin alfa. Potency test results revealed that the purified protein was biologically active. In brief, the structural and biological characteristics of expressed darbepoetin alfa were very similar to Aranesp which has been normally expressed in CHO. Our data also suggest that produced protein has potential to be developed for clinical use.

Effects of duloxetine on microRNA expression profile in frontal lobe and hippocampus in a mouse model of depression.

PubMed

Pan, Bing; Liu, Yamei

2015-01-01

Depression is a major mood disorder affecting people worldwide. The posttranscriptional gene regulation mediated by microRNAs (miRNAs) which may have critical roles in the pathogenesis of depression. However, to date, little is known about the effects of the antidepressant drug duloxetine on miRNA expression profile in chronic unpredictable mild stress (CUMS)-induced depression model in mice. Healthy adult male Kunming mice were randomly divided into three groups: control group, model group and duloxetine group. Sucrose preference test and open field test were used to represent the behavioral change. MiRNAs levels in frontal lobe and hippocampus of mice were analyzed using miRNA microarrays assay. We observed that long-term treatment with duloxetine significantly ameliorated the CUMS procedure-induced sucrose preference decreases and mice treated with duloxetine demonstrated a reversal of the number of crossings, and rearings reduced by CUMS. A significant upregulation of miR-132 and miR-18a in hippocampus in the duloxetine treatment group compared with model group, whereas the levels of miR-134 and miR-124a were significantly downregulated. Furthermore, miR-18a showed significant upregulation in frontal lobe in the duloxetine treatment group relative to model group. Our data showed that miRNA expression profile in frontal lobe and hippocampus was affected by duloxetine in mice model of depression. The effect was especially pronounced in the hippocampus, suggesting that hippocampus might be the action site of duloxetine, which presumably worked by regulating the expression of miRNA levels.

Anti-inflammatory and anti-fibrinolytic effects of thrombomodulin alfa through carboxypeptidase B2 in the presence of thrombin.

PubMed

Tawara, Shunsuke; Sakai, Takumi; Matsuzaki, Osamu

2016-11-01

Thrombomodulin (TM) alfa, a recombinant human soluble TM, enhances activation of pro-carboxypeptidase B2 (pro-CPB2) by thrombin. Activated pro-CPB2 (CPB2) exerts anti-inflammatory and anti-fibrinolytic activities. Therefore, TM alfa may also have anti-inflammatory and anti-fibrinolytic effects through CPB2. However, these effects of TM alfa have not been elucidated. In the present study, we investigated the effects of TM alfa on inactivation of complement component C5a as an anti-inflammatory effect and prolongation of clot lysis time as an anti-fibrinolytic effect via CPB2 in vitro. CPB2 activity and tissue factor-induced thrombin generation was examined by a chromogenic assay. C5a inactivation was evaluated by C-terminal cleavage of C5a and inhibition of C5a-induced human neutrophil migration. Clot lysis time prolongation was examined by a tissue-type plasminogen activator-induced clot lysis assay. CPB2 activity in human plasma was increased by TM alfa and thrombin in a concentration-dependent manner. TM alfa inhibited tissue factor-induced thrombin generation and enhanced pro-CPB2 activation in human plasma simultaneously. The mass spectrum of C5a treated with TM alfa, thrombin, and pro-CPB2 was decreased at 156m/z, indicating that TM alfa enhanced the processing of C5a to C-terminal-cleaved C5a, an inactive form of C5a. C5a-induced human neutrophil migration was decreased after C5a treatment with TM alfa, thrombin, and pro-CPB2. TM alfa prolonged the clot lysis time in human plasma, and this effect was completely abolished by addition of a CPB2 inhibitor. TM alfa exerts anti-inflammatory and anti-fibrinolytic effects through CPB2 in the presence of thrombin in vitro. Copyright © 2016 Elsevier Ltd. All rights reserved.

Direct medical costs and medication compliance among fibromyalgia patients: duloxetine initiators vs. pregabalin initiators.

PubMed

Sun, Peter; Peng, Xiaomei; Sun, Steve; Novick, Diego; Faries, Douglas E; Andrews, Jeffrey S; Wohlreich, Madelaine M; Wu, Andrew

2014-01-01

To assess and compare direct medical costs and medication compliance between patients with fibromyalgia who initiated duloxetine and patients with fibromyalgia who initiated pregabalin in 2008. A retrospective cohort study design was used based on a large US national commercial claims database (2006 to 2009). Patients with fibromyalgia aged 18 to 64 who initiated duloxetine or pregabalin in 2008 and who had continuous health insurance 1 year preceding and 1 year following the initiation were selected into duloxetine cohort or pregabalin cohort based on their initiated agent. Medication compliance was measured by total supply days, medication possession ratio (MPR), and proportion of patients with MPR ≥ 0.8. Direct medical costs were measured by annual costs per patient and compared between the cohorts in the year following the initiation. Propensity score stratification and bootstrapping methods were used to adjust for distribution bias, as well as cross-cohort differences in demographic, clinical and economic characteristics, and medication history prior to the initiation. Both the duloxetine (n = 3,033) and pregabalin (n = 4,838) cohorts had a mean initiation age around 49 years, 89% were women. During the postindex year, compared to the pregabalin cohort, the duloxetine cohort had higher totally annual supply days (273.5 vs. 176.6, P < 0.05), higher MPR (0.7 vs. 0.5, P < 0.05), and more patients with MPR ≥ 0.8 (45.1% vs. 29.4%, P < 0.05). Further, relative to pregabalin cohort, duloxetine cohort had lower inpatient costs ($2,994.9 vs. $4,949.6, P < 0.05), lower outpatient costs ($8,259.6 vs. $10,312.2, P < 0.05), similar medication costs ($5,214.6 vs. $5,290.8, P > 0.05), and lower total medical costs ($16,469.1 vs. $20,552.6, P < 0.05) in the postinitiation year. In a real-world setting, patients with fibromyalgia who initiated duloxetine in 2008 had better medication compliance and consumed less inpatient, outpatient, and total

Turoctocog alfa (NovoEight®)--from design to clinical proof of concept.

PubMed

Ezban, Mirella; Vad, Knud; Kjalke, Marianne

2014-11-01

Turoctocog alfa (NovoEight®) is a recombinant factor VIII (rFVIII) with a truncated B-domain made from the sequence coding for 10 amino acids from the N-terminus and 11 amino acids from the C-terminus of the naturally occurring B-domain. Turoctocog alfa is produced in Chinese hamster ovary (CHO) cells without addition of any human- or animal-derived materials. During secretion, some rFVIII molecules are cleaved at the C-terminal of the heavy chain (HC) at amino acid 720, and a monoclonal antibody binding C-terminal to this position is used in the purification process allowing isolation of the intact rFVIII. Viral inactivation is ensured by a detergent inactivation step as well as a 20-nm nano-filtration step. Characterisation of the purified protein demonstrated that turoctocog alfa was fully sulphated at Tyr346 and Tyr1664, which is required for optimal proteolytic activation by thrombin. Kinetic assessments confirmed that turoctocog alfa was activated by thrombin at a similar rate as seen for other rFVIII products fully sulphated at these positions. Tyr1680 was also fully sulphated in turoctocog alfa resulting in strong affinity (low nm Kd ) for binding to von Willebrand factor (VWF). Half-lives of 7.2 ± 0.9 h in F8-KO mice and 8.9 ± 1.8 h haemophilia A dogs supported that turoctocog alfa bound to VWF after infusion. Functional studies including thromboelastography analysis of human haemophilia A whole blood with added turoctocog alfa and effect studies in mice bleeding models demonstrated a dose-dependent effect of turoctocog alfa. The non-clinical data thus confirm the haemostatic effect of turoctocog alfa and, together with the comprehensive clinical evaluation, support the use as FVIII replacement therapy in patients with haemophilia A. © 2014 The Authors. European Journal of Haematology Published by John Wiley & Sons Ltd.

Efficacy and Safety of Peginterferon Alfa-2a (40KD) in Children with Chronic Hepatitis B: The PEG-B-ACTIVE Study.

PubMed

Wirth, Stefan; Zhang, Hongfei; Hardikar, Winita; Schwarz, Kathleen B; Sokal, Etienne; Yang, Weibo; Fan, Huimin; Morozov, Vyacheslav; Mao, Qing; Deng, Hong; Yang Huang; Yang, Lei; Frey, Nicolas; Nasmyth-Miller, Clare; Pavlovic, Vedran; Wat, Cynthia

2018-04-24

Children with chronic hepatitis B (CHB) represent an area of unmet medical need, due to increased lifetime risk of CHB sequelae and limited therapeutic options compared with adult CHB patients. The PEG-B-ACTIVE (NCT01519960) phase III study evaluated peginterferon (PegIFN) alfa-2a treatment in children aged 3 to <18 years with CHB. A total of 161 hepatitis B e antigen (HBeAg)-positive immune-active patients without advanced fibrosis/cirrhosis were randomized (2:1) to PegIFN alfa-2a (Group A, n = 101) or no treatment (Group B, n = 50); patients with advanced fibrosis were assigned to PegIFN alfa-2a (Group C, n = 10). PegIFN alfa-2a was administered for 48 weeks by body surface area category, based on 180 µg/1.73m 2 . HBeAg seroconversion rates at 24 weeks post-treatment were significantly higher in Group A (25.7% vs. 6%, P = 0.0043), as were the rates of Hepatitis B s antigen (HBsAg) clearance (8.9% vs. 0%, P = 0.03), hepatitis B virus (HBV) DNA <2,000 IU/mL (28.7% vs. 2.0%, P < 0.001) or undetectable (16.8% vs. 2.0%, P = 0.0069), and alanine aminotransferase (ALT) normalization (51.5% vs. 12%, P < 0.001). Safety, including incidence of ALT flares and neutropenia, was comparable to the established PegIFN alfa-2a profile in HBV-infected adults or hepatitis C virus-infected children. Changes in growth parameters were minimal during treatment and comparable to those in untreated patients. Safety and efficacy outcomes in Group C were in line with Group A. PegIFN alfa-2a treatment of children in the immune-active phase of CHB was efficacious and well tolerated, and associated with higher incidence of HBsAg clearance than in adults. This represents an important advance to the treatment options for children with CHB. This article is protected by copyright. All rights reserved. © 2018 by the American Association for the Study of Liver Diseases.

Face-to-face comparison of the predictive validity of two models of neuropathic pain in the rat: analgesic activity of pregabalin, tramadol and duloxetine.

PubMed

Le Cudennec, Camille; Castagné, Vincent

2014-07-15

We compared the preclinical analgesic activity of three marketed drugs with different pharmacological properties, pregabalin, tramadol and duloxetine, described as effective against neuropathic pain in the clinic. These drugs were tested against evoked pain in two different neuropathic models in the rat, the Bennett (CCI) and the Chung (SNL) models. The selected endpoints were tactile allodynia, tactile hyperalgesia, heat hyperalgesia and cold allodynia. Although all three drugs displayed analgesic activity, the effects observed varied according to the behavioral evaluation. Pregabalin showed clear analgesic effects against cold allodynia and tactile hyperalgesia in both the CCI and Chung models. Tramadol was active against all four endpoints in the Chung model with similar effects in the CCI model, apart from tactile allodynia. Duloxetine inhibited tactile allodynia and heat hyperalgesia in both neuropathic pain models. It also displayed efficacy against tactile hyperalgesia in the CCI model and against cold allodynia in the Chung model. These data confirm that the CCI and the Chung models of neuropathic pain do not detect the activity of analgesics with the same sensitivity. Furthermore, the mode of stimulation (tactile or thermal) and the type of endpoint (allodynia or hyperalgesia) can further influence the observed efficacy of gold standards as well as novel compounds developed for treating neuropathic pain symptoms. Copyright © 2014. Published by Elsevier B.V.

Duloxetine in the treatment of binge eating disorder with depressive disorders: a placebo-controlled trial.

PubMed

Guerdjikova, Anna I; McElroy, Susan L; Winstanley, Erin L; Nelson, Eric B; Mori, Nicole; McCoy, Jessica; Keck, Paul E; Hudson, James I

2012-03-01

This study evaluated duloxetine in the treatment of binge eating disorder (BED) with comorbid current depressive disorders. In this 12-week, double-blind, placebo-controlled trial, 40 patients with Diagnostic and Statistical Manual of Mental Disorders-IV-TR BED and a comorbid current depressive disorder received duloxetine (N = 20) or placebo (N = 20). The primary outcome measure was weekly binge eating day frequency. In the primary analysis, duloxetine (mean 78.7 mg/day) was superior to placebo in reducing weekly frequency of binge eating days (p = .04), binge eating episodes (p = .02), weight (p = .04), and Clinical Global Impression-Severity of Illness ratings for binge eating (p = .02) and depressive disorders (p = .01). Changes in body mass index and measures of eating pathology, depression, and anxiety did not differ between the two groups. Duloxetine may be effective for reducing binge eating, weight, and global severity of illness in BED with a comorbid current depressive disorder, but this finding needs confirmation in larger, placebo-controlled trials. Copyright © 2011 Wiley Periodicals, Inc.

Analytic model comparing the cost utility of TVT versus duloxetine in women with urinary stress incontinence.

PubMed

Jacklin, Paul; Duckett, Jonathan; Renganathan, Arasee

2010-08-01

The purpose of this study was to assess cost utility of duloxetine versus tension-free vaginal tape (TVT) as a second-line treatment for urinary stress incontinence. A Markov model was used to compare the cost utility based on a 2-year follow-up period. Quality-adjusted life year (QALY) estimation was performed by assuming a disutility rate of 0.05. Under base-case assumptions, although duloxetine was a cheaper option, TVT gave a considerably higher QALY gain. When a longer follow-up period was considered, TVT had an incremental cost-effectiveness ratio (ICER) of pound 7,710 ($12,651) at 10 years. If the QALY gain from cure was 0.09, then the ICER for duloxetine and TVT would both fall within the indicative National Institute for Health and Clinical Excellence willingness to pay threshold at 2 years, but TVT would be the cost-effective option having extended dominance over duloxetine. This model suggests that TVT is a cost-effective treatment for stress incontinence.

Duloxetine contributing to a successful multimodal treatment program for peripheral femoral neuropathy and comorbid 'reactive depression' in an adolescent.

PubMed

Kachko, Ludmyla; Ben Ami, Shiri; Liberman, Alon; Birk, Einat; Kronenberg, Sefi

2011-01-01

In the United States, duloxetine has been approved for the treatment of major depressive disorder, diabetic peripheral neuropathic pain and fibromyalgia in the adult population. Data regarding the use of duloxetine in the pediatric population, however, are very limited. Femoral nerve injury is a rare complication of cardiac catheterization. In the case described, duloxetine contributed to a successful multimodal treatment program for peripheral neuropathic pain due to femoral neuropathy in an adolescent with 'reactive depression' and conversion symptoms. To the best of the authors' knowledge, the present article is only the third such report on this dual use of duloxetine in children and adolescents, and the first report of such treatment following femoral neuropathy induced by cardiac catheterization.

Peginterferon Alfa-2a Injection

MedlinePlus

Peginterferon alfa-2a is used alone or in combination with other medications to treat chronic (long-term) hepatitis C ... people who show signs of liver damage. Peginterferon alfa-2a is also used to treat chronic hepatitis ...

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

PubMed

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

2016-01-01

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

Improvement with Duloxetine in an Adult ADHD Patient

ERIC Educational Resources Information Center

Tourjman, Smadar Valerie; Bilodeau, Mathieu

2009-01-01

Introduction: Attention-deficit/hyperactivity disorder (ADHD) is a common and disabling disorder among adults and is treated with stimulant and non stimulant medication. Objective: To report the case of a patient with ADHD showing good clinical response to duloxetine, a selective serotonin and norepinephrine reuptake inhibitor (SSNRI). Case…

Cost-effectiveness of duloxetine versus routine treatment for U.S. patients with diabetic peripheral neuropathic pain.

PubMed

Wu, Eric Q; Birnbaum, Howard G; Mareva, Milena N; Le, T Kim; Robinson, Rebecca L; Rosen, Amy; Gelwicks, Steve

2006-06-01

The purpose of this study was to compare the cost-effectiveness of duloxetine versus routine treatment in management of diabetic peripheral neuropathic pain (DPNP). Two hundred thirty-three patients with DPNP who completed a 12-week, double-blind, placebo-controlled, randomized, multicenter duloxetine trial were re-randomized into a 52-week, open-label trial of duloxetine 60 mg twice daily versus routine treatment. Routine treatment included pain management therapies. Effectiveness was measured by using the bodily pain domain (BP) of the Medical Outcomes Study Short Form 36 (SF-36). Costs were analyzed from 3 perspectives: third party payer (direct medical costs), employer (direct and indirect medical costs), and societal (patient's out-of-pocket costs and total medical costs). Costs of study medications were not included because of limited data. Bootstrap method was applied to calculate statistical inference of the incremental cost-effectiveness ratio (ICER). Routine treatment most frequently used included gabapentin (56%), venlafaxine (36%), and amitripytline (15%). From employer and societal perspectives, duloxetine was cost-effective (ICER= -342 dollars and -429 dollars, respectively, per unit of SF-36 BP; both P duloxetine trended toward cost-effectiveness (ICER= -249 dollars per unit of SF-36 BP; P duloxetine was more cost-effective than routine treatment in management of DPNP.

Interview with Dr Ghassan K Abou-Alfa.

PubMed

Abou-Alfa, G K

2016-11-01

Ghassan K Abou-Alfa joined the Gastrointestinal Oncology Service at Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College in New York back in 2001. Dr Abou-Alfa specializes in the treatment of gastrointestinal malignancies. Dr Abou-Alfa received his medical degree from the American University of Beirut, Lebanon, and completed his post-doctoral training at Yale University School of Medicine. His research is dedicated to finding novel therapies and improving the effectiveness of the current therapies for hepatocellular carcinoma, cholangiocarcinoma and gallbladder cancer, while continuing to understand the basic mechanisms of the diseases and its therapy. Dr Abou-Alfa has invested several years in helping develop multi-tyrosine kinases and more immune-modulator therapies. Dr Abou-Alfa has many publications in the field. He led on many occasions international teams of investigators. Dr Abou-Alfa serves as the chair of the National Cancer Institute (NCI) Task Force for Hepatobiliary Cancers and the chair of the AIDS Malignancy Consortium (AMC) Non-AIDS Defining Malignancies (NADC) Liver/GI Task Force. Dr Abou-Alfa also co-chairs the hepatobiliary cancers subgroup of the Alliance cooperative group, and is a cadre member of both the gastrointestinal cancers and pharmacogenomics and population pharmacology committees. Dr Abou-Alfa who has lectured worldwide on the subject on gastrointestinal malignancies, is also a strong advocate for raising awareness and support for improving the outcome of patients with this disease, and enhancing oncologic education worldwide.

Rescue Pharmacotherapy With Duloxetine for Selective Serotonin Reuptake Inhibitor Nonresponders in Late-Life Depression: Outcome and Tolerability

PubMed Central

Karp, Jordan F.; Whyte, Ellen M.; Lenze, Eric J.; Dew, Mary A.; Begley, Amy; Miller, Mark D.; Reynolds, Charles F.

2010-01-01

Background Up to 50% of depressed older adults either do not adequately respond to or are unable to tolerate treatment with a serotonin-specific reuptake inhibitor. On the basis of previous experience with serotonin-norepinephrine reuptake inhibitors, we predicted at least a 50% response rate to open-label treatment with duloxetine in subjects who were resistant to treatment with the selective serotonin reuptake inhibitor (SSRI) escitalopram. Method Community-dwelling subjects aged 65 years or older with current nonpsychotic major depressive disorder as established by the Structured Clinical Interview for DSM-IV received escitalopram under protocolized conditions between April 2004 and September 2006. Subjects who failed to meet response criteria or relapsed after achieving an initial response were subsequently switched to open treatment with duloxetine up to 120 mg/day. Side effects were assessed at every visit. Results Subjects (N = 40) switched to duloxetine had a mean (SD) age of 74.4 (7.0) years and a baseline (before escitalopram) 17-item Hamilton Rating Scale for Depression (HAM-D-17) score of 20.0 (3.5) and were predominantly female (65.0%) and white (82.5%). The mean (SD) maximum dose of duloxetine was 93.0 (27.8) mg/day. Subjects received this maximum dose for a median duration of 6.9 weeks. Fifty percent of subjects (N = 20) met criteria for full response, 17.5% (N = 7) were partial responders, and 32.5% (N = 13) did not respond. The median time to response was 12.0 weeks (95% CI = 8.4 to 14.6). Five of the subjects (12.5%) discontinued duloxetine because of intolerable side effects. Discussion These open-label data suggest that duloxetine at doses up to 120 mg/day is a well-tolerated and potentially effective treatment for older adults who fail to respond to an adequate trial of an SSRI. These results are preliminary, and future controlled studies are required to test the efficacy of rescue pharmacotherapy with duloxetine. Trial Registration

Considering benefits and harms of duloxetine for treatment of stress urinary incontinence: a meta-analysis of clinical study reports.

PubMed

Maund, Emma; Guski, Louise Schow; Gøtzsche, Peter C

2017-02-06

The European Medicines Agency makes clinical study reports publicly available and publishes reasons for not approving applications for marketing authorization. Duloxetine has been approved in Europe for the treatment of stress urinary incontinence in women. The reported adverse effects of duloxetine include mental health problems and suicidality. We obtained clinical study reports from the European Medicines Agency concerning use of this drug for stress urinary incontinence. We performed a meta-analysis of 4 randomized placebo-controlled trials of duloxetine (involving a total of 1913 patients) submitted to the European Medicines Agency for marketing approval for the indication of stress urinary incontinence in women. We used data from the clinical study reports (totalling 6870 pages and including individual patient data) to assess benefits (including frequency of incontinence and changes in quality-of-life scores, such as Patient Global Impression of Improvement rating) and harms (both general harms, including discontinuation because of adverse events, and harms related to suicidality, violent behaviour and their potential precursors, such as akathisia and activation [stimulating effects such as insomnia, anxiety and agitation]). Duloxetine was significantly better than placebo in terms of percentage change in weekly incontinence episodes (mean difference -13.56%, 95% confidence interval [CI] -21.59% to -5.53%) and change in Incontinence Quality of Life total score (mean difference 3.24, 95% CI 2.00 to 4.48). However, the effect sizes were small, and a sensitivity analysis (with removal of one trial) showed that the number needed to treat for a Patient Global Impression of Improvement rating of "much better or very much better" was 8 (95% CI 6 to 13). The numbers needed to harm were 7 (95% CI 6 to 8) for discontinuing because of an adverse event and 7 (95% CI 6 to 9) for experiencing an activation event. No suicidality, violence or akathisia events were noted

Lonoctocog Alfa: A Review in Haemophilia A.

PubMed

Al-Salama, Zaina T; Scott, Lesley J

2017-10-01

Lonoctocog alfa (rVIII-SingleChain; Afstyla ® ) is a novel single-chain recombinant factor VIII (FVIII) molecule, with a truncated B-domain and the heavy and light chains covalently linked to form a stable and homogenous drug that binds with high affinity to von Willebrand factor (VWF). Intravenous lonoctocog alfa is approved for the prophylaxis and treatment of bleeding in patients with haemophilia A in several countries worldwide. In two pivotal, multicentre trials, lonoctocog alfa was effective in the treatment of bleeding episodes and as prophylaxis, including for perioperative management in adults, adolescents and children. In terms of haemostatic efficacy in controlling bleeding episodes, overall treatment and investigator-assessed success rates were high across all age groups, with the majority of these bleeds controlled with a single injection of lonoctocog alfa. Low median spontaneous, overall and traumatic annualized bleeding rates were evident with prophylactic lonoctocog alfa regimens in both trials. Lonoctocog alfa was generally well-tolerated, with very low rates of injection-site reactions. No previously treated patient experienced an anaphylactic reaction or developed an inhibitor. In conclusion, lonoctocog alfa is an effective and generally well-tolerated alternative to conventional FVIII products for the treatment and prophylaxis of bleeding, including in the surgical setting, in adults, adolescents and children with haemophilia A.

Duloxetine and Subacute Pain after Knee Arthroplasty when Added to a Multimodal Analgesic Regimen: A Randomized, Placebo-controlled, Triple-blinded Trial.

PubMed

YaDeau, Jacques T; Brummett, Chad M; Mayman, David J; Lin, Yi; Goytizolo, Enrique A; Padgett, Douglas E; Alexiades, Michael M; Kahn, Richard L; Jules-Elysee, Kethy M; Fields, Kara G; Goon, Amanda K; Gadulov, Yuliya; Westrich, Geoffrey

2016-09-01

Duloxetine is effective for chronic musculoskeletal and neuropathic pain, but there are insufficient data to recommend the use of antidepressants for postoperative pain. The authors hypothesized that administration of duloxetine for 15 days would reduce pain with ambulation at 2 weeks after total knee arthroplasty. In this triple-blinded, randomized, placebo-controlled trial, patients received either duloxetine or placebo for 15 days, starting from the day of surgery. Patients also received a comprehensive multimodal analgesic regimen including neuraxial anesthesia, epidural analgesia, an adductor canal block, meloxicam, and oxycodone/acetaminophen as needed. The primary outcome was the pain score (0 to 10 numeric rating scale) with ambulation on postoperative day 14. One hundred six patients were randomized and analyzed. On day 14, duloxetine had no effect on pain with ambulation; mean pain was 3.8 (SD, 2.3) for placebo versus 3.5 (SD, 2.1) for duloxetine (difference in means [95% CI], 0.4 [-0.5 to 1.2]; P = 0.386). Symptoms potentially attributable to duloxetine discontinuation at study drug completion (nausea, anxiety) occurred among nine patients (duloxetine) and five patients (placebo); this was not statistically significant (P = 0.247). Statistically significant secondary outcomes included opioid consumption (difference in mean milligram oral morphine equivalents [95% CI], 8.7 [3.3 to 14.1], P = 0.002 by generalized estimating equation) over the postoperative period and nausea on day 1 (P = 0.040). There was no difference in other side effects or in anxiety and depression scores. When included as a part of a multimodal analgesic regimen for knee arthroplasty, duloxetine does not reduce subacute pain with ambulation.

Assessment of functional outcomes by Sheehan Disability Scale in patients with major depressive disorder treated with duloxetine versus selective serotonin reuptake inhibitors.

PubMed

Sheehan, David V; Mancini, Michele; Wang, Jianing; Berggren, Lovisa; Cao, Haijun; Dueñas, Héctor José; Yue, Li

2016-01-01

We compared functional impairment outcomes assessed with Sheehan Disability Scale (SDS) after treatment with duloxetine versus selective serotonin reuptake inhibitors (SSRIs) in patients with major depressive disorder. Data were pooled from four randomized studies comparing treatment with duloxetine and SSRIs (three double blind and one open label). Analysis of covariance, with last-observation-carried-forward approach for missing data, explored treatment differences between duloxetine and SSRIs on SDS changes during 8 to 12 weeks of acute treatment for the intent-to-treat population. Logistic regression analysis examined the predictive capacity of baseline patient characteristics for remission in functional impairment (SDS total score ≤ 6 and SDS item scores ≤ 2) at endpoint. Included were 2193 patients (duloxetine n = 1029; SSRIs n = 835; placebo n = 329). Treatment with duloxetine and SSRIs resulted in significantly (p < 0.01) greater improvements in the SDS total score versus treatment with placebo. Higher SDS (p < 0.0001) or 17-item Hamilton Depression Rating Scale baseline scores (p < 0.01) predicted lower probability of functional improvement after treatment with duloxetine or SSRIs. Female gender (p ≤ 0.05) predicted higher probability of functional improvement after treatment with duloxetine or SSRIs. Treatment with SSRIs and duloxetine improved functional impairment in patients with major depressive disorder. Higher SDS or 17-item Hamilton Depression Rating Scale baseline scores predicted less probability of SDS improvement; female gender predicted better improvement in functional impairment at endpoint. © 2015 The Authors. Human Psychopharmacology: Clinical and Experimental published by John Wiley & Sons, Ltd.

Chikungunya Virus: In Vitro Response to Combination Therapy With Ribavirin and Interferon Alfa 2a.

PubMed

Gallegos, Karen M; Drusano, George L; D Argenio, David Z; Brown, Ashley N

2016-10-15

We evaluated the antiviral activities of ribavirin (RBV) and interferon (IFN) alfa as monotherapy and combination therapy against chikungunya virus (CHIKV). Vero cells were infected with CHIKV in the presence of RBV and/or IFN alfa, and viral production was quantified by plaque assay. A mathematical model was fit to the data to identify drug interactions for effect. We ran simulations using the best-fit model parameters to predict the antiviral activity associated with clinically relevant regimens of RBV and IFN alfa as combination therapy. The model predictions were validated using the hollow fiber infection model (HFIM) system. RBV and IFN alfa were effective against CHIKV as monotherapy at supraphysiological concentrations. However, RBV and IFN alfa were highly synergistic for antiviral effect when administered as combination therapy. Simulations with our mathematical model predicted that a standard clinical regimen of RBV plus IFN alfa would inhibit CHIKV burden by 2.5 log10 following 24 hours of treatment. In the HFIM system, RBV plus IFN alfa at clinical exposures resulted in a 2.1-log10 decrease in the CHIKV burden following 24 hours of therapy. These findings validate the prediction made by the mathematical model. These studies illustrate the promise of RBV plus IFN alfa as a potential therapeutic strategy for the treatment of CHIKV infections. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Disposable screen-printed sensors for determination of duloxetine hydrochloride

PubMed Central

2012-01-01

A screen-printed disposable electrode system for the determination of duloxetine hydrochloride (DL) was developed using screen-printing technology. Homemade printing has been characterized and optimized on the basis of effects of the modifier and plasticizers. The fabricated bi-electrode potentiometric strip containing both working and reference electrodes was used as duloxetine hydrochloride sensor. The proposed sensors worked satisfactorily in the concentration range from 1.0 × 10-6-1.0 × 10-2 mol L-1 with detection limit reaching 5.0 × 10-7 mol L-1 and adequate shelf life of 6 months. The method is accurate, precise and economical. The proposed method has been applied successfully for the analysis of the drug in pure and in its dosage forms. In this method, there is no interference from any common pharmaceutical additives and diluents. Results of the analysis were validated statistically by recovery studies. PMID:22264225

Clinical consequences of initial duloxetine dosing strategies: Comparison of 30 and 60 mg QD starting doses

PubMed Central

Dunner, David L.; Wohlreich, Madelaine M.; Mallinckrodt, Craig H.; Watkin, John G.; Fava, Maurizio

2005-01-01

Background: To reduce the risk for treatment-emergent adverse events and increase patient compliance, clinicians frequently prescribe a suboptimal starting dose of antidepressants, with the goal of increasing the dose once the patient has demonstrated tolerability. Objective: The aim of this study was to examine the tolerability and effectiveness associated with an initial week of duloxetine hydrochloride treatment at 30 mg QD and subsequent dose increase to 60 mg QD, compared with a starting dose of 60 mg QD. Methods: In this open-label study, all patients met the criteria for major depressive disorder (MDD) described in the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Patients were required to wash out from previous antidepressant medications for 21 days, and were then randomized to receive duloxetine 30 or 60 mg QD for 1 week. After 1 week, patients receiving duloxetine 30 mg QD had their dose increased to 60 mg QD. Patients returned for assessments at weeks 2, 4, 6, 8, and 12. During the remainder of the 12-week study period, the duloxetine dose could be titrated based on the degree of response from 60 mg QD (minimum) to 120 mg QD (maximum), with 90 mg QD as an intermediate dose. Tolerability was assessed by means of discontinuation rates, spontaneously reported adverse events, changes in vital signs, and laboratory tests. Effectiveness measures included the 17-item Hamilton Rating Scale for Depression (HAMD17) total score, HAMD17 core and Maier subscales, individual HAMD17 items, the Hamilton Rating Scale for Anxiety total score, and the Clinical Global Impression of Severity. Results: One hundred thirty-seven patients were enrolled (82 women, 55 men; mean age, 42 years; duloxetine 30 mg QD, 67 patients; duloxetine 60 mg QD, 70 patients). The rate of discontinuation due to adverse events did not differ significantly between patients starting duloxetine at 30 mg QD and 60 mg QD (13

Open-label study of duloxetine for the treatment of obsessive-compulsive disorder.

PubMed

Dougherty, Darin D; Corse, Andrew K; Chou, Tina; Duffy, Amanda; Arulpragasam, Amanda R; Deckersbach, Thilo; Jenike, Michael A; Keuthen, Nancy J

2015-01-01

This study sought to investigate the efficacy of duloxetine for the treatment of obsessive-compulsive disorder (DSM-IV). Twenty individuals were enrolled in a 17-week, open-label trial of duloxetine at Massachusetts General Hospital. Data were collected between March 2007 and September 2012. Study measures assessing obsessive-compulsive disorder symptoms, quality of life, depression, and anxiety were administered at baseline and weeks 1, 5, 9, 13, and 17. The primary outcome measures were the Yale-Brown Obsessive Compulsive Scale and Clinical Global Improvement scale. For the 12 study completers, pre- and posttreatment analyses revealed significant improvements (P<.05) on clinician- and self-rated measures of obsessive-compulsive disorder symptoms and quality of life. Among the 12 completers, more than one-half (n=7) satisfied full medication response criteria. Intention-to-treat analyses (n=20) showed similar improvements (P<.05) on primary and secondary study outcome measures. The results of this study suggest that duloxetine may provide a significant reduction in symptoms for patients with obsessive-compulsive disorder. ClinicalTrials.gov NCT00464698; http://clinicaltrials.gov/ct2/show/NCT00464698?term=NCT00464698&rank=1. © The Author 2015. Published by Oxford University Press on behalf of CINP.

Peginterferon Alfa-2b Injection (Sylatron)

MedlinePlus

Peginterferon alfa-2b injection is used in people with malignant melanoma (a life-threatening cancer that begins in certain ... started within 84 days of the surgery. Peginterferon alfa-2b injection is in a class of medications ...

Occupancy of Norepinephrine Transporter by Duloxetine in Human Brains Measured by Positron Emission Tomography with (S,S)-[18F]FMeNER-D2.

PubMed

Moriguchi, Sho; Takano, Harumasa; Kimura, Yasuyuki; Nagashima, Tomohisa; Takahata, Keisuke; Kubota, Manabu; Kitamura, Soichiro; Ishii, Tatsuya; Ichise, Masanori; Zhang, Ming-Rong; Shimada, Hitoshi; Mimura, Masaru; Meyer, Jeffrey H; Higuchi, Makoto; Suhara, Tetsuya

2017-12-01

The norepinephrine transporter in the brain has been targeted in the treatment of psychiatric disorders. Duloxetine is a serotonin and norepinephrine reuptake inhibitor that has been widely used for the treatment of depression. However, the relationship between dose and plasma concentration of duloxetine and norepinephrine transporter occupancy in the human brain has not been determined. In this study, we examined norepinephrine transporter occupancy by different doses of duloxetine. We calculated norepinephrine transporter occupancies from 2 positron emission tomography scans using (S,S)-[18F]FMeNER-D2 before and after a single oral dose of duloxetine (20 mg, n = 3; 40 mg, n = 3; 60 mg, n =2). Positron emission tomography scans were performed from 120 to 180 minutes after an i.v. bolus injection of (S,S)-[18F]FMeNER-D2. Venous blood samples were taken to measure the plasma concentration of duloxetine just before and after the second positron emission tomography scan. Norepinephrine transporter occupancy by duloxetine was 29.7% at 20 mg, 30.5% at 40 mg, and 40.0% at 60 mg. The estimated dose of duloxetine inducing 50% norepinephrine transporter occupancy was 76.8 mg, and the estimated plasma drug concentration inducing 50% norepinephrine transporter occupancy was 58.0 ng/mL. Norepinephrine transporter occupancy by clinical doses of duloxetine was approximately 30% to 40% in human brain as estimated using positron emission tomography with (S,S)-[18F]FMeNER-D2. © The Author 2017. Published by Oxford University Press on behalf of CINP.

Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: a randomized clinical trial

PubMed Central

Smith, Ellen M. Lavoie; Pang, Herbert; Cirrincione, Constance; Fleishman, Stewart; Paskett, Electra D.; Ahles, Tim; Bressler, Linda R.; Fadul, Camilo E.; Knox, Chetaye; Le-Lindqwister, Nguyet; Gilman, Paul B.; Shapiro, Charles L.

2013-01-01

Context There are no known effective treatments for painful chemotherapy-induced peripheral neuropathy (CIPN). Objective The primary objective was to determine the effect of duloxetine 60 mg daily on CIPN “average” pain severity Design Randomized, double-blind, placebo-controlled crossover Setting Eight National Cancer Institute (NCI)-funded cooperative research networks recruited patients from community and academic settings between April 2008 and March 2011. Study follow-up was completed July 2012. Patients 231 patients ≥ 25 years of age were randomized (stratified by chemotherapy drug and CIPN comorbid risk) to receive either duloxetine followed by placebo or placebo followed by duloxetine. Eligible patients reported ≥ Grade 1 sensory CIPN per the NCI Common Toxicity Criteria for Adverse Events and ≥ 4/10 average CIPN-related pain following paclitaxel or oxaliplatin treatment. 81% completed the initial treatment period. Intervention The initial treatment consisted of duloxetine/placebo 30mg/one capsule daily for the first week, then 60mg/two capsules for four additional weeks Outcome Measure The primary hypothesis was that duloxetine would be more effective than placebo in decreasing CIPN pain. Pain severity was assessed using the Brief Pain Inventory-Short Form “average pain” item [0 (no pain) – 10 (as bad as can imagine)]. Results Individuals receiving duloxetine as initial treatment (weeks 1–5) reported a larger mean decrease in average pain (1.06; 95% CI: 0.72, 1.40) compared to placebo-treated patients (0.34; 95% CI: 0.01, 0.66) (p = 0.003) (effect size = 0.513). The observed mean difference in the average pain score between the duloxetine and placebo groups was 0.73 (95% CI: 0.26, 1.20). 59% of duloxetine-treated patients compared to 38% of placebo-treated patients reported decreased pain of any amount. Conclusions Among patients with painful CIPN, the use of duloxetine compared with placebo for 5 weeks resulted in a greater reduction in

Budget impact analysis of darbepoetin alfa every 3 weeks versus epoetin alfa every week for the treatment of chemotherapy-induced anaemia from a US payer's perspective.

PubMed

Rubin, Robert J; Glaspy, John A; Adams, John L; Mafilios, Michael S; Wang, Sharon M; Viswanathan, Hema N; Kallich, Joel D

2008-01-01

This analysis was conducted to compare the direct medical costs of treatment with darbepoetin alfa every 3 weeks (Q3W) and epoetin alfa every week (QW) in patients with chemotherapy-induced anaemia (CIA) from the payer's perspective. An analysis was conducted from a US health plan perspective to compare the annual budget impact for CIA with darbepoetin alfa Q3W and epoetin alfa QW over a 16-week treatment period. Dosing regimens were obtained from registration clinical trials. Mean doses, including dose adjustments, were 375.6 microg Q3W for darbepoetin alfa and 43,187 U QW for epoetin alfa. Costs of medical resources included drug acquisition and administration costs. The base case analysis resulted in a per-patient budget impact of $8,544 and $8,667 for darbepoetin alfa and epoetin alfa, respectively. Per member per month cost was $0.90 for darbepoetin alfa and $0.91 for epoetin alfa, based on an estimate of 2,735 CIA patients in a health plan population of 2.17 million. The analysis was most sensitive to drug dose, treatment period and drug price. Results suggest that per-patient direct medical costs of CIA treatment, when initiated at labelled starting doses, are comparable for darbepoetin alfa Q3W and epoetin alfa QW.

Phloretin either alone or in combination with duloxetine alleviates the STZ-induced diabetic neuropathy in rats.

PubMed

Balaha, Mohamed; Kandeel, Samah; Kabel, Ahmed

2018-05-01

Diabetic neuropathy (DN) is one of most disabling disorder complicating diabetes mellites (DM), which affects more than 50% of the all diabetic patients during the disease course. Duloxetine (DX) is one of the first-line medication that approved by FDA for management of DN, nevertheless, it is too costly and has many adverse effects. Recently, phloretin (PH) exhibited powerful euglycemic, antihyperlipidemic, antioxidant, and anti-inflammatory activities. Therefore, we investigated the in vivo possible antineuropathic activity of phloretin, besides, its modulating effects on duloxetine potency, in a rat model of DN. Twelve-week-old male Wistar rats received a single intraperitoneal injection of 55 mg/kg STZ to induce DM. Either DX (30 or 15 mg/kg dissolved in distilled water), PH (50 0r 25 mg/kg dissolved in 0.5% DMSO) or a combination of 15 mg/kg DX and 25 mg/kg PH, used daily orally for 4 weeks to treat DN, starting from the end of the 4 th week of DM development, when DN confirmed. Our finding showed that both DX and PH dose-dependently improved behavioral parameters (with the superiority of DX), sciatic nerve tissue antioxidant state, and suppressed tissue inflammatory cytokine, besides, they abrogated the tissue histopathological changes (with the superiority of PH). Moreover, DX augmented the DM metabolic disturbance and hepatic dysfunction, however, PH effectively amended these disorders. Furthermore, the low-dose combination of both, had the merits of both medications, with the alleviation of their disadvantages. Therefore, phloretin could be a promising agent in the management of DN either alone or in combination with duloxetine. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Total synthesis of fluoxetine and duloxetine through an in situ imine formation/borylation/transimination and reduction approach.

PubMed

Calow, Adam D J; Fernández, Elena; Whiting, Andrew

2014-08-28

We report efficient, catalytic, asymmetric total syntheses of both (R)-fluoxetine and (S)-duloxetine from α,β-unsaturated aldehydes conducting five sequential one-pot steps (imine formation/copper mediated β-borylation/transimination/reduction/oxidation) followed by the specific ether group formation which deliver the desired products (R)-fluoxetine in 45% yield (96% ee) and (S)-duloxetine in 47% yield (94% ee).

Susoctocog Alfa: A Review in Acquired Haemophilia A.

PubMed

Burness, Celeste B; Scott, Lesley J

2016-05-01

Intravenous susoctocog alfa (Obizur(®)) is a recombinant, B-domain deleted, porcine sequence antihaemophilic factor VIII (FVIII) product that has recently been approved for the treatment of bleeding episodes in adults with acquired haemophilia A (AHA). Intravenous susoctocog alfa was an effective and generally well tolerated treatment for serious bleeding episodes in adult patients with AHA in a multinational, phase II/III trial (n = 28 evaluable). Patients received an initial dose of susoctocog alfa 200 U/kg, with subsequent dosages based on target FVIII trough levels and clinical assessments. All patients had a positive haemostatic response (based on predefined criteria) of the primary bleed 24 h after the first infusion of susoctocog alfa, with the bleed successfully controlled at the time of final dosing in 86 % of patients. The most frequently reported adverse reaction (incidence >5 %) was the development of inhibitory antibodies against susoctocog alfa (porcine FVIII). Overall, 25 % of antibody naive patients developed anti-susoctocog alfa antibodies during the study. No serious treatment-related adverse events, thrombotic events or allergic reactions were reported during the trial. In conclusion, intravenous susoctocog alfa is a useful addition to the limited treatment options available for the management of acute bleeding episodes in adults with AHA.

Peginterferon alfa-2b and ribavirin: effective in patients with hepatitis C who failed interferon alfa/ribavirin therapy.

PubMed

Poynard, Thierry; Colombo, Massimo; Bruix, Jordi; Schiff, Eugene; Terg, Ruben; Flamm, Steven; Moreno-Otero, Ricardo; Carrilho, Flair; Schmidt, Warren; Berg, Thomas; McGarrity, Thomas; Heathcote, E Jenny; Gonçales, Fernando; Diago, Moises; Craxi, Antonio; Silva, Marcelo; Bedossa, Pierre; Mukhopadhyay, Pabak; Griffel, Louis; Burroughs, Margaret; Brass, Clifford; Albrecht, Janice

2009-05-01

Treatment with peginterferon alfa and ribavirin produces a sustained virologic response (SVR) in approximately 60% of hepatitis C virus (HCV)-infected patients. Alternate options are needed for patients who relapse or do not respond to therapy. This prospective, international, multicenter, open-label study evaluated efficacy and safety of peginterferon alfa-2b (1.5 microg/kg/wk) plus weight-based ribavirin (800-1400 mg/day) in 2333 chronic HCV-infected patients with significant fibrosis/cirrhosis whose previous interferon alfa/ribavirin therapy failed. Patients with undetectable HCV-RNA at treatment week (TW) 12 received 48 weeks of therapy; patients with detectable HCV-RNA at TW12 could enter maintenance studies at TW18; 188 patients with low/detectable HCV-RNA at TW12 continued therapy at the investigator's request. Overall, 22% of the patients attained SVR (56% with undetectable HCV-RNA and 12% with low/detectable HCV-RNA at TW12). SVR was better in relapsers (38%) than nonresponders (14%), regardless of previous treatment, and in patients previously treated with interferon-alfa/ribavirin (25%) than peginterferon alfa-ribavirin (17%). Predictors of response in patients with undetectable HCV-RNA at TW12 were genotype (2/3 vs 1, respectively; odds ratio [OR] 2.4; P < .0001), fibrosis score (F2 vs F4; OR, 2.2; F3 vs F4; OR, 1.7; P < .0001), and baseline viral load (< or =600,000 vs >600,000 IU/mL; OR, 1.4; P = .0223). These factors plus previous treatment and response were overall predictors of SVR. Safety was similar among fibrosis groups. Peginterferon alfa-2b plus weight-based ribavirin is effective and safe in patients who failed interferon alfa/ribavirin therapy. Genotype, baseline viral load, and fibrosis stage were predictors of response.

Physicochemical compatibility of mixtures of dornase alfa and tobramycin containing nebulizer solutions.

PubMed

Krämer, Irene; Schwabe, Astrid; Lichtinghagen, Ralf; Kamin, Wolfgang

2009-02-01

Patients suffering from cystic fibrosis (CF) often need to inhale multiple doses of different nebulizable drugs per day. Patients attempt to shorten the time consuming administration procedure by mixing drug solutions/suspensions for simultaneous inhalation. The objective of this experimental study was to determine whether mixtures of the nebulizer solution dornase alfa (Pulmozyme) with tobramycin nebulizer solutions (TOBI and GERNEBCIN 80 mg) are physico-chemically compatible. Drug combinations were prepared by mixing the content of one respule Pulmozyme with either one respule TOBI or one ampoule GERNEBCIN 80 mg. Test solutions were stored at room temperature and exposed to light. Dornase alfa activity and tobramycin concentrations were determined by using a kinetic colorimetric DNase activity assay and a fluorescence immunoassay, respectively. Physical compatibility was determined by visual inspection and measurements of pH and osmolality. Tobramycin concentration was not affected by mixing the drug products. In spite of the high variability of the dornase alfa potency assay, it is obvious that activity is especially affected by sodium metabisulfite, used as excipient in GERNEBCIN. Patients should be advised, not to mix Pulmozyme with GERNEBCIN because of the incompatibility reaction. Further analytical studies are needed in order to determine the integrity and activity of dornase alfa in mixtures of Pulmozyme with TOBI. Finally clinical studies are necessary in order to demonstrate equivalent efficacy and safety of simultaneous inhalation in comparison to consecutive inhalation of both drugs. (c) 2008 Wiley-Liss, Inc.

XM17 Follitropin Alfa (Ovaleap(®)): A Review in Reproductive Endocrine Disorders.

PubMed

Hoy, Sheridan M

2016-08-01

The subcutaneous recombinant human follicle-stimulating hormone XM17 follitropin alfa (Ovaleap(®)) is approved in the EU as a biosimilar of follitropin alfa (Gonal-f(®)) for use in all indications for which the reference product is approved, including as a multifollicular stimulant in women undergoing superovulation for assisted reproductive technology (ART) treatment. In a nonblind, phase I study in healthy female volunteers, the pharmacokinetic profile of XM17 follitropin alfa was bioequivalent to that of reference follitropin alfa following single dosing. Moreover, in a multinational, phase III study, the efficacy of XM17 follitropin alfa as a multifollicular stimulant was equivalent to that of reference follitropin alfa in terms of the number of retrieved oocytes (primary endpoint) in women undergoing controlled ovarian stimulation for ART treatment. There were no clinically relevant differences in oocyte quality between XM17 follitropin alfa and reference follitropin alfa, with biochemical, clinical and ongoing pregnancy rates and take-home baby rates not significantly differing between the treatment groups. XM17 follitropin alfa was generally well tolerated in this patient population, with its tolerability profile generally similar to that of reference follitropin alfa and with no new unexpected tolerability concerns identified. Thus, XM17 follitropin alfa is an effective treatment option in patients requiring follitropin alfa therapy for various reproductive endocrine disorders, providing a useful alternative to reference follitropin alfa.

Drotrecogin alfa (activated)...a sad final fizzle to a roller-coaster party.

PubMed

Angus, Derek C

2012-02-06

Following the failure of PROWESS-SHOCK to demonstrate efficacy, Eli Lilly and Company withdrew drotrecogin alfa (activated) from the worldwide market. Drotrecogin was initially approved after the original trial, PROWESS, was stopped early for overwhelming efficacy. These events prompt consideration of both the initial approval decision and the later decision to withdraw. It is regrettable that the initial decision was made largely on a single trial that was stopped early. However, the decision to approve was within the bounds of normal regulatory practice and was made by many approval bodies around the world. Furthermore, the overall withdrawal rate of approved drugs remains very low. The decision to withdraw was a voluntary decision by Eli Lilly and Company and likely reflected key business considerations. Drotrecogin does have important biologic effects, and it is probable that we do not know how best to select patients who would benefit. Overall, there may still be a small advantage to drotrecogin alfa, even used non-selectively, but the costs of determining such an effect with adequate certainty are likely prohibitive, and the point is now moot. In the future, we should consider ways to make clinical trials easier and quicker so that more information can be available in a timely manner when considering regulatory approval. At the same time, more sophisticated selection of patients seems key if we are to most wisely test agents designed to manipulate the septic host response.

In vitro stability, potency, and dissolution of duloxetine enteric-coated pellets after exposure to applesauce, apple juice, and chocolate pudding.

PubMed

Wells, Kevin A; Losin, William G

2008-07-01

Difficulty swallowing is a common problem in the clinical setting, particularly in elderly patients, and can significantly affect an individual's ability to maintain a proper level of nutrition. The purpose of this in vitro study was to determine if mixing duloxetine enteric-coated pellets in food substances is an acceptable alternative method for administering this oral formulation to patients with swallowing difficulties. To determine whether administration in food substances with varying pH values (applesauce and apple juice, pH = approximately 3.5; chocolate pudding, pH = approximately 5.5-6.0) affects the enteric coating of the formulation, duloxetine pellets (ie, the contents of a 20-mg duloxetine capsule) were exposed to applesauce, apple juice, and chocolate pudding at room temperature and tested in triplicate for potency and impurities; for dissolution, 6 replicates were tested. To assess product stability and integrity of the enteric coating, potency, impurities, and dissolution tests of the pellets were conducted and compared with pellets not exposed to food. The duloxetine pellets were extracted from the food material using a solution of 0.1 normal (N) hydrochloric acid (HCl) prepared from concentrated HCl (commercially available) and deionized water. For the potency and impurities tests, a 40:60 solution of acetonitrile and pH 8.0 phosphate buffer was used as the sample solvent to extract the active pharmaceutical ingredient from the formulation to prepare the samples for testing. The amount of active pharmaceutical ingredient released (in vitro dissolution) from the pellets after exposure to the food substances was determined using 2 media solutions, 0.1 N HCl followed by pH 6.8 phosphate buffer. Applesauce and chocolate pudding were selected as vehicles for oral administration, while apple juice was intended to be used as a wash for a nasogastric tube. Mean (SD) potency results for the 20-mg capsule strength were 20.256 (0.066), 20.222 (0.163), and

Cloning and expression of codon-optimized recombinant darbepoetin alfa in Leishmania tarentolae T7-TR.

PubMed

Kianmehr, Anvarsadat; Golavar, Raziyeh; Rouintan, Mandana; Mahrooz, Abdolkarim; Fard-Esfahani, Pezhman; Oladnabi, Morteza; Khajeniazi, Safoura; Mostafavi, Seyede Samaneh; Omidinia, Eskandar

2016-02-01

Darbepoetin alfa is an engineered and hyperglycosylated analog of recombinant human erythropoietin (EPO) which is used as a drug in treating anemia in patients with chronic kidney failure and cancer. This study desribes the secretory expression of a codon-optimized recombinant form of darbepoetin alfa in Leishmania tarentolae T7-TR. Synthetic codon-optimized gene was amplified by PCR and cloned into the pLEXSY-I-blecherry3 vector. The resultant expression vector, pLEXSYDarbo, was purified, digested, and electroporated into the L. tarentolae. Expression of recombinant darbepoetin alfa was evaluated by ELISA, reverse-transcription PCR (RT-PCR), Western blotting, and biological activity. After codon optimization, codon adaptation index (CAI) of the gene raised from 0.50 to 0.99 and its GC% content changed from 56% to 58%. Expression analysis confirmed the presence of a protein band at 40 kDa. Furthermore, reticulocyte experiment results revealed that the activity of expressed darbepoetin alfa was similar to that of its equivalent expressed in Chinese hamster ovary (CHO) cells. These data suggested that the codon optimization and expression in L. tarentolae host provided an efficient approach for high level expression of darbepoetin alfa. Copyright © 2015 Elsevier Inc. All rights reserved.

Impact of Pretreatment With Antidepressants on the Efficacy of Duloxetine in Terms of Mood Symptoms and Functioning: An Analysis of 15 Pooled Major Depressive Disorder Studies

PubMed Central

Barros, Bruno R.; Schacht, Alexander; Happich, Michael; Televantou, Foula; Berggren, Lovisa; Walker, Daniel J.

2014-01-01

Objective: This post hoc analysis aimed to determine whether patients with major depressive disorder (MDD) in duloxetine trials who were antidepressant naive or who were previously exposed to antidepressants exhibited differences in efficacy and functioning. Method: Data were pooled from 15 double-blind, placebo- and/or active-controlled duloxetine trials of adult patients with MDD conducted by Eli Lilly and Company. The individual studies took place between March 2000 and November 2009. Data were analyzed using 4 pretreatment subgroups: first-episode never treated, multiple-episode never treated, treated previously only with selective serotonin reuptake inhibitors (SSRIs), and previously treated with antidepressants other than just SSRIs. Measures included the 17-item Hamilton Depression Rating Scale (HDRS-17) total and somatic symptom subscale scores, Montgomery-Asberg Depression Rating Scale (MADRS) total score, and Sheehan Disability Scale total score. Response rates (50% and 30%) were based on the HDRS-17 total score and remission rates on either the HDRS-17 or MADRS total score. Results: Response and remission rates were significantly greater (P < .05 in 11 of 12 comparisons) for duloxetine versus placebo in the 4 subgroups. A trend of greater response and remission occurred for first-episode versus multiple-episode patients; both groups were generally higher than the antidepressant-treated groups. Mean changes in efficacy measures were mostly significantly greater (P < .05 in 13 of 16 comparisons) for duloxetine versus placebo within each pretreatment subgroup, with some (P < .05 in 2 of 24 comparisons) significant interaction effects between subgroups on HDRS-17 total and somatic symptoms scores. Conclusions: Duloxetine was generally superior to placebo on response and remission rates and in mean change on efficacy measures. Response and remission rates were numerically greater for first-episode versus multiple-episode and drug-treated patients. Mean change

Impact of pretreatment with antidepressants on the efficacy of duloxetine in terms of mood symptoms and functioning: an analysis of 15 pooled major depressive disorder studies.

PubMed

Barros, Bruno R; Schacht, Alexander; Happich, Michael; Televantou, Foula; Berggren, Lovisa; Walker, Daniel J; Dueñas, Hector J

2014-01-01

This post hoc analysis aimed to determine whether patients with major depressive disorder (MDD) in duloxetine trials who were antidepressant naive or who were previously exposed to antidepressants exhibited differences in efficacy and functioning. Data were pooled from 15 double-blind, placebo- and/or active-controlled duloxetine trials of adult patients with MDD conducted by Eli Lilly and Company. The individual studies took place between March 2000 and November 2009. Data were analyzed using 4 pretreatment subgroups: first-episode never treated, multiple-episode never treated, treated previously only with selective serotonin reuptake inhibitors (SSRIs), and previously treated with antidepressants other than just SSRIs. Measures included the 17-item Hamilton Depression Rating Scale (HDRS-17) total and somatic symptom subscale scores, Montgomery-Asberg Depression Rating Scale (MADRS) total score, and Sheehan Disability Scale total score. Response rates (50% and 30%) were based on the HDRS-17 total score and remission rates on either the HDRS-17 or MADRS total score. Response and remission rates were significantly greater (P < .05 in 11 of 12 comparisons) for duloxetine versus placebo in the 4 subgroups. A trend of greater response and remission occurred for first-episode versus multiple-episode patients; both groups were generally higher than the antidepressant-treated groups. Mean changes in efficacy measures were mostly significantly greater (P < .05 in 13 of 16 comparisons) for duloxetine versus placebo within each pretreatment subgroup, with some (P < .05 in 2 of 24 comparisons) significant interaction effects between subgroups on HDRS-17 total and somatic symptoms scores. Duloxetine was generally superior to placebo on response and remission rates and in mean change on efficacy measures. Response and remission rates were numerically greater for first-episode versus multiple-episode and drug-treated patients. Mean change differences on efficacy measures among

The oxidation of methionine-54 of epoetinum alfa does not affect molecular structure or stability, but does decrease biological activity.

PubMed

Labrenz, Steven R; Calmann, Melissa A; Heavner, George A; Tolman, Glen

2008-01-01

Erythropoietin therapy is used to treat severe anemia in renal failure and chemotherapy patients. One of these therapies based on recombinant human erythropoietin is marketed under the trade name of EPREX and utilizes epoetinum alfa as the active pharmaceutical ingredient. The effect of oxidation of methionine-54 on the structure and stability of the erythropoietin molecule has not been directly tested. We have observed partial and full chemical oxidation of methionine-54 to methionine-54 sulfoxide, accomplished using tert-Butylhydroperoxide and hydrogen peroxide, respectively. A blue shift in the fluorescence center of spectral mass wavelength was observed as a linear response to the level of methionine sulfoxide in the epoetinum alfa molecule, presumably arising from a local change in the environment near tryptophan-51, as supported by potassium iodide quenching studies. Circular dichroism studies demonstrated no change in the folded structure of the molecule with methionine oxidation. The thermal unfolding profiles of partial and completely oxidized epoetinum alfa overlap, with a T(m) of 49.5 degrees C across all levels of methionine sulfoxide content. When the protein was tested for activity, a decrease in biological activity was observed, correlating with methionine sulfoxide levels. An allosteric effect between Met54, Trp51, and residues involved in receptor binding is proposed. These results indicate that methionine oxidation has no effect on the folded structure and global thermodynamic stability of the recombinant human erythropoietin molecule. Oxidation can affect potency, but only at levels significantly in excess of those seen in EPREX.

Real-world utilization of darbepoetin alfa in cancer chemotherapy patients.

PubMed

Pan, Xiaoyun Lucy; Nordstrom, Beth L; MacLachlan, Sharon; Lin, Junji; Xu, Hairong; Sharma, Anjali; Chandler, David; Li, Xiaoyan Shawn

2017-01-01

Objectives To provide an understanding of darbepoetin alfa dose patterns in cancer patients undergoing myelosuppressive chemotherapy starting from 2011. Study design This is a retrospective cohort study using a proprietary outpatient oncology database. Methods Metastatic, solid tumor cancer patients receiving concomitant myelosuppressive chemotherapy and darbepoetin alfa with an associated hemoglobin <10 g/dL during 2011-2015 were identified. The analysis was restricted to the first continuous exposure to chemotherapy agents (maximum allowable gap of 90 days between consecutive exposures) with darbepoetin alfa for each eligible patient. Initial, maintenance, weekly, and cumulative doses of darbepoetin alfa were examined across all darbepoetin alfa users. Subgroup analyses were conducted by chemotherapy type, baseline hemoglobin level, year of chemotherapy, solid tumor type, and initial dosing schedule. Differences in weekly doses across subgroups were evaluated using Wilcoxon rank-sum tests. Results Among 835 eligible patients, over 90% were 50 years or older. Mean chemotherapy course duration was 248 days, and mean duration of darbepoetin alfa treatment was 106 days. The mean weekly darbepoetin alfa dose was 110 µg. Patients received a mean of 4.3 darbepoetin alfa injections in the first chemotherapy course. There were no statistically significant differences (all P values > .05) in weekly dose by chemotherapy type, baseline hemoglobin level, year of chemotherapy, or solid tumor type. Conclusion The average weekly darbepoetin alfa dose among metastatic cancer patients with chemotherapy-induced anemia from this study was 110 µg, which was lower than the labeled dosage for most adults. This estimate did not differ over time, across chemotherapy regimens, baseline hemoglobin levels, or solid tumor types.

Duloxetine and 8-OH-DPAT, but not fluoxetine, reduce depression-like behaviour in an animal model of chronic neuropathic pain.

PubMed

Hu, Bing; Doods, Henri; Treede, Rolf-Detlef; Ceci, Angelo

2016-04-21

The current study assessed whether antidepressant and/or antinociceptive drugs, duloxetine, fluoxetine as well as (±)-8-hydroxy-2-[di-n-propylamino] tetralin (8-OH-DPAT), are able to reverse depression-like behaviour in animals with chronic neuropathic pain. Chronic constriction injury (CCI) of the sciatic nerve in rats was selected as neuropathic pain model. Mechanical hypersensitivity and depression-like behaviour were evaluated 4 weeks after surgery by "electronic algometer" and forced swimming test (FST), which measured the time of immobility, and active behaviours climbing and swimming. The selective noradrenergic and serotonergic uptake blocker duloxetine (20mg/kg) and the selective 5-HT1A agonist 8-OH-DPAT (0.5mg/kg) significantly reversed both mechanical hypersensitivity and depression-like behaviour in CCI animals. Duloxetine significantly reversed depression-like behaviour in CCI rats by increasing the time of climbing and swimming, while 8-OH-DPAT attenuated depression-like behaviour mainly by increasing the time of swimming. However, the selective serotonergic uptake blocker fluoxetine (20mg/kg) failed to attenuate mechanical hypersensitivity and depression-like behaviour, possibly due to confounding pro-nociceptive actions at 5-HT3 receptors. These data suggest to target noradrenergic and 5-HT1A receptors for treatment of chronic pain and its comorbidity depression. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Successful within-patient dose escalation of olipudase alfa in acid sphingomyelinase deficiency.

PubMed

Wasserstein, Melissa P; Jones, Simon A; Soran, Handrean; Diaz, George A; Lippa, Natalie; Thurberg, Beth L; Culm-Merdek, Kerry; Shamiyeh, Elias; Inguilizian, Haig; Cox, Gerald F; Puga, Ana Cristina

2015-01-01

Olipudase alfa, a recombinant human acid sphingomyelinase (rhASM), is an investigational enzyme replacement therapy (ERT) for patients with ASM deficiency [ASMD; Niemann-Pick Disease (NPD) A and B]. This open-label phase 1b study assessed the safety and tolerability of olipudase alfa using within-patient dose escalation to gradually debulk accumulated sphingomyelin and mitigate the rapid production of metabolites, which can be toxic. Secondary objectives were pharmacokinetics, pharmacodynamics, and exploratory efficacy. Five adults with nonneuronopathic ASMD (NPD B) received escalating doses (0.1 to 3.0 mg/kg) of olipudase alfa intravenously every 2 weeks for 26 weeks. All patients successfully reached 3.0mg/kg without serious or severe adverse events. One patient repeated a dose (2.0 mg/kg) and another had a temporary dose reduction (1.0 to 0.6 mg/kg). Most adverse events (97%) were mild and all resolved without sequelae. The most common adverse events were headache, arthralgia, nausea and abdominal pain. Two patients experienced single acute phase reactions. No patient developed hypersensitivity or anti-olipudase alfa antibodies. The mean circulating half-life of olipudase alfa ranged from 20.9 to 23.4h across doses without accumulation. Ceramide, a sphingomyelin catabolite, rose transiently in plasma after each dose, but decreased over time. Reductions in sphingomyelin storage, spleen and liver volumes, and serum chitotriosidase activity, as well as improvements in infiltrative lung disease, lipid profiles, platelet counts, and quality of life assessments, were observed. This study provides proof-of-concept for the safety and efficacy of within-patient dose escalation of olipudase alfa in patients with nonneuronopathic ASMD. Copyright © 2015. Published by Elsevier Inc.

Dornase Alfa for Non-Cystic Fibrosis Pediatric Pulmonary Atelectasis.

PubMed

Thornby, Krisy-Ann; Johnson, Ashley; Axtell, Samantha

2014-08-01

To review the literature evaluating the efficacy of dornase alfa for non-cystic fibrosis pediatric patients with pulmonary atelectasis. Articles were retrieved after a search of MEDLINE/PubMed (1946 to April 2014), and International Pharmaceutical Abstracts (1970-April 2014) was performed using the terms dornase alfa, recombinant human deoxyribonuclease, pulmonary, persistent, and atelectasis. Other relevant articles referenced from the MEDLINE search were also utilized. Data sources were limited to English language clinical trials and case studies including only children; 8 clinical trials and 12 case reports met the criteria. Dornase alfa is used as an off-label treatment option for pulmonary atelectasis because limited treatment modalities exist after conventional therapy has failed. We evaluated 8 clinical trials and 12 case reports involving this pediatric population with varying primary diagnoses. The majority of patients experienced improvement in atelectasis, suggesting benefit after receiving treatment with dornase alfa. However, the outcomes were possibly confounded by those receiving combination therapies, varying primary diagnoses, and varying end points evaluated. Dornase alfa was overall well tolerated, with only a few patients experiencing worsening atelectasis posttreatment. Dornase alfa may be considered as a therapeutic option in non-cystic fibrosis pediatric patients with pulmonary atelectasis, who require treatment intervention when conventional therapy is unsuccessful. © The Author(s) 2014.

Treatment of anemia with darbepoetin alfa in systolic heart failure.

PubMed

Swedberg, Karl; Young, James B; Anand, Inder S; Cheng, Sunfa; Desai, Akshay S; Diaz, Rafael; Maggioni, Aldo P; McMurray, John J V; O'Connor, Christopher; Pfeffer, Marc A; Solomon, Scott D; Sun, Yan; Tendera, Michal; van Veldhuisen, Dirk J

2013-03-28

Patients with systolic heart failure and anemia have worse symptoms, functional capacity, and outcomes than those without anemia. We evaluated the effects of darbepoetin alfa on clinical outcomes in patients with systolic heart failure and anemia. In this randomized, double-blind trial, we assigned 2278 patients with systolic heart failure and mild-to-moderate anemia (hemoglobin level, 9.0 to 12.0 g per deciliter) to receive either darbepoetin alfa (to achieve a hemoglobin target of 13 g per deciliter) or placebo. The primary outcome was a composite of death from any cause or hospitalization for worsening heart failure. The primary outcome occurred in 576 of 1136 patients (50.7%) in the darbepoetin alfa group and 565 of 1142 patients (49.5%) in the placebo group (hazard ratio in the darbepoetin alfa group, 1.01; 95% confidence interval, 0.90 to 1.13; P=0.87). There was no significant between-group difference in any of the secondary outcomes. The neutral effect of darbepoetin alfa was consistent across all prespecified subgroups. Fatal or nonfatal stroke occurred in 42 patients (3.7%) in the darbepoetin alfa group and 31 patients (2.7%) in the placebo group (P=0.23). Thromboembolic adverse events were reported in 153 patients (13.5%) in the darbepoetin alfa group and 114 patients (10.0%) in the placebo group (P=0.01). Cancer-related adverse events were similar in the two study groups. Treatment with darbepoetin alfa did not improve clinical outcomes in patients with systolic heart failure and mild-to-moderate anemia. Our findings do not support the use of darbepoetin alfa in these patients. (Funded by Amgen; RED-HF ClinicalTrials.gov number, NCT00358215.).

Enhanced antitumor reactivity of tumor-sensitized T cells by interferon alfa

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

Vander Woude, D.L.; Wagner, P.D.; Shu, S.

Tumor-draining lymph node cells from mice bearing the methylcholanthrene-induced MCA 106 tumors can be sensitized in vitro to acquire antitumor reactivity. We examined the effect of interferon alfa on the function of cells that underwent in vitro sensitization in adoptive immunotherapy. Interferon alfa increased the antitumor reactivity of in vitro sensitized cells in the treatment of MCA 106 pulmonary metastases. This effect was evident in irradiated mice, indicating that a host response to the interferon alfa was not required. Interferon alfa treatment increased class I major histocompatibility complex antigen expression on tumor cells and increased their susceptibility to lysis bymore » in vitro sensitized cells. These results suggest that interferon alfa enhancement of adoptive immunotherapy was mediated by its effect on tumor cells. Interferon alfa may be a useful adjunct to the adoptive immunotherapy of human cancer.« less

ALFA: The new ALICE-FAIR software framework

NASA Astrophysics Data System (ADS)

Al-Turany, M.; Buncic, P.; Hristov, P.; Kollegger, T.; Kouzinopoulos, C.; Lebedev, A.; Lindenstruth, V.; Manafov, A.; Richter, M.; Rybalchenko, A.; Vande Vyvre, P.; Winckler, N.

2015-12-01

The commonalities between the ALICE and FAIR experiments and their computing requirements led to the development of large parts of a common software framework in an experiment independent way. The FairRoot project has already shown the feasibility of such an approach for the FAIR experiments and extending it beyond FAIR to experiments at other facilities[1, 2]. The ALFA framework is a joint development between ALICE Online- Offline (O2) and FairRoot teams. ALFA is designed as a flexible, elastic system, which balances reliability and ease of development with performance using multi-processing and multithreading. A message- based approach has been adopted; such an approach will support the use of the software on different hardware platforms, including heterogeneous systems. Each process in ALFA assumes limited communication and reliance on other processes. Such a design will add horizontal scaling (multiple processes) to vertical scaling provided by multiple threads to meet computing and throughput demands. ALFA does not dictate any application protocols. Potentially, any content-based processor or any source can change the application protocol. The framework supports different serialization standards for data exchange between different hardware and software languages.

Cost per successfully treated patient for vortioxetine versus duloxetine in adults with major depressive disorder: an analysis of the complete symptoms of depression and functional outcome.

PubMed

Christensen, Michael Cronquist; Munro, Vicki

2018-04-01

To determine the cost-effectiveness of vortioxetine vs duloxetine in adults with moderate-to-severe major depressive disorder (MDD) in Norway using a definition of a successfully treated patient (STP) that incorporates improvement in both mood symptoms and functional capacity. Using the population of patients who completed the 8-week CONNECT study, the cost-effectiveness of vortioxetine (n = 168) (10-20 mg/day) vs duloxetine (n = 176) (60 mg/day) was investigated for the treatment of adults in Norway with moderate-to-severe MDD and self-reported cognitive dysfunction over an 8-week treatment period. Cost-effectiveness was assessed in terms of cost per STP, defined as improvement in mood symptoms (≥50% decrease from baseline in Montgomery-Åsberg Depression Rating Scale total score) and change in UCSD [University of California San Diego] performance-based skills assessment [UPSA] score of ≥7. The base case analysis utilized pharmacy retail price (apotek utsalgspris (AUP)) for branded vortioxetine (Brintellix) and branded duloxetine (Cymbalta). After 8 weeks of antidepressant therapy, there were more STPs with vortioxetine than with duloxetine (27.4% vs 22.5%, respectively). The mean number needed to treat for each STP was 3.6 for vortioxetine and 4.4 for duloxetine, resulting in a lower mean cost per STP for vortioxetine (NOK [Norwegian Kroner] 3264) than for duloxetine (NOK 3310) and an incremental cost per STP of NOK 3051. The use of a more challenging change in the UPSA score from baseline (≥9) resulted in a mean cost per STP of NOK 3822 for vortioxetine compared with NOK 3983 for duloxetine and an incremental cost per STP of NOK 3181. Vortioxetine may be a cost-effective alternative to duloxetine, owing to its superior ability to improve functional capacity. The dual-response STP concept introduced here represents a more comprehensive analysis of the cost-effectiveness of antidepressants.

Clinical study of duloxetine hydrochloride combined with doxazosin for the treatment of pain disorder in chronic prostatitis/chronic pelvic pain syndrome: An observational study.

PubMed

Zhang, Mingxin; Li, Hanzhong; Ji, Zhigang; Dong, Dexin; Yan, Su

2017-03-01

To explore the safety and efficacy of the selective 5-serotonin and norepinephrine reuptake inhibitor duloxetine hydrochloride and alpha-adrenergic receptor blocker (alpha-blocker) doxazosin mesylate-controlled tablets in the treatment of pain disorder in chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).In all, 150 patients were enrolled and 126 patients completed the study (41 patients in the doxazosin group, 41 patients in the sertraline group, and 44 patients in the duloxetine group). This was an open randomized 6-month study. CP/CPPS patients who met the diagnostic criteria were randomized into 3 groups. The patients in the duloxetine group received doxazosin 4 mg + duloxetine 30 mg once a day, and the dosage of duloxetine was increased to 60 mg after a week. The patients in the doxazosin group received doxazosin 4 mg once a day. The patients in the sertraline group received doxazosin 4 mg + sertraline 50 mg once a day. National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) score, the short-form McGill Pain questionnaire (SF-MPQ), and the hospital anxiety and depression scale (HAD) were applied for evaluations during follow-up of 1, 3, and 6 months after treatment.There were slight positive significant correlations between NIH-CPSI scores and HAD scores, moderate positive significant correlations between the quality of life (QOL) and SF-MPQ, and slight positive significant correlations between HAD and QOL. The effective rate in the doxazosin group was 4.88%, 19.51%, and 56.10% after 1, 3, and 6 months, respectively (P < 0.05). The SF-MPQ score in the doxazosin group decreased to 1.80 ± 1.29, 2.66 ± 1.57, and 3.24 ± 1.67 after 1, 3, and 6 months, respectively (P < 0.05). The HAD score in the doxazosin group decreased to 2.24 ± 2.17, 4 ± 2.11, and 4.90 ± 2.62 after 1, 3, and 6 months, respectively (P < 0.05). The effective rate in the sertraline group was 9.76%, 36.59%, and 63

Real-world outcomes in patients with depression treated with duloxetine or a selective serotonin reuptake inhibitor in East Asia.

PubMed

Hong, Jihyung; Novick, Diego; Montgomery, William; Moneta, Maria Victoria; Dueñas, Héctor; Peng, Xiaomei; Haro, Josep Maria

2016-03-01

This study compared treatment outcomes in patients with major depressive disorder treated with either duloxetine with a daily dose of ≤60 mg or a selective serotonin reuptake inhibitor (SSRI) as monotherapy for up to 6 months in a naturalistic setting in East Asia. In addition, this study examined the impact of painful physical symptoms (PPS) on the effects of these treatments. This post-hoc analysis of data from a 6-month prospective observational study involving 1,549 major depressive disorder patients without sexual dysfunction focused on a subgroup of patients from East Asia (n = 587). Depression severity was measured using the Clinical Global Impression of Severity and the 16-item Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR16 ), whereas quality of life (QoL) was measured using EuroQoL instruments. PPS were rated using the modified Somatic Symptom Inventory. Multiple regression analyses were performed to compare the treatment outcomes. Duloxetine-treated patients had higher odds of achieving remission (odds ratio = 2.578, P < 0.001) and response (odds ratio = 2.704, P < 0.001) during follow-up, compared with SSRI-treated patients. They also had lower levels of disease severity and higher levels of QoL during follow-up. A similar pattern was observed in each subgroup of patients with and without PPS at baseline, but the effects of duloxetine relative to SSRIs were in general greater in patients with PPS. Patients treated with duloxetine had better treatment outcomes in terms of remission, response, depressive symptoms, and QoL, compared with SSRIs. Treatment with duloxetine may have additional advantages for patients with concurrent PPS. © 2015 Wiley Publishing Asia Pty Ltd.

A double blind, placebo controlled, phase II randomised cross-over trial investigating the use of duloxetine for the treatment of chemotherapy-induced peripheral neuropathy.

PubMed

Battaglini, Eva; Park, Susanna B; Barnes, Elizabeth H; Goldstein, David

2018-04-20

Chemotherapy-induced peripheral neuropathy (CIPN) is a significant side effect of cancer treatment, potentially leading to early cessation of chemotherapy, enduring symptoms and long-lasting disability. Evidence from preclinical and clinical studies suggests that duloxetine, a serotonin-noradrenaline reuptake inhibitor, may be effective in the symptomatic treatment of CIPN. This double blind, placebo controlled, phase II randomised cross-over trial aims to determine whether treatment with duloxetine results in a reduction in chronic neuropathic symptoms experienced as a result of neurotoxic chemotherapy treatment. Participants who have received neurotoxic chemotherapy and experience daily symptoms as a consequence of peripheral neuropathy will be randomly allocated to control or experimental group with a 1:1 allocation, stratified by chemotherapy type. The primary endpoint will be patient-reported CIPN symptoms, as assessed via the FACT/GOG-Ntx. As a secondary objective, the trial will investigate whether duloxetine improves neurophysiological parameters and functional status in patients who have received neurotoxic chemotherapy treatment. This trial will investigate the effectiveness of duloxetine in reducing neuropathic symptoms following chemotherapy treatment, and aims to provide insight into the mechanisms underlying the symptomatic relief that duloxetine may provide. These results will be informative in advancing clinical knowledge regarding the treatment of CIPN. Copyright © 2018 Elsevier Inc. All rights reserved.

Duloxetine in the long-term management of diabetic peripheral neuropathic pain: An open-label, 52-week extension of a randomized controlled clinical trial.

PubMed

Wernicke, Joachim F; Raskin, Joel; Rosen, Amy; Pritchett, Yili L; D'Souza, Deborah N; Iyengar, Smriti; Knopp, Kelly; Le, Trong K

2006-09-01

Duloxetine hydrochloride, a selective serotonin (5-HT) and norepinephrine (NE) reuptake inhibitor, is relatively balanced in its affinity for both 5-HT and NE reuptake inhibition and is the first US Food and Drug Administration-approved prescription drug for the management of diabetic peripheral neuropathic pain (DPNP). The aim of this study was to determine whether management of DPNP with duloxetine interferes with the treatment of diabetes. It also examined the tolerability of long-term exposure to duloxetine with regard to the progression of diabetic complications, and assessed the impact of DPNP management with duloxetine versus routine care. This was a 52-week, multicenter, re-randomized, open-label extension of a parallel, double-blind, randomized, placebo-controlled, acute (12-week) study. Patients who completed the duloxetine or placebo acute treatment period were randomly reassigned in a 2:1 ratio to treatment with duloxetine 60 mg BID or routine care for an additional 52 weeks. The study included male and female outpatients aged ≥18 years with a diagnosis of DPNP caused by type 1 or type 2 diabetes. Over the course of the 52-week study, visits were scheduled on the following weeks (of the extension phase of the study): 1 (via phone only), 2, 4, 8, 12, 20, 28, 40, and 52. Tolerability was assessed by review and analyses of discontinuation rates, adverse events (AEs), laboratory data, vital signs, electrocardiographic results, concomitant medications, and diabetic complications. Treatment-emergent AEs (TEAEs) were defined as AEs that appeared during therapy (were not present at baseline) or were exacerbated during treatment. Data on AEs and concomitant medications were collected at every visit. Data on blood pressure, heart rate, and significant hypoglycemic events were collected at every visit starting from week 2. Fasting clinical chemistry and electrolyte group laboratory assessments were done at every visit, starting from week 4. Electrocardiographic

Duloxetine in the long-term management of diabetic peripheral neuropathic pain: An open-label, 52-week extension of a randomized controlled clinical trial

PubMed Central

Wernicke, Joachim F.; Raskin, Joel; Rosen, Amy; Pritchett, Yili L.; D'Souza, Deborah N.; Iyengar, Smriti; Knopp, Kelly; Le, Trong K.

2006-01-01

Background: Duloxetine hydrochloride, a selective serotonin (5-HT) and norepinephrine (NE) reuptake inhibitor, is relatively balanced in its affinity for both 5-HT and NE reuptake inhibition and is the first US Food and Drug Administration-approved prescription drug for the management of diabetic peripheral neuropathic pain (DPNP). Objectives: The aim of this study was to determine whether management of DPNP with duloxetine interferes with the treatment of diabetes. It also examined the tolerability of long-term exposure to duloxetine with regard to the progression of diabetic complications, and assessed the impact of DPNP management with duloxetine versus routine care. Methods: This was a 52-week, multicenter, re-randomized, open-label extension of a parallel, double-blind, randomized, placebo-controlled, acute (12-week) study. Patients who completed the duloxetine or placebo acute treatment period were randomly reassigned in a 2:1 ratio to treatment with duloxetine 60 mg BID or routine care for an additional 52 weeks. The study included male and female outpatients aged ≥18 years with a diagnosis of DPNP caused by type 1 or type 2 diabetes. Over the course of the 52-week study, visits were scheduled on the following weeks (of the extension phase of the study): 1 (via phone only), 2, 4, 8, 12, 20, 28, 40, and 52. Tolerability was assessed by review and analyses of discontinuation rates, adverse events (AEs), laboratory data, vital signs, electrocardiographic results, concomitant medications, and diabetic complications. Treatment-emergent AEs (TEAEs) were defined as AEs that appeared during therapy (were not present at baseline) or were exacerbated during treatment. Data on AEs and concomitant medications were collected at every visit. Data on blood pressure, heart rate, and significant hypoglycemic events were collected at every visit starting from week 2. Fasting clinical chemistry and electrolyte group laboratory assessments were done at every visit, starting

Assessment of Relative Bioavailability of Moroctocog Alfa and Moroctocog Alfa (AF-CC) in Subjects With Severe Hemophilia A.

PubMed

Korth-Bradley, Joan; Rupon, Jeremy; Plotka, Anna; Charnigo, Robert; Rendo, Pablo

2018-05-01

An open-label, single-dose, randomized, two-period, crossover study comparing the pharmacokinetics of factor VIII activity in plasma (FVIII:C) after administration of an albumin-free presentation of moroctocog alfa (test) and moroctocog alfa manufactured using the previous technique (reference) was conducted in 30 (25 evaluable) male subjects who had severe hemophilia A (FVIII:C < 1 IU/dL). Blood samples were collected for 48 h after administration of each dose. C was assayed using a chromogenic substrate assay. The FVIII:C pharmacokinetic parameters were calculated using noncompartmental analysis. The presentations would be bioequivalent if the 90% confidence limits of the ratio of the geometric mean values of AUC inf and recovery fell within the interval of 80-125%. The bioequivalence criteria were met. A total of 10 treatment-related adverse events were observed in a total of nine subjects. All were mild and none was determined to be related to administration of study medication. © 2018 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Characterization of IXINITY® (Trenonacog Alfa), a Recombinant Factor IX with Primary Sequence Corresponding to the Threonine-148 Polymorph

PubMed Central

Monroe, Dougald M.; Jenny, Richard J.; Van Cott, Kevin E.; Saward, Laura L.

2016-01-01

The goal of these studies was to extensively characterize the first recombinant FIX therapeutic corresponding to the threonine-148 (Thr-148) polymorph, IXINITY (trenonacog alfa [coagulation factor IX (recombinant)]). Gel electrophoresis, circular dichroism, and gel filtration were used to determine purity and confirm structure. Chromatographic and mass spectrometry techniques were used to identify and quantify posttranslational modifications. Activity was assessed as the ability to activate factor X (FX) both with and without factor VIIIa (FVIIIa) and in a standard clotting assay. All results were consistent across multiple lots. Trenonacog alfa migrated as a single band on Coomassie-stained gels; activity assays were normal and showed <0.002 IU of activated factor IX (FIXa) per IU of FIX. The molecule has >97%  γ-carboxylation and underwent the appropriate structural change upon binding calcium ions. Trenonacog alfa was activated normally with factor XIa (FXIa); once activated it bound to FVIIIa and FXa. When activated to FIXa, it was inhibited efficiently by antithrombin. Glycosylation patterns were similar to plasma-derived FIX with sialic acid content consistent with the literature reports of good pharmacokinetic performance. These studies have shown that trenonacog alfa is a highly pure product with a primary sequence and posttranslational modifications consistent with the common Thr-148 polymorphism of plasma-derived FIX. PMID:26997955

Dornase alfa as postoperative therapy in cystic fibrosis sinonasal disease.

PubMed

Cimmino, Mariano; Nardone, Massimiliano; Cavaliere, Matteo; Plantulli, Angela; Sepe, Angela; Esposito, Valeria; Mazzarella, Giuseppina; Raia, Valeria

2005-12-01

To determine the benefit of nasally inhaled dornase alfa in patients with cystic fibrosis and nasal symptoms. Double-blind placebo-controlled trial. Cystic Fibrosis Regional Center of Campania at the University of Naples "Federico II." A total of 24 patients with cystic fibrosis and chronic sinusitis. Patients underwent sinonasal surgery during a 3-year period and received once-daily doses of either dornase alfa (2.5 mg) or hypotonic saline solution (5 mL) beginning 1 month after surgery and for a 12-month period. Primary outcomes were nasal-related symptoms and nasal endoscopic appearance; secondary outcomes were forced expiratory volume in 1 second, nasal computed tomography findings, and saccharine clearance test results. Patients were evaluated before and after treatment. After surgery, all outcomes were significantly improved for each treatment at 1 month (P<.05); primary outcomes were improved at 24 and 48 weeks in the group receiving dornase alfa (P<.05), and at 12 weeks in the group receiving placebo. Secondary outcomes were better in the dornase alfa group (P<.01) than in the placebo group at 12 months except for the saccharine clearance test results. In particular, median relative difference in forced expiratory volume in 1 second between dornase alfa and placebo was significantly improved in the dornase alfa group (P<.01). Nasally inhaled dornase alfa can be effective in patients with cystic fibrosis and sinonasal disease who do not respond to conventional therapy after surgical treatment. Further studies should be carried out to determine the long-term effect on sinus disease, recurrence of polyps, and quality of life.

Conestat alfa for the treatment of angioedema attacks

PubMed Central

Davis, Benjamin; Bernstein, Jonathan A

2011-01-01

Recently, multiple C1 inhibitor (C1-INH) replacement products have been approved for the treatment of hereditary angioedema (HAE). This review summarizes HAE and its current treatment modalities and focuses on findings from bench to bedside trials of a new C1-INH replacement, conestat alfa. Conestat alfa is unique among the other C1-INH replacement products because it is produced from transgenic rabbits rather than derived from human plasma donors, which can potentially allow an unlimited source of drug without any concern of infectious transmission. The clinical trial data generated to date indicate that conestat alfa is safe and effective for the treatment of acute HAE attacks. PMID:21753889

Duloxetine in the treatment of burning mouth syndrome refractory to conventional treatment: A case report.

PubMed

Kim, Yeon-Dong; Lee, Ji-Hye; Shim, Jee-Hoon

2014-06-01

Patients with burning mouth syndrome (BMS) report burning sensation and pain involving the tongue and oral mucosa without any apparent medical or dental cause. The pathogenesis of this syndrome remains unclear and there is currently no standard treatment. BMS is, therefore, often misdiagnosed and its management is complex. This lack of clinical expertise may result in decreased health-related quality of life and increased psychological distress among patients with BMS. The present case report involves a 77-year-old female patient with BMS refractory to conventional treatment with nerve block and medication, who was successfully treated with duloxetine. Duloxetine may become a new therapeutic option in the management of BMS. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

The ALFA project: A research platform to identify early pathophysiological features of Alzheimer's disease.

PubMed

Molinuevo, José Luis; Gramunt, Nina; Gispert, Juan Domingo; Fauria, Karine; Esteller, Manel; Minguillon, Carolina; Sánchez-Benavides, Gonzalo; Huesa, Gema; Morán, Sebastián; Dal-Ré, Rafael; Camí, Jordi

2016-06-01

The preclinical phase of Alzheimer's disease (AD) is optimal for identifying early pathophysiological events and developing prevention programs, which are shared aims of the ALFA project, including the ALFA registry and parent cohort and the nested ALFA+ cohort study. The ALFA parent cohort baseline visit included full cognitive evaluation, lifestyle habits questionnaires, DNA extraction, and MRI. The nested ALFA+ study adds wet and imaging biomarkers for deeper phenotyping. A total of 2743 participants aged 45 to 74 years were included in the ALFA parent cohort. We show that this cohort, mostly composed of cognitively normal offspring of AD patients, is enriched for AD genetic risk factors. The ALFA project represents a valuable infrastructure that will leverage with different studies and trials to prevent AD. The longitudinal ALFA+ cohort will serve to untangle the natural history of the disease and to model the preclinical stages to develop successful trials.

Agalsidase alfa: a review of its use in the management of Fabry disease.

PubMed

Keating, Gillian M

2012-10-01

The enzyme replacement therapy agalsidase alfa (Replagal®) has an amino acid sequence identical to that of native α-galactosidase A; intravenous agalsidase alfa 0.2 mg/kg every other week is indicated for the long-term treatment of patients with confirmed Fabry disease. This article reviews the efficacy and tolerability of agalsidase alfa in patients with Fabry disease, as well as summarizing its pharmacologic properties. Agalsidase alfa had beneficial effects in adult men with Fabry disease, according to the results of two randomized, double-blind, placebo-controlled, 6-month trials (n = 15 and 26). For example, left ventricular mass index was reduced to a significantly greater extent with agalsidase alfa than with placebo. Although the change in myocardial globotriaosylceramide content (primary endpoint in one study) did not significantly differ between agalsidase alfa and placebo recipients, the change in the Brief Pain Inventory (BPI) 'pain at its worst' score (reflecting neuropathic pain while without pain medications; primary endpoint in the second study) was improved to a significantly greater extent with agalsidase alfa than with placebo. In addition, the change in creatinine clearance, but not inulin clearance, significantly favored agalsidase alfa versus placebo recipients. Abnormalities in functional cerebral blood flow and cerebrovascular responses were also reversed with agalsidase alfa therapy. In extensions of these placebo-controlled trials, the reduction in left ventricular mass and improvements in BPI pain scores were maintained after longer-term agalsidase alfa therapy. The significant decline in estimated glomerular filtration rate (eGFR) seen after 48 months' agalsidase alfa treatment was mainly driven by a marked decline in eGFR seen in four patients with stage 3 chronic kidney disease at baseline (although the progression of decline appeared slower than that seen in historic controls); renal function appeared stable in patients with

The pharmacokinetics of a B-domain truncated recombinant factor VIII, turoctocog alfa (NovoEight®), in patients with hemophilia A.

PubMed

Jiménez-Yuste, V; Lejniece, S; Klamroth, R; Suzuki, T; Santagostino, E; Karim, F A; Saugstrup, T; Møss, J

2015-03-01

Turoctocog alfa (NovoEight(®)) is a human recombinant coagulation factor VIII (rFVIII) for the treatment of patients with hemophilia A. To evaluate the pharmacokinetics of turoctocog alfa in all age groups across clinical trials. Data from previously treated patients with severe hemophilia A (FVIII activity level of ≤ 1%) with no history of FVIII inhibitors, in a non-bleeding state, were included. The pharmacokinetics were assessed following a wash-out period and a subsequent single intravenous 50 IU kg(-1) dose of turoctocog alfa. Blood was sampled during a 48-h period postdose. Standard pharmacokinetic (PK) parameters were estimated on the basis of plasma FVIII activity vs. time (PK profiles) with non-compartmental methods. Furthermore, a population PK analysis was conducted. Data from 76 patients (aged 1-60 years) enrolled globally across six clinical trials were included, totaling 105 turoctocog alfa PK profiles. Single-dose PK results 3-6 months after the first dose of turoctocog alfa were comparable with the results obtained after the first dose. Similar PK characteristics were shown for different lots and strengths of the drug product. Overall, area under the plasma concentration (activity) curve from administration to infinity (AUC) and t1(/2) tended to increase with increasing age, with lower AUC and shorter t(1/2) being seen in children than in adolescents and adults. The PK profiles of turoctocog alfa and other commercially available plasma-derived FVIII and rFVIII products were similar in all age groups. The PK characteristics of turoctocog alfa have been thoroughly studied, and shown to be consistent over time, reproducible between different lots and strengths of drug product, and similar to those observed for other FVIII products. © 2014 International Society on Thrombosis and Haemostasis.

Prospective follow-up of 838 fetuses conceived after ovarian stimulation with corifollitropin alfa: comparative and overall neonatal outcome.

PubMed

Bonduelle, Maryse; Mannaerts, Bernadette; Leader, Arthur; Bergh, Christina; Passier, Dorrie; Devroey, Paul

2012-07-01

Is treatment with corifollitropin alfa, a new recombinant gonadotrophin with sustained follicle-stimulating activity, safe in terms of perinatal complications and birth defects in infants conceived following corifollitropin alfa treatment for contolled ovarian stimulation (COS)? In terms of neonatal outcome and risk of malformations, treatment with a single dose of corifollitropin alfa during COS is as safe as treatment with daily recombinant FSH (rFSH). This is the first pooled analysis of individual safety data in terms of neonatal outcome and major and minor congenital malformations collected following intervention trials of corifollitropin alfa. Pregnancy and follow-up studies were conducted prospectively and data were collected from all Phase II and III trials with corifollitropin alfa intervention, including two comparative randomized controlled trials (RCTs) in which patients received either a single dose of corifollitropin alfa or daily rFSH for the first 7 days of COS. Patients with ongoing pregnancies at 10 weeks after embryo transfer were followed up to labour and the health of the offspring was assessed up to 4-12 weeks after birth. Following corifollitropin alfa treatment prior to IVF or ICSI, the health of 677 pregnant women, 838 fetuses and 806 live born infants was evaluated. Among 440 fetuses in the corifollitropin alfa arm and 381 fetuses in the rFSH arm of the two RCTs, there were 424 (96.4%) and 370 (98.7%) live births, respectively. Neonatal characteristics, the frequency of premature births and the incidence of infant adverse events were similar in both treatment arms. The overall incidence of any congenital malformations in live born infants was 16.3 and 17.0%, with major malformation rates of 4.0 and 5.4% in the corifollitropin alfa and rFSH groups, respectively [odds ratio (OR) for major malformations, 0.71; 95% confidence interval, 0.36-1.38]. From 838 fetuses assessed in all corifollitropin alfa intervention trials, there were 806 (96

Multi-domain impact of elosufase alfa in Morquio A syndrome in the pivotal phase III trial.

PubMed

Hendriksz, Christian J; Giugliani, Roberto; Harmatz, Paul; Mengel, Eugen; Guffon, Nathalie; Valayannopoulos, Vassili; Parini, Rossella; Hughes, Derralynn; Pastores, Gregory M; Lau, Heather A; Al-Sayed, Moeenaldeen D; Raiman, Julian; Yang, Ke; Mealiffe, Matthew; Haller, Christine

2015-02-01

To report and discuss the multi-domain impact of elosulfase alfa, with focus on tertiary and composite endpoints, in the 24-week, randomized, double-blind, placebo-controlled phase 3 trial in patients with Morquio A syndrome (mucopolysaccharidosis IVA). Patients with Morquio A syndrome aged ≥5 years were randomized 1:1:1 to elosulfase alfa 2.0mg/kg/week (qw; N=58), elosulfase alfa 2.0mg/kg/every other week (qow; N=59), or placebo (N=59) for 24 weeks. Primary and secondary efficacy measures were 6-minute walk test (6MWT; primary), 3-minute stair climb test (3-MSCT) and urinary keratan sulfate (KS). Safety was also evaluated. Tertiary efficacy measures included respiratory function measures, activities of daily living (MPS Health Assessment Questionnaire [MPS-HAQ]), anthropometric, echocardiographic and radiographic measures, hearing and corneal clouding assessment. In order to fully characterize treatment impact in this heterogeneous disorder, the effect of elosulfase alfa on composite efficacy measures was evaluated as well. The study was not designed to have sufficient power for any of the tertiary outcomes. For most tertiary endpoints, subjects treated with the weekly dose of elosulfase alfa improved more than those receiving placebo. The largest treatment effects were seen in maximal voluntary ventilation (MVV), MPS-HAQ, height, and growth rate. The qow group appeared similar to placebo. The analysis of a pre-specified composite endpoint (combining changes from baseline in 6MWT, 3MSCT and MVV z-scores equally weighted) showed a modest positive impact of elosulfase alfa qw versus placebo group (P=0.053). As a pre-specified supportive analysis, the O'Brien Rank Sum composite endpoint (changes from baseline in 6MWT, 3MSC, and MVV), analysis also showed that the qw group performed better than the placebo group (P=0.011). In post-hoc analyses, combinations of other endpoints were also explored using the O'Brien Rank Sum test and showed statistically significant

Trenonacog alfa for prophylaxis, on-demand and perioperative management of hemophilia B.

PubMed

Brennan, Yvonne; Curnow, Jennifer; Favaloro, Emmanuel J

2018-01-01

Current treatment for hemophilia B involves replacing the missing coagulation factor IX (FIX) with either plasma-derived or recombinant (r) FIX. Trenonacog alfa is the third normal half-life rFIX that has been granted FDA approval. Area covered: In this review, the authors examine trenonacog alfa for the treatment of hemophilia B including prophylaxis, on-demand and perioperative hemostasis. They compare the PK profile to nonacog alfa and evaluate the drug's efficacy and safety from published studies. Expert opinion: Trenonacog alfa appears to be an effective and safe treatment option for patients with hemophilia B with a PK profile similar to that of nonacog alfa. Despite the advent of extended half-life rFIX and other novel therapeutic approaches, normal half-life rFIX products, including trenonacog alfa, are likely to continue to have a place in hemophilia B treatment for at least the immediate future while the new landscape takes shape, particularly in countries that cannot afford the newer treatments.

Comparison of the Pharmacoeconomics of Calfactant and Poractant Alfa in Surfactant Replacement erapy.

PubMed

Zayek, Michael M; Eyal, Fabien G; Smith, Robert C

2018-01-01

To compare the pharmacy costs of calfactant (Infasurf, ONY, Inc.) and poractant alfa (Curosurf, Chiesi USA, Inc., Cary, NC). The University of South Alabama Children's and Women's Hospital switched from calfactant to poractant alfa in 2013 and back to calfactant in 2015. Retrospectively, we used deidentified data from pharmacy records that provided type of surfactant administered, gestational age, birth weight, and number of doses on each patient. We examined differences in the number of doses by gestational ages and the differences in costs by birth weight cohorts because cost per dose is based on weight. There were 762 patients who received calfactant and 432 patients who received poractant alfa. The average number of doses required per patient was 1.6 administrations for calfactant-treated patients and 1.7 administrations for poractant alfa-treated patients, p = 0.03. A higher percentage of calfactant patients needed only 1 dose (53%) than poractant alfa patients (47%). The distribution of the number of doses for calfactant-treated patients was significantly lower than for the poractant alfa-patients, p < 0.001. Gestational age had no consistent effect on the number of doses required for either calfactant or poractant alfa. Per patient cost was higher for poractant alfa than for calfactant in all birth weight cohorts. Average per patient cost was $1160.62 for poractant alfa, 38% higher than the average per patient cost for calfactant ($838.34). Using poractant alfa for 22 months is estimated to have cost $202,732.75 more than it would have cost if the hospital had continued using calfactant. Our experience showed a strong pharmacoeconomic advantage for the use of calfactant compared to the use of poractant alfa because of similar average dosing and lower per patient drug costs.

Validated spectrophotometric method for the determination, spectroscopic characterization and thermal structural analysis of duloxetine with 1,2-naphthoquinone-4-sulphonate

NASA Astrophysics Data System (ADS)

Ulu, Sevgi Tatar; Elmali, Fikriye Tuncel

2012-03-01

A novel, selective, sensitive and simple spectrophotometric method was developed and validated for the determination of the antidepressant duloxetine hydrochloride in pharmaceutical preparation. The method was based on the reaction of duloxetine hydrochloride with 1,2-naphthoquinone-4-sulphonate (NQS) in alkaline media to yield orange colored product. The formation of this complex was also confirmed by UV-visible, FTIR, 1H NMR, Mass spectra techniques and thermal analysis. This method was validated for various parameters according to ICH guidelines. Beer's law is obeyed in a range of 5.0-60 μg/mL at the maximum absorption wavelength of 480 nm. The detection limit is 0.99 μg/mL and the recovery rate is in a range of 98.10-99.57%. The proposed methods was validated and applied to the determination of duloxetine hydrochloride in pharmaceutical preparation. The results were statistically analyzed and compared to those of a reference UV spectrophotometric method.

Cost-effectiveness analysis of treatment with peginterferon-alfa-2a versus peginterferon-alfa-2b for patients with chronic hepatitis C under the public payer perspective in Brazil

PubMed Central

2013-01-01

Background Chronic hepatitis C affects approximately 170 million people worldwide, and thus being one of the main causes of chronic liver disease. About 20% of patients with chronic hepatitis C will develop cirrhosis over 20 years, and present an increased risk of developing hepatic complications. Sustained virological response (SVR) is associated with a better prognosis compared to untreated patients and treatment failures. The objective of this analysis was to compare treatment costs and outcomes of pegylated interferon-alfa-2a versus pegylated interferon-alfa-2b, both associated with ribavirin, in the therapeutic scheme of 24 weeks and 48 week for hepatitis C genotypes 2/3 and genotype 1, respectively, under the Brazilian Public Health System (SUS) scenario. Methods To project disease progression, a Markov model was built based on clinical stages of chronic disease. A Delphi panel was conducted to evaluate medical resources related to each stage, followed by costing of related materials, services, procedures and pharmaceutical products. The evaluation was made from a public payer perspective. The source used for costing was government reimbursement procedures list (SAI/SIH–SUS). Drug acquisition costs were obtained from the Brazilian Official Gazette and “Banco de Preços em Saúde” (government official source). It was assumed a mean patient weight of 70 kg. Costs were reported in 2011 Brazilian Reais (US$1 ≈ $Brz1.80). A systematic review followed by a meta-analysis of the 7 identified randomized controlled trials (RCTs) which compared pegylated interferons, was conducted for obtaining relative efficacy of both drugs: for genotype 2/3, mean rate of SVR was 79.2% for peginterferon-alfa-2a and 73.8% for peginterferon-alfa-2b. For genotype 1, SVR mean rate was 42.09% versus 33.44% (peginterferon-alfa-2a and peginterferon-alfa-2b respectively). Time horizon considered was lifetime. Discount rate for costs and outcomes was 5%, according to Brazilian

Bioequivalence of HX575 (recombinant human epoetin alfa) and a comparator epoetin alfa after multiple intravenous administrations: an open-label randomised controlled trial.

PubMed

Sörgel, Fritz; Thyroff-Friesinger, Ursula; Vetter, Andrea; Vens-Cappell, Bernhard; Kinzig, Martina

2009-05-22

HX575 is a human recombinant epoetin alfa that was approved for use in Europe in 2007 under the European Medicines Agency biosimilar approval pathway. Therefore, in order to demonstrate the bioequivalence of HX575 to an existing epoetin alfa, the pharmacokinetic and pharmacodynamic response to steady state circulating concentrations of HX575 and a comparator epoetin alfa were compared following multiple intravenous administrations. An open, randomised, parallel group study was conducted in 80 healthy adult males. Subjects were randomised to multiple intravenous doses of 100 IU/kg body weight of HX575 or of the comparator epoetin alfa three-times-weekly for four weeks. Serum epoetin concentrations were measured using an enzyme-linked immunosorbent assay and pharmacokinetic parameters for the two treatments were compared. The time course and area under the effect curve ratio of haematological characteristics were used as surrogate parameters for efficacy evaluation. The haematological profiles of both treatments were similar, as determined from their population mean curves and the AUECHb ratio and 90% confidence interval (99.9% [98.5-101.2%]), the primary pharmacodynamic endpoint of this study. The pharmacokinetic parameters after the treatments showed minor differences after single dosing, but not at steady state doses. After multiple doses, HX575 was bioequivalent to the comparator with respect to the rate and extent of exposure of exogenous epoetin (AUCtau ratio and 90% confidence interval: 89.2% [82.5-96.2%]). Study medication was well tolerated with no clinically relevant differences between safety profiles of the treatments. Anti-epoetin antibodies were not detected. HX575 and the comparator epoetin alfa were bioequivalent at steady state circulating drug concentrations with respect to their pharmacokinetic profile and pharmacodynamic action. This supports the conclusion that HX575 and the comparator epoetin alfa, when administered intraveneously, will be

An Open-label, Single-dose, Pharmacokinetic Study of Factor VIII Activity After Administration of Moroctocog Alfa (AF-CC) in Male Chinese Patients With Hemophilia A.

PubMed

Liu, Hongzhong; Wu, Runhui; Hu, Pei; Sun, Feifei; Xu, Lihong; Liang, Yali; Nepal, Sunil; Qu, Peng Roger; Huard, Francois; Korth-Bradley, Joan M

2017-07-01

Hemophilia A represents up to 80% of all hemophilia cases in China. In patients with this condition, bleeding can be prevented and controlled by administering clotting factor VIII (FVIII). Since their initial availability, recombinant FVIII products have undergone several iterations to enhance their safety. Moroctocog alfa albumin-free cell culture (AF-CC) is among the third generation of recombinant FVIII products and received regulatory approval in China in August 2012. The present study characterizes the single-dose pharmacokinetic parameters of FVIII activity (FVIII:C) after administration of moroctocog alfa (AF-CC) in male Chinese patients with hemophilia A. This multicenter, open-label, single-dose study enrolled 13 male Chinese patients diagnosed with severe hemophilia A (FVIII:C <1%) and a history of at least 150 exposure-days to any FVIII-containing product. Eligible patients received a single dose of moroctocog alfa (AF-CC) 50 IU/kg IV within 10 minutes. Blood samples were collected within 2 hours before administration and through 72 hours after dosing. Pharmacokinetic parameters were assessed based on FVIII:C and were analyzed by age groups: ages 6 to <12 years (n = 3) and ≥12 years (n = 10). The mean plasma concentration-time profile for FVIII:C activity was consistently lower in patients aged 6 to <12 years compared with those aged ≥12 years. Geometric AUC 0-∞ and C max were approximately 57% and 28% lower in the younger patients relative to the older patients, respectively. A total of 4 adverse events occurred in 4 patients. Low-titer, transient FVIII inhibitors were observed in 2 patients and were considered serious adverse events. Neither case resulted in clinical manifestations nor required treatment. This is the first report of the pharmacokinetic parameters of FVIII:C after moroctocog alfa (AF-CC) in an all-Chinese population of males with hemophilia A. The pharmacokinetic profile in older patients was similar to that previously reported

Single therapeutic and supratherapeutic doses of corifollitropin alfa, a sustained follicle stimulant, do not prolong the QTcF-interval in healthy postmenopausal volunteers.

PubMed

de Kam, Pieter-Jan; van Kuijk, Jacqueline H M; Zandvliet, Anthe S; Thomsen, Torben

2015-09-01

Corifollitropin alfa (Elonva®) is the first hybrid follicle-stimulating hormone molecule with demonstrated sustained follicle-stimulating activity after a single subcutaneous injection. This trial evaluated if corifollitropin alfa is associated with QT/QTc prolongation and/ or proarrhythmic potential as compared to placebo in healthy post-menopausal women. Participants were healthy, postmenopausal women. Study treatments were corifollitropin alfa 150 μg, corifollitropin alfa 240 μg, and moxifloxacin 400 mg with placebo. This randomized, double blind, double-dummy, 4-period crossover trial compared single doses of corifollitropin alfa 150 μg (therapeutic dose), corifollitropin alfa 240 μg (supratherapeutic dose), and moxifloxacin 400 mg (positive control) with placebo. Corifollitropin alfa was administered on day 1 and moxifloxacin on day 2. The largest time-matched mean QTcF difference versus placebo for the therapeutic dose of corifollitropin alfa was 1.4 ms (upper limit of 1-sided 95% confidence interval (UL 95% CI) = 3.4 ms), and for the supratherapeutic dose was 1.2 ms (UL 95% CI = 3.6 ms). For both the therapeutic and the supratherapeutic dose of corifollitropin alfa and at all time points, the UL 95% CI for the time matched QTcF differences compared with placebo was below 10 ms, the threshold of relevance defined by the ICH E14 guideline. Single therapeutic and supratherapeutic doses of corifollitropin alfa are not associated with clinically relevant QT/QTc-interval prolongation in healthy post-menopausal women.

Timing of dornase alfa inhalation for cystic fibrosis.

PubMed

Dentice, Ruth; Elkins, Mark

2016-07-26

Inhalation of the enzyme dornase alfa reduces sputum viscosity and improves clinical outcomes of people with cystic fibrosis. This is an update of a previously published Cochrane review. To determine the effect of timing of dornase alfa inhalation on measures of clinical efficacy in people with cystic fibrosis (in relation to airway clearance techniques or time of day). Relevant randomised and quasi-randomised controlled trials were identified from the Cochrane Cystic Fibrosis Trials Register, Physiotherapy Evidence Database (PEDro), and international cystic fibrosis conference proceedings.Date of the most recent search: 25 April 2016. Any trial of dornase alfa in people with cystic fibrosis where timing of inhalation was the randomised element in the study with either: inhalation before compared to after airway clearance techniques; or morning compared to evening inhalation. Both authors independently selected trials, assessed risk of bias and extracted data with disagreements resolved by discussion. Relevant data were extracted and, where possible, meta-analysed. We identified 115 trial reports representing 55 studies, of which five studies (providing data on 122 participants) met our inclusion criteria. All five studies used a cross-over design. Intervention periods ranged from two to eight weeks. Four trials compared dornase alfa inhalation before versus after airway clearance techniques. Inhalation after instead of before airway clearance did not significantly change forced expiratory volume at one second. Similarly, forced vital capacity and quality of life were not significantly affected; forced expiratory flow at 25% was significantly worse with dornase alfa inhalation after airway clearance, mean difference -0.17 litres (95% confidence interval -0.28 to -0.05), based on the pooled data from two small studies in children (seven to 19 years) with well-preserved lung function. All other secondary outcomes were statistically non-significant.In one trial

Adoption and de-adoption of drotrecogin alfa for severe sepsis in the United States.

PubMed

Kahn, Jeremy M; Le, Tri Q

2016-04-01

Drotrecogin alfa was a landmark drug for treatment of severe sepsis, yet little is known about how it was adopted and de-adopted during its 10-year period of availability. We used hospitalization data on fee-for-service Medicare beneficiaries from 2002 to 2011 to characterize trends in the use of drotrecogin alfa in the United States. Drotrecogin alfa use peaked at 5.87 per 1000 severe sepsis hospitalizations in 2003 and then steadily declined to 0.94 administrations per 1000 severe sepsis hospitalizations in 2010. Large teaching hospitals were more likely to use drotrecogin alfa than small, nonteaching hospitals. The addition of "add-on payments" to hospitals for using drotrecogin alfa in 2002 was associated with significantly increased use (P < .0001), and the withdrawal of those payments in 2004 was associated significantly decreased use (P < .0001). Neither the publication of international sepsis guidelines with favorable drotrecogin alfa recommendations (in 2004 and 2008) nor the publication of a clinical trial focused on drotrecogin alfa (in 2005) were associated with consistent changes use (P > .05). Drotrecogin alfa use declined over time, with marked changes in use associated with drug-specific financial incentives but not the publication of clinical practice guidelines or clinical trials. Copyright © 2015 Elsevier Inc. All rights reserved.

GWAS-based machine learning approach to predict duloxetine response in major depressive disorder.

PubMed

Maciukiewicz, Malgorzata; Marshe, Victoria S; Hauschild, Anne-Christin; Foster, Jane A; Rotzinger, Susan; Kennedy, James L; Kennedy, Sidney H; Müller, Daniel J; Geraci, Joseph

2018-04-01

Major depressive disorder (MDD) is one of the most prevalent psychiatric disorders and is commonly treated with antidepressant drugs. However, large variability is observed in terms of response to antidepressants. Machine learning (ML) models may be useful to predict treatment outcomes. A sample of 186 MDD patients received treatment with duloxetine for up to 8 weeks were categorized as "responders" based on a MADRS change >50% from baseline; or "remitters" based on a MADRS score ≤10 at end point. The initial dataset (N = 186) was randomly divided into training and test sets in a nested 5-fold cross-validation, where 80% was used as a training set and 20% made up five independent test sets. We performed genome-wide logistic regression to identify potentially significant variants related to duloxetine response/remission and extracted the most promising predictors using LASSO regression. Subsequently, classification-regression trees (CRT) and support vector machines (SVM) were applied to construct models, using ten-fold cross-validation. With regards to response, none of the pairs performed significantly better than chance (accuracy p > .1). For remission, SVM achieved moderate performance with an accuracy = 0.52, a sensitivity = 0.58, and a specificity = 0.46, and 0.51 for all coefficients for CRT. The best performing SVM fold was characterized by an accuracy = 0.66 (p = .071), sensitivity = 0.70 and a sensitivity = 0.61. In this study, the potential of using GWAS data to predict duloxetine outcomes was examined using ML models. The models were characterized by a promising sensitivity, but specificity remained moderate at best. The inclusion of additional non-genetic variables to create integrated models may improve prediction. Copyright © 2017. Published by Elsevier Ltd.

Impact of patient characteristics on the pharmacokinetics of corifollitropin alfa during controlled ovarian stimulation.

PubMed

Zandvliet, Anthe S; Prohn, Marita; de Greef, Rik; van Aarle, Frank; McCrary Sisk, Christine; Stegmann, Barbara J

2016-07-01

The aim of the present study was to characterize the pharmacokinetic profile of corifollitropin alfa and examine the relationships between dose, intrinsic factors [body weight, body mass index (BMI), age and race] and corifollitropin alfa pharmacokinetics. Data from five phase II and III clinical trials of corifollitropin alfa were evaluated. All subjects included in the analysis received 60 - 180 μg corifollitropin alfa for controlled ovarian stimulation in a gonadotrophin-releasing hormone antagonist protocol followed by daily recombinant follicle stimulating hormone (rFSH) from day 8 onwards. Serum corifollitropin alfa levels (across the entire range of treatment) and total follicle stimulating hormone immunoreactivity levels (up to the start of rFSH treatment) were indicators of drug exposure. The analyses were performed using a nonlinear mixed-effects modelling approach. A total of 2630 subjects were treated with corifollitropin alfa, and 2557 subjects were evaluable for analysis. Body weight, BMI and race (Asian and Black vs. Caucasian) were significant determinants of corifollitropin alfa exposure. Dose-normalized corifollitropin alfa exposure was ~89% higher in women with a body weight of 50 kg vs. 90 kg (in subjects with a similar BMI of 24 kg m(-2) ); 14% higher in women with a BMI of 18 kg m(-2) vs. 32 kg m(-2) (provided they were of similar body weight); and ~15.7% lower in Asian subjects and 13% higher in Black subjects vs. Caucasian subjects. Body weight was the major determinant of corifollitropin alfa exposure; BMI and race (Asian and Black) were also determinants but to a lesser extent and without associated effects on clinical outcomes. Corifollitropin alfa dose adjustment is indicated, based on body weight but not for BMI or race. These recommendations are consistent with the product label. © 2016 The British Pharmacological Society.

Darbepoetin alfa therapeutic interchange protocol for anemia in dialysis.

PubMed

Brophy, Donald F; Ripley, Elizabeth Bd; Kockler, Denise R; Lee, Seina; Proeschel, Lori A

2005-11-01

Erythropoiesis-stimulating proteins, such as erythropoietin alfa and darbepoetin alfa, have positively impacted anemia management. These medications improve patient outcomes and quality of life. Their costs, however, remain a major barrier for health systems. To evaluate the development, implementation, and cost-effectiveness of an inpatient therapeutic interchange protocol for erythropoiesis-stimulating proteins at a large, tertiary care, university-affiliated health system. Virginia Commonwealth University Health System (VCUHS) developed and implemented a therapeutic interchange program to convert therapy for all inpatients undergoing dialysis from erythropoietin alfa to darbepoetin alfa for treatment of chronic kidney disease-related anemia. An evaluation of the economic impact of this program on drug expenditures over a fiscal quarter (2003) was conducted using historical comparator data (2002). Preliminary evaluation of the program demonstrated cost-savings and reduced drug utilization of erythropoiesis-stimulating proteins in hospitalized dialysis patients. For the first quarter of 2003 compared with the first quarter of 2002, VCUHS realized a cost-savings of nearly 10,000 US dollars, which was related to the program's aggressive screening procedure. When these data were normalized for equal numbers of patients in each group receiving one of the drugs, the actual cost-savings was over 2000 US dollars. These cost-savings are largely due to reduced utilization of these expensive biotechnology products with implementation of a dosing protocol. VCUHS has successfully developed and implemented a darbepoetin alfa therapeutic interchange protocol for hospitalized dialysis patients. This has translated into reduced use of erythropoiesis-stimulating proteins, resulting in cost-savings for the health system.

Development of anti-velaglucerase alfa antibodies in clinical trial-treated patients with Gaucher disease.

PubMed

Pastores, Gregory M; Turkia, Hadhami Ben; Gonzalez, Derlis E; Ida, Hiroyuki; Tantawy, Azza A G; Qin, Yulin; Qiu, Yongchang; Dinh, Quinn; Zimran, Ari

2016-07-01

Anti-drug antibodies may develop with biological therapies, possibly leading to a reduction of treatment efficacy and to allergic and other adverse reactions. Patients with Gaucher disease were tested for anti-drug antibodies every 6 or 12weeks in clinical studies of velaglucerase alfa enzyme replacement therapy, as part of a range of safety endpoints. In 10 studies between April 2004 and March 2015, 289 patients aged 2-84years (median 43years) were assessed for the development of anti-velaglucerase alfa antibodies. Sixty-four patients were treatment-naïve at baseline and 225 patients were switched to velaglucerase alfa from imiglucerase treatment. They received velaglucerase alfa treatment for a median of 36.4weeks (interquartile range 26.4-155.4weeks). Four patients (1.4%) became positive for anti-velaglucerase alfa IgG antibodies, two of whom had antibodies that were neutralizing in vitro, but there were no apparent changes in patients' platelet counts, hemoglobin levels or levels of CCL18 and chitotriosidase, suggestive of clinical deterioration after anti-velaglucerase alfa antibodies were detected, and no infusion-related adverse events were reported. Less than 2% of patients exposed to velaglucerase alfa tested positive for antibodies and there was no apparent correlation between anti-velaglucerase alfa antibodies and adverse events or pharmacodynamic or clinical responses. Copyright © 2016. Published by Elsevier Inc.

A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease.

PubMed

Pfeffer, Marc A; Burdmann, Emmanuel A; Chen, Chao-Yin; Cooper, Mark E; de Zeeuw, Dick; Eckardt, Kai-Uwe; Feyzi, Jan M; Ivanovich, Peter; Kewalramani, Reshma; Levey, Andrew S; Lewis, Eldrin F; McGill, Janet B; McMurray, John J V; Parfrey, Patrick; Parving, Hans-Henrik; Remuzzi, Giuseppe; Singh, Ajay K; Solomon, Scott D; Toto, Robert

2009-11-19

Anemia is associated with an increased risk of cardiovascular and renal events among patients with type 2 diabetes and chronic kidney disease. Although darbepoetin alfa can effectively increase hemoglobin levels, its effect on clinical outcomes in these patients has not been adequately tested. In this study involving 4038 patients with diabetes, chronic kidney disease, and anemia, we randomly assigned 2012 patients to darbepoetin alfa to achieve a hemoglobin level of approximately 13 g per deciliter and 2026 patients to placebo, with rescue darbepoetin alfa when the hemoglobin level was less than 9.0 g per deciliter. The primary end points were the composite outcomes of death or a cardiovascular event (nonfatal myocardial infarction, congestive heart failure, stroke, or hospitalization for myocardial ischemia) and of death or end-stage renal disease. Death or a cardiovascular event occurred in 632 patients assigned to darbepoetin alfa and 602 patients assigned to placebo (hazard ratio for darbepoetin alfa vs. placebo, 1.05; 95% confidence interval [CI], 0.94 to 1.17; P=0.41). Death or end-stage renal disease occurred in 652 patients assigned to darbepoetin alfa and 618 patients assigned to placebo (hazard ratio, 1.06; 95% CI, 0.95 to 1.19; P=0.29). Fatal or nonfatal stroke occurred in 101 patients assigned to darbepoetin alfa and 53 patients assigned to placebo (hazard ratio, 1.92; 95% CI, 1.38 to 2.68; P<0.001). Red-cell transfusions were administered to 297 patients assigned to darbepoetin alfa and 496 patients assigned to placebo (P<0.001). There was only a modest improvement in patient-reported fatigue in the darbepoetin alfa group as compared with the placebo group. The use of darbepoetin alfa in patients with diabetes, chronic kidney disease, and moderate anemia who were not undergoing dialysis did not reduce the risk of either of the two primary composite outcomes (either death or a cardiovascular event or death or a renal event) and was associated with an

Dornase alfa: a new option in the management of cystic fibrosis.

PubMed

Witt, D M; Anderson, L

1996-01-01

Recombinant human DNase I, or dornase alfa, is the first new therapy developed specifically for cystic fibrosis in almost 30 years. It selectively digests extracellular DNA and reduces the viscosity of purulent sputum. In clinical trials dornase alfa modestly improved pulmonary function, slightly decreasing the number of respiratory exacerbations requiring parenteral antibiotics compared with placebo. Phase III studies suggest that patients receiving dornase alfa also spend slightly fewer days in the hospital than those treated with placebo. The aerosolized preparation is safe and generally well tolerated. Voice alteration and sore throat are the most commonly reported adverse effects. Further research is necessary to determine the optimum time to initiate therapy and to evaluate the agent's pharmacoeconomic impact on the treatment of cystic fibrosis. Aerosolized dornase alfa should always be given in conjunction with standard cystic fibrosis therapies including antibiotics, chest physiotherapy, and pancreatic enzyme supplementation.

Recombinant factor VIIa analog in the management of hemophilia with inhibitors: results from a multicenter, randomized, controlled trial of vatreptacog alfa.

PubMed

Lentz, S R; Ehrenforth, S; Karim, F Abdul; Matsushita, T; Weldingh, K N; Windyga, J; Mahlangu, J N

2014-08-01

Vatreptacog alfa, a recombinant factor VIIa (rFVIIa) analog with three amino acid substitutions and 99% identity to native FVIIa, was developed to improve the treatment of hemophilic patients with inhibitors. To confirm the safety and assess the efficacy of vatreptacog alfa in treating bleeding episodes in hemophilic patients with inhibitors. In this international, multicenter, randomized, double-blind, active-controlled, crossover, confirmatory phase III trial (adept(™) 2) in patients with hemophilia A or B and inhibitors, bleeds were randomized 3 : 2 to treatment with vatreptacog alfa (one to three doses at 80 μg kg(-1) ) or rFVIIa (one to three doses at 90 μg kg(-1) ). Treatment failures after three doses of trial product (TP) were managed according to the local standard of care. In the 72 patients enrolled, 567 bleeds were treated with TP. Both vatreptacog alfa and rFVIIa gave 93% effective bleeding control at 12 h. Vatreptacog alfa was superior to rFVIIa in secondary efficacy outcomes, including the number of doses used to treat a bleed and sustained bleeding control 24-48 h after the first dose. Eight patients (11%) developed antibodies against vatreptacog alfa, including four with cross-reactivity against rFVIIa and one with an in vitro neutralizing effect to vatreptacog alfa. This large randomized controlled trial confirmed the well-established efficacy and safety profile of rFVIIa, and showed that vatreptacog alfa had similar or better efficacy than rFVIIa. However, because of the development of anti-drug antibodies, a positive benefit-risk profile is unlikely to be achieved with vatreptacog alfa. © 2014 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.

Evaluation of patient-rated stiffness associated with fibromyalgia: a post-hoc analysis of 4 pooled, randomized clinical trials of duloxetine.

PubMed

Bennett, Robert; Russell, I Jon; Choy, Ernest; Spaeth, Michael; Mease, Philip; Kajdasz, Daniel; Walker, Daniel; Wang, Fujun; Chappell, Amy

2012-04-01

Short-Form Health Survey bodily pain, and Sheehan Disability Scale total score. Variables related to severity of pain, pain interfering with daily activities, and physical functioning were predictors of change in stiffness. Stiffness scores were high in this population with FM and best correlated at baseline with BPI pain score and FIQ function. Not unexpectedly, improvement in stiffness with duloxetine correlated with many of the other markers of FM severity, presumably a result of amelioration in FM comorbidities. Copyright © 2012. Published by EM Inc USA.

Drotrecogin alfa (activated) in adults with septic shock.

PubMed

Ranieri, V Marco; Thompson, B Taylor; Barie, Philip S; Dhainaut, Jean-François; Douglas, Ivor S; Finfer, Simon; Gårdlund, Bengt; Marshall, John C; Rhodes, Andrew; Artigas, Antonio; Payen, Didier; Tenhunen, Jyrki; Al-Khalidi, Hussein R; Thompson, Vivian; Janes, Jonathan; Macias, William L; Vangerow, Burkhard; Williams, Mark D

2012-05-31

There have been conflicting reports on the efficacy of recombinant human activated protein C, or drotrecogin alfa (activated) (DrotAA), for the treatment of patients with septic shock. In this randomized, double-blind, placebo-controlled, multicenter trial, we assigned 1697 patients with infection, systemic inflammation, and shock who were receiving fluids and vasopressors above a threshold dose for 4 hours to receive either DrotAA (at a dose of 24 μg per kilogram of body weight per hour) or placebo for 96 hours. The primary outcome was death from any cause 28 days after randomization. At 28 days, 223 of 846 patients (26.4%) in the DrotAA group and 202 of 834 (24.2%) in the placebo group had died (relative risk in the DrotAA group, 1.09; 95% confidence interval [CI], 0.92 to 1.28; P=0.31). At 90 days, 287 of 842 patients (34.1%) in the DrotAA group and 269 of 822 (32.7%) in the placebo group had died (relative risk, 1.04; 95% CI, 0.90 to 1.19; P=0.56). Among patients with severe protein C deficiency at baseline, 98 of 342 (28.7%) in the DrotAA group had died at 28 days, as compared with 102 of 331 (30.8%) in the placebo group (risk ratio, 0.93; 95% CI, 0.74 to 1.17; P=0.54). Similarly, rates of death at 28 and 90 days were not significantly different in other predefined subgroups, including patients at increased risk for death. Serious bleeding during the treatment period occurred in 10 patients in the DrotAA group and 8 in the placebo group (P=0.81). DrotAA did not significantly reduce mortality at 28 or 90 days, as compared with placebo, in patients with septic shock. (Funded by Eli Lilly; PROWESS-SHOCK ClinicalTrials.gov number, NCT00604214.).

Long-term effect of epoetin alfa on clinical and biochemical markers in friedreich ataxia.

PubMed

Saccà, Francesco; Puorro, Giorgia; Marsili, Angela; Antenora, Antonella; Pane, Chiara; Casali, Carlo; Marcotulli, Christian; Defazio, Giovanni; Liuzzi, Daniele; Tatillo, Chiara; Cambriglia, Donata Maria; Schiano di Cola, Giuseppe; Giuliani, Luigi; Guardasole, Vincenzo; Salzano, Andrea; Ruvolo, Antonio; De Rosa, Anna; Cittadini, Antonio; De Michele, Giuseppe; Filla, Alessandro

2016-05-01

Friedreich ataxia is an autosomal recessive disease with no available therapy. Clinical trials with erythropoietin in Friedreich ataxia patients have yielded conflicting results, and the long-term effect of the drug remains unknown. We designed a double-blind, placebo-controlled, multicenter trial to test the efficacy of epoetin alfa on 56 patients with Friedreich ataxia. The primary endpoint of the study was the effect of epoetin alfa on peak oxygen uptake (VO2 max) at the cardiopulmonary exercise test. Secondary endpoints were frataxin levels in peripheral blood mononuclear cells, improvement in echocardiography findings, vascular reactivity, neurological progression, upper limb dexterity, safety, and quality of life. Epoetin alfa or placebo (1:1 ratio) was administered subcutaneously at a dose of 1200 IU/Kg of body weight every 12 weeks for 48 weeks. A total of 56 patients were randomized; 27 completed the study in the active treatment group, and 26 completed the study in the placebo group[KG1]. VO2 max was not modified after treatment (0.01 [-0.04 to 0.05]; P = .749), as well as most of the secondary endpoint measures, including frataxin. The 9-hole peg test showed a significant amelioration in the treatment group (-17.24 sec. [-31.5 to -3.0]; P = .018). The treatment was safe and well tolerated. Although results are not in favor of an effect of epoetin alfa in Friedreich ataxia, this is the largest trial testing its effect. It is still possible that epoetin alfa may show some symptomatic effect on upper-limb performance. This study provides class I evidence that erythropoietin does not ameliorate VO2 max in patients with Friedreich ataxia. © 2016 International Parkinson and Movement Disorder Society. © 2016 International Parkinson and Movement Disorder Society.

Pharmacodynamics of norepinephrine reuptake inhibition: Modeling the peripheral and central effects of atomoxetine, duloxetine, and edivoxetine on the biomarker 3,4-dihydroxyphenylglycol in humans.

PubMed

Kielbasa, William; Lobo, Evelyn

2015-12-01

Norepinephrine, a neurotransmitter in the autonomic sympathetic nervous system, is deaminated by monoamine oxidase to 3,4-dihydroxyphenylglycol (DHPG). Inhibition of the NE transporter (NET) using DHPG as a biomarker was evaluated using atomoxetine, duloxetine, and edivoxetine as probe NET inhibitors. Pharmacokinetic and pharmacodynamic data were obtained from healthy subjects (n = 160) from 5 clinical trials. An indirect response model was used to describe the relationship between drug plasma concentration and DHPG concentration in plasma and cerebrospinal fluid (CSF). The baseline plasma DHPG concentration (1130-1240 ng/mL) and Imax (33%-37%) were similar for the 3 drugs. The unbound plasma drug IC50 (IC50U ) based on plasma DHPG was 0.973 nM for duloxetine, 0.136 nM for atomoxetine, and 0.041 nM for edivoxetine. The baseline CSF DHPG concentration (1850-2260 ng/mL) was similar for the 3 drugs, but unlike plasma DHPG, the Imax for DHPG was 38% for duloxetine, 53% for atomoxetine, and75% for edivoxetine. The IC50U based on CSF DHPG was 2.72 nM for atomoxetine, 1.22 nM for duloxetine, and 0.794 nM for edivoxetine. These modeling results provide insights into the pharmacology of NET inhibitors and the use of DHPG as a biomarker. © 2015, The American College of Clinical Pharmacology.

Corifollitropin alfa versus recombinant follicle-stimulating hormone: an individual patient data meta-analysis.

PubMed

Griesinger, Georg; Boostanfar, Robert; Gordon, Keith; Gates, Davis; McCrary Sisk, Christine; Stegmann, Barbara J

2016-07-01

A meta-analysis was conducted of individual patient data (n = 3292) from three randomized controlled trials of corifollitropin alfa versus rFSH: Engage (150 µg corifollitropin alfa n = 756; 200 IU rFSH n = 750), Ensure (100 µg corifollitropin alfa n = 268; 150 IU rFSH n = 128), and Pursue (150 µg corifollitropin alfa n = 694; 300 IU rFSH n = 696). Women with regular menstrual cycles aged 18-36 and body weight >60 kg (Engage) or ≤60 kg (Ensure), or women aged 35-42 years and body weight ≥50 kg (Pursue), received a single injection (100 µg or 150 µg) of corifollitropin alfa (based on body weight and age) or daily rFSH. The difference (corifollitropin alfa minus rFSH) in the number of oocytes retrieved was +1.0 (95% CI: 0.5-1.5); vital pregnancy rate: -2.2% (95% CI: -5.3%-0.9%); ongoing pregnancy rate: -1.7% (95% CI: -4.7%-1.4%); and live birth rate: -2.0% (95% CI: -5.0%-1.1%). The odds ratio for overall OHSS was 1.15 (95% CI: 0.82-1.61), and for moderate-to-severe OHSS: 1.29 (95% CI: 0.81-2.05). A single dose of corifollitropin alfa for the first 7 days of ovarian stimulation is a generally well-tolerated and similarly effective treatment compared with daily rFSH. Copyright © 2016 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

Efficacy of Duloxetine in the Early Management of Urinary Continence after Radical Prostatectomy.

PubMed

Alan, Cabir; Eren, Ali E; Ersay, Ahmet R; Kocoglu, Hasan; Basturk, Gokhan; Demirci, Emrah

2015-05-01

To evaluate the efficacy of early duloxetine therapy in stress urinary incontinence occurring after radical prostatectomy (RP). Patients that had RP were randomly divided into 2 groups following the removal of the urinary catheter. Group A patients (n = 28) had pelvic floor exercise and duloxetine therapy. Group B patients (n = 30) had only pelvic floor exercise. The incontinence status of the patients and number of pads were recorded and 1-hour pad test and Turkish validation of International Consultation on Incontinence Questionnaire-Short Form test were applied to the patients at the follow-up. When the dry state of the patients was evaluated, 5, 17, 3, and 2 of 28 Group A patients stated that they were completely dry in the 3rd, 6th, 9th and 12th month respectively and pad use was stopped. There was no continence in 30 Group B in the first 3 months. Twelve, 6, and 8 patients stated that they were completely dry in the 6th, 9th and 12th month, respectively. But 3 of 4 patients in whom dryness could not be provided were using a mean of 7.6 pads in the first day and a mean of 1.3 pads after 1 year. When pad use of the patients was evaluated, the mean monthly number of pad use was determined to be 6.2 (4-8) in the initial evaluation, 2.7 (0-5) in the in 3rd month, 2 (0-3) in the 6th month and 1.6 (0-2) pad/d in the 9th month in the group taking medicine. The mean monthly number of pads used was determined to be 5.8 (4-8) in the initial evaluation, 4.3 (3-8) in the 3rd month, 3 (0-6) in the 6th month and 1.6 (0-6) pad/d in the 9th month in the group not taking medicine. According to the results, early duloxetine therapy in stress urinary incontinence that occurred after RP provided early continence.

Thermophysical and mechanical characterization of clay bricks reinforced by alfa or straw fibers

NASA Astrophysics Data System (ADS)

Elhamdouni, Y.; Khabbazi, A.; Benayad, C.; Mounir, S.; Dadi, A.

2017-03-01

This work is part of the valuation of local materials such as clay (earth), alfa fiber and straw fiber. The goal is to use these materials as bricks in rural construction. These materials are abundant, natural, and renewable. The objective of this work is to study the thermal and mechanical behavior of a new material by mixing clay (chosen as the binder) with different mass percentages of alfa fiber (0.5%, 1%, 2%, 3%, 4%), and to compare these results with those of materials often used in the construction of individual houses in rural Morocco (clay + straw). The results obtained prove to us that using straw fibers can reduce the thermal conductivity compared to alfa fiber, which allows to have energy savings of 2% to 7%. By against, alfa fibers can improve the mechanical behavior of clay-based materials when compared to the clay + straw material (an increase of 8% to 17% in the tractive resistance by bending and 6% to 18% for compression resistance). These results also specify the optimal usage conditions of these fibers (alfa and straw) in the clay bricks.

Spurious testosterone laboratory results in a patient taking synthetic alkaline phosphatase (asfotase alfa).

PubMed

Sofronescu, Alina G; Ross, Meredith; Rush, Eric; Goldner, Whitney

2018-04-27

We report a case of discordant total and free testosterone values in a patient with hypogonadism and juvenile hypophosphatasia after he initiated treatment with asfotase alfa, recombinant tissue non-specific alkaline phosphatase. Total testosterone was evaluated using immunoassay pre and post initiation of therapy with asfotase alfa, and free testosterone was evaluated using radioimmunoassay and LC-MS/MS while on asfotase alfa therapy. Total testosterone measured by immunoassay was normal prior to therapy with asfotase alfa, and was low post initiation of therapy. During the same time frame, free testosterone measured using RAI and total testosterone measured using LC-MS/MS were normal on asfotase alfa therapy. This suggests assay interference with the total testosterone immunoassay. When laboratory results are discordant or do not match the clinical impression, the possibility of assay interference should be considered. Alternative laboratory methods free of the interference should be selected to evaluate these patients. ALPL gene, Approved name: Alkaline phosphatase, liver/bone/kidney, Synonym: Tissue non-specific alkaline phosphatase (TNSAP). Copyright © 2018 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Comparison of the effects of agalsidase alfa and agalsidase beta on cultured human Fabry fibroblasts and Fabry mice.

PubMed

Sakuraba, Hitoshi; Murata-Ohsawa, Mai; Kawashima, Ikuo; Tajima, Youichi; Kotani, Masaharu; Ohshima, Toshio; Chiba, Yasunori; Takashiba, Minako; Jigami, Yoshifumi; Fukushige, Tomoko; Kanzaki, Tamotsu; Itoh, Kohji

2006-01-01

We compared two recombinant alpha-galactosidases developed for enzyme replacement therapy for Fabry disease, agalsidase alfa and agalsidase beta, as to specific alpha-galactosidase activity, stability in plasma, mannose 6-phosphate (M6P) residue content, and effects on cultured human Fabry fibroblasts and Fabry mice. The specific enzyme activities of agalsidase alfa and agalsidase beta were 1.70 and 3.24 mmol h(-1) mg protein(-1), respectively, and there was no difference in stability in plasma between them. The M6P content of agalsidase beta (3.6 mol/mol protein) was higher than that of agalsidase alfa (1.3 mol/mol protein). The administration of both enzymes resulted in marked increases in alpha-galactosidase activity in cultured human Fabry fibroblasts, and Fabry mouse kidneys, heart, spleen and liver. However, the increase in enzyme activity in cultured fibroblasts, kidneys, heart and spleen was higher when agalsidase beta was used. An immunocytochemical analysis revealed that the incorporated recombinant enzyme degraded the globotriaosyl ceramide accumulated in cultured Fabry fibroblasts in a dose-dependent manner, with the effect being maintained for at least 7 days. Repeated administration of agalsidase beta apparently decreased the number of accumulated lamellar inclusion bodies in renal tubular cells of Fabry mice.

Evaluation of Inhaled Dornase Alfa Administration in Non-Cystic Fibrosis Patients at a Tertiary Academic Medical Center.

PubMed

Torbic, Heather; Hacobian, Gaspar

2016-10-01

The use of dornase alfa in a non-cystic fibrosis population has been proposed to help improve atelectasis and secretions. Data evaluating dornase alfa in a non-cystic fibrosis population are limited, and the prescribing practices at a tertiary academic medical center are unknown. Adult patients ≥18 years of age were included if they received inhaled dornase alfa. Patients were excluded if they had cystic fibrosis. Data collected included demographic data, dornase alfa prescribing patterns, concomitant inhaled therapy, blood gas data, and documented efficacy and safety data. Seventy-six orders for dornase alfa therapy were included in the analysis. Of the patients, 18% had asthma and 19% had chronic obstructive pulmonary disease. Seventy-seven percent of the patients received concomitant inhaled therapy. Eighty-three percent of orders were for 2.5 mg of dornase alfa twice daily. The median (interquartile range [IQR]) number of doses received per patient was 6 (4-13) with a median (IQR) duration of 3 (2-7) days. After inhaled dornase alfa administration, 11% of patients were able to cough productively. No safety issues related to inhaled dornase alfa therapy were noted. Inhaled dornase alfa is commonly prescribed to improve atelectasis and secretions in a non-cystic fibrosis patient population at a tertiary academic medical center. © The Author(s) 2015.

Asfotase Alfa Treatment Improves Survival for Perinatal and Infantile Hypophosphatasia

PubMed Central

Rockman-Greenberg, Cheryl; Ozono, Keiichi; Riese, Richard; Moseley, Scott; Melian, Agustin; Thompson, David D.; Bishop, Nicholas; Hofmann, Christine

2016-01-01

Context: Hypophosphatasia (HPP) is an inborn error of metabolism that, in its most severe perinatal and infantile forms, results in 50–100% mortality, typically from respiratory complications. Objectives: Our objective was to better understand the effect of treatment with asfotase alfa, a first-in-class enzyme replacement therapy, on mortality in neonates and infants with severe HPP. Design/Setting: Data from patients with the perinatal and infantile forms of HPP in two ongoing, multicenter, multinational, open-label, phase 2 interventional studies of asfotase alfa treatment were compared with data from similar patients from a retrospective natural history study. Patients: Thirty-seven treated patients (median treatment duration, 2.7 years) and 48 historical controls of similar chronological age and HPP characteristics. Interventions: Treated patients received asfotase alfa as sc injections either 1 mg/kg six times per week or 2 mg/kg thrice weekly. Main Outcome Measures: Survival, skeletal health quantified radiographically on treatment, and ventilatory status were the main outcome measures for this study. Results: Asfotase alfa was associated with improved survival in treated patients vs historical controls: 95% vs 42% at age 1 year and 84% vs 27% at age 5 years, respectively (P < .0001, Kaplan-Meier log-rank test). Whereas 5% (1/20) of the historical controls who required ventilatory assistance survived, 76% (16/21) of the ventilated and treated patients survived, among whom 75% (12/16) were weaned from ventilatory support. This better respiratory outcome accompanied radiographic improvements in skeletal mineralization and health. Conclusions: Asfotase alfa mineralizes the HPP skeleton, including the ribs, and improves respiratory function and survival in life-threatening perinatal and infantile HPP. PMID:26529632

Cystic fibrosis clinical characteristics associated with dornase alfa treatment regimen change.

PubMed

VanDevanter, Donald R; Craib, Marcia L; Pasta, David J; Millar, Stefanie J; Morgan, Wayne J; Konstan, Michael W

2018-01-01

When the chronic respiratory therapy dornase alfa was made commercially available for cystic fibrosis (CF) more than 20 years ago, two regimens were approved: 2.5 mg inhaled once daily (QD) or twice daily (BID). In the intervening years, there has been little guidance as to when to use each regimen. We have studied clinical practice patterns captured in the Epidemiologic Study of CF (ESCF) during the decade following dornase alfa approval (1994-2005) to better understand clinical characteristics associated with QD versus BID dornase alfa use. Methods We studied the characteristics of ESCF patients who received either dornase alfa regimen for at least 12 months and who were then switched to the alternate regimen for at least 6 months and who had adequate data available around the time of the switch. Average lung function and weight-for-age (WFA) z-scores, numbers of intravenous (IV) antibiotic-treated pulmonary exacerbations, and prevalence of signs and symptoms were determined for 6-month periods capturing the beginning (FIRST) and the end (LAST) of the initial regimen, the 6 months preceding the final 6 months of the initial regimen (PRIOR), and the beginning of the second regimen (POST). Changes in values from FIRST to LAST, PRIOR to LAST, and LAST to POST were studied to better understand clinical scenarios associated with decisions to change regimens. A total of 1342 QD and 574 BID regimens were studied with median durations of 3.19 and 2.09 years, respectively. On average, patients beginning BID regimens had worse lung function and a greater number of pulmonary exacerbations treated with IV antibiotics than those beginning QD regimens. However, by the time of regimen switch, patients switching from QD to BID dornase alfa had experienced substantial deterioration with respect to pulmonary exacerbations and signs and symptoms, whereas patients switching from BID to QD had not. Interestingly, incidence of IV-treated pulmonary exacerbations and signs and symptom

Synthesis and characterization of pharmaceutical surfactant templated mesoporous silica: Its application to controlled delivery of duloxetine

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

Mani, Ganesh; Pushparaj, Hemalatha; Peng, Mei Mei

2014-03-01

Graphical abstract: - Highlights: • Usefulness of dual pharmaceutical surfactants in silica synthesis was evaluated. • Effects of concentration of secondary template (Tween-40) were studied. • Effects of fixed solvothermal condition on mesostructure formation were studied. • Duloxetine drug loading capability was studied. • Sustained release of duloxetine was evaluated. - Abstract: A new group of mesoporous silica nanoparticles (MSNs) were synthesized using combination pharmaceutical surfactants, Triton X-100 and Tween-40 as template and loaded with duloxetine hydrochloride (DX), for improving the sustained release of DX and patterns with high drug loading. Agglomerated spherical silica MSNs were synthesized by sol–gel andmore » solvothermal methods. The calcined and drug loaded MSNs were characterized using X-ray diffraction (XRD), Braunner–Emmett–Teller (BET), thermogravimetric analysis (TGA), Fourier-transform infrared (FT-IR) spectroscopy, scanning electron microscopy (SEM), differential scanning calorimetry (DSC), diffuse reflectance ultraviolet–visible (DRS-UV–vis) spectroscopy. MSNs with high surface area and pore volume were selected and studied for their DX loading and release. The selected MSNs can accommodate a maximum of 34% DX within it. About 90% was released at 200 h and hence, the synthesized MSNs were capable of engulfing DX and sustain its release. Further form the Ritger and Peppas, Higuchi model for mechanism drug release from all the MSN matrices follows anomalous transport or Non-Fickian diffusion with the ‘r’ and ‘n’ value 0.9 and 0.45 < n < 1, respectively. So, from this study it could be concluded that the MSNs synthesized using pharmaceutical templates were better choice of reservoir for the controlled delivery of drug which requires sustained release.« less

Roxadustat (FG-4592) Versus Epoetin Alfa for Anemia in Patients Receiving Maintenance Hemodialysis: A Phase 2, Randomized, 6- to 19-Week, Open-Label, Active-Comparator, Dose-Ranging, Safety and Exploratory Efficacy Study.

PubMed

Provenzano, Robert; Besarab, Anatole; Wright, Steven; Dua, Sohan; Zeig, Steven; Nguyen, Peter; Poole, Lona; Saikali, Khalil G; Saha, Gopal; Hemmerich, Stefan; Szczech, Lynda; Yu, K H Peony; Neff, Thomas B

2016-06-01

Roxadustat (FG-4592) is an oral hypoxia-inducible factor prolyl-hydroxylase inhibitor that promotes erythropoiesis through increasing endogenous erythropoietin, improving iron regulation, and reducing hepcidin. Phase 2, randomized (3:1), open-label, active-comparator, safety and efficacy study. Patients with stable end-stage renal disease treated with hemodialysis who previously had hemoglobin (Hb) levels maintained with epoetin alfa. Part 1: 6-week dose-ranging study in 54 individuals of thrice-weekly oral roxadustat doses versus continuation of intravenous epoetin alfa. Part 2: 19-week treatment in 90 individuals in 6 cohorts with various starting doses and adjustment rules (1.0-2.0mg/kg or tiered weight based) in individuals with a range of epoetin alfa responsiveness. Intravenous iron was prohibited. Primary end point was Hb level response, defined as end-of-treatment Hb level change (ΔHb) of -0.5g/dL or greater from baseline (part 1) and as mean Hb level ≥ 11.0g/dL during the last 4 treatment weeks (part 2). Hepcidin, iron parameters, cholesterol, and plasma erythropoietin (the latter in a subset). Baseline epoetin alfa doses were 138.3±51.3 (SD) and 136.3±47.7U/kg/wk in part 1 and 152.8±80.6 and 173.4±83.7U/kg/wk in part 2, in individuals randomly assigned to roxadustat and epoetin alfa, respectively. Hb level responder rates in part 1 were 79% in pooled roxadustat 1.5 to 2.0mg/kg compared to 33% in the epoetin alfa control arm (P=0.03). Hepcidin level reduction was greater at roxadustat 2.0mg/kg versus epoetin alfa (P<0.05). In part 2, the average roxadustat dose requirement for Hb level maintenance was ∼1.7mg/kg. The least-squares-mean ΔHb in roxadustat-treated individuals was comparable to that in epoetin alfa-treated individuals (about -0.5g/dL) and the least-squares-mean difference in ΔHb between both treatment arms was -0.03 (95% CI, -0.39 to 0.33) g/dL (mixed effect model-repeated measure). Roxadustat significantly reduced mean total

Duloxetine prevents the effects of prenatal stress on depressive-like and anxiety-like behavior and hippocampal expression of pro-inflammatory cytokines in adult male offspring rats.

PubMed

Zhang, Xiaosong; Wang, Qi; Wang, Yan; Hu, Jingmin; Jiang, Han; Cheng, Wenwen; Ma, Yuchao; Liu, Mengxi; Sun, Anji; Zhang, Xinxin; Li, Xiaobai

2016-12-01

Stress during pregnancy may cause neurodevelopmental and psychiatric disorders. However, the mechanisms are largely unknown. Currently, pro-inflammatory cytokines have been identified as a risk factor for depression and anxiety disorder. Unfortunately, there is very little research on the long-term effects of prenatal stress on the neuroinflammatory system of offspring. Moreover, the relationship between antidepressant treatment and cytokines in the central nervous system, especially in the hippocampus, an important emotion modulation center, is unclear. Therefore, the aim of this study was to determine the effects of prenatal chronic mild stress during development on affective-like behaviors and hippocampal cytokines in adult offspring, and to verify whether antidepressant (duloxetine) administration from early adulthood could prevent the harmful consequences. To do so, prenatally stressed and non-stressed Sprague-Dawley rats were treated with either duloxetine (10mg/kg/day) or vehicle from postnatal day 60 for 21days. Adult offspring were divided into four groups: 1) prenatal stress+duloxetine treatment, 2) prenatal stress+vehicle, 3) duloxetine treatment alone, and 4) vehicle alone. Adult offspring were assessed for anxiety-like behavior using the open field test and depression-like behavior using the forced swim test. Brains were analyzed for pro-inflammatory cytokine markers in the hippocampus via real-time PCR. Results demonstrate that prenatal stress-induced anxiety- and depression-like behaviors are associated with an increase in hippocampal inflammatory mediators, and duloxetine administration prevents the increased hippocampal pro-inflammatory cytokine interleukin-6 and anxiety- and depression-like behavior in prenatally stressed adult offspring. This research provides important evidence on the long-term effect of PNS exposure during development in a model of maternal adversity to study the pathogenesis of depression and its therapeutic interventions

Enzyme replacement therapy with taliglucerase alfa: 36-month safety and efficacy results in adult patients with Gaucher disease previously treated with imiglucerase.

PubMed

Pastores, Gregory M; Shankar, Suma P; Petakov, Milan; Giraldo, Pilar; Rosenbaum, Hanna; Amato, Dominick J; Szer, Jeffrey; Chertkoff, Raul; Brill-Almon, Einat; Zimran, Ari

2016-07-01

Taliglucerase alfa is the first available plant cell-expressed human recombinant therapeutic protein. It is indicated for treatment of patients with type 1 Gaucher disease (GD) in adult and pediatric patients in several countries. Study PB-06-002 examined the safety and efficacy of taliglucerase alfa for 9 months in patients who previously received imiglucerase. The results of adult patients from Study PB-06-002 who continued receiving taliglucerase alfa in extension Study PB-06-003 for up to 36 months are reported here. Eighteen patients received at least one dose of taliglucerase alfa in Study PB-06-003; 10 patients completed 36 total months of therapy, and four patients who transitioned to commercial drug completed 30-33 months of treatment. In patients who completed 36 total months of treatment, mean percent (±standard error) changes from baseline/time of switch to taliglucerase alfa to 36 months were as follows: hemoglobin concentration, -1.0% (±1.9%; n = 10); platelet count, +9.3% (±9.8%; n = 10); spleen volume measured in multiples of normal (MN), -19.8% (±9.9%; n = 7); liver volume measured in MN, +0.9% (±5.4%; n = 8); chitotriosidase activity, -51.5% (±8.1%; n = 10); and CCL18 concentration, -36.5 (±8.0%; n = 10). Four patients developed antidrug antibodies, including one with evidence of neutralizing activity in vitro. All treatment-related adverse events were mild or moderate and transient. The 36-month results of switching from imiglucerase to taliglucerase alfa treatment in adults with GD provide further data on the clinical safety and efficacy of taliglucerase alfa beyond the initial 9 months of the original study. www.clinicaltrials.gov identifier NCT00705939. Am. J. Hematol. 91:661-665, 2016. © 2016 Wiley Periodicals, Inc. © 2016 The Authors. American Journal of Hematology Published by Wiley Periodicals, Inc.

Prospective surveillance study of haemophilia A patients switching from moroctocog alfa or other factor VIII products to moroctocog alfa albumin-free cell culture (AF-CC) in usual care settings.

PubMed

Parra Lopez, Rafael; Nemes, Laszlo; Jimenez-Yuste, Victor; Rusen, Luminita; Cid, Ana R; Charnigo, Robert J; Baumann, James A; Smith, Lynne; Korth-Bradley, Joan M; Rendo, Pablo

2015-10-01

This prospective, open-label, postauthorisation safety surveillance study assessed clinically significant inhibitor development in patients with severe haemophilia A transitioning from moroctocog alfa or other factor VIII (FVIII) replacement products to reformulated moroctocog alfa (AF-CC). Males aged ≥ 12 years with severe haemophilia A (FVIII:C) < 1 IU/dl), > 150 exposure days (EDs) to recombinant or plasma-derived FVIII products, and no detectable inhibitor at screening were enrolled. Primary end point was the incidence of clinically significant FVIII inhibitor development. Secondary end points included annualised bleeding rate (ABR), less-than-expected therapeutic effect (LETE), and FVIII recovery. Patients were assigned to one of two cohorts based on whether they were transitioning to moroctocog alfa (AF-CC) from moroctocog alfa (cohort 1; n=146) or from another recombinant or plasma-derived FVIII product (cohort 2; n=62). Mean number of EDs on study was 94 (range, 1-139). Six positive FVIII inhibitor results, as determined by local laboratories, were reported in four patients; none were confirmed by a central laboratory, no inhibitor-related clinical manifestations were reported, and all anti-FVIII antibody assays were negative. Median ABRs were 23.4 and 3.4 in patients categorised at baseline as following on-demand and prophylactic regimens, respectively; 86.5% of bleeding episodes resolved after one infusion. LETE incidence was 0.06% and 0.19% in the on-demand and prophylaxis settings, respectively. FVIII recovery remained constant throughout the study. No new safety concerns were identified. This study found no increased risk of clinically significant FVIII inhibitor development in patients transitioning from moroctocog alfa or other FVIII replacement products to moroctocog alfa (AF-CC).

Long-term safety and efficacy of taliglucerase alfa in pediatric Gaucher disease patients who were treatment-naïve or previously treated with imiglucerase.

PubMed

Zimran, Ari; Gonzalez-Rodriguez, Derlis Emilio; Abrahamov, Aya; Cooper, Peter A; Varughese, Sheeba; Giraldo, Pilar; Petakov, Milan; Tan, Ee Shien; Chertkoff, Raul

2018-02-01

Taliglucerase alfa is an enzyme replacement therapy approved for treatment of Gaucher disease (GD) in children and adults in several countries. This multicenter extension study assessed the efficacy and safety of taliglucerase alfa in pediatric patients with GD who were treatment-naïve (n=10) or switched from imiglucerase (n=5). Patients received taliglucerase alfa 30 or 60U/kg (treatment-naïve) or the same dose as previously treated with imiglucerase every other week. In treatment-naïve patients, taliglucerase alfa 30 and 60U/kg, respectively, reduced mean spleen volume (-18.6 multiples of normal [MN] and -26.0MN), liver volume (-0.8MN and -0.9MN), and chitotriosidase activity (-72.7% and -84.4%), and increased mean Hb concentration (+2.0g/dL and +2.3g/dL) and mean platelet count (+38,200/mm 3 and +138,250/mm 3 ) from baseline through 36 total months of treatment. In patients previously treated with imiglucerase, these disease parameters remained stable through 33 total months of treatment with taliglucerase alfa. Most adverse events were mild/moderate; treatment was well tolerated. These findings extend the taliglucerase alfa safety and efficacy profile and demonstrate long-term clinical improvement in treatment-naïve children receiving taliglucerase alfa and maintenance of disease stability in children switched to taliglucerase alfa. Treatment was well-tolerated, with no new safety signals. This study is registered at www.clinicaltrials.gov as NCT01411228. Copyright © 2016 Shire Human Genetic Therapies, Inc. Published by Elsevier Inc. All rights reserved.

Monitoring guidance for patients with hypophosphatasia treated with asfotase alfa.

PubMed

Kishnani, Priya S; Rush, Eric T; Arundel, Paul; Bishop, Nick; Dahir, Kathryn; Fraser, William; Harmatz, Paul; Linglart, Agnès; Munns, Craig F; Nunes, Mark E; Saal, Howard M; Seefried, Lothar; Ozono, Keiichi

2017-09-01

Hypophosphatasia (HPP) is a rare, inherited, systemic, metabolic disorder caused by autosomal recessive mutations or a single dominant-negative mutation in the gene encoding tissue-nonspecific alkaline phosphatase (TNSALP). The disease is associated with a broad range of signs, symptoms, and complications, including impaired skeletal mineralization, altered calcium and phosphate metabolism, recurrent fractures, pain, respiratory problems, impaired growth and mobility, premature tooth loss, developmental delay, and seizures. Asfotase alfa is a human, recombinant enzyme replacement therapy that is approved in many countries for the treatment of patients with HPP. To address the unmet need for guidance in the monitoring of patients receiving asfotase alfa, an international panel of physicians with experience in diagnosing and managing HPP convened in May 2016 to discuss treatment monitoring parameters. The panel discussions focused on recommendations for assessing and monitoring patients after the decision to treat with asfotase alfa had been made and did not include recommendations for whom to treat. Based on the consensus of panel members, this review provides guidance on the monitoring of patients with HPP during treatment with asfotase alfa, including recommendations for laboratory, efficacy, and safety assessments and the frequency with which these should be performed during the course of treatment. Recommended assessments are based on patient age and include regular monitoring of biochemistry, skeletal radiographs, respiratory function, growth, pain, mobility and motor function, and quality of life. Because of the systemic presentation of HPP, a coordinated, multidisciplinary, team-based, patient-focused approach is recommended in the management of patients receiving asfotase alfa. Monitoring of efficacy and safety outcomes must be tailored to the individual patient, depending on medical history, clinical manifestations, availability of resources in the clinical

[Corifollitropin alfa compared to daily FSH in controlled ovarian stimulation for oocyte donors].

PubMed

Benchabane, M; Santulli, P; Maignien, C; Bourdon, M; De Ziegler, D; Chapron, C; Gayet, V

2017-02-01

To demonstrate that corifollitropin alfa is as effective as daily FSH in controlled ovarian stimulation of oocyte donors. From January 2013 to October 2015, 77 cycles controlled ovarian stimulation, derived from a continuous cohort of 77 oocyte donors, were analyzed. After synchronization by oestroprogestatif or estrogens, ovarian stimulation was started by corifollitropin alfa (Group corifollitropin alfa) or by daily FSH (Group daily FSH). In both groups, a GnRH antagonist was used for the prevention of premature surge of luteinizing hormone (LH). The induction of ovulation was induced by a GnRH agonist. The duration of treatment, estradiol rate, numbers of mature oocytes, fertilization rate, clinical and ongoing pregnancies rates were evaluated in the two groups. There is no difference for the age, the markers of ovarian reserve and the duration of treatment. The average rate of estradiol on the eighth day of the stimulation is lower for the corifollitropin alfa (845±694.5 vs 1742±1177.3, P<0.001), there is no difference in the number of mature oocytes retrieved (14.4 vs 13.4, P=0.979), with a fertilization rate significantly higher in the corifollitropin alfa group (59.8% vs 49.3%, P<0.001). The rate of ongoing pregnancies is higher but without reaching significant difference in this same group (36.6% vs 26%, P=0.277). As compared to daily FSH, corifollitropin alfa, in oocyte donors offers, advantages in terms of ease of use with identical efficiency. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Dynamic behavior of reactive aluminum nanoparticle-fluorinated acrylic (AlFA) polymer composites

NASA Astrophysics Data System (ADS)

Crouse, Christopher A.; White, Brad; Spowart, Jonathan E.

2011-06-01

The dynamic behavior of aluminum nanoparticle-fluorinated acrylic (AlFA) composite materials has been explored under high strain rates. Cylindrical pellets of the AlFA composite materials were mounted onto copper sabots and impacted against a rigid anvil at velocities between 100 and 400 m/s utilizing a Taylor gas gun apparatus to achieve strain rates on the order of 104 /s. A framing camera was used to record the compaction and reaction events that occurred upon contact of the pellet with the anvil. Under both open air and vacuum environments the AlFA composites demonstrated high reactivity suggesting that the particles are primarily reacting with the fluorinated matrix. We hypothesize, based upon the compaction history of these materials, that reaction is initiated when the oxide shells on the aluminum nanoparticles are broken due an interparticle contact deformation process. We have investigated this hypothesis through altering the particle loading in the AlFA composites as well as impact velocities. This data and the corresponding trends will be presented in detail.

Efficacy and safety of subcutaneous administration of lyophilized powder of alfa-erythropoietin to maintain hemoglobin concentrations among hemodialysis patients.

PubMed

Satirapoj, Bancha; Dispan, Rattanawan; Supasyndh, Ouppatham

2017-01-01

Anemia associated with chronic kidney disease (CKD) often requires treatment with recombinant human erythropoietin (EPO). This study investigated the therapeutic equivalence between lyophilized powder and standard liquid EPO alfa by subcutaneous (SC) administration in hemoglobin maintenance among patients on hemodialysis. This was a single-blinded, randomized, controlled, single-center, parallel-group study regarding the treatment of anemia among CKD patients on hemodialysis and being treated with stable doses of EPO alfa at least for 12 weeks. Anemic hemodialysis patients (n=63) received standard liquid or lyophilized powder EPO alfa for 24 weeks by SC administration. Achievement of the target hemoglobin concentration and safety and tolerability end points were documented. Baseline mean hemoglobin level was 11.1±0.7 g/dL using lyophilized powder EPO alfa and 11.2±0.9 g/dL using standard liquid EPO alfa. The baseline median dose of EPO alfa was 126.4 (interquartile range [IQR] 81.6-163.6) U/kg/week in the lyophilized powder EPO alfa group and 116.9 (IQR 76.5-144.1) U/kg/week in the standard liquid EPO alfa group. Treatment with SC lyophilized powder EPO alfa maintained mean hemoglobin and hematocrit concentrations after switching from standard liquid EPO alfa. No statistical significance between groups was reported for hemoglobin concentrations and weekly dose of EPO alfa during the study. No safety concerns were raised, including positive anti-EPO antibodies. In this study of anemia therapy among patients with end-stage renal disease on hemodialysis therapy, the SC injection of lyophilized powder EPO alfa was well tolerated and effectively maintained hemoglobin levels. Future studies of larger size and longer duration will be required to assess safety profiles.

Validation of the geriatric anxiety inventory in a duloxetine clinical trial for elderly adults with generalized anxiety disorder.

PubMed

Ball, Susan G; Lipsius, Sarah; Escobar, Rodrigo

2015-09-01

The Generalized Anxiety Inventory (GAI) has been developed for use in the assessment of anxiety symptoms in older adults (≥ 65 years), but previous validation work has not examined the psychometric qualities of the instrument in relation to treatment. The objective of this study was to examine the performance of the GAI for its internal reliability, convergent and divergent validity, and its sensitivity to treatment. Elderly patients with generalized anxiety disorder (GAD) participated in a 10-week double-blind study of duloxetine treatment for patients with GAD. Anxiety symptoms were assessed with the Hamilton Anxiety Rating Scale (HAMA), the Hospital Anxiety and Depression Scale (HADS) anxiety and depression subscales, and the GAI. Internal reliability of the GAI was assessed with Cronbach's α. Correlations among the HAMA, HADS, and GAI scores were analyzed to determine convergent and divergent validity. Patients were also compared on remission status using recommended cut-off scores for the GAI. Patients with GAD, who were at least 65 years of age, were randomly assigned to double-blind treatment with either duloxetine (N = 151) or placebo (N = 140) for 10 weeks acute therapy. The mean change on the GAI was significantly greater with duloxetine compared with placebo treatment (-8.36 vs. -4.96, respectively, p ≤ 0.001). The GAI demonstrated good internal consistency, good convergent and divergent validity, but suggested cut-off values for caseness with the GAI did not correspond to remission status as measured by the HAMA. Within an elderly patient population with GAD, the GAI demonstrated sound psychometric qualities and sensitivity to change with treatment.

Long-term efficacy and safety results of taliglucerase alfa up to 36 months in adult treatment-naïve patients with Gaucher disease.

PubMed

Zimran, Ari; Durán, Gloria; Mehta, Atul; Giraldo, Pilar; Rosenbaum, Hanna; Giona, Fiorina; Amato, Dominick J; Petakov, Milan; Muñoz, Eduardo Terreros; Solorio-Meza, Sergio Eduardo; Cooper, Peter A; Varughese, Sheeba; Chertkoff, Raul; Brill-Almon, Einat

2016-07-01

Taliglucerase alfa is an intravenous enzyme replacement therapy approved for treatment of type 1 Gaucher disease (GD), and is the first available plant cell-expressed recombinant therapeutic protein. Herein, we report long-term safety and efficacy results of taliglucerase alfa in treatment-naïve adult patients with GD. Patients were randomized to receive taliglucerase alfa 30 or 60 U/kg every other week, and 23 patients completed 36 months of treatment. Taliglucerase alfa (30 U/kg; 60 U/kg, respectively) resulted in mean decreases in spleen volume (50.1%; 64.6%) and liver volume (25.6%; 24.4%) with mean increases in hemoglobin concentration (16.0%; 35.8%) and platelet count (45.7%; 114.0%), and mean decreases in chitotriosidase activity (71.5%; 82.2%). All treatment-related adverse events were mild to moderate in intensity and transient. The most common adverse events were nasopharyngitis, arthralgia, upper respiratory tract infection, headache, pain in extremity, and hypertension. These 36-month results of taliglucerase alfa in treatment-naïve adult patients with GD demonstrate continued improvement in disease parameters with no new safety concerns. These findings extend the taliglucerase alfa clinical safety and efficacy dataset. www.clinicaltrials.gov identifier NCT00705939. Am. J. Hematol. 91:656-660, 2016. © 2016 Wiley Periodicals, Inc. © 2016 The Authors. American Journal of Hematology Published by Wiley Periodicals, Inc.

Switch from epoetin to darbepoetin alfa in hemodialysis: dose equivalence and hemoglobin stability.

PubMed

Arrieta, Javier; Moina, Iñigo; Molina, José; Gallardo, Isabel; Muñiz, María Luisa; Robledo, Carmen; García, Oscar; Vidaur, Fernando; Muñoz, Rosa Inés; Iribar, Izaskun; Aguirre, Román; Maza, Antonio

2014-01-01

The objective of the study reported here was to describe dose equivalence and hemoglobin (Hb) stability in a cohort of unselected hemodialysis patients who were switched simultaneously from epoetin alfa to darbepoetin alfa. This was a multicenter, observational, retrospective study in patients aged ≥18 years who switched from intravenous (IV) epoetin alfa to IV darbepoetin alfa in October 2007 (Month 0) and continued on hemodialysis for at least 24 months. The dose was adjusted to maintain Hb within 1.0 g/dL of baseline. We included 125 patients (59.7% male, mean [standard deviation (SD)] age 70.4 [13.4] years). No significant changes were observed in Hb levels (mean [SD] 11.9 [1.3] g/dL, 12.0 [1.5], 12.0 [1.5], and 12.0 [1.7] at Months -12, 0, 12 and 24, respectively, P=0.409). After conversion, the erythropoiesis-stimulating agent (ESA) dose decreased significantly (P<0.0001), with an annual mean of 174.7 (88.7) international units (IU)/kg/week for epoetin versus 95.7 (43.4) (first year) and 91.4 (42.7) IU/kg/week (second year) for darbepoetin (65% and 64% reduction, respectively). The ESA resistance index decreased from 15.1 (8.5) IU/kg/week/g/dL with epoetin to 8.1 (3.9) (first year) and 7.9 (4.0) (second year) with darbepoetin (P<0.0001). The conversion rate was 354:1 in patients requiring high (>200 IU/kg/week) doses of epoetin and 291:1 in patients requiring low doses. In patients on hemodialysis receiving ESAs, conversion from epoetin alfa to darbepoetin alfa was associated with an approximate and persistent reduction of 65% of the required dose. To maintain Hb stability, a conversion rate of 300:1 seems to be appropriate for most patients receiving low doses of epoetin alfa (≤200 IU/kg/week), while 350:1 would be better for patients receiving higher doses.

[Intraoperative floppy iris syndrome after treatment with duloxetine: coincidence, association, or causality?].

PubMed

González-Martín-Moro, J; González-López, J J; Zarallo-Gallardo, J; Fernández-Miguel, Y

2015-02-01

The case is presented of a severe Intraoperative Floppy Iris Syndrome (IFIS) in a patient that had been treated with duloxetine. Tamsulosin is the main etiological agent involved in IFIS. However several cases of IFIS, supposedly secondary to drugs of different groups have recently been reported in the literature. The authors use this case report as a means to discuss why most of these cases should be considered anecdotal evidence. Copyright © 2014 Sociedad Española de Oftalmología. Published by Elsevier España, S.L.U. All rights reserved.

Effects of switching from agalsidase Beta to agalsidase alfa in 10 patients with anderson-fabry disease.

PubMed

Pisani, A; Spinelli, L; Visciano, B; Capuano, I; Sabbatini, M; Riccio, E; Messalli, G; Imbriaco, M

2013-01-01

Anderson-Fabry disease (AFD) is a multiorgan X-linked lysosomal storage disease that particularly affects the heart, kidneys, and cerebrovascular system. Current treatment is enzyme replacement therapy (ERT) with agalsidase beta (Fabrazyme(®), Genzyme Corporation, Cambridge, MA, USA) or agalsidase alfa (Replagal(®), Shire Human Genetic Therapies AB, Lund, Sweden). It was recommended that patients switch to agalsidase alfa due to a manufacturing shortage of agalsidase beta beginning in June 2009. This study assessed the effect of switching to agalsidase alfa on clinical outcomes in patients with AFD previously treated with agalsidase beta. Ten patients (seven male, three female) with genetically confirmed AFD and at least 48 months' continuous data collected during treatment with agalsidase beta 1 mg/kg every other week were switched to agalsidase alfa 0.2 mg/kg every other week for at least 20 months, with prospective clinical evaluations every 6 months. Pre-switch data was collected retrospectively from patient charts. Cardiac functional parameters were assessed using magnetic resonance imaging. Results showed that renal function was normal (estimated glomerular filtration rate ≥90 mL/min/1.73 m(2)) in 8 of 10 patients prior to agalsidase alfa and generally remained stable after the switch. Cardiac mass decreased significantly (p < 0.05 vs pre-ERT) after agalsidase beta and remained unchanged after switching to agalsidase alfa. Symptoms of pain and health status scores did not deteriorate during agalsidase alfa therapy. Adverse events were mostly mild and infusion related. In conclusion, switching to agalsidase alfa was relatively well tolerated and associated with stable clinical status and preserved renal and cardiac function.

Collaborative study for the validation of an improved HPLC assay for recombinant IFN-alfa-2.

PubMed

Jönsson, K H; Daas, A; Buchheit, K H; Terao, E

2016-01-01

The current European Pharmacopoeia (Ph. Eur.) texts for Interferon (IFN)-alfa-2 include a nonspecific photometric protein assay using albumin as calibrator and a highly variable cell-based assay for the potency determination of the protective effects. A request was expressed by the Official Medicines Control Laboratories (OMCLs) for improved methods for the batch control of recombinant interferon alfa-2 bulk and market surveillance testing of finished products, including those formulated with Human Serum Albumin (HSA). A HPLC method was developed at the Medical Products Agency (MPA, Sweden) for the testing of IFN-alfa-2 products. An initial collaborative study run under the Biological Standardisation Programme (BSP; study code BSP039) revealed the need for minor changes to improve linearity of the calibration curves, assay reproducibility and robustness. The goal of the collaborative study, coded BSP071, was to transfer and further validate this improved HPLC method. Ten laboratories participated in the study. Four marketed IFN-alfa-2 preparations (one containing HSA) together with the Ph. Eur. Chemical Reference Substance (CRS) for IFN-alfa-2a and IFN-alfa-2b, and in-house reference standards from two manufacturers were used for the quantitative assay. The modified method was successfully transferred to all laboratories despite local variation in equipment. The resolution between the main and the oxidised forms of IFN-alfa-2 was improved compared to the results from the BSP039 study. The improved method even allowed partial resolution of an extra peak after the principal peak. Symmetry of the main IFN peak was acceptable for all samples in all laboratories. Calibration curves established with the Ph. Eur. IFN-alfa-2a and IFN-alfa-2b CRSs showed excellent linearity with intercepts close to the origin and coefficients of determination greater than 0.9995. Assay repeatability, intermediate precision and reproducibility varied with the tested sample within acceptable

Taliglucerase alfa: safety and efficacy across 6 clinical studies in adults and children with Gaucher disease.

PubMed

Zimran, Ari; Wajnrajch, Michael; Hernandez, Betina; Pastores, Gregory M

2018-02-23

Taliglucerase alfa is an enzyme replacement therapy (ERT) approved for treatment of adult and paediatric patients with Type 1 Gaucher disease (GD) in several countries and the first plant cell-expressed recombinant therapeutic protein approved by the US Food and Drug Administration for humans. Here, we review the findings across six key taliglucerase alfa clinical studies. A total of 33 treatment-naïve adult patients were randomized to taliglucerase alfa 30 U/kg or 60 U/kg in a 9-month, multicentre, randomized, double-blind, parallel-group, dose-comparison pivotal study, after which eligible patients continued into two consecutive extension studies; 17 treatment-naïve adult patients completed 5 total years of treatment with taliglucerase alfa. In the only ERT study focused on exclusively paediatric patients with GD, 11 treatment-naïve children were randomized to taliglucerase alfa 30 U/kg or 60 U/kg in a 12-month, multicentre, double-blind study; nine completed 3 total years of treatment in a dedicated paediatric extension study. The effect of switching patients from imiglucerase to taliglucerase alfa was also investigated in a separate 9-month study that included 26 adults and five children; 10 adults completed a total of 3 years and two children completed a total of 2.75 years of taliglucerase alfa treatment in the extension studies. All studies evaluated safety and spleen volume, liver volume, platelet count, haemoglobin concentration, and biomarkers as measures of efficacy. Detailed results from baseline through the end of these studies are presented. Taliglucerase alfa was well tolerated, and adverse events were generally mild/moderate in severity and transient. Treatment with taliglucerase alfa resulted in improvements (treatment-naïve patients) or stability (patients switched from imiglucerase) in visceral, haematologic, and biomarker parameters. Together, this comprehensive data set supports the treatment of adult and paediatric patients with GD

Pathophysiology of hypophosphatasia and the potential role of asfotase alfa.

PubMed

Orimo, Hideo

2016-01-01

Hypophosphatasia (HPP) is an inherited systemic bone disease that is characterized by bone hypomineralization. HPP is classified into six forms according to the age of onset and severity as perinatal (lethal), perinatal benign, infantile, childhood, adult, and odontohypophosphatasia. The causative gene of the disease is the ALPL gene that encodes tissue-nonspecific alkaline phosphatase (TNAP). TNAP is expressed ubiquitously, and its physiological role is apparent in bone mineralization. A defect in bone mineralization can manifest in several ways, including rickets or osteomalacia in HPP patients. Patients with severe forms suffer from respiratory failure because of hypoplastic chest, which is the main cause of death. They sometimes present with seizures due to a defect in vitamin B6 metabolism resulting from the lack of alkaline phosphatase activity in neuronal cells, which is also lethal. Patients with a mild form of the disease exhibit rickets or osteomalacia and a functional defect of exercise. Odontohypophosphatasia shows only dental manifestations. To date, 302 mutations in the ALPL gene have been reported, mainly single-nucleotide substitutions, and the relationships between phenotype and genotype have been partially elucidated. An established treatment for HPP was not available until the recent development of enzyme replacement therapy. The first successful enzyme replacement therapy in model mice using a modified human TNAP protein (asfotase alfa) was reported in 2008, and subsequently success in patients with severe form of the disease was reported in 2012. In 2015, asfotase alfa was approved in Japan in July, followed by in the EU and Canada in August, and then by the US Food and Drug Administration in the USA in October. It is expected that therapy with asfotase alfa will drastically change treatments and prognosis of HPP.

Efficacy and safety profile of boceprevir- or telaprevir-based triple therapy or dual peginterferon alfa-2a or alfa-2b plus ribavirin therapy in chronic hepatitis C: the real-world PegBase observational study.

PubMed

Mangia, Alessandra; Foster, Graham R; Berg, Christoph P; Curescu, Manuela; Ledinghen, Victor De; Habersetzer, François; Manolakopoulos, Spilios; Negri, Elisa; Papatheodoridis, George; Ahlers, Silke; Castillo, Marco; Bakalos, Georgios; Mauss, Stefan

2017-01-01

The aim of the study was to determine the efficacy and safety of triple therapy with a first-generation protease inhibitor (PI; boceprevir, telaprevir) plus peginterferon alfa-2a or -2b plus ribavirin, and dual therapy (peginterferon alfa-2a or -2b plus ribavirin) in patients with chronic hepatitis C (CHC) in routine clinical practice. PegBase was an international, prospective, observational study in which 4441 patients with CHC were enrolled in 27 countries. This analysis focuses on results in 4100 treatment-naïve and previously treated patients treated with PI-based triple therapy or dual therapy, according to the discretion of the investigator and local standards of practice. The primary efficacy outcome was sustained virological response after 12-week follow up (SVR12). SVR12 rates in treatment-naïve genotype (G) 1 patients were 56.6% and 62.9% for recipients of boceprevir plus peginterferon alfa-2a/ribavirin and boceprevir plus peginterferon alfa-2b/ribavirin, respectively, and 65.3% and 58.6% for recipients of telaprevir plus peginterferon alfa-2a/ribavirin and telaprevir plus peginterferon alfa-2b/ribavirin, respectively. In previously treated patients assigned to these four regimens, SVR12 rates were 43.6%, 48.3%, 60.3% and 56.1%, respectively. Among treatment-naïve patients assigned to peginterferon alfa-2a/ribavirin and peginterferon alfa-2b/ribavirin, respectively, SVR12 rates were 49.2% and 41.9% in G1 patients, 75.7% and 83.3% in G2 patients, 65.9% and 65.9% in G3 patients, and 49.7%, and 51.1% in G4 patients. The safety and tolerability of dual and triple therapy were consistent with previous reports. The efficacy and safety of first-generation PI-based triple-therapy and dual-therapy regimens in this real-world cohort were broadly comparable to those of previous studies.

Gateways to clinical trials.

PubMed

Bayes, M; Rabasseda, X; Prous, J R

2003-05-01

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies knowledge area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: 2F5, 2G12, abetimus sodium, ABI-007, adalimumab, adefovir dipivoxil, AE-941, alefacept, altropane, aminolevulinic acid hydrochloride, aminolevulinic acid methyl ester, aminopterin, anakinra, aprinocarsen sodium, atazanavir, atlizumab, atomoxetine hydrochloride; B7-1 vaccine, bevacizumab, biricodar dicitrate, BMS-188667, brasofensine sulfate, bryostatin 1; cantuzumab mertansine, CHS-828, cinacalcet hydrochloride, cipamfylline, creatine, CVT-3146; darbepoetin alfa, DITPA, drotrecogin alfa (activated), duloxetine hydrochloride; edatrexate, efalizumab, ENMD-0997, epoetin, erlosamide, esomeprazole magnesium, etiprednol dicloacetate, etoricoxib, everolimus, ezetimibe; fampridine, fenretinide, FTY-720; IGF-I/IGFBP-3, IL-1 cytokine trap, ilodecakin, interferon beta, ISIS-104838, ISIS-2503, ISIS-5132, ivabradine hydrochloride; lafutidine, lanthanum carbonate, l-Arginine hydrochloride, LEA29Y, lerdelimumab, levetiracetam, levobupivacaine hydrochloride, levosimendan, lopinavir; melagatran, mibefradil hydrochloride, miglustat, morphine-6-glucuronide; nesiritide; omalizumab, omapatrilat; p24-VLP, parecoxib sodium, peginterferon alfa-2a, peginterferon alfa-2b, pegsunercept, pitavastatin calcium, plevitrexed, prasterone, pregabalin, PRO-2000, prucalopride; rapacuronium bromide, rebimastat, RGA-0853, rubitecan, ruboxistaurin mesilate hydrate, RWJ-67657; S-16020-2, sarizotan, SLV-306, stiripentol; TA-CIN, tenecteplase, teriparatide, tezacitabine, tipifarnib, trabectedin, troglitazone; valdecoxib, vardenafil; Z-338, ziconotide.

Evaluating the transport layer of the ALFA framework for the Intel® Xeon Phi™ Coprocessor

NASA Astrophysics Data System (ADS)

Santogidis, Aram; Hirstius, Andreas; Lalis, Spyros

2015-12-01

The ALFA framework supports the software development of major High Energy Physics experiments. As part of our research effort to optimize the transport layer of ALFA, we focus on profiling its data transfer performance for inter-node communication on the Intel Xeon Phi Coprocessor. In this article we present the collected performance measurements with the related analysis of the results. The optimization opportunities that are discovered, help us to formulate the future plans of enabling high performance data transfer for ALFA on the Intel Xeon Phi architecture.

Sebelipase alfa improves atherogenic biomarkers in adults and children with lysosomal acid lipase deficiency.

PubMed

Wilson, Don P; Friedman, Mark; Marulkar, Sachin; Hamby, Tyler; Bruckert, Eric

Measures of atherogenic cholesterol, with and without concomitant use of lipid-lowering medications (LLMs), are reported with up to 52 weeks of sebelipase alfa treatment in children and adults with lysosomal acid lipase deficiency (LAL-D) participating in the phase 3 Acid Lipase Replacement Investigating Safety and Efficacy study (NCT01757184). To examine the effects of sebelipase alfa on levels of atherogenic biomarkers in the Acid Lipase Replacement Investigating Safety and Efficacy study. Data were prospectively collected for LDL particle (LDL-P) number, LDL-C, HDL-C, apolipoprotein B (apoB), apolipoprotein A1 (apoA1), and LDL-P size. Differences at week 20 between the sebelipase alfa and placebo groups were assessed for the overall LAL-D cohort and for patients receiving and not receiving LLMs. Changes from baseline after up to 52 weeks of treatment were also calculated for the overall cohort and separately for patients receiving and not receiving LLMs. Baseline values for LDL-C, LDL-P number, and apoB were elevated while HDL-C and apoA1 were low. Treatment with sebelipase alfa for 20 weeks significantly improved atherogenic measures compared with placebo irrespective of LLM usage. The reduction in LDL-C with sebelipase alfa was associated with a reduction in the LDL-P number. Treatment for up to 52 weeks was associated with sustained improvements of LDL-P, LDL-C, HDL-C, apoB, and apoA1, regardless of LLM use. Patients with LAL-D have high atherogenic risk. It is essential to address the underlying LAL deficiency to restore cholesterol homeostasis in LAL-D patients, as treatment with sebelipase alfa improves atherogenic measures regardless of LLM use and for a sustained period. Sebelipase alfa appears to reduce LDL-C by decreasing the LDL-P number, suggesting improvement in cardiovascular disease risk in LAL-D patients. Copyright © 2018 National Lipid Association. Published by Elsevier Inc. All rights reserved.

Elastic scattering and soft diffraction with ALFA

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

Puzo, P.

The ALFA detector in ATLAS aims at measuring the absolute luminosity and the total cross-section with 2-3% accuracy. Its uses elastically scattered protons whose impact position on a fiber detector, located 240 m away from the interaction point, allow a measurement of the scattering angle.

Assessment of hemoglobin responsiveness to epoetin alfa in patients on hemodialysis using a population pharmacokinetic pharmacodynamic model.

PubMed

Wu, Liviawati; Mould, Diane R; Perez Ruixo, Juan Jose; Doshi, Sameer

2015-10-01

A population pharmacokinetic pharmacodynamic (PK/PD) model describing the effect of epoetin alfa on hemoglobin (Hb) response in hemodialysis patients was developed. Epoetin alfa pharmacokinetics was described using a linear 2-compartment model. PK parameter estimates were similar to previously reported values. A maturation-structured cytokinetic model consisting of 5 compartments linked in a catenary fashion by first-order cell transfer rates following a zero-order input process described the Hb time course. The PD model described 2 subpopulations, one whose Hb response reflected epoetin alfa dosing and a second whose response was unrelated to epoetin alfa dosing. Parameter estimates from the PK/PD model were physiologically reasonable and consistent with published reports. Numerical and visual predictive checks using data from 2 studies were performed. The PK and PD of epoetin alfa were well described by the model. © 2015, The American College of Clinical Pharmacology.

Relationship between major depressive disorder and associated painful physical symptoms: analysis of data from two pooled placebo-controlled, randomized studies of duloxetine.

PubMed

Robinson, Michael J; Sheehan, David; Gaynor, Paula J; Marangell, Lauren B; Tanaka, Yoko; Lipsius, Sarah; Ohara, Fumihiro; Namiki, Chihiro

2013-11-01

The aim of this study was to evaluate the relationship between painful physical symptoms (PPS) and outcomes in major depressive disorder (MDD). Post-hoc analysis of two identically designed 8-week trials compared the efficacy of 60 mg/day duloxetine (N=523) with that of placebo (N=532) in treating PPS associated with MDD. The Montgomery-Åsberg Depression Rating Scale (MADRS) total score, the Brief Pain Inventory (BPI) average pain score, and the Sheehan Disability Scale global functional impairment score assessed depression symptoms, pain, and functioning, respectively. Remission was defined as a MADRS score of 10 or less, and the BPI response subgroup was defined as a 50% or greater reduction from baseline. Path analyses assessed relationships among variables. Duloxetine-treated patients who had a 50% or greater reduction in BPI score at endpoint had higher rates of remission. Path analysis indicated that 16% of likelihood of remission in depression symptoms was because of the direct effect of treatment, 41% because of pain reduction, and 43% because of functional improvement. Path analysis also indicated that 51% of improvement in functioning was attributed to pain improvement and 43% to mood improvement. Results demonstrate that improvement in pain and mood contributes to functional improvement, and pain reduction and functional improvement increase the likelihood of remission of depressive symptoms with duloxetine treatment in patients with both MDD and PPS at baseline.

Efficacy of switching between tumor necrosis factor-alfa inhibitors in psoriasis: results from the Italian Psocare registry.

PubMed

Piaserico, Stefano; Cazzaniga, Simone; Chimenti, Sergio; Giannetti, Alberto; Maccarone, Mara; Picardo, Mauro; Peserico, Andrea; Naldi, Luigi

2014-02-01

Some studies have shown that switching patients from one tumor necrosis factor (TNF)-alfa inhibitor to another may be beneficial when they have an inadequate response or an adverse event. We sought to assess the variables predicting the efficacy of the second TNF-alfa inhibitor in patients discontinuing the first TNF-alfa inhibitor. Data from all 5423 consecutive patients starting TNF-alfa inhibitor therapy for psoriasis between September 2005 and September 2010 who were included in the Italian Psocare registry were analyzed. In 105 patients who switched to a second TNF-alfa inhibitor who had complete follow-up data, 75% improvement in the Psoriasis Area Severity Index score (PASI 75) was reached by 29% after 16 weeks and by 45.6% after 24 weeks. Patients who switched because of secondary loss of efficacy (loss of initial PASI 75 response) or adverse events/intolerance were more likely to reach PASI 75 than those who switched as a result of primary inefficacy (PASI 75 never achieved) (hazard ratio 2.7, 95% confidence interval 1.3-5.5 vs hazard ratio 2.0, 95% confidence interval 1.0-3.9 and 1, respectively). There was a small number of patients with complete follow-up data. PASI 75 response in patients who switched from one anti-TNF-alfa agent to another was significantly reduced in patients who showed primary inefficacy of the first anti-TNF-alfa. Copyright © 2013 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

Impact of illegal trade on the quality of epoetin alfa in Thailand.

PubMed

Fotiou, Fotis; Aravind, Suresh; Wang, Ping-Ping; Nerapusee, Osot

2009-02-01

Reports from the World Health Organization have suggested that counterfeit medicines pose a serious problem in developing countries. An investigation of anti-erythropoietin antibody-mediated pure red cell aplasia in Thailand found evidence of drug smuggling, which may have serious safety implications. This study assessed the authenticity and quality of epoetin alfa samples in Thailand. Samples of epoetin alfa-prefilled syringes were collected from the pharmacies at 2 major hospitals (62 samples), 8 retail pharmacies (41 samples), and Thai authorities (30 samples confiscated from smugglers at 2 airports, and 6 samples from a condominium used by smugglers). These samples were tested against the European Union Pharmacopeia specifications for aggregate content in epoetins of <2%. The integrity of epoetin alfa distribution channels, coldchain processes (maintenance at 2 degrees C-8 degrees C), primary and secondary packaging components (eg, batch number, expiration date, appearance, letter size), and company's confidential features (eg, nature of the ink, type and quality of the paper, other covered features) were also investigated. The main outcome measures were protein aggregate content, determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis and Western blotting; and isoform distribution, assessed by isoelectric focusing and Western blotting. Epoetin alfa samples obtained from the company's cold-chain and authorized distribution channels met all quality standards, as did all epoetin alfa samples obtained from the hospital pharmacies. However, evidence showed that some samples were being smuggled or sold illegally through certain unauthorized retail pharmacies. The epoetin alfa samples obtained from both airports and the condominium were stored improperly at room temperature. Aggregate levels exceeded the specification of <2% in 11 samples from 2 of the retail pharmacies (range, 1.2%-3.1%), 15 samples from the Dongmuang Airport (range, 2.2%-17.0%), and

Pilot study of dornase alfa (Pulmozyme) therapy for acquired ventilator-associated infection in preterm infants.

PubMed

Scala, Melissa; Hoy, Deborah; Bautista, Maria; Palafoutas, Judith Jones; Abubakar, Kabir

2017-06-01

Evaluate the feasibility, safety, and efficacy of adjunctive treatment with dornase alfa in preterm patients with ventilator-associated pulmonary infection (VAPI) compared to standard care. We hypothesize that therapy with dornase alfa will be safe and well tolerated in the preterm population with no worsening of symptoms, oxygen requirement, or need for respiratory support. Prospective, randomized, blinded, pilot study comparing adjunctive treatment with dornase alfa to sham therapy. In addition to standard care, infants were randomized to receive dornase alfa 2.5 mg nebulized via endotracheal tube (ETT) every 12 hr for 7 days or sham therapy. ETT secretion gram stain and culture and chest X-ray (CXR) findings were evaluated. Respiratory support data were downloaded from the ventilator. Fourteen infants developed VAPI between 2012 and 2014; 11 enrolled in the study. Six received dornase alfa and five received sham therapy. Average gestational age at birth was 25 weeks and age at study entry was 31 days. There were no differences in demographics, ETT white blood cell count (WBC), CXR, or mean airway pressure (MAP) between the two groups. There was a trend towards decreased oxygen requirement (FiO2) in the treatment group that did not reach statistical significance. No side effects were observed in the treatment group. Treatment with dornase alfa is safe and treated infants had some improvement in FiO 2 requirement but no improvement in MAP. A larger randomized trial is needed to evaluate the efficacy of this therapy. Pediatr Pulmonol. 2017; 52:787-791. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

A novel approach using a minimal number of injections during the IVF/ICSI cycle: Luteal half-dose depot GnRH agonist following corifollitropin alfa versus the corifollitropin alfa with a GnRH-antagonist cycle.

PubMed

Haydardedeoğlu, Bülent; Kılıçdağ, Esra Bulgan

2016-01-01

Corifollitropin alfa is a good choice for assisted reproductive technology (ART) cycles because fewer injections are needed than with other agents. In this retrospective cohort, we analyzed luteal injected half-dose depot gonadotropin hormone-releasing hormone (GnRH) agonist cycles in women who received corifollitropin alfa and those who underwent a conventional corifollitropin alfa cycle with a GnRH antagonist. In this retrospective cohort, we analyzed luteal injected half-dose depot GnRH agonist cycles in women who received corifollitropin alfa and those who underwent a conventional corifollitropin alfa cycle with a GnRH antagonist at the Division of Reproductive Endocrinology and IVF Unit, Obstetrics and Gynecology Department, Başkent University School of Medicine, Adana, Turkey, from March 2014 to August 2015. The patient's baseline characteristics were similar between the two groups. Forty-five patients underwent the long protocol, in which a half-dose of depot GnRH agonist was administered on day 21 of the preceding cycle. Forty-nine patients underwent the GnRH-antagonist protocol. Corifollitropin alfa was administered on the menstrual cycle day 3. The mean ages of the two groups were similar (32.77±5.55 vs. 34.2±4.51 years ["for the long- and antagonist-protocol groups, respectively"]). The total number of retrieved oocytes, the fertilization rate, and the number of transferred embryos were similar between the two groups. The only significant difference between the two protocols was the number of injections during the controlled ovarian stimulation (COH) cycle, which included the depot-agonist injection in the long-protocol group (4.46±1.64 vs. 5.71±2.51, p=0.006). The clinical pregnancy and implantation rates were similar in the two protocols (16/45 [35.6%] vs. 16/49 [32.7%] for the intention to treat and 32.5±6.82% vs. 36.25±8.58%, respectively). Our results show that ART cycles could be performed with fewer injections using corifollitropin alfa and

Population Pharmacokinetics of Darbepoetin Alfa in Conjunction with Hypothermia for the Treatment of Neonatal Hypoxic-Ischemic Encephalopathy.

PubMed

Roberts, Jessica K; Stockmann, Chris; Ward, Robert M; Beachy, Joanna; Baserga, Mariana C; Spigarelli, Michael G; Sherwin, Catherine M T

2015-12-01

The aim of this study was to determine the population pharmacokinetics of darbepoetin alfa in hypothermic neonates with hypoxic-ischemic encephalopathy treated with hypothermia. Neonates ≥36 weeks gestation and <12 h postpartum with moderate to severe hypoxic-ischemic encephalopathy who were undergoing hypothermia treatment were recruited in this randomized, multicenter, investigational, new drug pharmacokinetic study. Two intravenous darbepoetin alfa treatment groups were evaluated: 2 and 10 µg/kg. Serum erythropoietin concentrations were measured using an enzyme-linked immunosorbent assay. Monolix 4.3.1 was used to estimate darbepoetin alfa clearance and volume of distribution. Covariates tested included: birthweight, gestational age, postnatal age, postmenstrual age, sex, Sarnat score, and study site. Darbepoetin alfa pharmacokinetics were well described by a one-compartment model with exponential error. Clearance and the volume of distribution were scaled by birthweight (centered on the mean) a priori. Additionally, gestational age (also centered on the mean) significantly affected darbepoetin alfa clearance. Clearance and volume of distribution were estimated as 0.0465 L/h (95% confidence interval 0.0392-0.0537) and 1.58 L (95% confidence interval 1.29-1.87), respectively. A one-compartment model successfully described the pharmacokinetics of darbepoetin alfa among hypothermic neonates treated for hypoxic-ischemic encephalopathy. Clearance decreased with increasing gestational age.

Daclatasvir plus peginterferon alfa and ribavirin for treatment-naive chronic hepatitis C genotype 1 or 4 infection: a randomised study.

PubMed

Hézode, Christophe; Hirschfield, Gideon M; Ghesquiere, Wayne; Sievert, William; Rodriguez-Torres, Maribel; Shafran, Stephen D; Thuluvath, Paul J; Tatum, Harvey A; Waked, Imam; Esmat, Gamal; Lawitz, Eric J; Rustgi, Vinod K; Pol, Stanislas; Weis, Nina; Pockros, Paul J; Bourlière, Marc; Serfaty, Lawrence; Vierling, John M; Fried, Michael W; Weiland, Ola; Brunetto, Maurizia R; Everson, Gregory T; Zeuzem, Stefan; Kwo, Paul Y; Sulkowski, Mark; Bräu, Norbert; Hernandez, Dennis; McPhee, Fiona; Wind-Rotolo, Megan; Liu, Zhaohui; Noviello, Stephanie; Hughes, Eric A; Yin, Philip D; Schnittman, Steven

2015-06-01

To evaluate the safety and efficacy of daclatasvir, an HCV NS5A inhibitor with pangenotypic activity, administered with peginterferon-alfa-2a/ribavirin. In this Phase 2b double-blind, placebo-controlled study, treatment-naive adults with HCV genotype 1 (N=365) or 4 (N=30) infection were randomly assigned (2:2:1) to daclatasvir 20 mg or 60 mg, or placebo once daily plus weekly peginterferon-alfa-2a and twice-daily ribavirin. Daclatasvir recipients achieving protocol-defined response (PDR; HCV-RNAalfa-2a/ribavirin for 24 weeks total duration or to placebo/peginterferon-alfa-2a/ribavirin for another 12 weeks. Patients without PDR and placebo patients continued peginterferon-alfa/ribavirin through Week 48. Primary efficacy endpoints were undetectable HCV-RNA at Weeks 4 and 12 (extended rapid virologic response, eRVR) and at 24 weeks post-treatment (sustained virologic response, SVR24) among genotype 1-infected patients. Overall, eRVR was achieved by 54.4% (80/147) of genotype 1-infected patients receiving daclatasvir 20 mg, 54.1% (79/146) receiving 60 mg versus 13.9% (10/72) receiving placebo. SVR24 was achieved among 87 (59.2%), 87 (59.6%), and 27 (37.5%) patients in these groups, respectively. Higher proportions of genotype 4-infected patients receiving daclatasvir 20 mg (66.7%; 8/12) or 60 mg (100.0%; 12/12) achieved SVR24 versus placebo (50.0%; 3/6). A majority of daclatasvir-treated patients achieved PDR and experienced less virologic failure and higher SVR24 rates with a shortened 24-week treatment duration. Adverse events occurred with similar frequency across all treatment groups. The combination of daclatasvir/peginterferon-alfa/ribavirin was generally well tolerated and achieved higher SVR24 rates compared with placebo/peginterferon-alfa/ribavirin among patients infected with HCV genotype 1 or 4. NCT01125189

Hyporesponsiveness to Darbepoetin Alfa in Patients With Heart Failure and Anemia in the RED-HF Study (Reduction of Events by Darbepoetin Alfa in Heart Failure): Clinical and Prognostic Associations.

PubMed

van der Meer, Peter; Grote Beverborg, Niels; Pfeffer, Marc A; Olson, Kurt; Anand, Inder S; Westenbrink, B Daan; McMurray, John J V; Swedberg, Karl; Young, James B; Solomon, Scott D; van Veldhuisen, Dirk J

2018-02-01

A poor response to erythropoiesis-stimulating agents such as darbepoetin alfa has been associated with adverse outcomes in patients with diabetes mellitus, chronic kidney disease, and anemia; whether this is also true in heart failure is unclear. We performed a post hoc analysis of the RED-HF trial (Reduction of Events by Darbepoetin Alfa in Heart Failure), in which 1008 patients with systolic heart failure and anemia (hemoglobin level, 9.0-12.0 g/dL) were randomized to darbepoetin alfa. We examined the relationship between the hematopoietic response to darbepoetin alfa and the incidence of all-cause death or first heart failure hospitalization during a follow-up of 28 months. For the purposes of the present study, patients in the lowest quartile of hemoglobin change after 4 weeks were considered nonresponders. The median initial hemoglobin change in nonresponders (n=252) was -0.25 g/dL and +1.00 g/dL in the remainder of patients (n=756). Worse renal function, lower sodium levels, and less use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers were independently associated with nonresponse. Although a low endogenous erythropoietin level helped to differentiate responders from nonresponders, its predictive value in a multivariable model was poor (C statistic=0.69). Nonresponders had a higher rate of all-cause death or first heart failure hospitalization (hazard ratio, 1.25; 95% confidence interval, 1.02-1.54) and a higher risk of all-cause mortality (hazard ratio, 1.30; 95% confidence interval, 1.04-1.63) than responders. A poor response to darbepoetin alfa was associated with worse outcomes in heart failure patients with anemia. Patients with a poor response were difficult to identify using clinical and biochemical biomarkers. URL: https://www.clinicaltrials.gov. Unique identifier: NCT00358215. © 2018 American Heart Association, Inc.

Development of Hypercalcemia in a Patient Receiving Peginterferon alfa-2a Therapy for Polycythemia Vera.

PubMed

Karne, Sheetal; Mainor, Candace B; Baer, Maria R

2016-06-01

Peginterferon alfa-2a (PEG-IFN alfa-2a) is commonly used to treat hepatitis C virus infection and is also being used increasingly to treat myeloproliferative neoplasms including polycythemia vera. Sarcoidosis associated with IFN therapy for treatment of hepatitis C is well described, with hypercalcemia occurring as a rare manifestation. We describe a 25-year-old man with polycythemia vera who became resistant to hydroxyurea after 6 years of treatment, requiring therapeutic phlebotomy procedures with increasing frequency for elevated hemoglobin and hematocrit levels. PEG-IFN alfa-2a was then initiated at 90 μg subcutaneously once/week and was progressively increased to 180 μg/week over the next 11 months, with normalization of his hemoglobin and hematocrit. The patient then developed hypercalcemia with low parathyroid hormone, parathyroid hormone-related protein, and 25-hydroxyvitamin D levels, and high 1,25-dihydroxyvitamin D and angiotensin-converting enzyme levels, without other evidence of sarcoidosis. PEG-IFN alfa-2a was discontinued, treatment with intravenous fluids and zoledronic acid was initiated, and the hypercalcemia resolved 10 weeks later. Use of the Naranjo Adverse Drug Reaction Probability Scale indicated a probable relationship (score of 7) between the patient's development of hypercalcemia and PEG-IFN alfa-2a therapy; the relationship could not be considered as definite because the patient was not rechallenged with the drug. To our knowledge, this is the first case report of IFN-induced hypercalcemia without other manifestations of sarcoidosis. Practitioners should be aware of hypercalcemia as a potential complication of PEG-IFN alfa-2a therapy, as well as its protracted time course, in patients with myeloproliferative neoplasms. © 2016 Pharmacotherapy Publications, Inc.

Clinical observation of patients with Fabry disease after switching from agalsidase beta (Fabrazyme) to agalsidase alfa (Replagal).

PubMed

Tsuboi, Kazuya; Yamamoto, Hiroshi

2012-09-01

Fabry disease is a rare, X-linked, inherited lysosomal storage disorder that can be treated with the enzymes agalsidase alfa (Replagal) and agalsidase beta (Fabrazyme). Currently, there is a global shortage of agalsidase beta, and this has increased global demand for agalsidase alfa. We assess the feasibility of switching patients on agalsidase beta treatment to agalsidase alfa instead. This analysis is part of an ongoing observational study involving 11 patients with Fabry disease in whom the treatment was switched from agalsidase beta (1 mg/kg every other week) to agalsidase alfa (0.2 mg/kg every other week). Data were collected for a minimum of 36 months: 24 months before and 12 months after the switch. Serial data were evaluated with respect to renal function, cardiac mass, pain, quality of life, and tolerability/safety. Indexes of renal function (estimated glomerular filtration rate) and cardiac mass (left-ventricular mass index), pain (Brief Pain Inventory), and quality of life (EuroQoL-Dimensions) clearly showed that, in patients switched to agalsidase alfa, Fabry disease stabilized during the 12 months of follow-up. Despite the limitations of this preliminary observational study, it was found that all the patients maintained disease stability when treated with agalsidase alfa, as evidenced by estimated glomerular filtration rate, left-ventricular mass index, pain scores, and quality-of-life indexes, throughout 12 months of follow-up.

The in vitro mucolytic effect of xylitol and dornase alfa on chronic rhinosinusitis mucus.

PubMed

Hardcastle, Tim; Jain, Ravi; Radcliff, Fiona; Waldvogel-Thurlow, Sharon; Zoing, Melissa; Biswas, Kristi; Douglas, Richard

2017-09-01

The overproduction and stagnation of purulent mucus impair mucociliary clearance and exacerbate the symptoms of chronic rhinosinusitis (CRS). There is a clinical need for effective topical mucolytic agents to facilitate removal of mucus and improve postoperative outcomes. The effects of xylitol (5%) and dornase alfa (1 mg/mL) on mucus and mucus crusts were investigated. Viscoelasticity and viscosity of wet mucus derived from 30 CRS patients was measured with a plate rheometer. Postoperative dried mucus crust dissolution was measured by examining peripheral transparency, central transparency, and border definition of treated crust samples from 17 CRS patients. Xylitol and dornase alfa reduced wet mucus viscoelasticity at a frequency of 0.1 Hz significantly more than the saline control. Treatments also produced significantly lower viscosities than saline at a shear rate of 10 and 100 seconds -1 . Xylitol and dornase alfa significantly decreased mucus crust border definition relative to saline. Xylitol and dornase alfa may be efficacious mucolytics, encouraging the breakdown of postoperative mucus crusts and the reduction of viscoelasticity and viscosity of wet mucus. In vivo study is required to evaluate the potential of these agents in treating recalcitrant CRS. © 2017 ARS-AAOA, LLC.

Phase IV randomized clinical study: Peginterferon alfa-2a with adefovir or entecavir pre-therapy for HBeAg-positive chronic hepatitis B.

PubMed

Hsu, Chao-Wei; Su, Wei-Wen; Lee, Chuan-Mo; Peng, Cheng-Yuan; Chuang, Wan-Long; Kao, Jia-Horng; Chu, Heng-Cheng; Huang, Yi-Hsiang; Chien, Rong-Nan; Liaw, Yun-Fan

2018-07-01

Efficacy of sequential therapy with nucleos(t)ide analogues and interferons versus monotherapy in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) remains unexplored. We aimed to assess efficacy and safety of sequential therapy with adefovir (ADV) or entecavir (ETV) followed by peginterferon (PEG-IFN) alfa-2a in Taiwanese patients with HBeAg-positive. This randomized, placebo-controlled, double-blind trial was conducted at nine sites in Taiwan from April 2010 to October 2013. Patients (N = 280) were randomized 1:1:1 to receive placebo, ETV or ADV alone for four weeks, combined with PEG-IFN alfa-2a for two weeks, then PEG-IFN alfa-2a alone for 46 weeks. The primary efficacy end point was HBeAg seroconversion at 48 weeks post-treatment. No significant differences were observed among groups for HBeAg seroconversion (PEG-IFN alfa-2a+placebo, 36.3%; PEG-IFN alfa-2a+ETV, 29.5%; and PEG-IFN alfa-2a+ADV, 27.4%), HBeAg loss (37.4%, 32.2%, and 28.6%, respectively) or change in hepatitis B surface antigen (HBsAg) levels from baseline (-0.56 IU/mL, -0.60 IU/mL, and -0.41 IU/mL, respectively). However, hepatitis B virus DNA levels were higher with PEG-IFN alfa-2a+placebo than PEG-IFN alfa+ETV at week 64 (p = 0.0412), 76 (p = 0.0311), and 88 (p = 0.0113), and alanine aminotransferase (ALT) normalization rate was higher with PEG-IFN alfa-2a+placebo than PEG-IFN alfa-2a+ADV (p = 0.0283) or PEG-IFN alfa-2a+ETV (p = 0.0369) at week 88. Sub-analysis of results revealed an association between on-treatment HBsAg and ALT levels and efficacy 48 weeks post-treatment. Safety was comparable among treatment groups. Pre-therapy with ADV or ETV followed by PEG-IFN alfa-2a is not superior to PEG-IFN alfa-2a monotherapy in Taiwanese patients with HBeAg-positive CHB. NCT: 00922207. Copyright © 2018. Published by Elsevier B.V.

[Corifollitropin alfa in women stimulated for the first time in in vitro fertilization programme].

PubMed

Vraná-Mardešićová, N; Vobořil, J; Melicharová, L; Jelínková, L; Vilímová, Š; Mardešić, T

2017-01-01

To compare results after stimulation with corifollitropin alfa (Elonva) in unselected group of women entering for the first time in in vitro fertilization programme (IVF) with results from Phase III randomized trials with selected groups of women. Prospective study. Sanatorium Pronatal, Praha. 40 unselected women with adequat ovarian reserve entering for the first time in IVF programme were stimulated with corifollitropin alfa and GnRH antagonists. Avarage age in the study group was 32,8 years (29-42 years), women younger then 36 and less then 60 kg received Elonva 100 µg , all others (age > 36 let, weight > 60 kg) Elonva 150 µg. Five days after egg retrieval one blastocyst was transferred (single embryo transfer - eSET). Our results were compared with the resuls in higly selected groups of women from Phase III randomized trials. After stimulation with corifollitropin alfa and GnRH antagonists on average 10,6 (9,2 ± 4,2) eggs could be retrieved, among them 7,3 (6,6 ± 3,9) were M II oocytes (68,9%) and fertilisation rate was 84,6%. After first embryo transfer ("fresh" embryos and embryos from "freeze all" cycles) 14 pregnancies were achieved (37,8%), three pregnancies were achieved later from transfer of frozen-thawed embryos (cumulative pregnancy rate 45,9%). There were three abortions. No severe hyperstimulation syndrom occured. Our results in unselected group of women stimulated for the first in an IVF programme with corifollitropin alfa are fully comparable with results published in randomized trials with selected group of patiens. Corifollitropin alfa in combination with daily GnRH antagonist can be successfully used in normal-responder patients stimulated for the first time in an IVF programmeKeywords: corifollitropin alfa, GnRH antagonists, ovarian stimulation, pregnancy.

Spotlight on taliglucerase alfa in the treatment of pediatric patients with type 1 Gaucher disease.

PubMed

Gupta, Punita; Pastores, Gregory M

2017-01-01

Gaucher disease (GD) is a heritable storage disorder caused by functional defects of the lysosomal acid β-glucosidase and the accumulation of glucosylceramide within macrophages, resulting in multiple organ dysfunction. There are three commercially available enzyme replacement therapy (ERT) products for the treatment of GD type 1 (GD1): imiglucerase, velaglucerase alfa, and taliglucerase alfa. Imiglucerase and velaglucerase alfa are produced in different mammalian cell systems; imiglucerase requires postproduction deglycosylation to expose terminal α-mannose residues, which are required for mannose receptor-mediated uptake by target macrophages. These steps are critical to the success of ERT for the treatment of visceral and hematologic manifestations of GD. Taliglucerase alfa is the first US Food and Drug Administration-approved plant-cell-expressed recombinant human protein, using carrot root cell cultures. Furthermore, it does not require postproduction glycosidic modifications. It is indicated for treatment of adults with GD1 in the US, Israel, Australia, Canada, Chile, Brazil, and other countries, and it is additionally approved for the treatment of pediatric patients in the US, Australia, and Canada and for the treatment of hematologic manifestations in pediatric patients with Type 3 GD in Canada and other countries. Our review focuses on the role of taliglucerase alfa in the pediatric population. A literature search through PubMed (from 1995 up till November 2016) of English language articles was performed with the following terms: Gaucher disease, lysosomal storage disease, taliglucerase. Secondary and tertiary references were obtained by reviewing related articles as well as the website www.Clinicaltrials.gov. It has been demonstrated that taliglucerase alfa is efficacious, with a well-established safety profile in pediatric, ERT-naïve patients with symptomatic GD1, as well as for those patients previously treated with imiglucerase.

Gateways to clinical trials.

PubMed

Bayés, M; Rabasseda, X; Prous, J R

2005-12-01

Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity. prous.com. This issue focuses on the following selection of drugs: 131I-chTNT; Abatacept, adalimumab, alemtuzumab, APC-8015, aprepitant, atazanavir sulfate, atomoxetine hydrochloride, azimilide hydrochloride; Bevacizumab, bortezomib, bosentan, buserelin; Caspofungin acetate, CC-4047, ChAGCD3, ciclesonide, clopidogrel, curcumin, Cypher; Dabigatran etexilate, dapoxetine hydrochloride, darbepoetin alfa, darusentan, denosumab, DMXB-Anabaseine, drospirenone, drospirenone/estradiol, duloxetine hydrochloride, dutasteride; Edodekin alfa, efaproxiral sodium, elaidic acid-cytarabine, erlotinib hydrochloride, ertapenem sodium, escitalopram oxalate, eszopiclone, etonogestrel/testosterone decanoate, exenatide; Fulvestrant; Gefitinib, glycine, GVS-111; Homoharringtonine; ICC-1132, imatinib mesylate, iodine (I131) tositumomab, i.v. gamma-globulin; Levetiracetam, levocetirizine, lintuzumab, liposomal nystatin, lumiracoxib, lurtotecan; Manitimus, mapatumumab, melatonin, micafungin sodium, mycophenolic acid sodium salt; Oblimersen sodium, OGX-011, olmesartan medoxomil, omalizumab, omapatrilat, oral insulin; Parathyroid hormone (human recombinant), pasireotide, peginterferon alfa-2a, peginterferon alfa-2b, peginterferon alfa-2b/ribavirin, phVEGF-A165, pimecrolimus, pitavastatin calcium, plerixafor hydrochloride, posaconazole, pramlintide acetate, prasterone, pregabalin, PT-141; Quercetin; Ranolazine, rosuvastatin calcium, rubitecan, rupatadine fumarate; Sardomozide, sunitinib malate; Tadalafil, talactoferrin alfa, tegaserod maleate, telithromycin, testosterone transdermal patch, TH-9507, tigecycline, tiotropium bromide, tipifarnib, tocilizumab, treprostinil sodium; Valdecoxib, vandetanib

Duloxetine HCl lipid nanoparticles: preparation, characterization, and dosage form design.

PubMed

Patel, Ketan; Padhye, Sameer; Nagarsenker, Mangal

2012-03-01

Solid lipid nanoparticles (SLNs) of duloxetine hydrochloride (DLX) were prepared to circumvent the problems of DLX, which include acid labile nature, high first-pass metabolism, and high-dosing frequency. The DLX-SLNs were prepared by using two different techniques, viz. solvent diffusion method and ultrasound dispersion method, and evaluated for particle size, zeta potential, entrapment efficiency, physical characteristics, and chemical stability. Best results were obtained when SLNs were prepared by ultrasound dispersion method using glyceryl mono stearate as solid lipid and DLX in ratio of 1:20 and mixture of polysorbate 80 and poloxamer 188 as surfactant in concentration of 3%. The mean particle size of formulation and entrapment efficiency was 91.7 nm and 87%, respectively, and had excellent stability in acidic medium. Differential scanning calorimetry and X-ray diffraction data showed complete amorphization of DLX in lipid. In vitro drug release from SLNs was observed for 48 h and was in accordance with Higuchi kinetics. In vivo antidepressant activity was evaluated in mice by forced swim test. DLX-SLNs showed significant enhancement in antidepressant activity at 24 h when administered orally in comparison to drug solution. These results confirm the potential of SLNs in enhancing chemical stability and improving the efficacy of DLX via oral route. The SLN dispersion was converted into solid granules by adsorbing on colloidal silicon dioxide and characterized for particle size after redispersion, morphology, and flow properties. Results indicated that nanoparticles were successfully adsorbed on the carrier and released SLNs when dispersed in water.

ALFA MHK Biological Monitoring Stationary deployment

DOE Data Explorer

Horne, John

2016-10-01

Acoustic backscatter data from a WBAT operating at 70kHz deployed at PMEC-SETS from April to September of 2016. 180 pings were collected at 1Hz every two hours, as part of the Advanced Laboratory and Field Arrays (ALFA) for Marine Energy project. Data was subject to preliminary processing (noise removal, a threshold of -75dB was applied, surface turbulence and data below 0.5m from the bottom was removed).

Clinical observation of patients with Fabry disease after switching from agalsidase beta (Fabrazyme) to agalsidase alfa (Replagal)

PubMed Central

Tsuboi, Kazuya; Yamamoto, Hiroshi

2012-01-01

Purpose: Fabry disease is a rare, X-linked, inherited lysosomal storage disorder that can be treated with the enzymes agalsidase alfa (Replagal) and agalsidase beta (Fabrazyme). Currently, there is a global shortage of agalsidase beta, and this has increased global demand for agalsidase alfa. We assess the feasibility of switching patients on agalsidase beta treatment to agalsidase alfa instead. Methods: This analysis is part of an ongoing observational study involving 11 patients with Fabry disease in whom the treatment was switched from agalsidase beta (1 mg/kg every other week) to agalsidase alfa (0.2 mg/kg every other week). Data were collected for a minimum of 36 months: 24 months before and 12 months after the switch. Serial data were evaluated with respect to renal function, cardiac mass, pain, quality of life, and tolerability/safety. Results: Indexes of renal function (estimated glomerular filtration rate) and cardiac mass (left-ventricular mass index), pain (Brief Pain Inventory), and quality of life (EuroQoL-Dimensions) clearly showed that, in patients switched to agalsidase alfa, Fabry disease stabilized during the 12 months of follow-up. Conclusion: Despite the limitations of this preliminary observational study, it was found that all the patients maintained disease stability when treated with agalsidase alfa, as evidenced by estimated glomerular filtration rate, left-ventricular mass index, pain scores, and quality-of-life indexes, throughout 12 months of follow-up. PMID:22498845

Acquisition of Learning by Facilitating Academics (Project ALFA). Final Evaluation Report, 1992-93. OREA Report.

ERIC Educational Resources Information Center

Bruno, Paula

This report assesses the Acquisition of Learning by Facilitating Academics (Project ALFA), which is designed to assist the academic progress of Haitian students at Lafayette High School in Brooklyn, New York. Project ALFA served a total of 62 students of limited English proficiency who had attended an English-speaking school system for less than 5…

Randomized double-blind trial of darbepoetin alfa in patients with symptomatic heart failure and anemia.

PubMed

Ghali, Jalal K; Anand, Inder S; Abraham, William T; Fonarow, Gregg C; Greenberg, Barry; Krum, Henry; Massie, Barry M; Wasserman, Scott M; Trotman, Marie-Louise; Sun, Yan; Knusel, Beat; Armstrong, Paul

2008-01-29

Substantial evidence suggests that anemia is an independent risk factor for worse outcomes in patients with heart failure (HF). The Study of Anemia in Heart Failure Trial (STAMINA-HeFT) is the largest multicenter, randomized, double-blind, placebo-controlled trial to date evaluating the effect of treating anemia in HF. Patients (N=319) with symptomatic HF, left ventricular ejection fraction < or = 40%, and hemoglobin > or = 9.0 g/dL and < or = 12.5 g/dL were randomized (double-blind) to placebo (N=157) or darbepoetin alfa (N=162) subcutaneously every 2 weeks for 1 year (target hemoglobin, 14.0+/-1.0 g/dL). The primary end point was change from baseline to week 27 in treadmill exercise time. Secondary end points were change from baseline in New York Heart Association class and quality of life at week 27. An additional prespecified efficacy analysis included the time to death by any cause or first HF-related hospitalization by 1 year. At baseline, the median (interquartile range) hemoglobin was 11.4 (10.9, 12.0) g/dL. At week 27, darbepoetin alfa treatment increased median (interquartile range) hemoglobin by 1.8 (1.1, 2.5) g/dL (placebo, 0.3 [-0.2, 1.0] g/dL; P<0.001). Of the patients treated with darbepoetin alfa, 85% achieved 2 consecutive hemoglobin levels of 14.0+/-1.0 g/dL during the study and experienced a hemoglobin increase of > or = 1.0 g/dL from baseline. By intent-to-treat analysis, darbepoetin alfa treatment did not significantly improve exercise duration, New York Heart Association class, or quality of life score compared with placebo. A nonsignificant trend was observed toward a lower risk of all-cause mortality or first HF hospitalization in darbepoetin alfa-treated patients compared with placebo (hazard ratio, 0.68; 95% CI, 0.43, 1.08; P=0.10). Occurrences of adverse events were similar in both treatment groups. In this study of patients with symptomatic HF and anemia, treatment with darbepoetin alfa was not associated with significant clinical

Gateways to clinical trials.

PubMed

Tomillero, A; Moral, M A

2009-06-01

(+)-Dapoxetine hydrochloride; Abatacept, Adalimumab, Agalsidase beta, Alemtuzumab, Alglucosidase alfa, Aliskiren fumarate, Ambrisentan, Amlodipine, Aripiprazole, Atrasentan, Azacitidine, Azelnidipine; Belotecan hydrochloride, Bevacizumab, Bilastine, Biphasic insulin aspart, Bortezomib, Bosentan; Caspofungin acetate, CG-100649, Cinacalcet hydrochloride, Clindamycin phosphate/ benzoyl peroxide; Dasatinib, Denosumab, Duloxetine hydrochloride, Dutasteride, Dutasteride/tamsulosin; Ecogramostim, Eculizumab, Eltrombopag olamine, EndoTAG-1, Erlotinib hydrochloride, Everolimus, Exenatide, Ezetimibe; FAHF-2, Fondaparinux sodium; Gefitinib, Golimumab; HEV-239, HSV-TK; Imatinib mesylate, Indium 111 ((111)In) ibritumomab tiuxetan, Influenza vaccine(surface antigen, inactivated, prepared in cell culture), Insulin glargine; Kisspeptin-54; Lidocaine/prilocaine, Lomitapide; Maraviroc, Mirodenafil hydrochloride, MK-8141, MVA-Ag85A; Nilotinib hydrochloride monohydrate; Olmesartan medoxomil; Paclitaxel-eluting stent, Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b, Pemetrexed disodium, Pitavastatin calcium, Prasugrel; Recombinant human relaxin H2, RHAMM R3 peptide, Rivaroxaban, Rosuvastatin calcium, RRz2; Sagopilone, Salinosporamide A, SB-509, Serlopitant, Sirolimus-eluting stent, Sorafenib, Sunitinib malate; Tadalafil, Temsirolimus, Teriparatide, TG-4010, Tositumomab/iodine (I131) tositumomab; Velusetrag Hydrochloride; Ximelagatran; Yttrium 90 (90Y) ibritumomab tiuxetan. Copyright 2009 Prous Science, S.A.U. or its licensors. All rights reserved.

25. VIEW SHOWING ENTRANCE TO SILO 'ALFA,' LOOKING WEST Everett ...

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

25. VIEW SHOWING ENTRANCE TO SILO 'ALFA,' LOOKING WEST Everett Weinreb, photographer, March 1988 - Mount Gleason Nike Missile Site, Angeles National Forest, South of Soledad Canyon, Sylmar, Los Angeles County, CA

Study protocol for a multi-institutional, randomised, double-blinded, placebo-controlled phase III trial investigating additive efficacy of duloxetine for neuropathic cancer pain refractory to opioids and gabapentinoids: the DIRECT study.

PubMed

Matsuoka, Hiromichi; Ishiki, Hiroto; Iwase, Satoru; Koyama, Atsuko; Kawaguchi, Takashi; Kizawa, Yoshiyuki; Morita, Tatsuya; Matsuda, Yoshinobu; Miyaji, Tempei; Ariyoshi, Keisuke; Yamaguchi, Takuhiro

2017-08-28

Management of patients with cancer suffering from neuropathic pain refractory to opioids and gabapentinoids remains an important challenge. Duloxetine is one of the choices after first-line treatment fails. The efficacy of duloxetine has been reported in patients with non-cancer disease and in chemotherapy-induced peripheral neuropathy, but no randomised clinical trials have examined its effects on neuropathic cancer pain refractory to first-line treatment. The objective of this study is to assess the analgesic efficacy of duloxetine in patients suffering from neuropathic cancer pain refractory to opioids and gabapentinoids. A multi-institutional, prospective, randomised, double-blind, placebo-controlled, two-parallel trial is planned. The inclusion criteria are adult patients with cancer suffering from neuropathic cancer pain refractory to opioids and gabapentinoids, patients with a Numerical Rating Scale (NRS) pain score of 4 or higher and patients with a total Hospital Anxiety and Depression Scale score of less than 20. Patients with chemotherapy-induced peripheral neuropathy are excluded. The study will take place at 14 sites across Japan. Participants will be randomised (1:1 allocation ratio) to a duloxetine intervention group or a placebo control group. Evaluations will be made at baseline (T0 randomisation), day 0 (T1), day 3 (T2) and day 10 (T3). The primary endpoint is defined as the difference in NRS score for pain intensity (average over the previous 24 hours) at T3 between the duloxetine and placebo groups. A sample size of 70 patients will be examined between July 2015 and March 2018. Ethics approval was obtained at all participating sites.The results of this study will be submitted for publication in international peer-reviewed journals and the key findings presented at international scientific conferences. UMIN000017647; Pre-results. 2.2, 26 April 2017. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article

24. OVERALL VIEW OF LOWEST LEVEL SILO ('ALFA'), LOOKING NORTHWEST ...

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

24. OVERALL VIEW OF LOWEST LEVEL SILO ('ALFA'), LOOKING NORTHWEST Everett Weinreb, photographer, March 1988 - Mount Gleason Nike Missile Site, Angeles National Forest, South of Soledad Canyon, Sylmar, Los Angeles County, CA

Recombinant LH (lutropin alfa) for the treatment of hypogonadotrophic women with profound LH deficiency: a randomized, double-blind, placebo-controlled, proof-of-efficacy study.

PubMed

Shoham, Z; Smith, H; Yeko, T; O'Brien, F; Hemsey, G; O'Dea, L

2008-09-01

To confirm the safety and efficacy of 75 IU lutropin alfa with concomitant follitropin alfa in inducing follicular development in women with profound gonadotrophin deficiency. Double-blind, randomized, placebo-controlled trial conducted in 25 medical centres in four countries. Thirty-nine patients with LH < 1.2 IU/l and FSH < 5.0 IU/l were treated with concomitant 75 IU lutropin alfa and 150 IU follitropin alfa or concomitant placebo and 150 IU follitropin alfa. Primary efficacy end-point (intent-to-treat): follicular development defined by (i) at least one follicle >or= 17 mm; (ii) serum E(2) level >or= 400 pmol/l on day of hCG administration (DhCG); and (iii) mid-luteal phase progesterone level >or= 25 nmol/l. In the analysis of evaluable patients, 66.7% (16 of 24) of patients given lutropin alfa achieved follicular development compared with 20.0% (2 of 10) of patients receiving placebo (P = 0.023). In the intent-to-treat analysis, follicular development was achieved in 65.4% (17 of 26) of patients receiving lutropin alfa and 15.4% (2 of 13) of patients receiving placebo (P = 0.006). The statistical difference between treatment groups was preserved when over-response leading to cycle cancellation was analysed as a failed response (P = 0.034). Lutropin alfa was well tolerated. Subcutaneous co-administration of 75 IU lutropin alfa with follitropin alfa is safe and effective in inducing follicular development in women with profound gonadotrophin deficiency.

Postictal ventricular tachycardia after electroconvulsive therapy treatment associated with a lithium-duloxetine combination.

PubMed

Heinz, Boeker; Lorenzo, Perniola; Markus, Risch; Holger, Himmighoffen; Beatrix, Roemer; Erich, Seifritz; Alain, Borgeat

2013-09-01

This report addresses the dilemma of continuing lithium prophylaxis and antidepressant therapy in view of cardiovascular adverse effects under electroconvulsive therapy (ECT) in patients with a long history of recurrent affective disorders. A severely depressed 48-year-old woman who had been treated with lithium for 18 years developed a ventricular tachycardia during ECT. Possible interaction with succinylcholine was taken into account, and rocuronium was used as an alternative muscle relaxant. Electroconvulsive therapy was continued without adverse effects after reduction of lithium and withdrawal from duloxetine. Systemic studies on cardiac adverse effects of serotonin and norepinephrine reuptake inhibitors and serotonin and norepinephrine reuptake inhibitor-lithium combinations during ECT are needed.

A phase 3 randomized placebo-controlled trial of darbepoetin alfa in patients with anemia and lower-risk myelodysplastic syndromes.

PubMed

Platzbecker, U; Symeonidis, A; Oliva, E N; Goede, J S; Delforge, M; Mayer, J; Slama, B; Badre, S; Gasal, E; Mehta, B; Franklin, J

2017-09-01

The use of darbepoetin alfa to treat anemia in patients with lower-risk myelodysplastic syndromes (MDS) was evaluated in a phase 3 trial. Eligible patients had low/intermediate-1 risk MDS, hemoglobin ⩽10 g/dl, low transfusion burden and serum erythropoietin (EPO) ⩽500 mU/ml. Patients were randomized 2:1 to receive 24 weeks of subcutaneous darbepoetin alfa 500 μg or placebo every 3 weeks (Q3W), followed by 48 weeks of open-label darbepoetin alfa. A total of 147 patients were randomized, with median hemoglobin of 9.3 (Q1:8.8, Q3:9.7) g/dl and median baseline serum EPO of 69 (Q1:36, Q3:158) mU/ml. Transfusion incidence from weeks 5-24 was significantly lower with darbepoetin alfa versus placebo (36.1% (35/97) versus 59.2% (29/49), P=0.008) and erythroid response rates increased significantly with darbepoetin alfa (14.7% (11/75 evaluable) versus 0% (0/35 evaluable), P=0.016). In the 48-week open-label period, dose frequency increased from Q3W to Q2W in 81% (102/126) of patients; this was associated with a higher hematologic improvement-erythroid response rate (34.7% (34/98)). Safety results were consistent with a previous darbepoetin alfa phase 2 MDS trial. In conclusion, 24 weeks of darbepoetin alfa Q3W significantly reduced transfusions and increased rates of erythroid response with no new safety signals in lower-risk MDS (registered as EudraCT#2009-016522-14 and NCT#01362140).

26. VIEW SHOWING ENTRANCE TO SILO 'ALFA,' LOOKING NORTH Marilyn ...

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

26. VIEW SHOWING ENTRANCE TO SILO 'ALFA,' LOOKING NORTH Marilyn Ziemer and Everett Weinreb, photographers, March 1988 - Mount Gleason Nike Missile Site, Angeles National Forest, South of Soledad Canyon, Sylmar, Los Angeles County, CA

Clinical Use of Dornase Alfa Is Associated with a Slower Rate of FEV1 Decline in Cystic Fibrosis

PubMed Central

Konstan, Michael W.; Wagener, Jeffrey S.; Pasta, David J.; Millar, Stefanie J.; Jacobs, Joan R.; Yegin, Ashley; Morgan, Wayne J.

2014-01-01

SUMMARY Objectives Randomized controlled trials of dornase alfa have shown forced expiratory volume in 1 second (FEV1) to improve in patients with cystic fibrosis (CF) but have not assessed change in the rate of lung function decline. We assessed the relationship of dornase alfa use and FEV1 decline using the Epidemiologic Study of CF (ESCF). Methodology Patients aged 8–38 years who had been enrolled in ESCF for 2 years when initially treated with dornase alfa were selected if they remained on treatment during the following 2 years. A comparator group included patients aged 8–38 who were not yet reported to have received dornase alfa. For each patient we estimated the annual rate of decline in FEV1 % predicted before and after the index using a mixed-effects model adjusted for age, gender, pulmonary exacerbations, respiratory therapies, and nutritional supplements. Results The dornase alfa group (n = 2,230) had a lower FEV1 % predicted at index and a more rapid decline during the pre-index period. The mean rate of FEV1 decline improved for the dornase alfa group; the improvement was similar in adults and children 8–17 years old but was not statistically significant in adults. The comparator group (n = 5,970) showed no change among adults and an increased rate of decline among children 8–17 years old. Conclusions The use of dornase alfa for a 2-year period is associated with a reduction in the rate of FEV1 decline. These results also demonstrate the value of using an observational study to assess the association of instituting new therapies in the clinical setting with changes in the rate of FEV1 decline in patients with CF. PMID:21438174

Long-term efficacy and safety results of taliglucerase alfa through 5years in adult treatment-naïve patients with Gaucher disease.

PubMed

Zimran, Ari; Durán, Gloria; Giraldo, Pilar; Rosenbaum, Hanna; Giona, Fiorina; Petakov, Milan; Terreros Muñoz, Eduardo; Solorio-Meza, Sergio Eduardo; Cooper, Peter A; Varughese, Sheeba; Alon, Sari; Chertkoff, Raul

2016-07-18

Taliglucerase alfa, the first available plant cell-expressed recombinant therapeutic protein, is an enzyme replacement therapy approved for Gaucher disease (GD). PB-06-001, a pivotal phase 3, multicenter, randomized, double-blind, parallel-dose study investigated taliglucerase alfa 30 or 60U/kg every other week through 9months in treatment-naïve adults with GD; 30-month extension study PB-06-003 followed. Patients completing PB-06-001 and PB-06-003 could continue treatment in PB-06-007. Nineteen patients enrolled in PB-06-007 (30U/kg, n=8; 60U/kg, n=9; dose adjusted, n=2); 17 completed 5 total years of treatment. In these 3 groups, respectively, taliglucerase alfa resulted in mean decreases in spleen volume (-8.7, -6.9, -12.4 multiples of normal), liver volume (-0.6, -0.4, -0.5 multiples of normal), chitotriosidase activity (-83.1%, -93.4%, -87.9%), and chemokine (CC motif) ligand 18 concentration (-66.7%, -83.3%, -78.9%), as well as mean increases in hemoglobin concentration (+2.1, +2.1, +1.8mg/dL) and platelet count (+31,871, +106,800, +34,000/mm 3 ). The most common adverse events were nasopharyngitis and arthralgia. Most adverse events were mild/moderate; no serious adverse events were considered treatment-related. These results demonstrate continued improvement of disease parameters during 5years of taliglucerase alfa therapy in 17 treatment-naive patients with no new safety concerns, extending the taliglucerase alfa clinical efficacy and safety dataset. This study was registered at www.clinicaltrials.gov as NCT01422187. Copyright © 2016 Elsevier Inc. All rights reserved.

28. VIEW OF ELECTRICAL HOLE INTO 'ALFA' SILO, LOOKING FROM ...

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

28. VIEW OF ELECTRICAL HOLE INTO 'ALFA' SILO, LOOKING FROM TOP Marily Ziemer and Everett Weinreb, photographers, March 1988 - Mount Gleason Nike Missile Site, Angeles National Forest, South of Soledad Canyon, Sylmar, Los Angeles County, CA

Peginterferon Lambda-1a/Ribavirin with Daclatasvir or Peginterferon Alfa-2a/Ribavirin with Telaprevir for Chronic Hepatitis C Genotype 1b.

PubMed

Flisiak, Robert; Kawazoe, Seiji; Znoyko, Olga; Assy, Nimer; Gadano, Adrian; Kao, Jia-Horng; Lee, Kwan-Sik; Zwirtes, Ricardo; Portsmouth, Simon; Dong, Yuping; Xu, Dong; Kumada, Hiromitsu; Srinivasan, Subasree

2016-11-01

The study objective was to compare the efficacy and safety of peginterferon lambda-1a combined with ribavirin/daclatasvir (Lambda/RBV/DCV), versus peginterferon alfa-2a combined with ribavirin/telaprevir (Alfa/RBV/TVR), in patients chronically infected with hepatitis C virus (HCV), genotype 1b. This was a prospective, randomized, open-label, phase 3 study (NCT01718158) in adults (aged ≥18 years) who were treatment naïve or prior relapsers to peginterferon alfa/ribavirin therapy. The primary endpoint was sustained virologic response at post-treatment follow-up week 12 (SVR12). Patients were randomized in a 2:1 ratio to receive 24 weeks of Lambda/RBV/DCV or response-guided 24 or 48 weeks of Alfa/RBV/TVR. Overall, 440 patients were treated (294 with Lambda/RBV/DCV; 146 with Alfa/RBV/TVR). The proportion of patients achieving SVR12 was 88.8% in the Lambda/RBV/DCV arm and 70.5% in the Alfa/RBV/TVR arm (difference between arms: 18.3%; 95% confidence interval: 9.9-25.7; P < 0.0001). Patients in the Lambda/RBV/DCV group had fewer rash-related adverse events (AEs), cytopenic abnormalities, flu-like symptoms, serious AEs, and discontinuations due to AEs, but more liver abnormalities than those in the Alfa/RBV/TVR group. In conclusion, treatment with Lambda/RBV/DCV led to higher SVR12 rates and a more favorable safety profile than Alfa/RBV/TVR in patients with chronic HCV, genotype 1b infection.

Clinical observation of patients with Fabry disease after switching from agalsidase beta (Fabrazyme) to agalsidase alfa (Replagal).

PubMed

Tsuboi, Kazuya; Yamamoto, Hiroshi

2012-09-01

Fabry disease is a rare, X-linked, inherited lysosomal storage disorder that can be treated with the enzymes agalsidasealfa (Replagal) and agalsidase beta (Fabrazyme). Currently, there is a global shortage of agalsidase beta, and this has increased global demand for agalsidase alfa. We assess the feasibility of switching patients on agalsidase beta treatment to agalsidase alfa instead. This analysis is part of an ongoing observational study involving 11 patients with Fabry disease in whom the treatment was switched from agalsidase beta (1 mg/kg every other week) to agalsidase alfa (0.2 mg/kg every other week). Data were collected for a minimum of 36 months: 24 months before and 12 months after the switch. Serial data were evaluated with respect to renal function, cardiac mass, pain, quality of life, and tolerability/safety. Indexes of renal function (estimated glomerular filtration rate) and cardiac mass (left-ventricular mass index), pain (Brief Pain Inventory), and quality of life (EuroQoL-Dimensions) clearly showed that, in patients switched to agalsidase alfa, Fabry disease stabilized during the 12 months of follow-up. Despite the limitations of this preliminary observational study, it was found that all the patients maintained disease stability when treated with agalsidase alfa, as evidenced by estimated glomerular filtration rate, left-ventricular mass index,pain scores, and quality-of-life indexes, throughout 12 months of follow-up.

Changes in the amino acid sequence of the recombinant human factor VIIa analog, vatreptacog alfa, are associated with clinical immunogenicity.

PubMed

Mahlangu, J N; Weldingh, K N; Lentz, S R; Kaicker, S; Karim, F A; Matsushita, T; Recht, M; Tomczak, W; Windyga, J; Ehrenforth, S; Knobe, K

2015-11-01

Vatreptacog alfa, a recombinant human factor VIIa (rFVIIa) analog developed to improve the treatment of bleeds in hemophilia patients with inhibitors, differs from native FVIIa by three amino acid substitutions. In a randomized, double-blind, crossover, confirmatory phase III trial (adept(™) 2), 8/72 (11%) hemophilia A or B patients with inhibitors treated for acute bleeds developed anti-drug antibodies (ADAs) to vatreptacog alfa. To characterize the formation of anti-vatreptacog alfa ADAs in hemophilia patients with inhibitors. This was a post hoc analysis of adept(™) 2. Immunoglobulin isotype determination, specificity analysis of rFVIIa cross-reactive antibodies, epitope mapping of rFVIIa single mutant analogs and pharmacokinetic (PK) profiling were performed to characterize the ADAs. Immunoglobulin isotyping indicated that the ADAs were of the immunoglobulin G subtype. In epitope mapping, none of the rFVIIa single mutant analogs (V158D, E296V or M298Q) contained the complete antibody epitope, confirming that the antibodies were specific for vatreptacog alfa. In two patients, for whom PK profiling was performed both before and after the development of ADAs, vatreptacog alfa showed a prolonged elimination phase following ADA development. During the follow-up evaluation, the rFVIIa cross-reactivity disappeared after the last vatreptacog alfa exposure, despite continued exposure to rFVIIa as part of standard care. Results from the vatreptacog alfa phase III trial demonstrate that the specific changes made, albeit relatively small, to the FVIIa molecule alter its clinical immunogenicity. © 2015 International Society on Thrombosis and Haemostasis.

Epoetin alfa improves survival after chemoradiation for Stage III esophageal cancer: Final results of a prospective observational study

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

Rades, Dirk; Tribius, Silke; Yekebas, Emre F.

Purpose: This prospective, nonrandomized study evaluates the effectiveness of epoetin alfa to maintain the hemoglobin levels at 12 to14 g/dL (optimal range for tumor oxygenation) during chemoradiation for Stage III esophageal cancer and its impact on overall survival (OS), metastatic-free survival (MFS), and locoregional control (LC). Methods and Materials: Ninety-six patients were included. Forty-two patients received epoetin alfa (150 IU/kg, 3 times a week) during radiotherapy, which was started at hemoglobin less than 13 g/dL and stopped at 14 g/dL or higher. Hemoglobin levels were measured weekly during RT. Results: Both groups were balanced for age, sex, performance status, tumormore » length/location, histology, grading, T-stage/N-stage, chemotherapy, treatment schedule, and hemoglobin before RT. Median change of hemoglobin was +0.3 g/dL/wk with epoetin alfa and -0.5 g/dL/wk without epoetin alfa. At least 60% of hemoglobin levels were 12 to 14 g/dL in 64% and 17% of the patients, respectively (p < 0.001). Patients who received epoetin alfa had better OS (32% vs. 8% at 2 years, p = 0.009) and LC (67% vs. 15% at 2 years, p = 0.001). MFS was not significantly different (42% vs. 18% at 2 years, p = 0.09). Conclusions: The findings suggest that epoetin alfa when used to maintain the hemoglobin levels at 12 to 14 g/dL can improve OS and LC of Stage III esophageal cancer patients.« less

Gateways to clinical trials.

PubMed

Bayes, M; Rabasseda, X; Prous, J R

2005-10-01

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: (-)-Epigallocatechin gallate, (Z)-4-hydroxytamoxifen; Ad.muIFN-beta AD-237, adalimumab, adefovir dipivoxil, agalsidase alfa, alemtuzumab, almotriptan, ALVAC vCP1452, alvimopan hydrate, ambrisentan, anakinra, anti-IFN-gamma MAb; Bimatoprost, BMS-188797, BMS-214662, bortezomib, bosentan, bovine lactoferrin; Caffeine, canertinib dihydrochloride, canfosfamide hydrochloride, cannabidiol, caspofungin acetate, cetuximab, cH36, ChimeriVax-JE, ciclesonide, cilansetron, cinacalcet hydrochloride, clopidogrel, CpG-7909, Cypher; Daptomycin, darbepoetin alfa, darifenacin hydrobromide, decitabine, denufosol tetrasodium, Dexamet, diindolemethane, drotrecogin alfa (activated), duloxetine hydrochloride, DX-9065a; E-7010, edaravone, efalizumab, eicosapentaenoic acid/docosahexaenoic acid, elacridar, eletriptan, emtricitabine, epratuzumab, erlotinib hydrochloride, ertapenem sodium, eszopiclone, everolimus, ezetimibe; Fludarabine, fondaparinux sodium; gamma-Hydroxybutyrate sodium, gavestinel sodium, gefitinib, granisetron-Biochronomer; Human Albumin, human insulin; Imatinib mesylate, indiplon, interleukin-2 XL, isatoribine, ISS-1018, i.v. gamma-globulin, ivabradine hydrochloride, ixabepilone; Lanthanum carbonate, L-arginine hydrochloride, liposomal doxorubicin, LY-450139; Magnesium sulfate, melatonin, motexafin gadolinium, mycophenolic acid sodium salt; Natalizumab, nesiritide, niacin/lovastatin; OGX-011, olmesartan medoxomil, omalizumab, ospemifene; PACAP38, panitumumab, parathyroid hormone (human recombinant), parecoxib sodium, patupilone, pegfilgrastim, peginterferon alfa-2a, peginterferon alfa-2b, peginterferon alfa-2b

Poractant alfa versus bovine lipid extract surfactant for infants 24+0 to 31+6 weeks gestational age: A randomized controlled trial.

PubMed

Lemyre, Brigitte; Fusch, Christoph; Schmölzer, Georg M; Rouvinez Bouali, Nicole; Reddy, Deepti; Barrowman, Nicholas; Huneault-Purney, Nicole; Lacaze-Masmonteil, Thierry

2017-01-01

To compare the efficacy and safety of poractant alfa and bovine lipid extract surfactant in preterm infants. Randomized, partially-blinded, multicenter trial. Infants <32 weeks needing surfactant before 48 hours were randomly assigned to receive poractant alfa or bovine lipid extract surfactant. The primary outcome was being alive and extubated at 48 hours post-randomization. Secondary outcomes included need for re-dosing, duration of respiratory support and oxygen, bronchopulmonary dysplasia, mortality and complications during administration. Three centers recruited 87 infants (mean 26.7 weeks and 906 grams) at a mean age of 5.9 hours, between March 2013 and December 2015. 21/42 (50%) were alive and extubated at 48 hours in the poractant alfa group vs 26/45 (57.8%) in the bovine lipid extract surfactant group; adjusted OR 0.76 (95% CI 0.30-1.93) (p = 0.56). No differences were observed in the need to re-dose. Duration of oxygen support (41.5 vs 62 days; adjusted OR 1.69 95% CI 1.02-2.80; p = 0.04) was reduced in infants who received poractant alfa. We observed a trend in bronchopulmonary dysplasia among survivors (51.5% vs 72.1%; adjusted OR 0.35 95%CI 0.12-1.04; p = 0.06) favoring poractant alfa. Twelve infants died before discharge, 9 in the poractant alfa group and 3 in the bovine lung extract group. Severe airway obstruction following administration was observed in 0 (poractant alfa) and 5 (bovine lipid extract surfactant) infants (adjusted OR 0.09 95%CI <0.01-1.27; p = 0.07). No statistically significant difference was observed in the proportion of infants alive and extubated within 48h between the two study groups. Poractant alfa may be more beneficial and associated with fewer complications than bovine lipid extract surfactant. However, we observed a trend towards higher mortality in the poractant alfa group. Larger studies are needed to determine whether observed possible benefits translate in shorter hospital admissions, or other long term benefits and

Switch From Epoetin Beta to Darbepoetin Alfa Treatment of Anemia in Taiwanese Hemodialysis Patients: Dose Equivalence by Hemoglobin Stratification.

PubMed

Liao, Shang-Chih; Hung, Cheng-Chieh; Lee, Chien-Te; Lee, Chih-Hsiung; Lee, Chin-Chan; Lin, Chun-Liang; Sun, Chiao-Yin; Cheng, Ben-Chung; Yang, Chih-Chao; Wu, Chien-Hsing; Chen, Jin-Bor

2016-08-01

This multicenter study was designed to assess the hemoglobin (Hb) stability and conversion ratio of the switch from epoetin beta to darbepoetin alfa in Taiwanese hemodialysis (HD) patients. A total of 135 HD patients were enrolled and randomized with intravenous darbepoetin alfa or epoetin beta. The study duration was 24 weeks. Equivalent doses and conversion ratios were assessed with respect to Hb stratification: low Hb (≥8.0 g/dL to ≤10.0 g/dL) and high Hb (>10.0 g/dL to ≤11.0 g/dL). The results showed stable Hb levels in the study period. At week 24, the conversion ratio was higher for high Hb than low Hb (296.4 IU/dose epoetin beta: 1 µg/dose darbepoetin alfa. vs. 277.2 IU/dose epoetin beta: 1 µg/dose darbepoetin alfa). In conclusion, the conversion ratio in the present study was higher than 1 µg: 200 IU for darbepoetin alfa: epoetin for treating anemia in Taiwanese HD patients. © 2016 International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy.

Using Interferon Alfa Before Tyrosine Kinase Inhibitors May Increase Survival in Patients With Metastatic Renal Cell Carcinoma: A Turkish Oncology Group (TOG) Study.

PubMed

Artaç, Mehmet; Çoşkun, Hasan Şenol; Korkmaz, Levent; Koçer, Murat; Turhal, Nazım Serdar; Engin, Hüseyin; Dede, İsa; Paydaş, Semra; Öksüzoğlu, Berna; Bozcuk, Hakan; Demirkazık, Ahmet

2016-08-01

We aimed to investigate the outcomes of interferon alfa and sequencing tyrosine kinase inhibitors (TKIs) in patients with metastatic renal cell carcinoma. This multicenter study assessing the efficacy of TKIs after interferon alfa therapy in the first-line setting in patients with metastatic renal cell carcinoma. Patients (n = 104) from 8 centers in Turkey, who had been treated with interferon alfa in the first-line setting, were included in the study. Prognostic factors were evaluated for progression-free survival (PFS). The median age of the patients was 57 years. The median PFS of the patients treated with interferon alfa in the first-line was 3.6 months. A total of 61 patients received TKIs (sunitinib, n = 58; sorafenib, n = 3) after progression while on interferon alfa. The median PFS among the TKI-treated patients was 13.2 months. In the univariate analysis for interferon alfa treatment, neutrophil and hemoglobin level, platelet count, and Karnofsky performance status were the significant factors associated with PFS. In the univariate analysis for TKI treatment, neutrophil and hemoglobin levels were the significant factors for PFS. The median total PFS of the patients who had been treated with first-line interferon alfa and second-line TKIs was 24.9 months. This study showed that first-line interferon alfa treatment before TKIs may improve the total PFS in patients with metastatic renal cell carcinoma. Copyright © 2016 Elsevier Inc. All rights reserved.

Sinonasal inhalation of dornase alfa administered by vibrating aerosol to cystic fibrosis patients: a double-blind placebo-controlled cross-over trial.

PubMed

Mainz, Jochen G; Schien, Claudia; Schiller, Isabella; Schädlich, Katja; Koitschev, Assen; Koitschev, Christiane; Riethmüller, Joachim; Graepler-Mainka, Uta; Wiedemann, Bärbel; Beck, James F

2014-07-01

Chronic rhinosinusitis significantly impairs CF patients' quality of life and overall health. The Pari-Sinus™ device delivers vibrating aerosol effectively to paranasal sinuses. After a small pilot study to assess sinonasal inhalation of dornase alfa and placebo (isotonic saline) on potential sinonasal outcome measures, we present the subsequent prospective double-blind placebo-controlled crossover-trial. 23 CF patients were randomised to inhale either dornase alfa or isotonic saline for 28 days with the Pari-Sinus™ and after 28 days (wash-out) crossed over to the alternative treatment. The primary outcome parameter was primary nasal symptom score in the disease-specific quality of life Sino-Nasal Outcome-Test-20 (SNOT-20: nasal obstruction/sneezing/runny nose/thick nasal discharge/reduced smelling). Primary nasal symptoms improved significantly with dornase alfa compared with no treatment, while small improvements with isotonic saline did not reach significance. SNOT-20 overall scores improved significantly after dornase alfa compared with isotonic saline (p=0.017). Additionally, sinonasal dornase alfa but not isotonic saline significantly improved pulmonary function (FEF75-25: p=0.021). Vibrating sinonasal inhalation of dornase alfa reduces rhinosinusitis symptoms in CF. Copyright © 2014 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Cost-benefit analysis of interferon alfa-2b in treatment of hairy cell leukemia.

PubMed

Ozer, H; Golomb, H M; Zimmerman, H; Spiegel, R J

1989-04-19

The clinical benefits as well as the cost benefits of use of recombinant interferon (IFN) alfa-2b instead of conventional chemotherapy (primarily chlorambucil) for progressive hairy cell leukemia were assessed retrospectively on the basis of 12 months of clinical data from 128 patients treated with IFN alfa-2b. Data from 71 matched historical control patients who had received conventional treatment were used for survival analysis. Hematologic response (reversal of cytopenias) was achieved by 18% of the control patients versus 73% of the IFN-treated patients. This response was associated with virtual elimination of the need for transfusions and splenectomy as well as dramatic decreases in the frequency of fatal infections (22.5% vs. 1.6%) and the 12-month mortality rate (28% vs. 3.1%). Direct costs per patient per year for medical care (transfusions, antibiotic treatment, splenectomy, and chemotherapy) of those receiving IFN alfa-2b were 2.8-fold lower than costs for medical care of control patients ($5,027 vs. $14,046). Indirect costs, which reflect the present value of future earnings lost due to premature death, were 13.3-fold lower for IFN-treated patients than for control patients ($4,771 vs. $63,507). Our analysis demonstrates that IFN alfa-2b offers substantial clinical and cost advantages to patients with hairy cell leukemia and that the introduction of this therapy using novel biotechnology furthers the health care community's commitment to cost containment.

Duloxetine in OsteoArthritis (DOA) study: study protocol of a pragmatic open-label randomised controlled trial assessing the effect of preoperative pain treatment on postoperative outcome after total hip or knee arthroplasty

PubMed Central

Blikman, T; Rienstra, W; van Raaij, T M; ten Hagen, A J; Dijkstra, B; Zijlstra, W P; Bulstra, S K; van den Akker-Scheek, I; Stevens, M

2016-01-01

Introduction Residual pain is a major factor in patient dissatisfaction following total hip arthroplasty or total knee arthroplasty (THA/TKA). The proportion of patients with unfavourable long-term residual pain is high, ranging from 7% to 34%. There are studies indicating that a preoperative degree of central sensitisation (CS) is associated with poorer postoperative outcomes and residual pain. It is thus hypothesised that preoperative treatment of CS could enhance postoperative outcomes. Duloxetine has been shown to be effective for several chronic pain syndromes, including knee osteoarthritis (OA), in which CS is most likely one of the underlying pain mechanisms. This study aims to evaluate the postoperative effects of preoperative screening and targeted duloxetine treatment of CS on residual pain compared with care-as-usual. Methods and analysis This multicentre, pragmatic, prospective, open-label, randomised controlled trial includes patients with idiopathic hip/knee OA who are on a waiting list for primary THA/TKA. Patients at risk for CS will be randomly allocated to the preoperative duloxetine treatment programme group or the care-as-usual control group. The primary end point is the degree of postoperative pain 6 months after THA/TKA. Secondary end points at multiple time points up to 12 months postoperatively are: pain, neuropathic pain-like symptoms, (pain) sensitisation, pain catastrophising, joint-associated problems, physical activity, health-related quality of life, depressive and anxiety symptoms, and perceived improvement. Data will be analysed on an intention-to-treat basis. Ethics and dissemination The study is approved by the local Medical Ethics Committee (METc 2014/087) and will be conducted according to the principles of the Declaration of Helsinki (64th, 2013) and the Good Clinical Practice standard (GCP), and in compliance with the Medical Research Involving Human Subjects Act (WMO). Trial registration number 2013-004313-41; Pre

A multicenter, open-label extension study of velaglucerase alfa in Japanese patients with Gaucher disease: Results after a cumulative treatment period of 24months.

PubMed

Ida, Hiroyuki; Tanaka, Akemi; Matsubayashi, Tomoko; Murayama, Kei; Hongo, Teruaki; Lee, Hak-Myung; Mellgard, Björn

2016-07-01

Enzyme replacement therapy (ERT) with exogenous glucocerebrosidase is indicated to treat symptomatic Gaucher disease (GD), a rare, inherited metabolic disorder. ERT with velaglucerase alfa, which is produced in a human cell line using gene activation technology, was studied in a 12-month phase III trial in Japanese patients with type 1 or 3 GD who were switched from imiglucerase ERT (n=6); the current, open-label, 12-month extension study was designed to assess longer-term safety and efficacy. Two adult and three pediatric patients (aged <18years) were enrolled into the extension study. Every-other-week intravenous infusions were administered for 63-78weeks at average doses between 51.5 and 60.7units/kg. Three non-serious adverse events were considered related to velaglucerase alfa treatment, but no patient discontinued from the study. Six serious but non-drug-related adverse events were reported. No patient tested positive for anti-velaglucerase alfa antibodies. Hemoglobin concentrations, platelet counts, and liver and spleen volumes (normalized to body weight) in these patients were generally stable over a cumulative 24-month period from the baseline of the parent trial. The data suggest that velaglucerase alfa was well tolerated and maintained clinical stability in Japanese GD patients over 2years after switching from imiglucerase. ClinicalTrials.gov identifier NCT01842841. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Species-specific effects of neuregulin-1β (cimaglermin alfa) on glucose handling in animal models and humans with heart failure.

PubMed

Huang, Zhihong; Sawyer, Douglas B; Troy, Erika L; McEwen, Corissa; Cleator, John H; Murphy, Abigail; Caggiano, Anthony O; Eisen, Andrew; Parry, Tom J

2017-10-01

Neuregulin-1β is a member of the neuregulin family of growth factors and is critically important for normal development and functioning of the heart and brain. A recombinant version of neuregulin-1β, cimaglermin alfa (also known as glial growth factor 2 or GGF2) is being investigated as a possible therapy for heart failure. Previous studies suggest that neuregulin-1β stimulation of skeletal muscle increases glucose uptake and, specifically, sufficient doses of cimaglermin alfa acutely produce hypoglycemia in pigs. Since acute hypoglycemia could be a safety concern, blood glucose changes in the above pig study were further investigated. In addition, basal glucose and glucose disposal were investigated in mice. Finally, as part of standard clinical chemistry profiling in a single ascending-dose human safety study, blood glucose levels were evaluated in patients with heart failure after cimaglermin alfa treatment. A single intravenous injection of cimaglermin alfa at doses of 0.8mg/kg and 2.6mg/kg in mice resulted in a transient reduction of blood glucose concentrations of approximately 20% and 34%, respectively, at 2h after the treatment compared to pre-treatment levels. Similar results were observed in diabetic mice. Treatment with cimaglermin alfa also increased blood glucose disposal following oral challenge in mice. However, no significant alterations in blood glucose concentrations were found in human heart failure patients at 0.5 and 2h after treatment with cimaglermin alfa over an equivalent human dose range, based on body surface area. Taken together, these data indicate strong species differences in blood glucose handling after cimaglermin alfa treatment, and particularly do not indicate that this phenomenon should affect human subjects. Copyright © 2017 Elsevier Inc. All rights reserved.

VizieR Online Data Catalog: Arecibo Pulsar-ALFA (PALFA) survey. IV. (Lazarus+, 2015)

NASA Astrophysics Data System (ADS)

Lazarus, P.; Brazier, A.; Hessels, J. W. T.; Karako-Argaman, C.; Kaspi, V. M.; Lynch, R.; Madsen, E.; Patel, C.; Ransom, S. M.; Scholz, P.; Swiggum, J.; Zhu, W. W.; Allen, B.; Bogdanov, S.; Camilo, F.; Cardoso, F.; Chatterjee, S.; Cordes, J. M.; Crawford, F.; Deneva, J. S.; Ferdman, R.; Freire, P. C. C.; Jenet, F. A.; Knispel, B.; Lee, K. J.; van Leeuwen, J.; Lorimer, D. R.; Lyne, A. G.; McLaughlin, M. A.; Siemens, X.; Spitler, L. G.; Stairs, I. H.; Stovall, K.; Venkataraman, A.

2016-02-01

The Arecibo Pulsar-ALFA (PALFA) survey observations have been restricted to the two regions of the Galactic plane (|b|<5°) visible from the Arecibo observatory, the inner Galaxy (32°<~l<~77°), and the outer Galaxy (168°<~l<~214°). Integration times are 268s and 180s for inner and outer Galaxy observations, respectively. Observations conducted with the 7-beam Arecibo L-band Feed Array (ALFA) receiver of the Arecibo Observatory William E. Gordon 305m Telescope have a bandwidth of 322MHz centered at 1375MHz. PALFA survey data have been recorded with the Mock spectrometers since 2009. (2 data files).

Autoantibodies to alfa-fodrin in patients with Hashimoto thyroiditis and Sjögren's syndrome: possible markers for a common secretory disorder.

PubMed

Szanto, Antonia; Csipo, Istvan; Horvath, Ildiko; Biro, Edit; Szodoray, Peter; Zeher, Margit

2008-09-01

Presence of autoantibodies to alfa-fodrin was investigated in patients with Sjögren's syndrome (n = 61), Hashimoto thyroiditis (n = 27), Sjögren's syndrome associated with Hashimoto thyroiditis (n = 31) and in healthy persons (n = 77). In each group, level of alfa-fodrin antibodies was higher than in the controls. There was no significant difference in their presence either between patients with Hashimoto thyroiditis with or without Sjögren's syndrome, or-in IgA isotype-between Sjögren's and Hashimoto thyroiditis patients. Correlation was found between the level of IgG alfa-fodrin and anti-thyroglobulin antibodies. Based on these findings, fodrin can be associated with both endocrine and exocrine glandular secretion. Antibodies to alfa-fodrin might have a role in the pathogenesis of Hashimoto thyroiditis concerning the "final common effectory pathway", secretion. Alfa-fodrin antibodies can be good markers of secretory disorders. Assessment of these autoantibodies might help the diagnosis and follow-up of patients with impaired secretory capability of not only autoimmune origin.

Astronaut Scott Carpenter practices in the ALFA trainer at Langley

NASA Technical Reports Server (NTRS)

1962-01-01

Project Mercury Astronaut M. Scott Carpenter practices in the Air Lubricated Free Attitude (ALFA) trainer located at NASA's Manned Spacecraft Center at Langley AFB, Virginia. This trainer allows the astronaut to see the image of the earth's surface at his feet while manually controlling the spacecraft.

Mood alterations during interferon-alfa therapy in patients with chronic hepatitis C: evidence for an overlap between manic/hypomanic and depressive symptoms.

PubMed

Constant, Aymery; Castera, Laurent; Dantzer, Robert; Couzigou, Patrice; de Ledinghen, Victor; Demotes-Mainard, Jacques; Henry, Chantal

2005-08-01

Psychiatric side effects are common during interferon-alfa (IFN-alfa) therapy and often responsible for early treatment discontinuation, thus limiting its therapeutic potential. Depression is considered the hallmark of these side effects. However, irritability, anger/hostility, and manic/hypomanic episodes have also been reported, suggesting that these symptoms are important features of IFN-alfa-induced neuropsychiatric side effects. The aim of this prospective study was to use item-by-item analysis to thoroughly characterize neuropsychiatric symptoms occurring during early IFN-alfa therapy in a large cohort of patients with chronic hepatitis C. Ninety-three previously IFN-alfa-naive patients treated with pegylated IFN-alfa plus ribavirin for chronic hepatitis C were studied. Neuropsychiatric assessments were conducted before initiation and after weeks 4 and 12 of antiviral therapy. They included the Mini-International Neuropsychiatric Interview, the 10-item Montgomery-Asberg Depression Rating Scale, the State-Trait Anxiety Inventory, and the Brief Fatigue Inventory. Psychiatric events occurred in 30 patients (32%). They consisted of mood disorders in all cases: mania in 3 cases (10%), irritable hypomania in 15 cases (50%), and depressive mixed states in 12 cases (40%). Neurovegetative symptoms appeared within 4 weeks in most patients. In patients who developed mood disorders, sadness and depressive thoughts were present but minimal in severity. In contrast, inner tension and anxiety symptoms increased significantly over time only in these patients. Our results suggest that IFN-alfa-induced mood disorders are common and consist of an overlap between depressive and manic symptoms rather than a mere depression. The impact of such findings on therapeutic management should be investigated.

Valorization of Tunisian alfa fibres and sumac tannins for the elaboration of biodegradable insulating panels

NASA Astrophysics Data System (ADS)

Saad, Houda; Charrier, Bertrand; Ayed, Naceur; Charrier-El-Bouhtoury, Fatima

2017-10-01

Alfa leaves are important renewable raw materials in Tunisia where they are used basically in handcrafts and paper industry. Sumac is also an abundant species in Tunisia known for its high tannin content and is basically used in traditional medicine. To valorize these natural resources, we studied, for the first time, the possibility of making insulating panels based on alfa fibres and sumac tannins based adhesive. Firstly, alfa leaves were treated with an alkali solution as it is one of the standard procedures commonly used in the paper industry to extract cellulosic fibres. Mercerization effects were studied by characterizing fibres thermal properties and fibres surface morphology. Secondly, the sumac tannin based resin was formulated and characterized. Finally, the insulating panel was elaborated and characterized by determining its thermal conductivity. The thermal gravimetric analysis results show improvement in the thermal stability of fibres after alkali treatment. Environmental Scanning Electron Microscopy showed changes on treated alfa surface which could promote the fibre-matrix adhesion. The reactivity of sumac tannins to formaldehyde test (Stiasny number) showed the possible use of sumac tannins in wood adhesive formulation. Thermomechanical analysis and strength analysis of sumac tannin/hexamin based resin highlighted acceptable bonding properties. The thermal conductivity measurement showed an average value equal to 0.110 W/m K. Contribution to the topical issue "Materials for Energy harvesting, conversion and storage II (ICOME 2016)", edited by Jean-Michel Nunzi, Rachid Bennacer and Mohammed El Ganaoui

Predictive Factors for Beneficial Response to Interferon-alfa Therapy in Chronic Hepatitis C

PubMed Central

Yoon, Seung-Kew; Kim, Sung Soo; Park, Young Min; Shim, Kyu Sik; Lee, Chang Don; Sun, Hee Sik; Park, Doo Ho; Kim, Boo Sung; Ryu, Wang Shick; Cho, Joong Myung

1995-01-01

Objectives: Interferon is the only established teatment for chronic hepatitis C but the host-dependent or virus-related factors affecting the response rate to interferon therapy are not yet dear. The purpose of this study was to investigate the factors predictive of response to interferon-alfa therapy in chronic hepatitis C. Methods: Twenty-five consecutive patients with chronic hepatitis C were randomized to three regimens of interferon-alfa: group A (n=7, 3MU every day for 3 months), group B (n=8, 3MU every other day for 3 months) and group C (n=10, 3MU every other day for 6 months), We quantified serum HC RNA levels by competitive reverse transcription-polymerase chain reaction (RT-PCR)and performed HCV genotyping using type-specific primers deduced from the NS5 region of the HCV genome. We also attempted to identify which demographic, biochemical and histologic factors in addition to virus-related factors would significantly predict beneficial response to interferon by multivariate analysis. Results: Sustained responders were 8 (36.4%), nonsustained responders were 2 (9.1%) and nonresponders were 12 (54.5%) of 22 patients who had received complete therapy. The initial HCV RNA level (logarithmic transformed copy numbers per ml of serum)in sustained responders (5.75±0.39) was significantly lower than that of nonsustained responders (6.80±0.71)and nonresponders (6.70±0.52) (p<0.05). In multivariate multiple logistic regression analysis, the serum HCV RNA level before therapy was only the independent predictor of a sustained response to interferon-alfa therapy (p=0.001). Conclusions: Serum HCV RNA level before therapy was the most useful predictor of a sustained response to interferon-alfa therapy for chronic hepatitis C. PMID:7495780

A Patient Friendly Corifollitropin Alfa Protocol without Routine Pituitary Suppression in Normal Responders

PubMed Central

Wang, Huai-Ling; Lai, Hsing-Hua; Chuang, Tzu-Hsuan; Shih, Yu-Wei; Huang, Shih-Chieh; Lee, Meng-Ju; Chen, Shee-Uan

2016-01-01

The release of corifollitropin alfa simplifies daily injections of short-acting recombinant follicular stimulating hormone (rFSH), and its widely-used protocol involves short-acting gonadotropins supplements and a fixed GnRH antagonist regimen, largely based on follicle size. In this study, the feasibility of corifollitropin alfa without routine pituitary suppression was evaluated. A total of 288 patients were stimulated by corifollitropin alfa on cycle day 3 following with routine serum hormone monitoring and follicle scanning every other day after 5 days of initial stimulation, and a GnRH antagonist (0.25 mg) was only used prophylactically when the luteinizing hormone (LH) was ≧ 6 IU/L (over half of the definitive LH surge). The incidence of premature LH surge (≧ 10 IU/L) was 2.4% (7/288) before the timely injection of a single GnRH antagonist, and the elevated LH level was dropped down from 11.9 IU/L to 2.2 IU/L after the suppression. Two hundred fifty-one patients did not need any antagonist (87.2% [251/288]) throughout the whole stimulation. No adverse effects were observed regarding oocyte competency (fertilization rate: 78%; blastocyst formation rate: 64%). The live birth rate per OPU cycle after the first cryotransfer was 56.3% (161/286), and the cumulative live birth rate per OPU cycle after cyrotransfers was 69.6% (199/286). Of patients who did and did not receive GnRH antagonist during stimulation, no significant difference existed in the cumulative live birth rates (78.4% vs. 68.3%, p = 0.25). The results demonstrated that the routine GnRH antagonist administration is not required in the corifollitropin-alfa cycles using a flexible and hormone-depended antagonist regimen, while the clinical outcome is not compromised. This finding reveals that the use of a GnRH antagonist only occasionally may be needed. PMID:27100388

A Patient Friendly Corifollitropin Alfa Protocol without Routine Pituitary Suppression in Normal Responders.

PubMed

Wang, Huai-Ling; Lai, Hsing-Hua; Chuang, Tzu-Hsuan; Shih, Yu-Wei; Huang, Shih-Chieh; Lee, Meng-Ju; Chen, Shee-Uan

2016-01-01

The release of corifollitropin alfa simplifies daily injections of short-acting recombinant follicular stimulating hormone (rFSH), and its widely-used protocol involves short-acting gonadotropins supplements and a fixed GnRH antagonist regimen, largely based on follicle size. In this study, the feasibility of corifollitropin alfa without routine pituitary suppression was evaluated. A total of 288 patients were stimulated by corifollitropin alfa on cycle day 3 following with routine serum hormone monitoring and follicle scanning every other day after 5 days of initial stimulation, and a GnRH antagonist (0.25 mg) was only used prophylactically when the luteinizing hormone (LH) was ≧ 6 IU/L (over half of the definitive LH surge). The incidence of premature LH surge (≧ 10 IU/L) was 2.4% (7/288) before the timely injection of a single GnRH antagonist, and the elevated LH level was dropped down from 11.9 IU/L to 2.2 IU/L after the suppression. Two hundred fifty-one patients did not need any antagonist (87.2% [251/288]) throughout the whole stimulation. No adverse effects were observed regarding oocyte competency (fertilization rate: 78%; blastocyst formation rate: 64%). The live birth rate per OPU cycle after the first cryotransfer was 56.3% (161/286), and the cumulative live birth rate per OPU cycle after cyrotransfers was 69.6% (199/286). Of patients who did and did not receive GnRH antagonist during stimulation, no significant difference existed in the cumulative live birth rates (78.4% vs. 68.3%, p = 0.25). The results demonstrated that the routine GnRH antagonist administration is not required in the corifollitropin-alfa cycles using a flexible and hormone-depended antagonist regimen, while the clinical outcome is not compromised. This finding reveals that the use of a GnRH antagonist only occasionally may be needed.

A phase IB study of ipilimumab with peginterferon alfa-2b in patients with unresectable melanoma.

PubMed

Brohl, Andrew S; Khushalani, Nikhil I; Eroglu, Zeynep; Markowitz, Joseph; Thapa, Ram; Chen, Y Ann; Kudchadkar, Ragini; Weber, Jeffrey S

2016-01-01

Ipilimumab and peginterferon alfa-2b are established systemic treatment options for melanoma that have distinct mechanisms of action. Given the need for improved therapies for advanced melanoma, we conducted an open-label, single institution, phase Ib study to assess the safety and tolerability of using these two agents in combination. Study treatment consisted of ipilimumab given every 3 weeks, for a total of four infusions, concurrent with peginterferon alfa-2b administered subcutaneous weekly for a total of 12 weeks. This was followed by maintenance therapy with peginterferon alfa-2b administered subcutaneously weekly for up to 144 additional weeks. The study was designed as a two-stage dose escalation scheme with continuous dose-limiting toxicity monitoring during the induction phase. Thirty one patients received at least 1 dose of study treatment and 30 were assessable for efficacy endpoints. We found that ipilimumab at 3 mg/kg dosing with peginterfeon alfa-2b at 2 μg/kg/week was the maximum tolerated dose of this combination. The incidence of grade 3 drug-related adverse events (AEs) was 45.2%. There were no grade 4/5 AEs. The overall response rate was 40% by immune-related response criteria. Median progression-free survival was 5.9 months. The median overall survival was not reached with at a median follow-up of 35.8 months. We report that the combination of ipilimumab at 3 mg/kg dosing combined with peginterfeon alfa-2b at 2 μg/kg/week demonstrated an acceptable toxicity profile and a promising efficacy signal. Further study of this combination is warranted. ClinicalTrials.gov identifier: NCT01496807, Registered December 19th, 2011.

Corifollitropin alfa compared with follitropin beta in poor responders undergoing ICSI: a randomized controlled trial.

PubMed

Kolibianakis, E M; Venetis, C A; Bosdou, J K; Zepiridis, L; Chatzimeletiou, K; Makedos, A; Masouridou, S; Triantafillidis, S; Mitsoli, A; Tarlatzis, B C

2015-02-01

Does substituting 150 µg corifollitropin alfa for 450 IU follitropin beta during the first 7 days of ovarian stimulation in proven poor responders, result in retrieval of a non-inferior number (<1.5 fewer) of cumulus oocyte complexes (COCs)? A single s.c. dose of 150 µg corifollitropin alfa on the first day of ovarian stimulation, followed if necessary, from Day 8 onwards, with 450 IU of follitropin beta/day, is not inferior to daily doses of 450 IU follitropin beta. The 95% CI of the difference between medians in the number of oocytes retrieved was -1 to +1 within the safety margin of 1.5. Recent data from retrospective studies suggest that the use of corifollitropin alfa in poor responders is promising since it could simplify ovarian stimulation without compromising its outcome. Seventy-nine women with previous poor ovarian response undergoing ICSI treatment were enrolled in this open label, non-inferiority, randomized clinical trial (RCT). Inclusion criteria were: previous poor response to ovarian stimulation (≤4 COCs) after maximal stimulation, age <45 years, regular spontaneous menstrual cycle, body mass index: 18-32 kg/m(2) and basal follicle stimulating hormone ≤20 IU/l. On Day 2 of the menstrual cycle, patients were administered either a single s.c dose of 150 µg corifollitropin alfa (n = 40) or a fixed daily dose of 450 IU of follitropin beta (n = 39). In the corifollitropin alfa group, 450 IU of follitropin beta were administered from Day 8 of stimulation until the day of human chorionic gonadotrophin (hCG) administration, if necessary. To inhibit premature luteinizing hormone surge, the gonadotrophin releasing hormone antagonist ganirelix was used. Triggering of final oocyte maturation was performed using 250 µg of recombinant hCG, when at least two follicles reached 17 mm in mean diameter. The number of COCs retrieved was not statistically different between the corifollitropin alfa and the follitropin beta groups [Median 3 versus 2, 95% CI 2

Maintenance therapy with peginterferon alfa-2b does not prevent hepatocellular carcinoma in cirrhotic patients with chronic hepatitis C.

PubMed

Bruix, Jordi; Poynard, Thierry; Colombo, Massimo; Schiff, Eugene; Burak, Kelly; Heathcote, Elizabeth J L; Berg, Thomas; Poo, Jorge-Luis; Mello, Carlos Brandao; Guenther, Rainer; Niederau, Claus; Terg, Ruben; Bedossa, Pierre; Boparai, Navdeep; Griffel, Louis H; Burroughs, Margaret; Brass, Clifford A; Albrecht, Janice K

2011-06-01

Several studies have reported that low doses of interferon can delay the development of hepatocellular carcinoma (HCC) and progression of chronic hepatitis C. We investigated the incidence of clinical events among participants of the Evaluation of PegIntron in Control of Hepatitis C Cirrhosis (EPIC)3 program. Data were analyzed from an open-label randomized study of patients with chronic hepatitis C who had failed to respond to interferon alfa plus ribavirin. All patients had compensated cirrhosis with no evidence of HCC. Patients received peginterferon alfa-2b (0.5 μg/kg/week; n=311) or no treatment (controls, n=315) for a maximum period of 5 years or until 98 patients had a clinical event (hepatic decompensation, HCC, death, or liver transplantation). The primary measure of efficacy was time until the first clinical event. There was no significant difference in time to first clinical event among patients who received peginterferon alfa-2b compared with controls (hazard ratio [HR], 1.452; 95% confidence interval [CI]: 0.880-2.396). There was no decrease in the development of HCC with therapy. The time to disease progression (clinical events or new or enlarged varices) was significantly longer for patients who received peginterferon alfa-2b compared with controls (HR, 1.564; 95% CI: 1.130-2.166). In a prospectively defined subanalysis of patients with baseline portal hypertension, peginterferon alfa-2b significantly increased the time to first clinical event compared with controls (P=.016). There were no new safety observations. Maintenance therapy with peginterferon alfa-2b is not warranted in all patients and does not prevent HCC. However, there is a potential clinical benefit of long-term suppressive therapy in patients with preexisting portal hypertension. Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

Drotrecogin alfa (activated): real-life use and outcomes for the UK

PubMed Central

Rowan, Kathryn M; Welch, Catherine A; North, Emma; Harrison, David A

2008-01-01

Introduction In March 2001, the results of the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study were published, which indicated a 6.1% absolute reduction in 28-day mortality. Drotrecogin alfa (activated; DrotAA) was subsequently approved for use in patients with severe sepsis. Methods In December 2002, critical care units in England, Wales and Northern Ireland were invited to participate in an audit of DrotAA. Data for each infusion of DrotAA were linked to case mix and outcome data from a national audit. Use of DrotAA was described and a nonrandomized comparison of effectiveness was conducted. Results 1,292 infusions of DrotAA were recorded in 112 units; 61% commenced during the first 24 hours in the unit. The majority (77%) of patients had three or more organs failing; lung (42%) and abdomen (40%) were the most common primary sites of infection. Crude hospital mortality was high (45%); at 28 days, only 18% had left acute hospital and 19% were still in the unit. For 30%, the full 96-hour infusion was not completed; 24% of infusions were interrupted; 8.1% experienced one or more serious adverse events, of which 77% were serious bleeding events. Of eight relative risks estimated from individually-matched (0.75 to 0.85) and propensity-matched (0.82 to 0.90) controls, seven were consistent with the results of PROWESS. Restricting the analysis to patients receiving DrotAA during the first 24 hours resulted in larger treatment effects (relative risks 0.62 to 0.81). For all matches, similar patterns were seen across subgroups. No effect of DrotAA was seen for two organs failing or lower severity scores, compared with a significant mortality reduction for three or more organs failing or higher severity scores. Conclusion Use of DrotAA was approximately one in 16 for admissions meeting the definition for severe sepsis and with two or more organs failing. Patients receiving DrotAA were younger and more severely ill but were less

Altruism, personal benefit, and anxieties: a phenomenological study of healthy volunteers' experiences in a placebo‐controlled trial of duloxetine

PubMed Central

Kwakye, Isaac N.; Garner, Matthew; Baldwin, David S.; Bamford, Susan; Pinkney, Verity

2016-01-01

Objective The objective of this study was to develop an in‐depth understanding of healthy volunteers' experiences of mental health trials. Methods A qualitative study was nested within a healthy volunteer placebo‐controlled trial of duloxetine, a psychotropic drug used for treating patients with major depression and generalized anxiety disorder. Eight participants were interviewed, and data were analyzed using interpretative phenomenological analysis. Results Interviewees described volunteering for the trial because they were interested in research, wanted the monetary incentive, wanted to help researchers, and wanted to be part of something. On entering the trial, participants considered the possible risks and described feeling anxious, excited, and determined; they had some clear expectations and some loosely held hopes about what would happen. During the trial, participants were curious about whether they were taking duloxetine or placebo, self‐monitored their bodies' reactions, and guessed which treatment they received. On being un‐blinded to treatment allocation after completing the trial, some participants' guesses were confirmed, but others were surprised, and a few were disappointed. Conclusions Small changes to advertising/consent materials to reflect volunteers' motivations could improve recruitment rates to similar trials; “active” placebos might be particularly useful for maintaining blinding in healthy volunteer trials; and sensitive procedures are needed for un‐blinding participants to treatment allocation. © 2016 The Authors. Human Psychopharmacology: Clinical and Experimental published by John Wiley & Sons, Ltd. PMID:27378326

Evaluation of pharmacokinetics, user handling, and tolerability of peginterferon alfa-2a (40 kDa) delivered via a disposable autoinjector device

PubMed Central

Varunok, Peter; Lawitz, Eric; Beavers, Kimberly L; Matusow, Gary; Leong, Ruby; Lambert, Nathalie; Bernaards, Coen; Solsky, Jonathan; Brennan, Barbara J; Wat, Cynthia; Bertasso, Anne

2011-01-01

Background Peginterferon alfa-2a (40 kDa) is currently administered using a prefilled syringe. The peginterferon alfa-2a disposable autoinjector is a new safety-engineered device designed to facilitate injection and reduce the risk of needlestick injuries. The analysis of two open-label Phase I trials evaluated the pharmacokinetics, successful administration, and tolerability of peginterferon alfa-2a when using the autoinjector. The studies were performed to support the filing and registration of the autoinjector device. Methods In trial 1, 50 healthy adult subjects received one 180 μg dose of peginterferon alfa-2a via the autoinjector. Serial blood samples were collected predose, up to 336 hours following drug administration, and at follow-up (28 ± 3 days post-dosing) for noncompartmental pharmacokinetic analysis. Trial 2 randomized 60 adult patients with chronic hepatitis C to 180 μg peginterferon alfa-2a once weekly by the autoinjector or prefilled syringe for 3 weeks followed by the alternative device (prefilled syringe or autoinjector, respectively) for 3 weeks. Patients also received ribavirin. Administration by the devices was evaluated under direct observation by a study staff member and by patient subjective assessment. Results In trial 1, following a single dose of peginterferon alfa-2a, the maximum plasma concentration was 16.1 ± 5.3 ng/mL (mean ± standard deviation), and area under the concentration time curve (0–168 hours) was 1996 ± 613 ng · hour/mL, similar to that reported using a vial/syringe or prefilled syringe. In trial 2, few patients showed handling difficulties with either device. Generally, patients were observed to be more satisfied and confident, followed instructions better, and successfully initiated injection with the autoinjector versus the prefilled syringe. Patients reported the autoinjector to be more convenient and easier to use. No pain or discomfort was experienced using the autoinjector. The autoinjector safety profile

Is dibotermin alfa a cost-effective substitute for autologous iliac crest bone graft in single level lumbar interbody spine fusion?

PubMed

Svedbom, Axel; Paech, Daniel; Leonard, Catherine; Donnell, David; Song, Fujian; Boszcyk, Bronek; Rothenfluh, Dominique A; Lloyd, Andrew; Borgman, Benny

2015-11-01

To evaluate the cost-effectiveness of dibotermin alfa compared with autologous iliac crest bone graft (ICBG) for patients undergoing single level lumbar interbody spinal fusion in a UK hospital setting. An individual patient data (IPD) meta-analysis of six randomized controlled clinical trials and two single arm trials compared dibotermin alfa on an absorbable collagen implantation matrix (ACIM) (n = 456) and ICBG (n = 244) on resource use, re-operation rates, and SF-6D (Short form 6-dimension) health utility (total N = 700). Failure-related second surgery, operating time, post-operative hospital stay, and quality-adjusted life years (QALYs) derived from the IPD meta-analysis were included as inputs in an economic evaluation undertaken to assess the cost-effectiveness of dibotermin alfa/ACIM versus ICBG for patients undergoing single level lumbar interbody spinal fusion. A four year time horizon and the United Kingdom (UK) National Health Service (NHS) and Personal Social Services (PSS) perspective was adopted in the base case, with sensitivity analyses performed to gauge parameter uncertainty. In the base case analysis, patients treated using dibotermin alfa/ACIM (12 mg pack) accrued 0.055 incremental QALYs at an incremental cost of £ 737, compared with patients treated with ICBG. This resulted in an incremental cost-effectiveness ratio (ICER) of £ 13,523, indicating that at a willingness-to-pay threshold of £ 20,000, dibotermin alfa/ACIM is a cost-effective intervention relative to ICBG from the NHS and PSS perspective. In a UK hospital setting, dibotermin alfa/ACIM is a cost-effective substitute for ICBG for patients who require lumbar interbody arthrodesis.

A study on the safety and efficacy of reveglucosidase alfa in patients with late-onset Pompe disease.

PubMed

Byrne, Barry J; Geberhiwot, Tarekegn; Barshop, Bruce A; Barohn, Richard; Hughes, Derralynn; Bratkovic, Drago; Desnuelle, Claude; Laforet, Pascal; Mengel, Eugen; Roberts, Mark; Haroldsen, Peter; Reilley, Kristin; Jayaram, Kala; Yang, Ke; Walsh, Liron

2017-08-24

Late-onset Pompe disease is a rare genetic neuromuscular disorder caused by lysosomal acid alpha-glucosidase (GAA) deficiency that ultimately results in mobility loss and respiratory failure. Current enzyme replacement therapy with recombinant human (rh)GAA has demonstrated efficacy in subjects with late-onset Pompe disease. However, long-term effects of rhGAA on pulmonary function have not been observed, likely related to inefficient delivery of rhGAA to skeletal muscle lysosomes and associated deficits in the central nervous system. To address this limitation, reveglucosidase alfa, a novel insulin-like growth factor 2 (IGF2)-tagged GAA analogue with improved lysosomal uptake, was developed. This study evaluated the pharmacokinetics, safety, and exploratory efficacy of reveglucosidase alfa in 22 subjects with late-onset Pompe disease who were previously untreated with rhGAA. Reveglucosidase alfa plasma concentrations increased linearly with dose, and the elimination half-life was <1.2 h. Eighteen of 22 subjects completed 72 weeks of treatment. The most common adverse events were hypoglycemia (63%), dizziness, fall, headache, and nausea (55% for each). Serious adverse events included hypersensitivity (n = 1), symptomatic hypoglycemia (n = 2), presyncope (n = 1), and acute cardiac failure (n = 1). In the dose-escalation study, all treated subjects tested positive for anti-reveglucosidase alfa, anti-rhGAA, anti-IGF1, and anti-IGF2 antibodies at least once. Subjects receiving 20 mg/kg of reveglucosidase alfa demonstrated increases in predicted maximum inspiratory pressure (13.9%), predicted maximum expiratory pressure (8.0%), forced vital capacity (-0.4%), maximum voluntary ventilation (7.4 L/min), and mean absolute walking distance (22.3 m on the 6-min walk test) at 72 weeks. Additional studies are needed to further assess the safety and efficacy of this approach. Improvements in respiratory muscle strength, lung function, and walking endurance

Correction of anaemia through the use of darbepoetin alfa improves chemotherapeutic outcome in a murine model of Lewis lung carcinoma

PubMed Central

Shannon, A M; Bouchier-Hayes, D J; Condron, C M; Toomey, D

2005-01-01

Darbepoetin alfa (Aranesp®, Amgen) is a novel erythropoiesis-stimulating protein with a serum half-life longer than recombinant human erythropoietin (Epo), used in the treatment of cancer-associated anaemia. Anaemia is known to adversely affect prognosis and response to treatment in cancer patients. Solid tumours contain regions of hypoxia due to poor vascular supply and cellular compaction. Although hypoxic stress usually results in cell death, hypoxia-resistant tumour cells are genetically unstable and often acquire a drug-resistant phenotype. Increasing tumour oxygenation and perfusion during treatment could have the doubly beneficial outcome of reducing the fraction of treatment-resistant cells, while increasing drug delivery to previously hypoxic tissue. In this study, we examined the effect of darbepoetin alfa on chemotherapy sensitivity and delivery in an in vivo model of Lewis lung carcinoma, shown here to express the Epo receptor (EpoR). We identified that weekly darbepoetin alfa treatment, commencing 10 days before chemotherapy, resulted in a significant reduction in tumour volume compared to chemotherapy alone. This was mediated by the prevention of anaemia, a reduction in tumour hypoxia and a concomitant increase in drug delivery. Darbepoetin alfa treatment alone did not modulate the growth of the EpoR-expressing tumour cells. This study identifies an important role for darbepoetin alfa in increasing the therapeutic index of chemotherapy. PMID:15999100

Cryo-EM reconstruction of AlfA from Bacillus subtilis reveals the structure of a simplified actin-like filament at 3.4-Å resolution.

PubMed

Szewczak-Harris, Andrzej; Löwe, Jan

2018-03-27

Low copy-number plasmid pLS32 of Bacillus subtilis subsp. natto contains a partitioning system that ensures segregation of plasmid copies during cell division. The partitioning locus comprises actin-like protein AlfA, adaptor protein AlfB, and the centromeric sequence parN Similar to the ParMRC partitioning system from Escherichia coli plasmid R1, AlfA filaments form actin-like double helical filaments that arrange into an antiparallel bipolar spindle, which attaches its growing ends to sister plasmids through interactions with AlfB and parN Because, compared with ParM and other actin-like proteins, AlfA is highly diverged in sequence, we determined the atomic structure of nonbundling AlfA filaments to 3.4-Å resolution by cryo-EM. The structure reveals how the deletion of subdomain IIB of the canonical actin fold has been accommodated by unique longitudinal and lateral contacts, while still enabling formation of left-handed, double helical, polar and staggered filaments that are architecturally similar to ParM. Through cryo-EM reconstruction of bundling AlfA filaments, we obtained a pseudoatomic model of AlfA doublets: the assembly of two filaments. The filaments are antiparallel, as required by the segregation mechanism, and exactly antiphasic with near eightfold helical symmetry, to enable efficient doublet formation. The structure of AlfA filaments and doublets shows, in atomic detail, how deletion of an entire domain of the actin fold is compensated by changes to all interfaces so that the required properties of polymerization, nucleotide hydrolysis, and antiparallel doublet formation are retained to fulfill the system's biological raison d'être.

Pegylated interferons Lambda-1a and alfa-2a display different gene induction and cytokine and chemokine release profiles in whole blood, human hepatocytes and peripheral blood mononuclear cells.

PubMed

Freeman, J; Baglino, S; Friborg, J; Kraft, Z; Gray, T; Hill, M; McPhee, F; Hillson, J; Lopez-Talavera, J C; Wind-Rotolo, M

2014-06-01

Pegylated interferon-lambda-1a (Lambda), a type III interferon (IFN) in clinical development for the treatment of chronic HCV infection, has shown comparable efficacy and an improved safety profile to a regimen based on pegylated IFN alfa-2a (alfa). To establish a mechanistic context for this improved profile, we investigated the ex vivo effects of Lambda and alfa on cytokine and chemokine release, and on expression of IFN-stimulated genes (ISGs) in primary human hepatocytes and peripheral blood mononuclear cells (PBMCs) from healthy subjects. Our findings were further compared with changes observed in blood analysed from HCV-infected patients treated with Lambda or alfa in clinical studies. mRNA transcript and protein expression of the IFN-λ-limiting receptor subunit was lower compared with IFN-α receptor subunits in all cell types. Upon stimulation, alfa and Lambda induced ISG expression in hepatocytes and PBMCs, although in PBMCs Lambda-induced ISG expression was modest. Furthermore, alfa and Lambda induced release of cytokines and chemokines from hepatocytes and PBMCs, although differences in their kinetics of induction were observed. In HCV-infected patients, alfa treatment induced ISG expression in whole blood after single and repeat dosing. Lambda treatment induced modest ISG expression after single dosing and showed no induction after repeat dosing. Alfa and Lambda treatment increased IP-10, iTAC, IL-6, MCP-1 and MIP-1β levels in serum, with alfa inducing higher levels of all mediators compared with Lambda. Overall, ex vivo and in vivo induction profiles reported in this analysis strongly correlate with clinical observations of fewer related adverse events for Lambda vs those typically associated with alfa. © 2014 John Wiley & Sons Ltd.

Duloxetine in OsteoArthritis (DOA) study: study protocol of a pragmatic open-label randomised controlled trial assessing the effect of preoperative pain treatment on postoperative outcome after total hip or knee arthroplasty.

PubMed

Blikman, T; Rienstra, W; van Raaij, T M; ten Hagen, A J; Dijkstra, B; Zijlstra, W P; Bulstra, S K; van den Akker-Scheek, I; Stevens, M

2016-03-01

Residual pain is a major factor in patient dissatisfaction following total hip arthroplasty or total knee arthroplasty (THA/TKA). The proportion of patients with unfavourable long-term residual pain is high, ranging from 7% to 34%. There are studies indicating that a preoperative degree of central sensitisation (CS) is associated with poorer postoperative outcomes and residual pain. It is thus hypothesised that preoperative treatment of CS could enhance postoperative outcomes. Duloxetine has been shown to be effective for several chronic pain syndromes, including knee osteoarthritis (OA), in which CS is most likely one of the underlying pain mechanisms. This study aims to evaluate the postoperative effects of preoperative screening and targeted duloxetine treatment of CS on residual pain compared with care-as-usual. This multicentre, pragmatic, prospective, open-label, randomised controlled trial includes patients with idiopathic hip/knee OA who are on a waiting list for primary THA/TKA. Patients at risk for CS will be randomly allocated to the preoperative duloxetine treatment programme group or the care-as-usual control group. The primary end point is the degree of postoperative pain 6 months after THA/TKA. Secondary end points at multiple time points up to 12 months postoperatively are: pain, neuropathic pain-like symptoms, (pain) sensitisation, pain catastrophising, joint-associated problems, physical activity, health-related quality of life, depressive and anxiety symptoms, and perceived improvement. Data will be analysed on an intention-to-treat basis. The study is approved by the local Medical Ethics Committee (METc 2014/087) and will be conducted according to the principles of the Declaration of Helsinki (64th, 2013) and the Good Clinical Practice standard (GCP), and in compliance with the Medical Research Involving Human Subjects Act (WMO). 2013-004313-41; Pre-results. Published by the BMJ Publishing Group Limited. For permission to use (where not already

Human factors engineering and design validation for the redesigned follitropin alfa pen injection device.

PubMed

Mahony, Mary C; Patterson, Patricia; Hayward, Brooke; North, Robert; Green, Dawne

2015-05-01

To demonstrate, using human factors engineering (HFE), that a redesigned, pre-filled, ready-to-use, pre-asembled follitropin alfa pen can be used to administer prescribed follitropin alfa doses safely and accurately. A failure modes and effects analysis identified hazards and harms potentially caused by use errors; risk-control measures were implemented to ensure acceptable device use risk management. Participants were women with infertility, their significant others, and fertility nurse (FN) professionals. Preliminary testing included 'Instructions for Use' (IFU) and pre-validation studies. Validation studies used simulated injections in a representative use environment; participants received prior training on pen use. User performance in preliminary testing led to IFU revisions and a change to outer needle cap design to mitigate needle stick potential. In the first validation study (49 users, 343 simulated injections), in the FN group, one observed critical use error resulted in a device design modification and another in an IFU change. A second validation study tested the mitigation strategies; previously reported use errors were not repeated. Through an iterative process involving a series of studies, modifications were made to the pen design and IFU. Simulated-use testing demonstrated that the redesigned pen can be used to administer follitropin alfa effectively and safely.

Clinical observations on enzyme replacement therapy in patients with Fabry disease and the switch from agalsidase beta to agalsidase alfa.

PubMed

Lin, Hsiang-Yu; Huang, Yu-Hsiu; Liao, Hsuan-Chieh; Liu, Hao-Chuan; Hsu, Ting-Rong; Shen, Chia-I; Li, Shao-Tzu; Li, Cheng-Fang; Lee, Li-Hong; Lee, Pi-Chang; Huang, Chun-Kai; Chiang, Chuan-Chi; Lin, Shuan-Pei; Niu, Dau-Ming

2014-04-01

Fabry disease is an X-linked inherited lysosomal storage disease that can be treated with the enzymes of agalsidase beta (Fabrazyme) and agalsidase alfa (Replagal). Since June 2009, viral contamination of Genzyme's production facility has resulted in a worldwide shortage of agalsidase beta, leading to the switch to agalsidase alfa for patients with Fabry disease in Taiwan. The medical records were retrospectively reviewed for nine male patients with Fabry disease from the start of agalsidase beta treatment until the switch to agalsidase alfa for at least 1 year. After 12-112 months of enzyme replacement therapy (ERT), decreased plasma globotriaosylsphingosine (lyso-Gb3) was found in five out of seven patients, indicating improvement in disease severity. Among the six patients with available echocardiographic data at baseline and after ERT, all six experienced reductions of left ventricular mass index. Renal function, including microalbuminuria and estimated glomerular filtration rate, showed stability after ERT. Mainz Severity Score Index scores revealed that all nine patients remained stable at 12 months after switching to agalsidase alfa. ERT improved or stabilized cardiac status and stabilized renal function, while reducing plasma lyso-Gb3. ERT was well tolerated, even among the three patients who had hypersensitivity reactions. The switch of ERT from agalsidase beta to agalsidase alfa appears to be safe after 1 year of follow-up for Taiwanese patients with Fabry disease. Copyright © 2013. Published by Elsevier B.V.

Reveglucosidase alfa (BMN 701), an IGF2-Tagged rhAcid α-Glucosidase, Improves Respiratory Functional Parameters in a Murine Model of Pompe Disease.

PubMed

Peng, Jeffrey; Dalton, Jill; Butt, Mark; Tracy, Kristin; Kennedy, Derek; Haroldsen, Peter; Cahayag, Rhea; Zoog, Stephen; O'Neill, Charles A; Tsuruda, Laurie S

2017-02-01

Pompe disease is a rare neuromuscular disorder caused by an acid α-glucosidase (GAA) deficiency resulting in glycogen accumulation in muscle, leading to myopathy and respiratory weakness. Reveglucosidase alfa (BMN 701) is an insulin-like growth factor 2-tagged recombinant human acid GAA (rhGAA) that enhances rhGAA cellular uptake via a glycosylation-independent insulin-like growth factor 2 binding region of the cation-independent mannose-6-phosphate receptor (CI-MPR). The studies presented here evaluated the effects of Reveglucosidase alfa treatment on glycogen clearance in muscle relative to rhGAA, as well as changes in respiratory function and glycogen clearance in respiratory-related tissue in a Pompe mouse model (GAA tm1Rabn /J). In a comparison of glycogen clearance in muscle with Reveglucosidase alfa and rhGAA, Reveglucosidase alfa was more effective than rhGAA with 2.8-4.7 lower EC 50 values, probably owing to increased cellular uptake. The effect of weekly intravenous administration of Reveglucosidase alfa on respiratory function was monitored in Pompe and wild-type mice using whole body plethysmography. Over 12 weeks of 20-mg/kg Reveglucosidase alfa treatment in Pompe mice, peak inspiratory flow (PIF) and peak expiratory flow (PEF) stabilized with no compensation in respiratory rate and inspiratory time during hypercapnic and recovery conditions compared with vehicle-treated Pompe mice. Dose-related decreases in glycogen levels in both ambulatory and respiratory muscles generally correlated to changes in respiratory function. Improvement of murine PIF and PEF were similar in magnitude to increases in maximal inspiratory and expiratory pressure observed clinically in late onset Pompe patients treated with Reveglucosidase alfa (Byrne et al., manuscript in preparation). Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

Evaluation of results obtained with corifollitropin alfa after poor ovarian response in previous cycle using recombinant follicular stimulating hormone in the long-term protocol.

PubMed

Salgueiro, Lister L; Rolim, Juliana R; Moura, Bernardo R L; Machado, Suelen P P; Haddad, Carolina

2016-08-01

This study evaluated the use of Corifollitropin alfa in patients with previous poor response to recombinant follicle stimulating hormone in long-term protocols using gonadotropin-releasing hormone. Twenty-seven poor responders to previous treatment with the long term protocol using the recombinant follicle stimulating hormone (Group 1) were selected and then submitted to a second attempt using the same long term protocol with Corifollitropin alfa instead of the recombinant follicle stimulating hormone (Group 2).Ovarian down-regulation was achieved using subcutaneous administration of Leuprolide Acetate. Ovarian stimulation was performed with recombinant follicle stimulating hormone until the administration of human chorionic gonadotropin, followed by follicular aspiration (Group 1). Group 2 was submitted to this same protocol using Corifollitropin alfa instead of recombinant follicle stimulating hormone. There were significant differences in the number of aspirated oocytes, percentage of mature oocytes, amount of injected oocytes and transferred embryos - with all of these parameters being increased in the Corifollitropin alfa group. In addition, the rates of pregnancy and ongoing pregnancy were also significantly higher in the Corifollitropin alfa group. The present study demonstrated that the use of Corifollitropin alfa in the long-term protocol could be a highly effective alternative for patients with poor ovarian response, who were unsuccessful in a previous treatment with In Vitro Fertilization - Intracytoplasmic Sperm Injection.

A Randomized Study of Peginterferon Lambda-1a Compared to Peginterferon Alfa-2a in Combination with Ribavirin and Telaprevir in Patients with Genotype-1 Chronic Hepatitis C.

PubMed

Flisiak, Robert; Shiffman, Mitchell; Arenas, Juan; Cheinquer, Hugo; Nikitin, Igor; Dong, Yuping; Rana, Khurram; Srinivasan, Subasree

2016-01-01

A randomized, double-blind, multinational, phase 3 study was conducted comparing the efficacy and safety of peginterferon lambda-1a (Lambda)/ribavirin (RBV)/telaprevir (TVR) vs. peginterferon alfa-2a (Alfa)/RBV/TVR in patients with chronic hepatitis C virus (HCV) genotype-1 (GT-1) infection. Patients (treatment-naïve or relapsers on prior Alfa/RBV treatment) were randomly assigned in a 2:1 ratio to receive Lambda/RBV/TVR or Alfa/RBV/TVR. Total duration of treatment was either 24 or 48 weeks (response-guided treatment), with TVR administered for the first 12 weeks. The primary endpoint was the proportion of patients who achieved a sustained virologic response at post treatment week 12 (SVR12), which was tested for noninferiority of Lambda/RBV/TVR. A total of 838 patients were enrolled, and 617 were treated; 411 and 206 patients received Lambda/RBV/TVR and Alfa/RBV/TVR, respectively. The majority of patients were treatment-naïve, with HCV GT-1b and a high baseline viral load (≥800,000 IU/mL). Less than 10% of patients had cirrhosis (Lambda, 7.5%; Alfa, 6.8%). Lambda/RBV/TVR did not meet the criterion for noninferiority (lower bound of the treatment difference interval was -12.3%); the SVR12 in all patients (modified intent-to-treat) was 76.2% in the Lambda arm and 82.0% in the Alfa arm. Overall, the frequency of adverse events in each arm was comparable (Lambda, 91.7%; Alfa, 97.1%). As expected based on the safety profile of the 2 interferons, there were more hepatobiliary events observed in the Lambda arm and more hematologic events in the Alfa arm. In this comparison of Lambda/RBV/TVR and Alfa/RBV/TVR in patients who were treatment-naïve or had relapsed on prior Alfa/RBV treatment, Lambda failed to demonstrate noninferiority based on SVR12 results. Treatment with Lambda/RBV/TVR was associated with a higher incidence of relapse. More patients discontinued Lambda/RBV/TVR treatment during the first 4 weeks of study treatment, mainly due to hepatobiliary

Effects of MDMA alone and after pretreatment with reboxetine, duloxetine, clonidine, carvedilol, and doxazosin on pupillary light reflex.

PubMed

Hysek, Cédric M; Liechti, Matthias E

2012-12-01

Pupillometry can be used to characterize autonomic drug effects. This study was conducted to determine the autonomic effects of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy), administered alone and after pretreatment with reboxetine, duloxetine, clonidine, carvedilol, and doxazosin, on pupillary function. Infrared pupillometry was performed in five placebo-controlled randomized studies. Each study included 16 healthy subjects (eight men, eight women) who received placebo-MDMA (125 mg), placebo-placebo, pretreatment-placebo, or pretreatment-MDMA using a crossover design. MDMA produced mydriasis, prolonged the latency, reduced the response to light, and shortened the recovery time. The impaired reflex response was associated with subjective, cardiostimulant, and hyperthermic drug effects and returned to normal within 6 h after MDMA administration when plasma MDMA levels were still high. Mydriasis was associated with changes in plasma MDMA concentration over time and longer-lasting. Both reboxetine and duloxetine interacted with the effects of MDMA on pupillary function. Clonidine did not significantly reduce the mydriatic effects of MDMA, although it produced miosis when administered alone. Carvedilol and doxazosin did not alter the effects of MDMA on pupillary function. The MDMA-induced prolongation of the latency to and reduction of light-induced miosis indicate indirect central parasympathetic inhibition, and the faster recovery time reflects an increased sympathomimetic action. Both norepinephrine and serotonin mediate the effects of MDMA on pupillary function. Although mydriasis is lasting and mirrors the plasma concentration-time curve of MDMA, the impairment in the reaction to light is associated with the subjective and other autonomic effects of MDMA and exhibits acute tolerance.

Accurate Learning with Few Atlases (ALFA): an algorithm for MRI neonatal brain extraction and comparison with 11 publicly available methods.

PubMed

Serag, Ahmed; Blesa, Manuel; Moore, Emma J; Pataky, Rozalia; Sparrow, Sarah A; Wilkinson, A G; Macnaught, Gillian; Semple, Scott I; Boardman, James P

2016-03-24

Accurate whole-brain segmentation, or brain extraction, of magnetic resonance imaging (MRI) is a critical first step in most neuroimage analysis pipelines. The majority of brain extraction algorithms have been developed and evaluated for adult data and their validity for neonatal brain extraction, which presents age-specific challenges for this task, has not been established. We developed a novel method for brain extraction of multi-modal neonatal brain MR images, named ALFA (Accurate Learning with Few Atlases). The method uses a new sparsity-based atlas selection strategy that requires a very limited number of atlases 'uniformly' distributed in the low-dimensional data space, combined with a machine learning based label fusion technique. The performance of the method for brain extraction from multi-modal data of 50 newborns is evaluated and compared with results obtained using eleven publicly available brain extraction methods. ALFA outperformed the eleven compared methods providing robust and accurate brain extraction results across different modalities. As ALFA can learn from partially labelled datasets, it can be used to segment large-scale datasets efficiently. ALFA could also be applied to other imaging modalities and other stages across the life course.

Advanced Laboratory and Field Arrays (ALFA) OWC Phase 1 Test

DOE Data Explorer

Bret Bosma

2016-11-07

Data from Phase 1 testing of a single ALFA OWC device at the O.H. Hinsdale Wave Research Laboratory (HWRL) at Oregon State University in Fall of 2016. Contains two zip files of raw data, one of project data ("array"), and a diagram of the device with dimensions. A "readme" file in the project data archive under "Docs" helps to explains the project data.

Agalsidase alfa versus agalsidase beta for the treatment of Fabry disease: an international cohort study

PubMed Central

Biegstraaten, Marieke; Wanner, Christoph; Sirrs, Sandra; Mehta, Atul; Elliott, Perry M; Oder, Daniel; Watkinson, Oliver T; Bichet, Daniel G; Khan, Aneal; Iwanochko, Mark; Vaz, Frédéric M; van Kuilenburg, André B P; West, Michael L; Hughes, Derralynn A; Hollak, Carla E M

2018-01-01

Background Two recombinant enzymes (agalsidase alfa 0.2 mg/kg/every other week and agalsidase beta 1.0 mg/kg/every other week) have been registered for the treatment of Fabry disease (FD), at equal high costs. An independent international initiative compared clinical and biochemical outcomes of the two enzymes. Methods In this multicentre retrospective cohort study, clinical event rate, left ventricular mass index (LVMI), estimated glomerular filtration rate (eGFR), antibody formation and globotriaosylsphingosine (lysoGb3) levels were compared between patients with FD treated with agalsidase alfa and beta at their registered dose after correction for phenotype and sex. Results 387 patients (192 women) were included, 248 patients received agalsidase alfa. Mean age at start of enzyme replacement therapy was 46 (±15) years. Propensity score matched analysis revealed a similar event rate for both enzymes (HR 0.96, P=0.87). The decrease in plasma lysoGb3 was more robust following treatment with agalsidase beta, specifically in men with classical FD (β: −18 nmol/L, P<0.001), persisting in the presence of antibodies. The risk to develop antibodies was higher for patients treated with agalsidase beta (OR 2.8, P=0.04). LVMI decreased in a higher proportion following the first year of agalsidase beta treatment (OR 2.27, P=0.03), while eGFR slopes were similar. Conclusions Treatment with agalsidase beta at higher dose compared with agalsidase alfa does not result in a difference in clinical events, which occurred especially in those with more advanced disease. A greater biochemical response, also in the presence of antibodies, and better reduction in left ventricular mass was observed with agalsidase beta. PMID:29437868

Agalsidase alfa versus agalsidase beta for the treatment of Fabry disease: an international cohort study.

PubMed

Arends, Maarten; Biegstraaten, Marieke; Wanner, Christoph; Sirrs, Sandra; Mehta, Atul; Elliott, Perry M; Oder, Daniel; Watkinson, Oliver T; Bichet, Daniel G; Khan, Aneal; Iwanochko, Mark; Vaz, Frédéric M; van Kuilenburg, André B P; West, Michael L; Hughes, Derralynn A; Hollak, Carla E M

2018-05-01

Two recombinant enzymes (agalsidase alfa 0.2 mg/kg/every other week and agalsidase beta 1.0 mg/kg/every other week) have been registered for the treatment of Fabry disease (FD), at equal high costs. An independent international initiative compared clinical and biochemical outcomes of the two enzymes. In this multicentre retrospective cohort study, clinical event rate, left ventricular mass index (LVMI), estimated glomerular filtration rate (eGFR), antibody formation and globotriaosylsphingosine (lysoGb3) levels were compared between patients with FD treated with agalsidase alfa and beta at their registered dose after correction for phenotype and sex. 387 patients (192 women) were included, 248 patients received agalsidase alfa. Mean age at start of enzyme replacement therapy was 46 (±15) years. Propensity score matched analysis revealed a similar event rate for both enzymes (HR 0.96, P=0.87). The decrease in plasma lysoGb3 was more robust following treatment with agalsidase beta, specifically in men with classical FD (β: -18 nmol/L, P<0.001), persisting in the presence of antibodies. The risk to develop antibodies was higher for patients treated with agalsidase beta (OR 2.8, P=0.04). LVMI decreased in a higher proportion following the first year of agalsidase beta treatment (OR 2.27, P=0.03), while eGFR slopes were similar. Treatment with agalsidase beta at higher dose compared with agalsidase alfa does not result in a difference in clinical events, which occurred especially in those with more advanced disease. A greater biochemical response, also in the presence of antibodies, and better reduction in left ventricular mass was observed with agalsidase beta. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

De novo weekly and biweekly darbepoetin alfa dosing in pediatric patients with chronic kidney disease.

PubMed

Warady, Bradley A; Barcia, John; Benador, Nadine; Jankauskiene, Augustina; Olson, Kurt; Podracka, Ludmila; Shavkin, Aleksey; Srivaths, Poyyapakkam; Wong, Cynthia J; Petersen, Jeffrey

2018-01-01

Darbepoetin alfa is a commonly prescribed erythropoiesis-stimulating agent (ESA) for correcting anemia in pediatric chronic kidney disease (CKD) patients. However, little information exists on its use in ESA-naïve patients. This study evaluated the efficacy and safety of darbepoetin alfa in pediatric patients initiating ESA therapy. One-hundred sixteen pediatric ESA-naïve subjects (aged 1-18 years) with CKD stages 3-5D and hemoglobin (Hb) <10 g/dl from 43 centers in the US, Europe, and Mexico were randomized by age (three groups) and dialysis status (yes vs. no) to receive darbepoetin alfa once weekly (QW) or every 2 weeks (Q2W) subcutaneously (not on dialysis and peritoneal dialysis subjects) and intravenously (hemodialysis subjects). The drug was titrated to achieve Hb levels of 10.0-12.0 g/dl over 25 weeks. Patient- and parent-reported health-related outcomes were measured by the Pediatric Quality of Life Inventory (PedsQL™) in children ≥2 years. In both groups, mean Hb concentrations increased to ≥11.0 g/dl over the first 3 months of treatment and remained stable within the 10.0-12.0 g/dl target range. The median time to achieve hemoglobin ≥10 g/dl was slightly longer for subjects <12 years (QW and Q2W, both 28 days) vs. those ≥12 years (23 and 22 days, respectively). Adverse event profiles were similar between groups, with QW, four (7%) and Q2W, five (9%). PedsQL™ scores showed modest increases. Darbepoetin alfa can be safely administered either QW or Q2W to ESA-naïve pediatric patients with CKD-related anemia to achieve Hb targets of 10.0-12.0 g/dl.

Long-term velaglucerase alfa treatment in children with Gaucher disease type 1 naïve to enzyme replacement therapy or previously treated with imiglucerase.

PubMed

Smith, Laurie; Rhead, William; Charrow, Joel; Shankar, Suma P; Bavdekar, Ashish; Longo, Nicola; Mardach, Rebecca; Harmatz, Paul; Hangartner, Thomas; Lee, Hak-Myung; Crombez, Eric; Pastores, Gregory M

2016-02-01

Gaucher Disease type 1 (GD1) often manifests in childhood. Early treatment with enzyme replacement therapy (ERT) may prevent disease complications. We report the assessment of velaglucerase alfa ERT in pediatric GD1 patients who participated in a long-term extension study (HGT-GCB-044, ClinicalTrials.gov Identifier NCT00635427). Safety and efficacy were evaluated in pediatric patients receiving velaglucerase alfa 30-60U/kg by intravenous infusion every other week. In addition to key hematological and visceral efficacy assessments, exploratory assessments conducted specifically in pediatric patients included evaluation of height, bone age, bone marrow burden, and Tanner stage of puberty. The study included 24 pediatric patients. Fifteen patients were naïve to ERT on entry into the preceding trials TKT032 (12-month trial) or HGT-GCB-039 (9-month trial): in the preceding trials, ten of these 15 patients received velaglucerase alfa and five patients received imiglucerase ERT. Nine patients in the study were previously treated with imiglucerase for >30months and were switched to velaglucerase alfa in the preceding trial TKT034 (12-month trial). Cumulative ERT exposure in the clinical studies ranged from 2.0 to 5.8years. Three serious adverse events, including a fatal convulsion, were reported; none were deemed related to velaglucerase alfa. One patient tested positive for anti-velaglucerase alfa antibodies. An efficacy assessment at 24months showed that velaglucerase alfa had positive effects on primary hematological and visceral parameters in treatment-naïve patients, which were maintained with longer-term treatment. Disease parameters were stable in patients switched from long-term imiglucerase ERT. Exploratory results may suggest benefits of early treatment to enable normal growth in pediatric patients. The safety profile and clinical response seen in pediatric patients are consistent with results reported in adults. Copyright © 2016 Shire Development LLC

Gateways to clinical trials.

PubMed

Tomillero, A; Moral, M A

2009-04-01

(+)-Dapoxetine hydrochloride, [(123)I]-BZA, 9-Aminocamptothecin; Abacavir sulfate/lamivudine, Adalimumab, Adefovir dipivoxil, Alemtuzumab, Alvocidib hydrochloride, Ambrisentan, Amsilarotene, Anacetrapib, Anakinra, Apricitabine, Aripiprazole, Arsenic trioxide, Atazanavir sulfate, Atazanavir/ritonavir, Atrasentan, Azacitidine; Banoxantrone, Bazedoxifene acetate, Bevacizumab, Bexarotene, Biphasic insulin aspart, Bortezomib, Bosentan, Bromfenac; Cachectin, Calcipotriol/betamethasone dipropionate, Canakinumab, Carfilzomib, CAT-354, CCX-282, Certolizumab pegol, Cetuximab, Choline fenofibrate, Clevudine, Clofarabine, CNTO-328, Corifollitropin alfa, Crofelemer; Daptomycin, Darbepoetin alfa, Darunavir, Dasatinib, Decitabine, Deferasirox, Denosumab, Duloxetine hydrochloride, Dutasteride; Emtricitabine, Enfuvirtide, Entecavir, Epoetin zeta, Erlotinib hydrochloride, Escitalopram oxalate, Eslicarbazepine acetate, Eszopiclone, Etravirine, Everolimus, Exenatide, Ezetimibe, Ezetimibe/simvastatin; Farglitazar, Febuxostat, Fosamprenavir calcium, FX-06; Gabapentin enacarbil, Gefitinib; HIVIS DNA; Imatinib mesylate, INCB- 18424, Indacaterol, Inotuzumab ozogamicin, Insulin detemir; JNJ-26854165; Lacosamide, Landiolol, Laromustine, Lenalidomide, Liposomal doxorubicin, L-NAME, Lopinavir, Lopinavir/ritonavir, Lumiracoxib; Maraviroc, Mepolizumab, Methoxy polyethylene glycol- epoetin-beta, Miglustat, MK-0493, MVA-CMDR, Mycophenolic acid sodium salt; Natalizumab, Nepafenac, Neratinib, Neridronic acid, Nesiritide, Nilotinib hydrochloride monohydrate; Olmesartan medoxomil, Omacetaxine mepesuccinate, Omalizumab; Paclitaxel poliglumex, Palifermin, Patupilone, Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b, Peginterferon alfa-2b/ ribavirin, Pemetrexed disodium, PHA-848125, Pitavastatin calcium, Posaconazole, Povidone-iodine liposome complex, Prasugrel, Pregabalin, Prucalopride; Raltegravir potassium, Retigabine, Revaprazan hydrochloride, rhFSH, Rilpivirine, Rivaroxaban, Romidepsin

Switching from entecavir to PegIFN alfa-2a in patients with HBeAg-positive chronic hepatitis B: a randomised open-label trial (OSST trial).

PubMed

Ning, Qin; Han, Meifang; Sun, Yongtao; Jiang, Jiaji; Tan, Deming; Hou, Jinlin; Tang, Hong; Sheng, Jifang; Zhao, Mianzhi

2014-10-01

Durable post-treatment response is uncommon in chronic hepatitis B (CHB) patients on nucleos(t)ide analogue therapy. Response, response predictors and safety were assessed in patients who switched from long-term entecavir (ETV) to peginterferon alfa-2a. Hepatitis B e antigen (HBeAg)-positive CHB patients who had received ETV for 9-36 months, with HBeAg <100 PEIU/ml and HBV DNA ⩽1000 copies/ml, were randomised 1:1 to receive peginterferon alfa-2a 180 μg/week or ETV 0.5mg/day for 48 weeks. The primary endpoint was HBeAg seroconversion at week 48 (ClinicalTrials.gov: NCT00940485). 200 patients were randomised; 197 received ⩾1 study drug dose. Five patients who were anti-HBe-positive at baseline were excluded from the modified intention-to-treat population (peginterferon alfa-2a, n = 94; ETV, n = 98). Patients who switched to peginterferon alfa-2a achieved higher week 48 HBeAg seroconversion rates vs. those who continued ETV (14.9% vs. 6.1%; p = 0.0467). Only patients receiving peginterferon alfa-2a achieved HBsAg loss (8.5%). Among peginterferon alfa-2a-treated patients with HBeAg loss and HBsAg <1500 IU/ml at randomisation, 33.3% and 22.2% achieved HBeAg seroconversion and HBsAg loss, respectively. Early on-treatment HBsAg decline predicted response at week 48; highest rates were observed in patients with week 12 HBsAg <200 IU/ml (HBeAg seroconversion, 66.7%; HBsAg loss, 77.8%). Alanine aminotransferase elevations were not associated with viral rebound (n = 38). Peginterferon alfa-2a was well-tolerated. For patients who achieve virological suppression with ETV, switching to a finite course of peginterferon alfa-2a significantly increases rates of HBeAg seroconversion and HBsAg loss. A response-guided approach may identify patients with the greatest chance of success. Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Vortioxetine, but not escitalopram or duloxetine, reverses memory impairment induced by central 5-HT depletion in rats: evidence for direct 5-HT receptor modulation.

PubMed

Jensen, Jesper Bornø; du Jardin, Kristian Gaarn; Song, Dekun; Budac, David; Smagin, Gennady; Sanchez, Connie; Pehrson, Alan Lars

2014-01-01

Depressed patients suffer from cognitive dysfunction, including memory deficits. Acute serotonin (5-HT) depletion impairs memory and mood in vulnerable patients. The investigational multimodal acting antidepressant vortioxetine is a 5-HT3, 5-HT7 and 5-HT1D receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and 5-HT transporter (SERT) inhibitor that enhances memory in normal rats in novel object recognition (NOR) and conditioned fear (Mørk et al., 2013). We hypothesized that vortioxetine's 5-HT receptor mechanisms are involved in its memory effects, and therefore investigated these effects in 5-HT depleted rats. Four injections of the irreversible tryptophan hydroxylase inhibitor 4-chloro-dl-phenylalanine methyl ester hydrochloride (PCPA, 86mg/kg, s.c.) induced 5-HT depletion, as measured in hippocampal homogenate and microdialysate. The effects of acute challenge with vortioxetine or the 5-HT releaser fenfluramine on extracellular 5-HT were measured in PCPA-treated and control rats. PCPA's effects on NOR and spontaneous alternation (SA) performance were assessed along with the effects of acute treatment with 5-hydroxy-l-tryptophan (5-HTP), vortioxetine, the selective 5-HT reuptake inhibitor escitalopram, or the 5-HT norepinephrine reuptake inhibitor duloxetine. SERT occupancies were estimated by ex vivo autoradiography. PCPA depleted central 5-HT by >90% in tissue and microdialysate, and impaired NOR and SA performance. Restoring central 5-HT with 5-HTP reversed these deficits. At similar SERT occupancies (>90%) vortioxetine, but not escitalopram or duloxetine, restored memory performance. Acute fenfluramine significantly increased extracellular 5-HT in control and PCPA-treated rats, while vortioxetine did so only in control rats. Thus, vortioxetine restores 5-HT depletion impaired memory performance in rats through one or more of its receptor activities. © 2013 Published by Elsevier B.V. and ECNP.

Pancreatitis induced by pegylated interferon alfa-2b in a patient affected by chronic hepatitis C.

PubMed

Cecchi, Enrica; Forte, Paolo; Cini, Elisabetta; Banchelli, Grazia; Ferlito, Chiara; Mugelli, Alessandro

2004-01-01

A middle-aged man was admitted to the ED because of nausea and vomiting, abdominal distention and fainting. A blood analysis revealed high levels of serum amylase and lipase, confirming a diagnosis of acute pancreatitis. The history showed that the patient had self-administered a single dose of pegylated interferon alfa-2b and ribavirin daily for 7 days for chronic hepatitis C. The medications were stopped and his condition gradually improved. In agreement with the literature and the Naranjo algorythm result, pegylated interferon alfa-2b is associated with acute pancreatitis. Identification of a few signs and symptoms is the first 'signal' in preventing a serious drug-induced adverse event.

Efficacy and safety of enzyme-replacement-therapy with agalsidase alfa in 36 treatment-naïve Fabry disease patients.

PubMed

Tsuboi, Kazuya; Yamamoto, Hiroshi

2017-06-07

Fabry disease (FD) is an X-linked lysosomal storage disorder resulting from the α-galactosidase A gene mutations. Enzyme-replacement-therapy (ERT) products for FD currently used include agalsidase alfa and agalsidase beta. There are many reports on efficacy and safety of ERT. However, most of the previous studies are done as a retrospective medical records analysis. The Japan Fabry Research - 002 (JFR-002) was a prospective observational clinical study of 36 ERT-naïve FD patients (14 men and 22 women) at baseline (BL) and after initiation of ERT with agalsidase alfa 0.2 mg/kg every two weeks, a median period 62.5 months. The parameters measured included globotriaosylceramide (Gb3), globotriaosylsphingosine (Lyso-Gb3), left ventricular mass index (LVMI), brain natriuretic peptide (BNP), high-sensitivity troponin I (hs-Trop I), estimated glomerular filtration rate (eGFR), and anti-agalsidase alfa IgG antibody formation. All parameters remained steady during ERT treatment period. BNP levels in 14 patients whose BL levels were within the normal range (<19.5 pg/mL) remained within the same range, while 22 patients whose BL levels were abnormally high (≥19.5 pg/mL) gradually showed decreased levels after start of ERT. Gb3 and Lyso-Gb3 levels remarkably decreased after the initiation of ERT and remained low. The JFR-002 suggests that agalsidase alfa is effective in maintaining organ function in FD patients, and that the incidence of infusion reactions related to the treatment with agalsidase alfa is low, indicating the good tolerability to this ERT. The JFR-002 was retrospectively registered at Japan Medical Association Center for Clinical Trials (Registration number: JMA-IIA00291 ) on May 19th, 2017.

Mortality risk of darbepoetin alfa versus epoetin alfa in patients with CKD: systematic review and meta-analysis.

PubMed

Wilhelm-Leen, Emilee R; Winkelmayer, Wolfgang C

2015-07-01

Epoetin alfa (EPO) and darbepoetin alfa (DPO) are erythropoiesis-stimulating agents that are widely and interchangeably used for the treatment of anemia in patients with advanced chronic kidney disease and end-stage renal disease. No study has specifically compared the risks of hard study outcomes between EPO and DPO, including mortality. Systematic review of the literature and meta-analysis. Patients enrolled in randomized trials comparing EPO versus DPO for the treatment of anemia in adults with chronic kidney disease, including those requiring dialysis. We conducted a systematic search of the literature (PubMed, CENTRAL, SCOPUS, and EMBASE, all years) and industry resources, using predefined search terms and data abstraction tools. We then summarized key characteristics and findings of these trials and performed a random-effects meta-analysis of trials with at least 3 months' duration to identify the summary OR of mortality between patients randomly assigned to DPO versus EPO. DPO versus EPO. All-cause mortality. We identified 9 trials that met the stated inclusion criteria. Overall, 2,024 patients were included in the meta-analysis, of whom 126 died during follow-up, which ranged from 20 to 52 weeks. We found no significant difference in mortality between patients randomly assigned to DPO versus EPO (OR, 1.33; 95% CI, 0.88-2.01). No treatment heterogeneity across studies was detected (Q statistic=4.60; P=0.8). Generalizability to nontrial populations is uncertain. Few trials directly comparing DPO and EPO have been conducted and follow-up was limited. In aggregate, no effect of specific erythropoiesis-stimulating agent on mortality was identified, but the confidence limits were wide and remained compatible with considerable harm from DPO. Absent adequately powered randomized trials, observational postmarketing comparative effectiveness studies comparing these erythropoiesis-stimulating agents are required to better characterize the long-term safety profiles of

Results from a large multinational clinical trial (guardian™1) using prophylactic treatment with turoctocog alfa in adolescent and adult patients with severe haemophilia A: safety and efficacy.

PubMed

Lentz, S R; Misgav, M; Ozelo, M; Salek, S Z; Veljkovic, D; Recht, M; Cerqueira, M; Tiede, A; Brand, B; Mancuso, M E; Seremetis, S; Lindblom, A; Martinowitz, U

2013-09-01

Recombinant factor VIII (rFVIII) products provide a safe and efficacious replacement therapy for prophylaxis and treatment of bleeding episodes in patients with severe haemophilia A. This multinational, open-label, non-controlled trial investigated the safety and efficacy of turoctocog alfa, a new rFVIII product. The primary objective was to evaluate safety. A total of 150 patients (24 adolescents and 126 adults) with severe haemophilia A (FVIII activity ≤ 1%), with at least 150 exposure days (EDs) to any FVIII product and no history of inhibitors were enrolled, and 146 patients (97%) completed the trial. All patients received prophylaxis with turoctocog alfa for approximately 6 months and had a mean of 85 EDs during the trial. None of the patients developed FVIII inhibitors, there were no indications of early FVIII inhibitor development and no safety concerns were identified. A total of 225 adverse events were reported in 100 (67%) patients, with the most common being events associated with dosing procedures, headaches, and nasopharyngitis. A total of 499 bleeding episodes were reported during the trial, the majority (89%) were controlled with 1-2 infusions of turoctocog alfa. Based on patient reports, the success rate (defined as 'excellent' or 'good' haemostatic response) for treatment of bleeding episodes was 81%. The overall median annualized bleeding rate was 3.7 (interquartile range: 8.7) bleeds/patient/year. In conclusion, turoctocog alfa provides a new, safe and effective alternative for prophylaxis and treatment of bleeding episodes in patients with haemophilia A. © 2013 John Wiley & Sons Ltd.

An open-label clinical trial to investigate the efficacy and safety of corifollitropin alfa combined with hCG in adult men with hypogonadotropic hypogonadism.

PubMed

Nieschlag, Eberhard; Bouloux, Pierre-Marc G; Stegmann, Barbara J; Shankar, R Ravi; Guan, Yanfen; Tzontcheva, Anjela; McCrary Sisk, Christine; Behre, Hermann M

2017-03-07

Hypogonadotropic hypogonadism (HH) in men results in insufficient testicular function and deficiencies in testosterone and spermatogenesis. Combinations of human chorionic gonadotropin (hCG) and recombinant follicle-stimulating hormone (recFSH) have been successful in the treatment of HH. Corifollitropin alfa is a long-acting FSH-analog with demonstrated action in women seeking infertility care. The aim of this study was to investigate the efficacy and safety of corifollitropin alfa combined with hCG to increase testicular volume and induce spermatogenesis in men with HH. This was a Phase III, multi-center, open-label, single-arm trial of corifollitropin alfa in azoospermic men aged 18 to 50 years with HH. After 16 weeks of pretreatment of 23 subjects with hCG alone, 18 subjects with normalized testosterone (T) levels who remained azoospermic entered the 52-week combined treatment phase with hCG twice-weekly and 150 μg corifollitropin alfa every other week. The increase in testicular volume (primary efficacy endpoint) and induction of spermatogenesis resulting in a sperm count ≥1 × 10 6 /mL (key secondary efficacy endpoint) during 52 weeks of combined treatment were assessed. Safety was evaluated by the presence of anti-corifollitropin alfa antibodies and the occurrence of adverse events (AEs). Mean (±SD) testicular volume increased from 8.6 (±6.09) mL to 17.8 (±8.93) mL (geometric mean fold increase, 2.30 [95% CI: 2.03, 2.62]); 14 (77.8%) subjects reached a sperm count ≥1 × 10 6 /mL. No subject developed confirmed anti-corifollitropin alfa antibodies during the trial. Treatment was generally well tolerated. Corifollitropin alfa 150 μg administrated every other week combined with twice-weekly hCG for 52 weeks increased testicular volume significantly, and induced spermatogenesis in >75% of men with HH who had remained azoospermic after hCG treatment alone. ClinicalTrials.gov: NCT01709331 .

Survival and long-term outcomes in late-onset Pompe disease following alglucosidase alfa treatment: a systematic review and meta-analysis.

PubMed

Schoser, Benedikt; Stewart, Andrew; Kanters, Steve; Hamed, Alaa; Jansen, Jeroen; Chan, Keith; Karamouzian, Mohammad; Toscano, Antonio

2017-04-01

A number of studies have assessed the efficacy of alglucosidase alfa as an enzyme replacement therapy (ERT) on motor and respiratory endpoints in patients with late-onset Pompe disease (LOPD). A previous review evaluated the clinical efficacy and safety of alglucosidase alfa; however, it is difficult to draw inferences from individual studies due to small patient populations, particularly in evaluating the benefit on survival. To evaluate the current evidence on the long-term efficacy of alglucosidase alfa with regard to survival, motor, and respiratory function in patients with LOPD in relation to the natural progression of the disease, a new systematic literature review was performed identifying studies that assessed either mortality, percent predicted forced vital capacity (% FVC), or the 6-min walk test (6MWT) among treated and untreated LOPD patients. Patient overlap was avoided by removing smaller studies or ensuring the use of only one conflicting study per outcome. Mortality was modeled using Poisson models for each treatment group. Outcomes were modeled using first- and second-order fractional polynomial meta-analysis with fixed- and random-effects. Meta-regression was used to explore sources of heterogeneity. Twenty-two publications pertaining to 19 studies/trials were selected, including 438 patients when accounting for overlaps, with the average study duration being 45.7 months. Patients treated with alglucosidase alfa in these studies had a nearly five-fold lower mortality rate than untreated patients (rate ratio: 0.21; 95 % credible interval: 0.11, 0.41). On average, % FVC declined consistently among untreated patients, including a 2.3 % decline after 12 months follow-up and 6.2 % decline after 48 months. This is in contrast to alglucosidase alfa-treated patients, who, on average, improved rapidly, with an increase of 1.4 % FVC after 2 months, followed by a slow regression back to baseline over a three-year period. Nonetheless, the relative

Efficacy of corifollitropin alfa followed by recombinant follicle-stimulating hormone in a gonadotropin-releasing hormone antagonist protocol for Korean women undergoing assisted reproduction.

PubMed

Park, Hyo Young; Lee, Min Young; Jeong, Hyo Young; Rho, Yong Sook; Song, Sang Jin; Choi, Bum-Chae

2015-06-01

To evaluate the effect of a gonadotropin-releasing hormone (GnRH) antagonist protocol using corifollitropin alfa in women undergoing assisted reproduction. Six hundred and eighty-six in vitro fertilization-embryo transfer (IVF)/intracytoplasmic sperm injection (ICSI) cycles were analyzed. In 113 cycles, folliculogenesis was induced with corifollitropin alfa and recombinant follicle stimulating hormone (rFSH), and premature luteinizing hormone (LH) surges were prevented with a GnRH antagonist. In the control group (573 cycles), premature LH surges were prevented with GnRH agonist injection from the midluteal phase of the preceding cycle, and ovarian stimulation was started with rFSH. The treatment duration, quality of oocytes and embryos, number of embryo transfer (ET) cancelled cycles, risk of ovarian hyperstimulation syndrome (OHSS), and the chemical pregnancy rate were evaluated in the two ovarian stimulation protocols. There were no significant differences in age and infertility factors between treatment groups. The treatment duration was shorter in the corifollitropin alfa group than in the control group. Although not statistically significant, the mean numbers of matured (86.8% vs. 85.1%) and fertilized oocytes (84.2% vs. 83.1%), good embryos (62.4% vs. 60.3%), and chemical pregnancy rates (47.2% vs. 46.8%) were slightly higher in the corifollitropin alfa group than in the control group. In contrast, rates of ET cancelled cycles and the OHSS risk were slightly lower in the corifollitropin alfa group (6.2% and 2.7%) than in the control group (8.2% and 3.5%), although these differences were also not statistically significant. Although no significant differences were observed, the use of corifollitropin alfa seems to offer some advantages to patients because of its short treatment duration, safety, lower ET cancellation rate and reduced risk of OHSS.

In Vivo Evaluation of the Acute Pulmonary Response to Poractant Alfa and Bovactant Treatments in Lung-Lavaged Adult Rabbits and in Preterm Lambs with Respiratory Distress Syndrome.

PubMed

Ricci, Francesca; Salomone, Fabrizio; Kuypers, Elke; Ophelders, Daan; Nikiforou, Maria; Willems, Monique; Krieger, Tobias; Murgia, Xabier; Hütten, Matthias; Kramer, Boris W; Bianco, Federico

2017-01-01

Poractant alfa (Curosurf ® ) and Bovactant (Alveofact ® ) are two animal-derived pulmonary surfactants preparations approved for the treatment of neonatal respiratory distress syndrome (nRDS). They differ in their source, composition, pharmaceutical form, and clinical dose. How much these differences affect the acute pulmonary response to treatment is unknown. Comparing these two surfactant preparations in two different animal models of respiratory distress focusing on the short-term response to treatment. Poractant alfa and Bovactant were administered in a 50-200 mg/kg dose range to surfactant-depleted adult rabbits with acute respiratory distress syndrome induced by lavage and to preterm lambs (127-129 days gestational age) with nRDS induced by developmental immaturity. The acute impact of surfactant therapy on gas exchange and pulmonary mechanics was assessed for 1 h in surfactant-depleted rabbits and for 3 h in preterm lambs. Overall, treatment with Bovactant 50 mg/kg or Poractant alfa 50 mg/kg did not achieve full recovery of the rabbits' respiratory conditions, as indicated by significantly lower arterial oxygenation and carbon dioxide values. By contrast, the two approved doses for clinical use of Poractant alfa (100 and 200 mg/kg) achieved a rapid and sustained recovery in both animal models. The comparison of the ventilation indices of the licensed doses of Bovactant (50 mg/kg) and Poractant alfa (100 mg/kg) showed a superior performance of the latter preparation in both animal models. At equal phospholipid doses, Poractant alfa was superior to Bovactant in terms of arterial oxygenation in both animal models. In preterm lambs, surfactant replacement therapy with Poractant alfa at either 100 or 200 mg/kg was associated with significantly higher lung gas volumes compared to Bovactant treatment with 100 mg/kg. At the licensed doses, the acute pulmonary response to Poractant alfa was significantly better than the one observed after

Survival in infants treated with sebelipase Alfa for lysosomal acid lipase deficiency: an open-label, multicenter, dose-escalation study.

PubMed

Jones, Simon A; Rojas-Caro, Sandra; Quinn, Anthony G; Friedman, Mark; Marulkar, Sachin; Ezgu, Fatih; Zaki, Osama; Gargus, J Jay; Hughes, Joanne; Plantaz, Dominique; Vara, Roshni; Eckert, Stephen; Arnoux, Jean-Baptiste; Brassier, Anais; Le Quan Sang, Kim-Hanh; Valayannopoulos, Vassili

2017-02-08

Infants presenting with lysosomal acid lipase deficiency have marked failure to thrive, diarrhea, massive hepatosplenomegaly, anemia, rapidly progressive liver disease, and death typically in the first 6 months of life; the only available potential treatment has been hematopoietic stem cell transplantation, which is associated with high morbidity and mortality in this population. The study objective was to evaluate safety and efficacy (including survival) of enzyme replacement with sebelipase alfa in infants with lysosomal acid lipase deficiency. This is an ongoing multicenter, open-label, phase 2/3 study conducted in nine countries. The study enrolled infants with growth failure prior to 6 months of age with rapidly progressive lysosomal acid lipase deficiency; they received once-weekly doses of sebelipase alfa initiated at 0.35 mg/kg with intrapatient dose escalation up to 5 mg/kg. The main outcome of interest is survival to 12 months and survival beyond 24 months of age. Nine patients were enrolled; median age at baseline was 3.0 months (range 1.1-5.8 months). Sixty-seven percent (exact 95% CI 30%-93%) of sebelipase alfa-treated infants survived to 12 months of age compared with 0% (exact 95% CI 0%-16%) for a historical control group (n = 21). Patients who survived to age 12 months exhibited improvements in weight-for-age, reductions in markers of liver dysfunction and hepatosplenomegaly, and improvements in anemia and gastrointestinal symptoms. Three deaths occurred early (first few months of life), two patients died because of advanced disease, and a third patient died following complications of non-protocol-specified abdominal paracentesis. A fourth death occurred at 15 months of age and was related to other clinical conditions. The five surviving patients have survived to age ≥24 months with continued sebelipase alfa treatment; all have displayed marked improvement in growth parameters and liver function. Serious adverse events considered

The Synchrony and Diachrony of Bosnian-Croatian-Serbian Adjectival Long-Form Allomorphy (ALFA)

ERIC Educational Resources Information Center

Pennington, James Joshua

2010-01-01

In Bosnian-Croatian-Serbian (BCS), the gentive (G) and dative/locative (DL) cases exhibit adjectival long-form allomorphy (ALFA). The genitive -"og" -"oga" and the DL -"om" -"ome" -"omu" stand in free variation, inasmuch as when one form is substituted for another the truth value of an utterance…

Sebelipase alfa over 52 weeks reduces serum transaminases, liver volume and improves serum lipids in patients with lysosomal acid lipase deficiency

PubMed Central

Valayannopoulos, Vassili; Malinova, Vera; Honzík, Tomas; Balwani, Manisha; Breen, Catherine; Deegan, Patrick B.; Enns, Gregory M.; Jones, Simon A.; Kane, John P.; Stock, Eveline O.; Tripuraneni, Radhika; Eckert, Stephen; Schneider, Eugene; Hamilton, Gavin; Middleton, Michael S.; Sirlin, Claude; Kessler, Bruce; Bourdon, Christopher; Boyadjiev, Simeon A.; Sharma, Reena; Twelves, Chris; Whitley, Chester B.; Quinn, Anthony G.

2014-01-01

Background and aims Lysosomal Acid Lipase Deficiency is an autosomal recessive enzyme deficiency resulting in lysosomal accumulation of cholesteryl esters and triglycerides. LAL-CL04, an ongoing extension study, investigates the long-term effects of sebelipase alfa, a recombinant human lysosomal acid lipase. Methods Sebelipase alfa (1 mg/kg or 3 mg/kg) was infused every-other-week to eligible subjects. Safety and tolerability assessments, including liver function, lipid profiles and liver volume assessment, were carried out at regular intervals. Results 216 infusions were administered to eight adult subjects through Week 52 during LAL-CL04. At Week 52, mean alanine aminotransferase and aspartate aminotransferase were normal with mean change from baseline of −58% and −40%. Mean change for low density lipoprotein, total cholesterol, triglyceride and high-density lipoprotein were −60%, −39%, −36%, and +29%, respectively. Mean liver volume by magnetic resonance imaging and hepatic proton density fat fraction decreased (12% and 55%, respectively). Adverse events were mainly mild and unrelated to sebelipase alfa. Infusion-related reactions were uncommon: three events of moderate severity were reported in two subjects; one patient's event was suggestive of hypersensitivity-like reaction, but additional testing did not confirm this, and the subject has successfully re-started sebelipase alfa. Of samples tested to date, no anti-drug antibodies have been detected. Conclusions Long-term dosing with sebelipase alfa in Lysosomal Acid Lipase-Deficient patients is well tolerated and produces sustained reductions in transaminases, improvements in serum lipid profile and reduction in hepatic fat fraction. A randomized, placebo-controlled phase 3 trial in children and adults is underway (ARISE: NCT01757184). PMID:24993530

Copper(II)-catalyzed enantioselective hydrosilylation of halo-substituted alkyl aryl and heteroaryl ketones: asymmetric synthesis of (R)-fluoxetine and (S)-duloxetine.

PubMed

Zhou, Ji-Ning; Fang, Qiang; Hu, Yi-Hu; Yang, Li-Yao; Wu, Fei-Fei; Xie, Lin-Jie; Wu, Jing; Li, Shijun

2014-02-14

A set of reaction conditions has been established to facilitate the non-precious copper-catalyzed enantioselective hydrosilylation of a number of structurally diverse β-, γ- or ε-halo-substituted alkyl aryl ketones and α-, β- or γ-halo-substituted alkyl heteroaryl ketones under air to afford a broad spectrum of halo alcohols in high yields and good to excellent enantioselectivities (up to 99% ee). The developed procedure has been successfully applied to the asymmetric synthesis of antidepressant drugs (R)-fluoxetine and (S)-duloxetine, which highlighted its synthetic utility.

Switch from agalsidase beta to agalsidase alfa in the enzyme replacement therapy of patients with Fabry disease in Latin America.

PubMed

Ripeau, Diego; Amartino, Hernán; Cedrolla, Martín; Urtiaga, Luis; Urdaneta, Bella; Cano, Marilis; Valdez, Rita; Antongiovanni, Norberto; Masllorens, Francisca

2017-01-01

There are currently two available enzyme replacement therapies for Fabry disease and little information regarding efficacy and safety of switching therapies. Between 2009 and 2012 there was a worldwide shortage of agalsidase beta and patients on that enzyme were switched to agalsidase alfa. This retrospective observational study assessed a 2-year period of efficacy and safety in a population of Fabry patients, in Argentina (30 patients) and Venezuela (3 patients), who switched therapies from algasidase beta to agalsidase alfa. Thirty-three patients completed 24-months follow-up after the switch (age 32.4 ± 2.0, range 10.0-55.9 years; male: female 23:10). Measures of renal function such as estimated glomerular filtration rate remained almost unchanged in 31 patients without end stage renal disease over the 2 years after switching and urine protein excretion continued stable. Cardiac functional parameters: left ventricular mass index, interventricular septum, left ventricular posterior wall showed no significant change from baseline in the 33 patients. Quality of life, pain and disease severity scores were mostly unchanged after 24-months and agalsidase alfa was generally well tolerated. Our findings showed there is no significant change in the efficacy measured through the renal or cardiac function, quality of life, pain, disease severity scoring and safety for at least 2 years after switching from agalsidase beta to agalsidase alfa.

Economic evaluation of duloxetine as a first-line treatment for painful diabetic peripheral neuropathy in Mexico.

PubMed

Carlos, Fernando; Ramírez-Gámez, Jocelyn; Dueñas, Héctor; Galindo-Suárez, Rosa María; Ramos, Elisa

2012-01-01

To perform an economic evaluation of duloxetine, pregabalin, and both branded and generic gabapentin for managing pain in patients with painful diabetic peripheral neuropathy (PDPN) in Mexico. The analysis was conducted using a 3-month decision model, which compares duloxetine 60 mg once daily (DUL), pregabalin 150 mg twice daily (PGB), and gabapentin 600 mg three-times daily (GBP) for PDPN patients with moderate-to-severe pain. A systematic review was performed and placebo-adjusted risk ratios for achieving good pain relief (GPR), adverse events (AE), and withdrawal owing to intolerable AE were calculated. Direct medical costs included drug acquisition and additional visits due to lack of efficacy (poor pain relief) or intolerable AE. Unit costs were taken from local sources. Adherence rates were used to estimate the expected drug costs. All costs are expressed in 2010 Mexican Pesos (MXN). Utility values drawn from published literature were applied to health states. The proportion of patients with GPR and quality-adjusted life years (QALY) were assessed. Branded-GBP was dominated by all the other options. PGB was more costly and less effective than DUL. Compared with branded-GBP and PGB, DUL led to savings of 1.01 and 1.74 million MXN (per 1000 patients). The incremental cost per QALY gained with DUL used instead of generic-GBP was $102 433 MXN. This amount is slightly lower than the estimated gross domestic product per capita in Mexico for 2010. During a second-order Monte Carlo simulation, DUL had the highest probability of being cost-effective (61%), followed by generic-GBP (25%) and PGB (14%). Study limitations include a short timeframe and using data from different dosage schemes for GBP and PGB. This study suggests that DUL provides overall savings and better health outcomes compared with branded-GBP and PGB. Administering DUL rather than generic-GBP is a cost-effective intervention to manage PDPN in Mexico.

The efficacy and safety of adjuvant interferon-alfa therapy in the evolving treatment landscape for resected high-risk melanoma.

PubMed

Trinh, Van Anh; Zobniw, Chrystia; Hwu, Wen-Jen

2017-08-01

Patients with resected stage II or III melanoma are at high risk of recurrence, with 5-year mortality rate of 40-60%. Adjuvant interferon-alfa has demonstrated a small RFS and OS benefit versus observation in this patient population. However, the adjuvant treatment landscape is evolving rapidly. Areas covered: This review aims to summarize the safety and efficacy profiles of adjuvant IFNα/PEG-IFNα, revisit the controversy surrounding its application, and reappraise its position in the rapidly changing treatment landscape of resected melanoma. A literature search using PubMed database was undertaken using search words melanoma, interferon-alfa, pegylated interferon-alfa, adjuvant therapy. Expert opinion: Currently, there is no international consensus regarding the optimal dosing schedule for adjuvant IFNα, but HD IFNα-2b remains the most widely used regimen. The AEs of HD IFNα-2b are substantial; however, toxicity management experience amassed over the past 2 decades has significantly improved safety. Many exciting studies are ongoing to examine the roles of immune checkpoint inhibitors and BRAF-targeted therapies in the adjuvant setting and will further delineate the role of adjuvant IFNα.

Sebelipase alfa over 52 weeks reduces serum transaminases, liver volume and improves serum lipids in patients with lysosomal acid lipase deficiency.

PubMed

Valayannopoulos, Vassili; Malinova, Vera; Honzík, Tomas; Balwani, Manisha; Breen, Catherine; Deegan, Patrick B; Enns, Gregory M; Jones, Simon A; Kane, John P; Stock, Eveline O; Tripuraneni, Radhika; Eckert, Stephen; Schneider, Eugene; Hamilton, Gavin; Middleton, Michael S; Sirlin, Claude; Kessler, Bruce; Bourdon, Christopher; Boyadjiev, Simeon A; Sharma, Reena; Twelves, Chris; Whitley, Chester B; Quinn, Anthony G

2014-11-01

Lysosomal acid lipase deficiency is an autosomal recessive enzyme deficiency resulting in lysosomal accumulation of cholesteryl esters and triglycerides. LAL-CL04, an ongoing extension study, investigates the long-term effects of sebelipase alfa, a recombinant human lysosomal acid lipase. Sebelipase alfa (1mg/kg or 3mg/kg) was infused every-other-week to eligible subjects. Safety and tolerability assessments, including liver function, lipid profiles and liver volume assessment, were carried out at regular intervals. 216 infusions were administered to eight adult subjects through week 52 during LAL-CL04. At week 52, mean alanine aminotransferase and aspartate aminotransferase levels were normal with mean change from baseline of -58% and -40%. Mean changes for low-density lipoprotein, total cholesterol, triglyceride and high-density lipoprotein were -60%, -39%, -36%, and +29%, respectively. Mean liver volume by magnetic resonance imaging and hepatic proton density fat fraction decreased (12% and 55%, respectively). Adverse events were mainly mild and unrelated to sebelipase alfa. Infusion-related reactions were uncommon: three events of moderate severity were reported in two subjects; one patient's event was suggestive of a hypersensitivity-like reaction, but additional testing did not confirm this, and the subject has successfully re-started sebelipase alfa. Of samples tested to date, no anti-drug antibodies have been detected. Long-term dosing with sebelipase alfa in lysosomal acid lipase-deficient patients is well tolerated and produces sustained reductions in transaminases, improvements in serum lipid profile and reduction in the hepatic fat fraction. A randomized, placebo-controlled phase 3 trial in children and adults is underway (ARISE: NCT01757184). Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Improved inflammatory activity with peginterferon alfa-2b maintenance therapy in non-cirrhotic prior non-responders: a randomized study.

PubMed

Poynard, Thierry; Bruix, Jordi; Schiff, Eugene R; Diago, Moises; Berg, Thomas; Moreno-Otero, Ricardo; Lyra, Andre C; Carrilho, Flair; Griffel, Louis H; Boparai, Navdeep; Jiang, Ruiyun; Burroughs, Margaret; Brass, Clifford A; Albrecht, Janice K

2013-03-01

Therapeutic options for patients failing hepatitis C retreatment are limited. EPIC(3) included a prospective trial assessing long-term peginterferon alfa-2b (PegIFNα-2b) maintenance therapy in patients with METAVIR fibrosis scores (MFS) of F2 or F3 who previously failed hepatitis C retreatment. Patients with F2/F3 MFS who failed retreatment were randomized to PegIFNα-2b (0.5 μg/kg/week, n=270) or observation (n=270) for 36 months. Blinded liver biopsies obtained before retreatment and after maintenance therapy were evaluated using MFS and activity scores, and confirmatory testing was performed using FibroTest and ActiTest. In total, 348 patients had paired biopsies: 192 patients had missing post-treatment biopsies and were considered as having no change in fibrosis/activity scores. In total, 16% of patients receiving PegIFNα-2b and 11% of observation patients had improvement in MFS (p=0.32). More PegIFNα-2b than observation patients had improvement in activity score (20% vs. 9%; p <0.001). Among patients treated for >2.5 years, improvement in MFS or activity score was more common with PegIFNα-2b than observation (21% vs. 14%, p=0.08 and 26% vs. 10%, p <0.001). FibroTest and ActiTest evaluations indicated significant benefit associated with PegIFNα-2b in terms of reduced fibrosis progression and improved activity score. The safety profile of PegIFNα-2b was similar to previous studies. PegIFNα-2b did not significantly improve MFS estimated by biopsy compared with observation; however, activity scores were significantly improved and MFS trended toward increased improvement with treatment durations >2.5 years. Both FibroTest and ActiTest were significantly improved during maintenance therapy. Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Safety, immunogenicity, and clinical outcomes in patients with Morquio A syndrome participating in 2 sequential open-label studies of elosulfase alfa enzyme replacement therapy (MOR-002/MOR-100), representing 5 years of treatment.

PubMed

Hendriksz, Christian; Santra, Saikat; Jones, Simon A; Geberhiwot, Tarekegn; Jesaitis, Lynne; Long, Brian; Qi, Yulan; Hawley, Sara M; Decker, Celeste

2018-04-01

antibodies was associated with increased drug half-life and decreased drug clearance. Despite formation of antidrug-binding (total antidrug antibodies, TAb) and in vitro neutralizing antibodies (NAb) in all patients, these types of immunogenicity to elosulfase alfa were not correlated with safety or clinical outcomes. In contrast with the reported natural history of Morquio A, no trends toward decreasing endurance, respiratory function, or ability to perform activities of daily living were observed in this cohort over the 5-year period. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Transfer of interferon alfa into human breast milk.

PubMed

Kumar, A R; Hale, T W; Mock, R E

2000-08-01

Originally assumed to be antiviral substances, the efficacy of interferons in a number of pathologies, including malignancies, multiple sclerosis, and other immune syndromes, is increasingly recognized. This study provides data on the transfer of interferon alfa (2B) into human milk of a patient receiving massive intravenous doses for the treatment of malignant melanoma. Following an intravenous dose of 30 million IU, the amount of interferon transferred into human milk was only slightly elevated (1551 IU/mL) when compared to control milk (1249 IU/mL). These data suggest that even following enormous doses, interferon is probably too large in molecular weight to transfer into human milk in clinically relevant amounts.

Treatment of Fabry Disease: Outcome of a Comparative Trial with Agalsidase Alfa or Beta at a Dose of 0.2 mg/kg

PubMed Central

Vedder, Anouk C.; Linthorst, Gabor E.; Houge, Gunnar; Groener, Johannna E.M.; Ormel, Els E.; Bouma, Berto J.; Aerts, Johannes M.F.G.; Hirth, Asle; Hollak, Carla E.M.

2007-01-01

Background Two different enzyme preparations, agalsidase alfa (ReplagalTM, Shire) and beta (FabrazymeTM, Genzyme), are registered for treatment of Fabry disease. We compared the efficacy of and tolerability towards the two agalsidase preparations administered at identical protein dose in a randomized controlled open label trial. Methodology/Principal Findings Thirty-four Fabry disease patients were treated with either agalsidase alfa or agalsidase beta at equal dose of 0.2 mg/kg biweekly. Primary endpoint was reduction in left ventricular mass after 12 and 24 months of treatment. Other endpoints included occurrence of treatment failure (defined as progression of cardiac, renal or cerebral disease), glomerular filtration rate, pain, anti-agalsidase antibodies, and globotriaosylceramide levels in plasma and urine. After 12 and 24 months of treatment no reduction in left ventricular mass was seen, which was not different between the two treatment groups. Also, no differences in glomerular filtration rate, pain and decline in globotriaosylceramide levels were found. Antibodies developed only in males (4/8 in the agalsidase alfa group and 6/8 in the agalsidase beta group). Treatment failure within 24 months of therapy was seen in 8/34 patients: 6 male patients (3 in each treatment group) and 2 female patients (both agalsidase alfa). The occurrence of treatment failures did not differ between the two treatment groups; χ2 = 0.38 p = 0.54. Conclusion Our study revealed no difference in reduction of left ventricular mass or other disease parameters after 12 and 24 months of treatment with either agalsidase alfa or beta at a dose of 0.2 mg/kg biweekly. Treatment failure occurred frequently in both groups and seems related to age and severe pre-treatment disease. Trial Registration International Standard Randomized Clinical Trial ISRCTN45178534 PMID:17622343

Treatment of Fabry disease: outcome of a comparative trial with agalsidase alfa or beta at a dose of 0.2 mg/kg.

PubMed

Vedder, Anouk C; Linthorst, Gabor E; Houge, Gunnar; Groener, Johannna E M; Ormel, Els E; Bouma, Berto J; Aerts, Johannes M F G; Hirth, Asle; Hollak, Carla E M

2007-07-11

Two different enzyme preparations, agalsidase alfa (Replagal(TM), Shire) and beta (Fabrazyme(TM), Genzyme), are registered for treatment of Fabry disease. We compared the efficacy of and tolerability towards the two agalsidase preparations administered at identical protein dose in a randomized controlled open label trial. Thirty-four Fabry disease patients were treated with either agalsidase alfa or agalsidase beta at equal dose of 0.2 mg/kg biweekly. Primary endpoint was reduction in left ventricular mass after 12 and 24 months of treatment. Other endpoints included occurrence of treatment failure (defined as progression of cardiac, renal or cerebral disease), glomerular filtration rate, pain, anti-agalsidase antibodies, and globotriaosylceramide levels in plasma and urine. After 12 and 24 months of treatment no reduction in left ventricular mass was seen, which was not different between the two treatment groups. Also, no differences in glomerular filtration rate, pain and decline in globotriaosylceramide levels were found. Antibodies developed only in males (4/8 in the agalsidase alfa group and 6/8 in the agalsidase beta group). Treatment failure within 24 months of therapy was seen in 8/34 patients: 6 male patients (3 in each treatment group) and 2 female patients (both agalsidase alfa). The occurrence of treatment failures did not differ between the two treatment groups; chi(2) = 0.38 p = 0.54. Our study revealed no difference in reduction of left ventricular mass or other disease parameters after 12 and 24 months of treatment with either agalsidase alfa or beta at a dose of 0.2 mg/kg biweekly. Treatment failure occurred frequently in both groups and seems related to age and severe pre-treatment disease. International Standard Randomized Clinical Trial ISRCTN45178534 [http://www.controlled-trials.com/ISRCTN45178534].

Enzyme replacement therapy with velmanase alfa (human recombinant alpha-mannosidase): Novel global treatment response model and outcomes in patients with alpha-mannosidosis.

PubMed

Harmatz, Paul; Cattaneo, Federica; Ardigò, Diego; Geraci, Silvia; Hennermann, Julia B; Guffon, Nathalie; Lund, Allan; Hendriksz, Christian J; Borgwardt, Line

2018-06-01

Alpha-mannosidosis is an ultra-rare monogenic disorder resulting from a deficiency in the lysosomal enzyme alpha-mannosidase, with a prevalence estimated to be as low as 1:1,000,000 live births. The resulting accumulation of mannose-rich oligosaccharides in all tissues leads to a very heterogeneous disorder with a continuum of clinical manifestations with no distinctive phenotypes. Long-term enzyme replacement therapy (ERT) with velmanase alfa is approved in Europe for the treatment of non-neurological manifestations in patients with mild to moderate alpha-mannosidosis. The clinical heterogeneity and rarity of the disease limit the sensitivity of single parameters to detect clinically relevant treatment effects. Thus, we propose a novel multiple variable responder analysis to evaluate the efficacy of ERT for alpha-mannosidosis and present efficacy analyses for velmanase alfa using this method. Global treatment response to velmanase alfa (defined by response to ≥2 domains comprising pharmacodynamic, functional, and quality of life outcomes) was applied post hoc to data from the pivotal placebo-controlled rhLAMAN-05 study and to the longer-term integrated data from all patients in the clinical development program (rhLAMAN-10). After 12 months of treatment, a global treatment response was achieved by 87% of patients receiving velmanase alfa (n = 15) compared with 30% of patients receiving placebo (n = 10). Longer-term data from all patients in the clinical program (n = 33) showed 88% of patients were global responders, including all (100%) pediatric patients (n = 19) and the majority (71%) of adult patients (n = 14). The responder analysis model demonstrates a clinically meaningful treatment effect with velmanase alfa and supports the early initiation and continued benefit of longer-term treatment of all patients with alpha-mannosidosis with this ERT. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Feasibility of corifollitropin alfa/GnRH antagonist protocol combined with GnRH agonist triggering and freeze-all strategy in polycystic ovary syndrome patients.

PubMed

Hwang, Jiann-Loung; Chen, Shee-Uan; Chen, Hen-Ju; Chen, Hsin-Fu; Yang, Yu-Shih; Chang, Chin-Hao; Seow, Kok-Min; Tzeng, Chii-Ruey; Lin, Yu-Hung

2018-06-01

The long-acting corifollitropin alfa is comparable to FSH in terms of pregnancy outcomes in normal responders and poor responders. Corifollitropin alfa has never been studied in polycystic ovary syndrome (PCOS) patients because of concerns of excessive ovarian stimulation and ovarian hyperstimulation syndrome (OHSS). The purpose of the study was to evaluate if corifollitropin alfa can be used in PCOS patients. Forty PCOS patients who were going to undergo in vitro fertilization were enrolled in this study. A single injection of corifollitropin alfa was administered on cycle day 2 or day 3. From stimulation day 8 onwards, daily FSH was administered until the day of final oocyte maturation. Cetrorelix was administered from stimulation day 5 to prevent premature LH surge. Final oocyte maturation was triggered by: acetate. All embryos were cryopreserved and replaced in subsequent cycles. All 40 patients were subjected to oocyte retrieval, and none developed moderate or severe ovarian hyperstimulation syndrome (0%, 95% CI 0-0.088). For each patient, an average of 23.4 (±7.4; 95% CI 21.0-25.7) oocytes were retrieved and a mean of 11.7 (±6.4; 95% CI 9.6-13.8) embryos were frozen. Mean serum estradiol level on the day of GnRHa triggering was 7829.9 pg/ml (±3297; 95% CI 6775-8885). The cumulated ongoing pregnancy rate after 3 frozen-thawed embryo transfers was 75.0% (95% CI 61.6%-88.4%). The results suggest that corifollitropin alfa/GnRH antagonist protocol can be used in PCOS patients, in combination with GnRHa triggering and embryo cryopreservation. Copyright © 2017. Published by Elsevier B.V.

ARECIBO PULSAR SURVEY USING ALFA: PROBING RADIO PULSAR INTERMITTENCY AND TRANSIENTS

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

Deneva, J. S.; Cordes, J. M.; McLaughlin, M. A.

We present radio transient search algorithms, results, and statistics from the ongoing Arecibo Pulsar ALFA (PALFA) survey of the Galactic plane. We have discovered seven objects through a search for isolated dispersed pulses. All of these objects are Galactic and have measured periods between 0.4 and 4.7 s. One of the new discoveries has a duty cycle of 0.01%, smaller than that of any other radio pulsar. We discuss the impact of selection effects on the detectability and classification of intermittent sources, and compare the efficiencies of periodicity and single-pulse (SP) searches for various pulsar classes. For some cases wemore » find that the apparent intermittency is likely to be caused by off-axis detection or a short time window that selects only a few bright pulses and favors detection with our SP algorithm. In other cases, the intermittency appears to be intrinsic to the source. No transients were found with DMs large enough to require that they originate from sources outside our Galaxy. Accounting for the on-axis gain of the ALFA system, as well as the low gain but large solid-angle coverage of far-out sidelobes, we use the results of the survey so far to place limits on the amplitudes and event rates of transients of arbitrary origin.« less

Longer-term outcomes of darbepoetin alfa versus epoetin alfa in patients with ESRD initiating hemodialysis: a quasi-experimental cohort study.

PubMed

Winkelmayer, Wolfgang C; Chang, Tara I; Mitani, Aya A; Wilhelm-Leen, Emilee R; Ding, Victoria; Chertow, Glenn M; Brookhart, M Alan; Goldstein, Benjamin A

2015-07-01

Adequately powered studies directly comparing hard clinical outcomes of darbepoetin alfa (DPO) versus epoetin alfa (EPO) in patients undergoing dialysis are lacking. Observational, registry-based, retrospective cohort study; we mimicked a cluster-randomized trial by comparing mortality and cardiovascular events in US patients initiating hemodialysis therapy in facilities (almost) exclusively using DPO versus EPO. Nonchain US hemodialysis facilities; each facility switching from EPO to DPO (2003-2010) was matched for location, profit status, and facility type with one EPO facility. Patients subsequently initiating hemodialysis therapy in these facilities were assigned their facility-level exposure. DPO versus EPO. All-cause mortality, cardiovascular mortality; composite of cardiovascular death, nonfatal myocardial infarction (MI), and nonfatal stroke. Unadjusted and adjusted HRs from Cox proportional hazards regression models. Of 508 dialysis facilities that switched to DPO, 492 were matched with a similar EPO facility; 19,932 (DPO: 9,465 [47.5%]; EPO: 10,467 [52.5%]) incident hemodialysis patients were followed up for 21,918 person-years during which 5,550 deaths occurred. Almost all baseline characteristics were tightly balanced. The demographics-adjusted mortality HR for DPO (vs EPO) was 1.06 (95% CI, 1.00-1.13) and was materially unchanged after adjustment for all other baseline characteristics (HR, 1.05; 95% CI, 0.99-1.12). Cardiovascular mortality did not differ between groups (HR, 1.05; 95% CI, 0.94-1.16). Nonfatal outcomes were evaluated among 9,455 patients with fee-for-service Medicare: 4,542 (48.0%) in DPO and 4,913 (52.0%) in EPO facilities. During 10,457 and 10,363 person-years, 248 and 372 events were recorded, respectively, for strokes and MIs. We found no differences in adjusted stroke or MI rates or their composite with cardiovascular death (HR, 1.10; 95% CI, 0.96-1.25). Nonrandom treatment assignment, potential residual confounding. In incident

Corifollitropin alfa compared to daily rFSH or HP-HMG in GnRH antagonist controlled ovarian stimulation protocol for patients undergoing assisted reproduction.

PubMed

Souza, Priscila Morais Galvão; Carvalho, Bruno Ramalho de; Nakagawa, Hitomi Miura; Rassi, Thalita Reis Esselin; Barbosa, Antônio César Paes; Silva, Adelino Amaral

2017-06-01

This study aimed to compare the outcomes of controlled ovarian stimulation (COS) with corifollitropin alfa versus daily recombinant follicle-stimulating hormone (rRFSH) or highly purified human menopausal gonadotropin (HP-HMG) in patients undergoing in vitro fertilization (IVF) cycles based on gonadotropin-releasing hormone (GnRH) antagonist protocols. The primary endpoints were total number of oocytes and mature oocytes. This retrospective study looked into 132 controlled ovarian stimulation cycles from IVF or oocyte cryopreservation performed in a private human reproduction center between January 1 and December 31, 2014. Enrollment criteria: women aged < 40 years submitted to COS with corifollitropin alfa 100µg or 150µg (n = 26) and rFSH or HP-HMG in the first seven days of treatment with daily doses of 150-225 IU (n = 106); all subjects were on GnRH antagonist protocols. The groups had similar mean ages and duration of stimulation. The mean number ± standard deviation of total aspirated oocytes and MII oocytes was 11.9±10 and 10.3±7.9 in the corifollitropin alfa group, and 10.9±7.2 and 8.6±5.7 in the group on rFSH or HMG (p>0.05). There were no significant differences in fertilization (76.9% vs. 76.8%, p=1.0), biochemical pregnancy (66.7% vs. 47.2%, p=0.1561) or embryo implantation rates (68.7% vs. 50%, p=0.2588) between the groups using corifollitropin alfa and rFSH or HMG, respectively. Corifollitropin alfa seems to be as effective as rFSH or HP-HMG when used in the first seven days of ovulation induction for patients undergoing assisted reproduction in GnRH antagonist protocols.

Analgesic Effects of Duloxetine on Formalin-Induced Hyperalgesia and Its Underlying Mechanisms in the CeA

PubMed Central

Zhang, Lie; Yin, Jun-Bin; Hu, Wei; Zhao, Wen-Jun; Fan, Qing-Rong; Qiu, Zhi-Chun; He, Ming-Jie; Ding, Tan; Sun, Yan; Kaye, Alan D.; Wang, En-Ren

2018-01-01

In rodents, the amygdala has been proposed to serve as a key center for the nociceptive perception. Previous studies have shown that extracellular signal-regulated kinase (ERK) signaling cascade in the central nucleus of amygdala (CeA) played a functional role in inflammation-induced peripheral hypersensitivity. Duloxetine (DUL), a serotonin and noradrenaline reuptake inhibitor, produced analgesia on formalin-induced spontaneous pain behaviors. However, it is still unclear whether single DUL pretreatment influences formalin-induced hypersensitivity and what is the underlying mechanism. In the current study, we revealed that systemic pretreatment with DUL not only dose-dependently suppressed the spontaneous pain behaviors, but also relieved mechanical and thermal hypersensitivity induced by formalin hindpaw injection. Consistent with the analgesic effects of DUL on the pain behaviors, the expressions of Fos and pERK that were used to check the neuronal activities in the spinal cord and CeA were also dose-dependently reduced following DUL pretreatment. Meanwhile, no emotional aversive behaviors were observed at 24 h after formalin injection. The concentration of 5-HT in the CeA was correlated with the dose of DUL in a positive manner at 24 h after formalin injection. Direct injecting 5-HT into the CeA suppressed both the spontaneous pain behaviors and hyperalgesia induced by formalin injection. However, DUL did not have protective effects on the formalin-induced edema of hindpaw. In sum, the activation of CeA neurons may account for the transition from acute pain to long-term hyperalgesia after formalin injection. DUL may produce potent analgesic effects on the hyperalgesia and decrease the expressions of p-ERK through increasing the concentration of serotonin in the CeA. PMID:29692727

Analgesic Effects of Duloxetine on Formalin-Induced Hyperalgesia and Its Underlying Mechanisms in the CeA.

PubMed

Zhang, Lie; Yin, Jun-Bin; Hu, Wei; Zhao, Wen-Jun; Fan, Qing-Rong; Qiu, Zhi-Chun; He, Ming-Jie; Ding, Tan; Sun, Yan; Kaye, Alan D; Wang, En-Ren

2018-01-01

In rodents, the amygdala has been proposed to serve as a key center for the nociceptive perception. Previous studies have shown that extracellular signal-regulated kinase (ERK) signaling cascade in the central nucleus of amygdala (CeA) played a functional role in inflammation-induced peripheral hypersensitivity. Duloxetine (DUL), a serotonin and noradrenaline reuptake inhibitor, produced analgesia on formalin-induced spontaneous pain behaviors. However, it is still unclear whether single DUL pretreatment influences formalin-induced hypersensitivity and what is the underlying mechanism. In the current study, we revealed that systemic pretreatment with DUL not only dose-dependently suppressed the spontaneous pain behaviors, but also relieved mechanical and thermal hypersensitivity induced by formalin hindpaw injection. Consistent with the analgesic effects of DUL on the pain behaviors, the expressions of Fos and pERK that were used to check the neuronal activities in the spinal cord and CeA were also dose-dependently reduced following DUL pretreatment. Meanwhile, no emotional aversive behaviors were observed at 24 h after formalin injection. The concentration of 5-HT in the CeA was correlated with the dose of DUL in a positive manner at 24 h after formalin injection. Direct injecting 5-HT into the CeA suppressed both the spontaneous pain behaviors and hyperalgesia induced by formalin injection. However, DUL did not have protective effects on the formalin-induced edema of hindpaw. In sum, the activation of CeA neurons may account for the transition from acute pain to long-term hyperalgesia after formalin injection. DUL may produce potent analgesic effects on the hyperalgesia and decrease the expressions of p-ERK through increasing the concentration of serotonin in the CeA.

Impact of weight-based ribavirin with peginterferon alfa-2b in African Americans with hepatitis C virus genotype 1.

PubMed

Jacobson, Ira M; Brown, Robert S; McCone, Jonathan; Black, Martin; Albert, Clive; Dragutsky, Michael S; Siddiqui, Firdous A; Hargrave, Thomas; Kwo, Paul Y; Lambiase, Louis; Galler, Greg W; Araya, Victor; Freilich, Bradley; Harvey, Joann; Griffel, Louis H; Brass, Clifford A

2007-10-01

WIN-R (Weight-based dosing of pegINterferon alfa-2b and Ribavirin) was a multicenter, randomized, open-label, investigator-initiated trial involving 236 community and academic sites in the United States, comparing response to pegylated interferon (PEG-IFN) alfa-2b plus a flat or weight-based dose of ribavirin (RBV) in treatment-naive patients with chronic hepatitis C and compensated liver disease. Patients were randomized to receive PEG-IFN alfa-2b at 1.5 microg/kg/week plus flat-dose (800 mg/day) or weight-based-dose RBV (800 mg/day for weight <65 kg, 1000 mg/day for 65-85 kg, 1200 mg/day for >85-105 kg, or 1400 mg/day for >105-<125 kg). Sustained virologic response (SVR; undetectable [<125 IU/mL] hepatitis C virus [HCV] RNA at end of follow-up) in patients > or =65 kg was the primary end point. Low SVR rates have been reported among African American individuals, in whom there is a preponderance of HCV genotype 1. This subanalysis of WIN-R was conducted to evaluate the efficacy of weight-based dosing among African American individuals with genotype 1 infection enrolled in the trial. Of 362 African American patients in the primary efficacy analysis, 188 received RBV flat dosing and 174 received weight-based dosing. SVR rates were higher (21% versus 10%; P = 0.0006) and relapse rates were lower (22% versus 30%) in the weight-based-dose group than in the flat-dose group. Safety and rates of drug discontinuation were similar between the 2 groups. Weight-based dosing of RBV is more effective than flat dosing in combination with PEG-IFN alfa-2b in African American individuals with HCV genotype 1. Even with weight-based dosing, response rates in African American individuals are lower than reported in other ethnic groups.

Comprehensive long-term efficacy and safety of recombinant human alpha-mannosidase (velmanase alfa) treatment in patients with alpha-mannosidosis.

PubMed

Lund, Allan M; Borgwardt, Line; Cattaneo, Federica; Ardigò, Diego; Geraci, Silvia; Gil-Campos, Mercedes; De Meirleir, Linda; Laroche, Cécile; Dolhem, Philippe; Cole, Duncan; Tylki-Szymanska, Anna; Lopez-Rodriguez, Monica; Guillén-Navarro, Encarna; Dali, Christine I; Héron, Bénédicte; Fogh, Jens; Muschol, Nicole; Phillips, Dawn; Van den Hout, J M Hannerieke; Jones, Simon A; Amraoui, Yasmina; Harmatz, Paul; Guffon, Nathalie

2018-05-03

Long-term outcome data provide important insights into the clinical utility of enzyme replacement therapies. Such data are presented for velmanase alfa in the treatment of alpha-mannosidosis (AM). Patient data (n = 33; 14 adults, 19 paediatric) from the clinical development programme for velmanase alfa were integrated in this prospectively-designed analysis of long-term efficacy and safety. Patients who participated in the phase I/II or phase III trials and were continuing to receive treatment after completion of the trials were invited to participate in a comprehensive evaluation visit to assess long-term outcomes. Primary endpoints were changes in serum oligosaccharide and the 3-minute stair climb test (3MSCT). Mean (SD) treatment exposure was 29.3 (15.2) months. Serum oligosaccharide levels were significantly reduced in the overall population at 12 months (mean change: -72.7%, P < 0.001) and remained statistically significant at last observation (-62.8%, P < 0.001). A mean improvement of +9.3% in 3MSCT was observed at 12 months (P = 0.013), which also remained statistically significant at last observation (+13.8%, P = 0.004), with a more pronounced improvement detected in the paediatric subgroup. No treatment-emergent adverse events were reported leading to permanent treatment discontinuation. Patients treated with velmanase alfa experienced improvements in biochemical and functional measures that were maintained for up to 4 years. Long term follow-up is important and further supports the use of velmanase alfa as an effective and well-tolerated treatment for AM. Based on the currently available data set, no baseline characteristic can be predictive of treatment outcome. Early treatment during paediatric age showed better outcome in functional endpoints.

Fast radio burst discovered in the Arecibo pulsar ALFA survey

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

Spitler, L. G.; Freire, P. C. C.; Lazarus, P.

Recent work has exploited pulsar survey data to identify temporally isolated, millisecond-duration radio bursts with large dispersion measures (DMs). These bursts have been interpreted as arising from a population of extragalactic sources, in which case they would provide unprecedented opportunities for probing the intergalactic medium; they may also be linked to new source classes. Until now, however, all so-called fast radio bursts (FRBs) have been detected with the Parkes radio telescope and its 13-beam receiver, casting some concern about the astrophysical nature of these signals. Here we present FRB 121102, the first FRB discovery from a geographic location other thanmore » Parkes. FRB 121102 was found in the Galactic anti-center region in the 1.4 GHz Pulsar Arecibo L-band Feed Array (ALFA) survey with the Arecibo Observatory with a DM = 557.4 ± 2.0 pc cm{sup –3}, pulse width of 3.0 ± 0.5 ms, and no evidence of interstellar scattering. The observed delay of the signal arrival time with frequency agrees precisely with the expectation of dispersion through an ionized medium. Despite its low Galactic latitude (b = –0.°2), the burst has three times the maximum Galactic DM expected along this particular line of sight, suggesting an extragalactic origin. A peculiar aspect of the signal is an inverted spectrum; we interpret this as a consequence of being detected in a sidelobe of the ALFA receiver. FRB 121102's brightness, duration, and the inferred event rate are all consistent with the properties of the previously detected Parkes bursts.« less

Serum HBV RNA as a Predictor of Peginterferon Alfa-2a (40KD) Response in Patients With HBeAg-Positive Chronic Hepatitis B.

PubMed

van Bömmel, Florian; van Bömmel, Alena; Krauel, Alexander; Wat, Cynthia; Pavlovic, Vedran; Yang, Lei; Deichsel, Danilo; Berg, Thomas; Böhm, Stephan

2018-05-08

Hepatitis B virus (HBV) RNA is a novel serum biomarker that has the potential to predict treatment response in patients with chronic hepatitis B. We explored whether HBV RNA serum levels can predict hepatitis B e antigen (HBeAg) seroconversion in patients treated with peginterferon alfa-2a. Serum samples from HBeAg-positive patients previously treated with peginterferon alfa-2a in two large randomized controlled trials were retrospectively analyzed. HBV RNA levels were measured using a real-time polymerase chain reaction assay. Ability of individual biomarkers to predict HBeAg seroconversion at 24 weeks post-treatment was evaluated using receiver operating characteristics (ROC) analyses. The study included 131 subjects (70% male, 96% Asians, 35% HBV genotypes B and 61% C), 76 treated with peginterferon alfa-2a alone and 55 in combination with LAM. Median HBV RNA levels were significantly lower, at all time points, in patients achieving HBeAg seroconversion. Levels of HBV RNA at treatment weeks 12 and 24 showed good ability to predict HBeAg seroconversion (AUROC scores >0.75, p<0.001). A HBV RNA cutoff of >5.5 log10 copies/mL identified 30% of non-responders at week 12 (negative predictive value >90%). Serum HBV RNA is an early predictor of HBeAg seroconversion in patients treated with peginterferon alfa-2a.

A Phase 3 Trial of Sebelipase Alfa in Lysosomal Acid Lipase Deficiency.

PubMed

Burton, Barbara K; Balwani, Manisha; Feillet, François; Barić, Ivo; Burrow, T Andrew; Camarena Grande, Carmen; Coker, Mahmut; Consuelo-Sánchez, Alejandra; Deegan, Patrick; Di Rocco, Maja; Enns, Gregory M; Erbe, Richard; Ezgu, Fatih; Ficicioglu, Can; Furuya, Katryn N; Kane, John; Laukaitis, Christina; Mengel, Eugen; Neilan, Edward G; Nightingale, Scott; Peters, Heidi; Scarpa, Maurizio; Schwab, K Otfried; Smolka, Vratislav; Valayannopoulos, Vassili; Wood, Marnie; Goodman, Zachary; Yang, Yijun; Eckert, Stephen; Rojas-Caro, Sandra; Quinn, Anthony G

2015-09-10

Lysosomal acid lipase is an essential lipid-metabolizing enzyme that breaks down endocytosed lipid particles and regulates lipid metabolism. We conducted a phase 3 trial of enzyme-replacement therapy in children and adults with lysosomal acid lipase deficiency, an underappreciated cause of cirrhosis and severe dyslipidemia. In this multicenter, randomized, double-blind, placebo-controlled study involving 66 patients, we evaluated the safety and effectiveness of enzyme-replacement therapy with sebelipase alfa (administered intravenously at a dose of 1 mg per kilogram of body weight every other week); the placebo-controlled phase of the study was 20 weeks long and was followed by open-label treatment for all patients. The primary end point was normalization of the alanine aminotransferase level. Secondary end points included additional disease-related efficacy assessments, safety, and side-effect profile. Substantial disease burden at baseline included a very high level of low-density lipoprotein cholesterol (≥190 mg per deciliter) in 38 of 66 patients (58%) and cirrhosis in 10 of 32 patients (31%) who underwent biopsy. A total of 65 of the 66 patients who underwent randomization completed the double-blind portion of the trial and continued with open-label treatment. At 20 weeks, the alanine aminotransferase level was normal in 11 of 36 patients (31%) in the sebelipase alfa group and in 2 of 30 (7%) in the placebo group (P=0.03), with mean changes from baseline of -58 U per liter versus -7 U per liter (P<0.001). With respect to prespecified key secondary efficacy end points, we observed improvements in lipid levels and reduction in hepatic fat content (P<0.001 for all comparisons, except P=0.04 for triglycerides). The number of patients with adverse events was similar in the two groups; most events were mild and were considered by the investigator to be unrelated to treatment. Sebelipase alfa therapy resulted in a reduction in multiple disease-related hepatic and

HBsAg Loss with Peg-interferon Alfa-2a in Hepatitis B Patients with Partial Response to Nucleos(t)ide Analog: New Switch Study.

PubMed

Hu, Peng; Shang, Jia; Zhang, Wenhong; Gong, Guozhong; Li, Yongguo; Chen, Xinyue; Jiang, Jianning; Xie, Qing; Dou, Xiaoguang; Sun, Yongtao; Li, Yufang; Liu, Yingxia; Liu, Guozhen; Mao, Dewen; Chi, Xiaoling; Tang, Hong; Li, Xiaoou; Xie, Yao; Chen, Xiaoping; Jiang, Jiaji; Zhao, Ping; Hou, Jinlin; Gao, Zhiliang; Fan, Huimin; Ding, Jiguang; Zhang, Dazhi; Ren, Hong

2018-03-28

Background and Aims: Hepatitis B surface antigen (HBsAg) loss is seldom achieved with nucleos(t)ide analog (NA) therapy in chronic hepatitis B patients but may be enhanced by switching to finite pegylated-interferon (Peg-IFN) alfa-2a. We assessed HBsAg loss with 48- and 96-week Peg-IFN alfa-2a in chronic hepatitis B patients with partial response to a previous NA. Methods: Hepatitis B e antigen (HBeAg)-positive patients who achieved HBeAg loss and hepatitis B virus DNA <200 IU/mL with previous adefovir, lamivudine or entecavir treatment were randomized 1:1 to receive Peg-IFN alfa-2a for 48 ( n = 153) or 96 weeks ( n = 150). The primary endpoint of this study was HBsAg loss at end of treatment. The ClinicalTrials.gov identifier is NCT01464281. Results: At the end of 48 and 96 weeks' treatment, 14.4% (22/153) and 20.7% (31/150) of patients, respectively, who switched from NA to Peg-IFN alfa-2a cleared HBsAg. Rates were similar irrespective of prior NA or baseline HBeAg seroconversion. Among those who cleared HBsAg by the end of 48 and 96 weeks' treatment, 77.8% (14/18) and 71.4% (20/28), respectively, sustained HBsAg loss for a further 48 weeks. Baseline HBsAg <1500 IU/mL and week 24 HBsAg <200 IU/mL were associated with the highest rates of HBsAg loss at the end of both 48- and 96-week treatment (51.4% and 58.7%, respectively). Importantly, extending treatment from 48 to 96 weeks enabled 48.3% (14/29) more patients to achieve HBsAg loss. Conclusions: Patients on long-term NA who are unlikely to meet therapeutic goals can achieve high rates of HBsAg loss by switching to Peg-IFN alfa-2a. HBsAg loss rates may be improved for some patients by extending treatment from 48 to 96 weeks, although the differences in our study cohort were not statistically significant. Baseline and on-treatment HBsAg may predict HBsAg loss with Peg-IFN alfa-2a.

Immunogenicity of glycans on biotherapeutic drugs produced in plant expression systems—The taliglucerase alfa story

PubMed Central

Rup, Bonita; Alon, Sari; Amit-Cohen, Bat-Chen; Brill Almon, Einat; Chertkoff, Raul; Rudd, Pauline M.

2017-01-01

Plants are a promising alternative for the production of biotherapeutics. Manufacturing in-planta adds plant specific glycans. To understand immunogenic potential of these glycans, we developed a validated method to detect plant specific glycan antibodies in human serum. Using this assay, low prevalence of pre-existing anti-plant glycan antibodies was found in healthy humans (13.5%) and in glucocerebrosidase-deficient Gaucher disease (GD) patients (5%). A low incidence (9% in naïve patient and none in treatment experienced patients) of induced anti-plant glycan antibodies was observed in GD patients after up to 30 months replacement therapy treatment with taliglucerase alfa, a version of human glucocerebrosidase produced in plant cells. Detailed evaluation of clinical safety and efficacy endpoints indicated that anti-plant glycan antibodies did not affect the safety or efficacy of taliglucerase alfa in patients. This study shows the benefit of using large scale human trials to evaluate the immunogenicity risk of plant derived glycans, and indicates no apparent risk related to anti-plant glycan antibodies. PMID:29088235

Immunogenicity of glycans on biotherapeutic drugs produced in plant expression systems-The taliglucerase alfa story.

PubMed

Rup, Bonita; Alon, Sari; Amit-Cohen, Bat-Chen; Brill Almon, Einat; Chertkoff, Raul; Tekoah, Yoram; Rudd, Pauline M

2017-01-01

Plants are a promising alternative for the production of biotherapeutics. Manufacturing in-planta adds plant specific glycans. To understand immunogenic potential of these glycans, we developed a validated method to detect plant specific glycan antibodies in human serum. Using this assay, low prevalence of pre-existing anti-plant glycan antibodies was found in healthy humans (13.5%) and in glucocerebrosidase-deficient Gaucher disease (GD) patients (5%). A low incidence (9% in naïve patient and none in treatment experienced patients) of induced anti-plant glycan antibodies was observed in GD patients after up to 30 months replacement therapy treatment with taliglucerase alfa, a version of human glucocerebrosidase produced in plant cells. Detailed evaluation of clinical safety and efficacy endpoints indicated that anti-plant glycan antibodies did not affect the safety or efficacy of taliglucerase alfa in patients. This study shows the benefit of using large scale human trials to evaluate the immunogenicity risk of plant derived glycans, and indicates no apparent risk related to anti-plant glycan antibodies.

Gateways to clinical trials.

PubMed

Bayes, M; Rabasseda, X; Prous, J R

2005-01-01

Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: (-)-Epigallocatechin gallate; ACP-103, Ad.Egr.TNF.11 D, adalimumab, AF-IL 12, AIDSVAX gp120 B/B, alefacept, alemtuzumab, a-Galactosylceramide, ALVAC vCP 1452, alvimopan hydrate, alvocidib hydrochloride, aminolevulinic acid hydrochloride, aminolevulinic acid methyl ester, anakinra, anidulafungin, antarelix, aprepitant, aripiprazole, arsenic sulfide, asoprisnil, atazanavir sulfate, atomoxetine hydrochloride; Bevacizumab, bimatoprost, BMS-184476, bortezomib, bosentan, botulinum toxin type B, BrachySil, brivudine; Caffeine, calcipotriol/betamethasone dipropionate, cannabidiol, capsaicin for injection, caspofungin acetate, CC-4047, cetuximab, CGP-36742, clofazimine, CpG-7909, Cypher; Darbepoetin alfa, dextromethorphan/quinidine sulfate, dimethylfumarate, dronabinol/cannabidiol, drotrecogin alfa (activated), duloxetine hydrochloride, dutasteride; Ecogramostim, efalizumab, eletriptan, emtricitabine, enfuvirtide, eplerenone, esomeprazole magnesium, estradiol acetate, eszopiclone, etoricoxib, exenatide, ezetimibe, ezetimibe/simvastatin; Fampridine, fondaparinux sodium, fosamprenavir calcium; Gefitinib, GPI-0100; hA 20, HTU-PA, human insulin, HuOKT 3 gamma 1(Ala 234-Ala 235), hyaluronic acid; Icatibant, imatinib mesylate, Indiplon, INKP-100, INKP-102, iodine (I131) tositumomab, istradefylline, IV gamma-globulin, ivabradine hydrochloride, ixabepilone; Lacosamide, landiolol, lanthanum carbonate, lasofoxifene tartrate, LB-80380, lenalidomide, lidocaine/tetracaine, linezolid, liposomal doxorubicin, liposomal vincristine sulfate, lopinavir, lopinavir/ritonavir, lumiracoxib, lurtotecan; Maribavir, morphine glucuronide, MVA-5 T

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

PubMed

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

2013-07-01

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

Cost-effectiveness analysis of adding low dose ribavirin to peginterferon alfa-2a for treatment of chronic hepatitis C infected thalassemia major patients in iran.

PubMed

Mehrazmay, Alireza; Alavian, Seyed Moayed; Moradi-Lakeh, Maziar; Mokhtari Payam, Mahdi; Hashemi-Meshkini, Amir; Behnava, Bita; Miri, Seyyed Mohammad; Karimi Elizee, Pegah; Tabatabaee, Seyed Vahid; Keshvari, Maryam; Bagheri Lankarani, Kamran

2013-01-01

The prevalence of hepatitis C in Iran is 1% and 18% in general population and thalassemia patients respectively. The cost effectiveness analysis of adding Ribavirin to Peginterferon alfa-2a (PEG IFN alfa-2a) as a combination treatment strategy of chronic hepatitis C in thalassemia patients in comparison with monotherapy could help clinicians and policy makers to provide the best treatment for the patients. In this study we aimed to assess whether adding Ribavirin to PEG IFN alfa-2a is a cost effective strategy in different genotypes and different subgroups of 280 patients with chronic hepatitis C infection from the perspective of society in Iranian setting. A cost effectiveness analysis including all costs and outcomes of treatments for chronic hepatitis C infected thalassemia major patients was conducted. We constructed a decision tree of treatment course in which a hypothetical cohort of 100 patients received "PEG IFN alfa-2a" or "Peg IFN alfa-2a plus Ribavirin." The cost analysis was based on cost data for 2008 and we used 9300 Iranian Rials (IR Rial) as exchange rate declared by the Iranian Central Bank on that time to calculating costs by US Dollar (USD). To evaluate whether a strategy is cost effective, one time and three times of GDP per capita were used as threshold based on recommendation of the World Health Organization. The Incremental Cost Effectiveness Ratio (ICER) for combination therapy in genotype-1 and genotypes non-1 subgroups was 2,673 and 19,211 US dollars (USD) per one Sustain Virological Response (SVR), respectively. In low viral load and high viral load subgroups, the ICER was 5,233 and 14,976 USD per SVR, respectively. The calculated ICER for combination therapy in subgroup of patients with previously resistant to monotherapy was 13,006 USD per SVR. Combination therapy in previously resistant patients to combination therapy was a dominant strategy. Adding low dose of Ribavirin to PEG IFN alfa-2a for treatment of chronic hepatitis C patients

Successful management of enzyme replacement therapy in related fabry disease patients with severe adverse events by switching from agalsidase Beta (fabrazyme(®)) to agalsidase alfa (replagal (®)).

PubMed

Tsuboi, Kazuya; Yamamoto, Hiroshi; Somura, Fuji; Goto, Hiromi

2015-01-01

Enzyme replacement therapy (ERT) is the only approved therapy for Fabry disease. In June 2009, there was a worldwide shortage of agalsidase beta, necessitating dose reductions or switching to agalsidase alfa in some patients. We present two cases of Fabry disease (a parent and a child) who received agalsidase beta for 27 months at the licensed dose and 10 months at a reduced dose, followed by a switch to agalsidase alfa for 28 months. Case 1, a 26-year-old male had severe coughing and fatigue during ERT with agalsidase beta requiring antitussive and asthmatic drug therapy. After switching to agalsidase alfa, the coughing gradually resolved completely. Case 2, a 62-year-old female had advanced cardiac manifestations at the time of diagnosis. Despite receiving ERT with the approved dose of agalsidase beta, she experienced aggravation of congestive heart failure and was hospitalized. After switching to agalsidase alfa with standard care in heart disease, BNP level, echocardiographic parameters, eGFR rate and lyso-Gb3 levels were improved or stabilized. We report on two Fabry disease patients who experienced severe adverse events while on approved and/or reduced doses of agalsidase beta. Switching to agalsidase alfa associated with standard care in heart disease led to resolution or improvement in the cardiorespiratory status. And reduction in dose associated with standard care in respiratory disease was useful for decrease in cough and fatigue. Plasma BNP level was useful for monitoring heart failure and the effects of ERT.

Astronaut Scott Carpenter - Practices - Air Lubricated Free Attitude (ALFA) Trainer - Langley AFB, VA

NASA Image and Video Library

1962-01-01

S62-01145 (1961) --- Project Mercury astronaut M. Scott Carpenter practices manual control of a spacecraft in the Air Lubricated Free Attitude (ALFA) trainer located at NASA?s Langley Air Force Base, Virginia. This trainer allows the astronaut to see the image of Earth?s surface at his feet while manually controlling the spacecraft. Carpenter has been selected as the prime pilot of the United States? second orbital flight. Photo credit: NASA

Acquisition of Learning by Facilitating Academics (Project ALFA). Final Evaluation Report, 1993-94. OER Report.

ERIC Educational Resources Information Center

Augustin, Marc

The Acquisition of Learning by Facilitating Academics (Project ALFA) was an Elementary and Secondary Education Act Title VII-funded project in its second year in 1993-94. The project operated at a high school in Brooklyn, and served 75 Haitian-speaking students of limited English proficiency with fewer than 5 years in an English-speaking school.…

A redesigned follitropin alfa pen injector for infertility: results of a market research study

PubMed Central

Abbotts, Carole; Salgado-Braga, Cristiana; Audibert-Gros, Céline

2011-01-01

Background: The purpose of this study was to evaluate patient-learning and nurse-teaching experiences when using a redesigned prefilled, ready-to-use follitropin alfa pen injector. Methods: Seventy-three UK women of reproductive age either administering daily treatment with self-injectable gonadotropins or about to start gonadotropin treatment for infertility (aged 24–47 years; 53 self-injection-experienced and 20 self-injection-naïve) and 28 nurses from UK infertility clinics were recruited for the study. Following instruction, patients and nurses used the redesigned follitropin alfa pen to inject water into an orange and completed questionnaires to evaluate their experiences with the pen immediately after the simulated injections. Results: Most (88%, n = 64) patients found it easy to learn how to use the pen. Among injection-experienced patients, 66% (n = 35) agreed that the redesigned pen was easier to learn to use compared with their current method and 70% (n = 37) also said they would prefer its use over current devices for all injectable fertility medications. All nurses considered the redesigned pen easy to learn and believed it would be easy to teach patients how to use. Eighty-six percent (n = 24) of the nurses thought it was easy to teach patients to determine the remaining dose to be dialed and injected in a second pen if the initial dose was incomplete. Compared with other injection devices, 96% (n = 27) thought it was “much easier” to “as easy” to teach patients to use the redesigned pen. Based on ease of teaching, 68% (n = 19) of nurses would choose to teach the pen in preference to any other injection method. Almost all (93%, n = 26) nurses considered that having the same pen format for a range of injectable gonadotropins would facilitate teaching and learning self-injection. Conclusion: In this market research study with infertile patients and infertility nurses, the redesigned follitropin alfa pen was perceived as easy to learn, easy to

Using ALFA for high throughput, distributed data transmission in the ALICE O2 system

NASA Astrophysics Data System (ADS)

Wegrzynek, A.; ALICE Collaboration

2017-10-01

ALICE (A Large Ion Collider Experiment) is a heavy-ion detector designed to study the physics of strongly interacting matter (the Quark-Gluon Plasma at the CERN LHC (Large Hadron Collider). ALICE has been successfully collecting physics data in Run 2 since spring 2015. In parallel, preparations for a major upgrade of the computing system, called O2 (Online-Offline), scheduled for the Long Shutdown 2 in 2019-2020, are being made. One of the major requirements of the system is the capacity to transport data between so-called FLPs (First Level Processors), equipped with readout cards, and the EPNs (Event Processing Node), performing data aggregation, frame building and partial reconstruction. It is foreseen to have 268 FLPs dispatching data to 1500 EPNs with an average output of 20 Gb/s each. In overall, the O2 processing system will operate at terabits per second of throughput while handling millions of concurrent connections. The ALFA framework will standardize and handle software related tasks such as readout, data transport, frame building, calibration, online reconstruction and more in the upgraded computing system. ALFA supports two data transport libraries: ZeroMQ and nanomsg. This paper discusses the efficiency of ALFA in terms of high throughput data transport. The tests were performed with multiple FLPs pushing data to multiple EPNs. The transfer was done using push-pull communication patterns and two socket configurations: bind, connect. The set of benchmarks was prepared to get the most performant results on each hardware setup. The paper presents the measurement process and final results - data throughput combined with computing resources usage as a function of block size. The high number of nodes and connections in the final set up may cause race conditions that can lead to uneven load balancing and poor scalability. The performed tests allow us to validate whether the traffic is distributed evenly over all receivers. It also measures the behaviour of

Clinical experience with darbepoietin alfa (NESP) in children undergoing hemodialysis.

PubMed

De Palo, Tommaso; Giordano, Mario; Palumbo, Fabrizio; Bellantuono, Rosa; Messina, Giovanni; Colella, Vincenzo; Caringella, Angela D

2004-03-01

Darbepoietin alfa (NESP) is a new long-acting erythropoietin, with a half-life 3 times longer than the old epoietins. In the present study, we evaluated the efficacy of NESP in a group of children on hemodialysis. Seven children, five male and two female, with a mean age of 11.5 +/- 3 years and a mean weight of 34.1 +/- 11 kg, were enrolled in the study. All had been treated for at least 6 months with epoietin alfa at a mean dose of 106 +/- 76 IU/kg 3 times/week i.v. They were then given NESP at a mean dose of 1.59 +/- 1.19 microg/kg once a week i.v., according to the suggested conversion index (weekly epoietin alfa dose/200=weekly NESP dose). Anemia was evaluated at the end of a dialysis session. This was especially important for children less compliant with water restriction. Serum ferritin and percentage transferrin saturation (TSAT) were also monitored, as were dialysis efficacy (Kt/V), blood pressure, and heparin requirements. Before starting the new treatment, all patients had an adequate mean hemoglobin (Hb) level (11.19 +/- 1.7 g/dl) and an adequate iron status (TSAT 24.2 +/- 11.5, serum ferritin 220 +/- 105 mg/dl). Five of the seven patients were also treated with intravenous ferric gluconate (10-20 mg/kg per week). Six children were on antihypertensive treatment. After the 1st month of treatment, we observed an excessive increase in Hb, 12.3 +/- 1.7 g/dl, (P<0.05), with severe hypertension in the youngest two patients (Hb>13 g/dl). A short discontinuation of the medication, followed by restarting at a decreased dosage, allowed us to continue with the treatment. At the 2nd month of follow-up, a mean plasma Hb level of 12.2 +/- 1.2 g/dl was observed, with a NESP mean dose of 0.79 +/- 0.4 microg/kg per week. Steady state was reached at 3 months, with a mean Hb of 11.8 +/- 1.4 g/dl and a mean NESP dose of 0.51 +/- 0.18 microg/kg per week (P<0.05). These results persisted at 6 months of follow-up; only one child had a persistent increase in platelet level (373

Effects of solution conditions on methionine oxidation in albinterferon alfa-2b and the role of oxidation in its conformation and aggregation.

PubMed

Chou, Danny K; Krishnamurthy, Rajesh; Manning, Mark Cornell; Randolph, Theodore W; Carpenter, John F

2013-02-01

Physical and chemical degradation of therapeutic proteins can occur simultaneously. In this study, our first objective was to investigate how solution conditions that impact conformational stability of albinterferon alfa-2b, a recombinant fusion protein, modulate rates of methionine (Met) oxidation. Another objective of this work was to determine whether oxidation affects conformation and rate of aggregation of the protein. The protein was subjected to oxidation in solutions of varying pH, ionic strength, and excipients by the addition of 0.02% tertiary-butyl hydroperoxide (TBHP). The rate of formation of Met-sulfoxide species was monitored by reversed-phase high-performance liquid chromatography and compared across solution conditions. Albinterferon alfa-2b exhibited susceptibility to Met oxidation during exposure to TBHP that was highly dependent on solution parameters, but there was not a clear correlation between oxidation rate and protein conformational stability. Met oxidation resulted in significant perturbation of both secondary and tertiary structure of albinterferon alfa-2b as shown by both far-ultraviolet (UV) and near-UV circular dichroism. Moreover, oxidation of the protein caused a noticeable reduction in the protein's resistance to thermal denaturation. Surprisingly, despite its negative effect on solution structure and conformational stability, oxidation actually reduced the protein's aggregation rate during agitation at room temperature as well as during quiescent incubation at 40°C. Oxidation of the protein resulted in improved colloidal stability of the protein, which is manifested by a more positive B(22) value in the oxidized protein. Thus, the reduced aggregation rate after oxidation suggests that increased colloidal stability of oxidized albinterferon alfa-2b counteracted oxidation-induced decreases in conformational stability. Copyright © 2012 Wiley Periodicals, Inc.

The association of darbepoetin alfa with hemoglobin and health-related quality of life in patients with chronic kidney disease not receiving dialysis.

PubMed

Abu-Alfa, Ali K; Sloan, Lance; Charytan, Chaim; Sekkarie, Mohamed; Scarlata, Debra; Globe, Denise; Audhya, Paul

2008-04-01

Anemia of chronic kidney disease (CKD) decreases patients' health-related quality of life (HRQoL). The objective of this subanalysis was to determine the effect of every-other-week (Q2W) darbepoetin alfa on hemoglobin (Hb) levels and HRQoL measures in subjects with CKD who are naïve to erythropoiesis-stimulating agents (ESAs). STAAR was a 52-week, multicenter, single-arm study. Subject inclusion criteria included: > or = 18 years of age and creatinine clearance < or = 70 mL/min or estimated glomerular filtration rate < or = 60 mL/min/1.73 m(2) but not receiving dialysis. Subjects included in this subanalysis were previously naïve to ESAs, had Hb < 11 g/dL, were initiated on subcutaneous Q2W darbepoetin alfa to achieve a Hb level not to exceed 12 g/dL, and had responses to at least one question on the KDQOL-CRI forms administered at baseline, week 12, and week 52. Of 911 ESA-naïve subjects enrolled in the study, 277 (30.4%) were included in this subanalysis. The majority of subanalysis subjects were Caucasian (63.2%) and/or women (54.5%). Mean Hb concentrations and all KDQOL-CRI scores improved significantly between baseline and week 12 (p < 0.0001), and were maintained until week 52. Darbepoetin alfa was well tolerated. Darbepoetin alfa initiated Q2W achieved and maintained Hb targets, and significantly improved and maintained HRQoL in study subjects with CKD. Limitations of the study must be considered when extrapolating these results to assess the benefits of treatment on HRQoL in the general CKD population.

Long-term Immunogenicity of Elosulfase Alfa in the Treatment of Morquio A Syndrome: Results From MOR-005, a Phase III Extension Study.

PubMed

Long, Brian; Tompkins, Troy; Decker, Celeste; Jesaitis, Lynne; Khan, Shahid; Slasor, Peter; Harmatz, Paul; O'Neill, Charles A; Schweighardt, Becky

2017-01-01

Elosulfase alfa is an enzyme replacement therapy for the treatment of Morquio A syndrome (mucopolysaccharidosis IVA), a lysosomal storage disorder caused by a deficiency of the enzyme N-acetylgalactose-amine-6-sulfatase. We previously reported immunogenicity data from our 24-week placebo-controlled Phase III study, MOR-004. Here, we report the long-term immunogenicity profile of elosulfase alfa from MOR-005, the Phase III extension trial to assess potential correlations between antidrug antibodies and efficacy and safety profile outcomes throughout 120 weeks of treatment. The long-term immunogenicity of elosulfase alfa was evaluated in patients with Morquio A syndrome in an open-label extension study for a total of 120 weeks. All patients received 2.0 mg/kg elosulfase alfa either weekly or every other week before establishment of 2.0 mg/kg/wk as the recommended dose, at which time all patients received weekly treatment. Efficacy measures were compared with those from the MOR-004 baseline, enabling analysis of changes over 120 weeks. The primary efficacy measure was the change from baseline in 6-minute walk test. Secondary measures included changes from baseline in 3-minute stair climb test and normalized urine keratan sulfate, a pharmacodynamic metric. All patients treated with elosulfase alfa developed antidrug total antibodies (TAb) by week 24 of MOR-004. In the extension study, all patients, including those who had previously received placebo, were TAb positive by study week 36 (MOR-005 week 12). All patients remained TAb positive throughout the study, and TAb titers were similar across treatment groups at week 120. Nearly all patients tested positive for neutralizing antibodies (NAb) at least once, with incidence of NAb positivity peaking at 85.9% at study week 36, then steadily declining to 66.0% at study week 120. In all treatment groups, mean urine keratan sulfate remained below treatment-naive baseline despite the presence of antidrug antibodies. No

Reduction of Plasma Globotriaosylsphingosine Levels After Switching from Agalsidase Alfa to Agalsidase Beta as Enzyme Replacement Therapy for Fabry Disease.

PubMed

Goker-Alpan, Ozlem; Gambello, Michael J; Maegawa, Gustavo H B; Nedd, Khan J; Gruskin, Daniel J; Blankstein, Larry; Weinreb, Neal J

2016-01-01

Agalsidase alfa and agalsidase beta, recombinant enzyme preparations for treatment of Fabry disease (FD), have different approved dosing schedules: 0.2 mg/kg and 1.0 mg/kg every other week (EOW), respectively. This open-label, multicenter, exploratory phase 4 study evaluated plasma globotriaosylsphingosine (lyso-GL-3) and plasma and urine globotriaosylceramide (GL-3) levels at baseline and 2, 4, and 6 months after the switch from agalsidase alfa (0.2 mg/kg EOW for ≥12 months) to agalsidase beta (1.0 mg/kg EOW) in 15 male patients with FD. Immunoglobulin (Ig)G antidrug antibody titers were assessed, and safety was monitored throughout the study. Plasma lyso-GL-3 concentrations decreased significantly within 2 months after switch and reductions continued through month 6 (mean absolute changes, -12.8, -16.1, and -16.7 ng/mL at 2, 4, and 6 months, respectively; all P < 0.001). The mean percentage reduction from baseline was 39.5% (P < 0.001) at month 6. For plasma GL-3, the mean absolute change from baseline (-0.9 μg/mL) and percentage reduction (17.9%) at month 6 were both significant (P < 0.05). Urine GL-3 measurements showed intra-patient variability and changes from baseline were not significant. No clinical outcomes were assessed in this 6-month study, and, therefore, no conclusions can be drawn regarding the correlation of observed reductions in glycosphingolipid concentrations with clinically relevant outcomes. There were no differences in IgG antidrug antibody titers between the two enzymes. The switch from agalsidase alfa to agalsidase beta was well tolerated. Plasma lyso-GL-3 and GL-3 levels reduced after switching from agalsidase alfa to agalsidase beta, indicating that agalsidase beta has a greater pharmacodynamic effect on these markers at the recommended dose. These data further support the use of agalsidase beta 1.0 mg/kg EOW as enzyme replacement therapy in FD.

Economic impact of ovarian stimulation with corifollitropin alfa versus conventional daily gonadotropins in oocyte donors: a randomized study.

PubMed

Cruz, María; Alamá, Pilar; Muñoz, Manuel; Collado, Diana; Blanes, Carlos; Solbes, Enrique; Requena, Antonio

2017-06-01

Assisted reproductive technologies are well-established treatments for many types of subfertility representing substantial economic and healthcare implications for patients, healthcare providers and society as a whole. In order to optimize outcomes according to the type of gonadotrophins within an oocyte donor programme, we performed an economic evaluation based on data collected in a multicentre, prospective, randomized study within three private clinics belonging to the IVI Group. Results showed no relevant between-group differences in the clinical variables. According to the economic analysis, ovarian stimulation with corifollitropin alfa increased the overall cost of the treatment as well as the cost per retrieved and effective oocyte, although the differences were not statistically significant. In conclusion, cost savings can be achieved using cheaper gonadotrophins during ovarian stimulation. The cost of corifollitropin alfa compared with recombinant FSH and highly purified human menopausal gonadotrophin should be considered when making treatment decisions. Copyright © 2017 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

Large, comparative, randomized double-blind trial confirming noninferiority of pregnancy rates for corifollitropin alfa compared with recombinant follicle-stimulating hormone in a gonadotropin-releasing hormone antagonist controlled ovarian stimulation protocol in older patients undergoing in vitro fertilization.

PubMed

Boostanfar, Robert; Shapiro, Bruce; Levy, Michael; Rosenwaks, Zev; Witjes, Han; Stegmann, Barbara J; Elbers, Jolanda; Gordon, Keith; Mannaerts, Bernadette

2015-07-01

To compare corifollitropin alfa with recombinant FSH treatment in terms of the vital pregnancy rate in older patients undergoing IVF. Phase 3 randomized, double-blind, noninferiority trial. Multicenter trial. A total of 1,390 women aged 35-42 years. A single injection of 150 μg of corifollitropin alfa or daily 300 IU of recombinant FSH for the first 7 days then daily recombinant FSH until three follicles reach ≥17 mm in size. Ganirelix was started on stimulation day 5 up to and including the day of recombinant hCG administration. If available, two good quality embryos were transferred on day 3. Vital pregnancy rate (PR), number of oocytes, and live birth rate. Vital PRs per started cycle were 23.9% in the corifollitropin alfa group and 26.9% in the recombinant FSH group, with an estimated difference (95% confidence interval) of -3.0% (-7.4 to 1.4). The mean (SD) number of recovered oocytes per started cycle was 10.7 (7.2) and 10.3 (6.8) in the corifollitropin alfa and the recombinant FSH groups, respectively, with an estimated difference of 0.5 (-0.2 to 1.2). The live birth rates per started cycle were 21.3% in the corifollitropin alfa group and 23.4% in the recombinant FSH group, with an estimated difference (95% confidence interval) -2.3% (-6.5 to 1.9). The incidence of serious adverse events was 0.4% versus 2.7% in the corifollitropin alfa and recombinant FSH groups, respectively, and of ovarian hyperstimulation syndrome (OHSS; all grades) was 1.7% in both groups. Treatment with corifollitropin alfa was proven noninferior to daily recombinant FSH with respect to vital PRs, number of oocytes retrieved, and live birth rates, and was generally well tolerated. NCT01144416. Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Effectiveness and cost-effectiveness of transmural collaborative care with consultation letter (TCCCL) and duloxetine for major depressive disorder (MDD) and (sub)chronic pain in collaboration with primary care: design of a randomized placebo-controlled multi-Centre trial: TCC:PAINDIP.

PubMed

de Heer, Eric W; Dekker, Jack; van Eck van der Sluijs, Jonna F; Beekman, Aartjan Tf; van Marwijk, Harm Wj; Holwerda, Tjalling J; Bet, Pierre M; Roth, Joost; Hakkaart-Van Roijen, Leona; Ringoir, Lianne; Kat, Fiona; van der Feltz-Cornelis, Christina M

2013-05-24

The comorbidity of pain and depression is associated with high disease burden for patients in terms of disability, wellbeing, and use of medical care. Patients with major and minor depression often present themselves with pain to a general practitioner and recognition of depression in such cases is low, but evolving. Also, physical symptoms, including pain, in major depressive disorder, predict a poorer response to treatment. A multi-faceted, patient-tailored treatment programme, like collaborative care, is promising. However, treatment of chronic pain conditions in depressive patients has, so far, received limited attention in research. Cost effectiveness of an integrated approach of pain in depressed patients has not been studied. This study is a placebo controlled double blind, three armed randomized multi centre trial. Patients with (sub)chronic pain and a depressive disorder are randomized to either a) collaborative care with duloxetine, b) collaborative care with placebo or c) duloxetine alone. 189 completers are needed to attain sufficient power to show a clinically significant effect of 0.6 SD on the primary outcome measures (PHQ-9 score). Data on depression, anxiety, mental and physical health, medication adherence, medication tolerability, quality of life, patient-doctor relationship, coping, health resource use and productivity will be collected at baseline and after three, six, nine and twelve months. This study enables us to show the value of a closely monitored integrated treatment model above usual pharmacological treatment. Furthermore, a comparison with a placebo arm enables us to evaluate effectiveness of duloxetine in this population in a real life setting. Also, this study will provide evidence-based treatments and tools for their implementation in practice. This will facilitate generalization and implementation of results of this study. Moreover, patients included in this study are screened for pain symptoms, differentiating between nociceptive

Chronic treatment with prazosin or duloxetine lessens concurrent anxiety-like behavior and alcohol intake: evidence of disrupted noradrenergic signaling in anxiety-related alcohol use

PubMed Central

Skelly, Mary J; Weiner, Jeff L

2014-01-01

Background Alcohol use disorders have been linked to increased anxiety, and enhanced central noradrenergic signaling may partly explain this relationship. Pharmacological interventions believed to reduce the excitatory effects of norepinephrine have proven effective in attenuating ethanol intake in alcoholics as well as in rodent models of ethanol dependence. However, most preclinical investigations into the effectiveness of these drugs in decreasing ethanol intake have been limited to acute observations, and none have concurrently assessed their anxiolytic effects. The purpose of these studies was to examine the long-term effectiveness of pharmacological interventions presumed to decrease norepinephrine signaling on concomitant ethanol self-administration and anxiety-like behavior in adult rats with relatively high levels of antecedent anxiety-like behavior. Methods Adult male Long-Evans rats self-administered ethanol on an intermittent access schedule for eight to ten weeks prior to being implanted with osmotic minipumps containing either an a1-adrenoreceptor antagonist (prazosin, 1.5 mg/kg/day), a β1/2-adrenoreceptor antagonist (propranolol, 2.5 mg/kg/day), a serotonin/norepinephrine reuptake inhibitor (duloxetine, 1.5 mg/kg/day) or vehicle (10% dimethyl sulfoxide). These drugs were continuously delivered across four weeks, during which animals continued to have intermittent access to ethanol. Anxiety-like behavior was assessed on the elevated plus maze before treatment and again near the end of the drug delivery period. Results Our results indicate that chronic treatment with a low dose of prazosin or duloxetine significantly decreases ethanol self-administration (P < 0.05). Furthermore, this decrease in drinking is accompanied by significant reductions in the expression of anxiety-like behavior (P < 0.05). Conclusions These findings suggest that chronic treatment with putative inhibitors of central noradrenergic signaling may attenuate ethanol intake via a

Chronic treatment with prazosin or duloxetine lessens concurrent anxiety-like behavior and alcohol intake: evidence of disrupted noradrenergic signaling in anxiety-related alcohol use.

PubMed

Skelly, Mary J; Weiner, Jeff L

2014-07-01

Alcohol use disorders have been linked to increased anxiety, and enhanced central noradrenergic signaling may partly explain this relationship. Pharmacological interventions believed to reduce the excitatory effects of norepinephrine have proven effective in attenuating ethanol intake in alcoholics as well as in rodent models of ethanol dependence. However, most preclinical investigations into the effectiveness of these drugs in decreasing ethanol intake have been limited to acute observations, and none have concurrently assessed their anxiolytic effects. The purpose of these studies was to examine the long-term effectiveness of pharmacological interventions presumed to decrease norepinephrine signaling on concomitant ethanol self-administration and anxiety-like behavior in adult rats with relatively high levels of antecedent anxiety-like behavior. Adult male Long-Evans rats self-administered ethanol on an intermittent access schedule for eight to ten weeks prior to being implanted with osmotic minipumps containing either an a1-adrenoreceptor antagonist (prazosin, 1.5 mg/kg/day), a β1/2-adrenoreceptor antagonist (propranolol, 2.5 mg/kg/day), a serotonin/norepinephrine reuptake inhibitor (duloxetine, 1.5 mg/kg/day) or vehicle (10% dimethyl sulfoxide). These drugs were continuously delivered across four weeks, during which animals continued to have intermittent access to ethanol. Anxiety-like behavior was assessed on the elevated plus maze before treatment and again near the end of the drug delivery period. Our results indicate that chronic treatment with a low dose of prazosin or duloxetine significantly decreases ethanol self-administration (P < 0.05). Furthermore, this decrease in drinking is accompanied by significant reductions in the expression of anxiety-like behavior (P < 0.05). These findings suggest that chronic treatment with putative inhibitors of central noradrenergic signaling may attenuate ethanol intake via a reduction in anxiety-like behavior.

Charging properties of cassiterite (alfa-SnO2) surfaces

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

Rosenqvist, Jorgen K; Machesky, Michael L.; Vlcek, L.

The acid-base properties of cassiterite (alfa-SnO2) surfaces at 10 50 C were studied using potentiometric titrations of powder suspensions in aqueous NaCl and RbCl media. The proton sorption isotherms exhibited common intersection points in the pH-range 4.0 to 4.5 at all conditions and the magnitude of charging was similar but not identical in NaCl and RbCl. The hydrogen bonding configuration at the oxide-water interface, obtained from classical Molecular Dynamics (MD) simulations, was analyzed in detail and the results were explicitly incorporated in calculations of protonation constants for the reactive surface sites using the revised MUSIC model. The calculations indicated thatmore » the terminal SnOH2 group is more acidic than the bridging Sn2OH group, with protonation constants (log KH) of 3.60 and 5.13 at 25 C, respectively. This is contrary to the situation on the isostructural alfa-TiO2 (rutile), apparently due to the difference in electronegativity between Ti and Sn. MD simulations and speciation calculations indicated considerable differences in the speciation of Na+ and Rb+, despite the similarities in overall charging. Adsorbed sodium ions are almost exclusively found in bidentate surface complexes, while adsorbed rubidium ions form comparable amounts of bidentate and tetradentate complexes. Also, the distribution of adsorbed Na+ between the different complexes shows a considerable dependence on surface charge density (pH), while the distribution of adsorbed Rb+ is almost independent of pH. A Surface Complexation Model (SCM) capable of accurately describing both the measured surface charge and the MD predicted speciation of adsorbed Na+/Rb+ was formulated. According to the SCM, the deprotonated terminal group (SnOH-0.40) and the protonated bridging group (Sn2OH+0.36) dominate the surface speciation over the entire pH-range (2.7 10), illustrating the ability of positively and negatively charged surface groups to coexist. Complexation of the medium

The Effect of Drotrecogin Alfa (activated) on Long-Term Survival after Severe Sepsis

PubMed Central

Angus, Derek C.; Laterre, Pierre-Francois; Helterbrand, Jeff; Ely, E. Wesley; Ball, Daniel E.; Garg, Rekha; Weissfeld, Lisa A.; Bernard, Gordon

2016-01-01

Objective To determine long-term survival for subjects with severe sepsis enrolled in the previous multicenter trial (PROWESS) of drotrecogin alfa (activated) [DrotAA] versus placebo. Design Retrospective, cross-sectional, blinded follow-up of subjects enrolled in a previous randomized, controlled trial. Setting 164 tertiary care institutions in 11 countries. Interventions DrotAA (n=850), 24 μg/kg/h for 96 hours, or placebo (n=840). Participants The 1690 subjects with severe sepsis enrolled and treated with study drug in PROWESS, of whom 1220 were alive at 28 days (the end of the original PROWESS follow-up). Measurements and Main Results Long-term survival data were collected. We had follow-up information on 100% of subjects at 28 days, 98% at hospital discharge, 94% at 3 months, and 93% at 1 year. The longest follow-up was 3.6 years. Hospital survival was higher with DrotAA versus placebo (70.3% vs. 65.1%, p=0.03). There was no statistically significant difference in duration of survival time or in landmark survival rates in subjects who received DrotAA compared with those who received placebo, [median duration of survival = 1113d vs. 846d for DrotAA vs. placebo, p=0.10; landmark survival rates for DrotAA vs. placebo, 66.1% vs. 62.4% at 3 months (p=0.11), 62.2% vs. 60.3% at 6 months (p=0.44), 58.9% vs. 57.2% at 1 year (p=0.49), and 52.6% vs. 49.3% at 2½ years (p=0.21)]. There was a significant interaction (p=0.0008) between treatment assignment and baseline APACHE II scores, suggesting qualitative differences in treatment effect with severity of illness. Subjects with APACHE II ≥25 had better survival time with DrotAA (median duration of survival: 450d vs. 71d, p=0.0005). Survival rates were also higher at landmark timepoints [DrotAA vs. placebo, 58.9% vs. 48.4% at 3 months (p=0.003), 55.2% vs. 45.3% at 6 months (p=0.005), 52.1% vs. 41.3% at 1 year (p=0.002), and 41.7% vs. 32.9% at 2½ years (p=0.001)]. In the APACHE II <25 group there was no significant

Gateways to clinical trials.

PubMed

Tomillero, A; Moral, M A

2009-10-01

[Methoxy-11c]PD-153035; Afamelanotide, Agalsidase beta, Alemtuzumab, Alkaline phosphatase, Amlodipine, Anecortave acetate, Apixaban, Aripiprazole, Atomoxetine hydrochloride; Bevacizumab, Bortezomib, Bosentan, Botulinum toxin type B, Brimonidine tartrate/timolol maleate, Brivudine; Canakinumab, Cetuximab, Chlorotoxin, Cinaciguat; Dapagliflozin, Decitabine, Duloxetine hydrochloride; Elagolix sodium, Eplerenone, Eritoran tetrasodium, Escitalopram oxalate, Etoricoxib, Ezetimibe; Fospropofol disodium; G-207, Gabapentin enacarbil, Gefitinib, Golimumab; Human plasmin; Inotuzumab ozogamicin, Insulin glargine, Insulin glulisine, Istaroxime, Ixabepilone; KLH; Levodopa/carbidopa/entacapone; Miglustat, Mitumprotimut-T, MP-470; Oblimersen sodium, Olmesartan medoxomil; P53-SLP, PAN-811, Patupilone, Pazopanib hydrochloride, PC-515, Peginterferon alfa-2a, Pegylated arginine deiminase 20000, Pemetrexed disodium, Plitidepsin, Pregabalin; Rasagiline mesilate, Rotigotine; SCH-697243, Sirolimus-eluting stent, Sumatriptan succinate/naproxen sodium, Sunitinib malate; Tadalafil, Tapentadol hydrochloride, TMC-207; V-211, Valganciclovir hydrochloride; Zolpidem tartrate. Copyright 2009 Prous Science, S.A.U. or its licensors. All rights reserved.

DAHANCA 10 - Effect of darbepoetin alfa and radiotherapy in the treatment of squamous cell carcinoma of the head and neck. A multicenter, open-label, randomized, phase 3 trial by the Danish head and neck cancer group.

PubMed

Overgaard, Jens; Hoff, Camilla Molich; Hansen, Hanne Sand; Specht, Lena; Overgaard, Marie; Lassen, Pernille; Andersen, Elo; Johansen, Jørgen; Andersen, Lisbeth Juhler; Evensen, Jan Folkvard; Alsner, Jan; Grau, Cai

2018-04-01

To evaluate if correction of low hemoglobin (Hb) levels by means of darbepoetin alfa improves the outcomes of radiotherapy in patients with squamous cell carcinoma of the head and neck (HNSCC). Patients eligible for primary radiotherapy and who had Hb values below 14.0 g/dl were randomized to receive accelerated fractionated radiotherapy with or without darbepoetin alfa. Patients also received the hypoxic radiosensitizer nimorazole. Darbepoetin alfa was given weekly during radiotherapy or until the Hb value exceeded 15.5 g/dl. Following a planned interim analysis which showed inferiority of the experimental treatment the trial was stopped after inclusion of 522 patients (of a planned intake of 600). Of these, 513 were eligible for analysis (254 patients treated with darbepoetin alfa and 259 patients in the control group). Overall, the patients were distributed according to the stratification parameters (gender, T and N staging, tumor site). Treatment with darbepoetin alfa increased the Hb level to the planned value in 81% of the patients. The compliance was good without excess serious adverse events. The results showed a poorer outcome with a 5-year cumulative loco-regional failure rate of 47% vs. 34%, Hazard Ratio (HR): 1.53 [1.16-2.02], for the darbepoetin alfa vs. control arm, respectively. This was also seen for the endpoints of event-free survival (HR: 1.36 [1.09-1.69]), disease-specific death (HR: 1.43 [1.08-1.90]), and overall survival (HR: 1.30 [1.02-1.64]). There was no enhanced risk of cardio-vascular events observed in the experimental arm or any significant differences in acute or late radiation related morbidity. All univariate analyses were confirmed in a multivariate setting. Correction of the Hb level with darbepoetin alfa during radiotherapy of patients with HNSCC resulted in a significantly poorer tumor control and survival. Copyright © 2018 Elsevier B.V. All rights reserved.

Update on role of agalsidase alfa in management of Fabry disease

PubMed Central

Ramaswami, Uma

2011-01-01

Fabry disease (FD) is an X-linked lysosomal storage disorder that affects both men and women. The manifestations of this heterogeneous disease are multisystemic and progressive. Prior to the development of enzyme replacement therapy, the management and treatment for Fabry disease was largely nonspecific and supportive. Because enzyme replacement therapy became commercially available in 2001, a variety of clinical benefits in Fabry patients have been consistently reported, including improved renal pathology and cardiac function, and reduced severity of neuropathic pain and improved pain-related quality of life. This update focuses on published data on the efficacy and tolerability of enzyme replacement therapy with agalsidase alfa, and gives a brief overview on some of the outstanding management issues in the treatment of this complex disease. PMID:21552486

Safety and efficacy of turoctocog alfa (NovoEight®) during surgery in patients with haemophilia A: results from the multinational guardian™ clinical trials

PubMed Central

Santagostino, E; Lentz, S R; Misgav, M; Brand, B; Chowdary, P; Savic, A; Kilinc, Y; Amit, Y; Amendola, A; Solimeno, L P; Saugstrup, T; Matytsina, I

2015-01-01

Recombinant factor VIII (rFVIII) products provide a safe and efficacious replacement therapy for prevention and treatment of bleeding episodes in patients with haemophilia A. The present investigations from the multinational, open-label guardian™ clinical trials assessed the haemostatic response of turoctocog alfa (NovoEight®), a rFVIII product, in patients with severe haemophilia A (FVIII ≤ 1%) undergoing surgery. All patients had a minimum of 50 exposure days to any FVIII product prior to surgery and no history of inhibitors. A total of 41 procedures (13 orthopaedic, 19 dental and 9 general) were performed in 33 patients aged 4–59 years. Of the 41 procedures, 15 were major surgeries in 13 patients and 26 were minor surgeries in 21 patients. The success rate for haemostatic response was 100% (success was defined as ‘excellent’ or ‘good’ haemostatic outcome). Turoctocog alfa consumption on the day of surgery ranged from 27 to 153 IU kg−1. The mean daily dose declined over time, while retaining adequate FVIII coverage as measured by trough levels. Overall, no safety issues were identified. No thrombotic events were observed and none of the patients developed FVIII inhibitors. In conclusion, the present results show that turoctocog alfa was effective in controlling blood loss by obtaining a sufficient haemostatic response in patients with severe haemophilia A undergoing surgery. PMID:25273984

Gateways to clinical trials.

PubMed

Bayes, M; Rabasseda, X; Prous, J R

2006-03-01

Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: 131I-labetuzumab; Abacavir sulfate, abatacept, adalimumab, ademetionine, adjuvanted influenza vaccine, alefacept, alemtuzumab, amlodipine, amphotericin B, anakinra, aripiprazole, aspirin, axitinib; Betamethasone dipropionate, bevacizumab, biphasic insulin aspart, bortezomib, bosentan, botulinum toxin type B, BQ-123; Calcium folinate, canertinib dihydrochloride, carboplatin, carmustine, cetirizine hydrochloride, cetuximab, cholecalciferol, ciclesonide, ciclosporin, cinacalcet hydrochloride, cisplatin, clarithromycin, clofazimine, cold-adapted influenza vaccine trivalent, CpG-7909; Darbepoetin alfa, darifenacin hydrobromide, DB-289, desloratadine, Dexamet, dicycloverine hydrochloride, dimethyl fumarate, docetaxel, dolastatin 10, drospirenone, drospirenone/estradiol, duloxetine hydrochloride; Ecogramostim, edotecarin, efaproxiral sodium, enalapril maleate, epoetin beta, epoprostenol sodium, epratuzumab, erlotinib hydrochloride, escitalopram oxalate, estradiol, etanercept; Fluconazole, fludarabine phosphate, fluorouracil; Gefitinib, gemcitabine, Ghrelin (human), glibenclamide, glimepiride, GTI-2040; Haloperidol, human insulin, hydrocortisone probutate; Imatinib mesylate, indisulam, influenza vaccine, inhaled insulin, insulin aspart, insulin glulisine, insulin lispro, irinotecan, ispronicline; Lamivudine, lamivudine/zidovudine/abacavir sulfate, lapatinib, letrozole, levocetirizine, lomustine, lonafarnib, lumiracoxib;Magnesium sulfate, MD-1100, melphalan, metformin hydrochloride, methotrexate, metoclopramide hydrochloride, mitiglinide calcium hydrate, monophosphoryl lipid A, montelukast sodium, motexafin gadolinium

Reduced dose and duration of peginterferon alfa-2b and weight-based ribavirin in patients with genotype 2 and 3 chronic hepatitis C.

PubMed

Manns, Michael; Zeuzem, Stefan; Sood, Ajit; Lurie, Yoav; Cornberg, Markus; Klinker, Hartwig; Buggisch, Peter; Rössle, Martin; Hinrichsen, Holger; Merican, Ismail; Ilan, Yaron; Mauss, Stefan; Abu-Mouch, Saif; Horban, Andryes; Müller, Thomas H; Welsch, Christoph; Chen, Rongdean; Faruqi, Rab; Pedicone, Lisa D; Wedemeyer, Heiner

2011-09-01

There is increasing interest in identifying patients with chronic hepatitis C genotype 2 or 3 infection in whom it is possible to lower the burden of therapy while retaining high levels of efficacy. Treatment-naive patients with chronic hepatitis C genotype 2/3 infection were randomized to receive peginterferon alfa-2b (1.5μg/kg/wk) for 24weeks (group A); peginterferon alfa-2b (1.0μg/kg/wk) for 24weeks (group B); or peginterferon alfa-2b (1.5μg/kg/wk) for 16weeks (group C), each in combination with weight-based ribavirin (800-1200mg/d). The study population comprised two cohorts: the Hep-Net cohort enrolled in Germany and an International cohort enrolled at study sites throughout Europe and Asia. The primary end point was sustained virological response (SVR). The study included 682 patients; 80.2% had genotype 3 infection. In the intent-to-treat population, SVR rates were 66.5%, 64.3%, and 56.6% in groups A, B, and C, and were similar in Asian and white patients. Treatment differences (A vs. B and A vs. C) failed to reach the predefined margin for noninferiority of -10%; and thus groups B and C failed to show noninferiority relative to group A. Among patients with undetectable HCV RNA at week 4, SVR rates were 75.3%, 75.9%, and 72.4%, respectively. Relapse rates were 17.8%, 16.3%, and 29.3%, respectively. Treatment-emergent serious adverse events were highest in group A and lowest in group C, and adverse events leading to discontinuation were similar across treatment arms. For patients with chronic hepatitis C genotype 2/3 infection, 24weeks of peginterferon alfa-2b (1.5μg/kg/wk) plus weight-based ribavirin remains a standard-of-care therapy; however, treatment for 16weeks may be considered for patients with undetectable HCV RNA at week 4 of the treatment. Copyright © 2011. Published by Elsevier B.V.

Gateways to clinical trials.

PubMed

Bayés, M; Rabasseda, X; Prous, J R

2006-10-01

Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issues focuses on the following selection of drugs: (-)-Epigallocatechin gallate, (-)-gossypol, 2-deoxyglucose, 3,4-DAP, 7-monohydroxyethylrutoside; Ad5CMV-p53, adalimumab, adefovir dipivoxil, ADH-1, alemtuzumab, aliskiren fumarate, alvocidib hydrochloride, aminolevulinic acid hydrochloride, aminolevulinic acid methyl ester, amrubicin hydrochloride, AN-152, anakinra, anecortave acetate, antiasthma herbal medicine intervention, AP-12009, AP-23573, apaziquone, aprinocarsen sodium, AR-C126532, AR-H065522, aripiprazole, armodafinil, arzoxifene hydrochloride, atazanavir sulfate, atilmotin, atomoxetine hydrochloride, atorvastatin, avanafil, azimilide hydrochloride; Bevacizumab, biphasic insulin aspart, BMS-214662, BN-83495, bortezomib, bosentan, botulinum toxin type B; Caspofungin acetate, cetuximab, chrysin, ciclesonide, clevudine, clofarabine, clopidogrel, CNF-1010, CNTO-328, CP-751871, CX-717, Cypher; Dapoxetine hydrochloride, darifenacin hydrobromide, dasatinib, deferasirox, dextofisopam, dextromethorphan/quinidine sulfate, diclofenac, dronedarone hydrochloride, drotrecogin alfa (activated), duloxetine hydrochloride, dutasteride; Edaravone, efaproxiral sodium, emtricitabine, entecavir, eplerenone, epratuzumab, erlotinib hydrochloride, escitalopram oxalate, etoricoxib, ezetimibe, ezetimibe/simvastatin; Finrozole, fipamezole hydrochloride, fondaparinux sodium, fulvestrant; Gabapentin enacarbil, gaboxadol, gefitinib, gestodene, ghrelin (human); Human insulin, human papillomavirus vaccine; Imatinib mesylate, immunoglobulin intravenous (human), indiplon, insulin detemir, insulin glargine, insulin glulisine, intranasal insulin, istradefylline, i.v. gamma

Proactive infectious disease approach to dermatologic patients who are taking tumor necrosis factor-alfa antagonists: Part I. Risks associated with tumor necrosis factor-alfa antagonists.

PubMed

Chirch, Lisa M; Cataline, Philip R; Dieckhaus, Kevin D; Grant-Kels, Jane M

2014-07-01

Tumor necrosis factor-alfa levels are linked to disease severity in patients with inflammatory conditions, such as psoriasis. Inhibitors of this cytokine are commonly used with significant success in the treatment of such inflammatory disorders. Their use, however, can be plagued by infectious complications. An awareness of potential infections associated with these therapies is critical in order to maximize preventive efforts both before and during therapy. This review provides a guide for dermatologists caring for patients in need of this type of biologic therapy to preemptively address the infectious risks. Part I of this continuing medical education article reviews background information on the various infectious risks associated with tumor necrosis factor inhibitor therapy and appropriate historical data to obtain in the context of pretherapy evaluations. Copyright © 2014 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

Peginterferon alfa-2b and weight-based or flat-dose ribavirin in chronic hepatitis C patients: a randomized trial.

PubMed

Jacobson, Ira M; Brown, Robert S; Freilich, Bradley; Afdhal, Nezam; Kwo, Paul Y; Santoro, John; Becker, Scott; Wakil, Adil E; Pound, David; Godofsky, Eliot; Strauss, Robert; Bernstein, David; Flamm, Steven; Pauly, Mary Pat; Mukhopadhyay, Pabak; Griffel, Louis H; Brass, Clifford A

2007-10-01

This prospective, multicenter, community-based and academic-based, open-label, investigator-initiated, U.S. study evaluated efficacy and safety of pegylated interferon (PEG-IFN) alfa-2b plus a flat or weight-based dose of ribavirin (RBV) in adults with chronic hepatitis C. Patients (n = 5027) were randomly assigned to receive PEG-IFN alfa-2b 1.5 microg/kg/week plus flat-dose (800 mg/day) or weight-based (800-1400 mg/day) RBV for 48 weeks (patients with genotype 1, 4, 5, or 6) and for 24 or 48 weeks (genotype 2/3 patients). Primary end point was sustained virologic response (undetectable [<125 IU/mL] serum hepatitis C virus RNA at 24-week follow-up). Sustained virologic response, but not end-of-treatment, rates were significantly higher with weight-based than with flat-dose RBV (44.2% versus 40.5%; P = 0.008). Sustained virologic response rates by intention-to-treat analysis were 34.0% and 28.9%, respectively, in genotype 1 patients (P = 0.005) and 31.2% and 26.7%, respectively, in genotype 1 patients with high baseline viral load (P = 0.056). In genotype 2/3 patients, rates were not significantly different (61.8% and 59.5%, respectively) regardless of treatment duration. Besides greater hemoglobin reductions with weight-based RBV, safety profiles were similar across RBV dosing groups, including the 1400-mg/day group. PEG-IFN alfa-2b plus weight-based RBV is more effective than flat-dose RBV, particularly in genotype 1 patients, providing equivalent efficacy across all weight groups. RBV 1400 mg/day is appropriate for patients 105 to 125 kg. For genotype 2/3 patients, 24 weeks of treatment with flat-dose RBV is adequate; no evidence of additional benefit of extending treatment to 48 weeks was demonstrated.

Use of activated protein C has no avail in the early phase of acute pancreatitis.

PubMed

Akay, Sinan; Ozutemiz, Omer; Yenisey, Cigdem; Simsek, Nilufer Genc; Yuce, Gul; Batur, Yucel

2008-01-01

Sepsis and acute pancreatitis have similar pathogenetic mechanisms that have been implicated in the progression of multiple organ failure. Drotrecogin alfa, an analogue of endogenous protein C, reduces mortality in clinical sepsis. Our objective was to evaluate the early therapeutic effects of activated protein C (APC) in a rat model of acute necrotizing pancreatitis. Acute necrotizing pancreatitis was induced by intraductal injection of 5% Na taurocholate. Hourly bolus injections of saline or recombinant human APC (drotrecogin alfa) was commenced via femoral venous catheter four hours after the induction of acute pancreatitis. The experiment was terminated nine hours after pancreatitis induction. Animals in group one (n=20) had a sham operation while animals in group two (n=20) received saline and animals in group three (n=20) received drotrecogin alfa boluses after acute pancreatitis induction. Pancreatic tissue for histopathologic scores and myeloperoxidase, glutathione reductase, glutathione peroxidase, and catalase activities were collected, and blood for serum amylase, urea, creatinine, and interleukin-6 measurements was withdrawn. Serum amylase activity was significantly lower in the APC treated group than the untreated group (17,435+/-432 U/L vs. 27,426+/-118 U/L, respectively). While the serum interleukin-6 concentration in the APC untreated group was significantly lower than the treated group (970+/-323 pg/mL vs. 330+/-368 pg/mL, respectively). In the early phase of acute pancreatitis, drotrecogin alfa treatment did not result in a significant improvement in oxidative and inflammatory parameters or renal functions.

Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia.

PubMed

Welsch, Patrick; Üçeyler, Nurcan; Klose, Petra; Walitt, Brian; Häuser, Winfried

2018-02-28

-analysis using a random-effects model. We assessed the evidence using GRADE and created a 'Summary of findings' table. We added eight new studies with 1979 participants for a total of 18 included studies with 7903 participants. Seven studies investigated duloxetine and nine studies investigated milnacipran against placebo. One study compared desvenlafaxine with placebo and pregabalin. One study compared duloxetine with L-carnitine. The majority of studies were at unclear or high risk of bias in three to five domains.The quality of evidence of all comparisons of desvenlafaxine, duloxetine and milnacipran versus placebo in studies with a parallel design was low due to concerns about publication bias and indirectness, and very low for serious adverse events due to concerns about publication bias, imprecision and indirectness. The quality of evidence of all comparisons of duloxetine and desvenlafaxine with other active drugs was very low due to concerns about publication bias, imprecision and indirectness.Duloxetine and milnacipran had no clinically relevant benefit over placebo for pain relief of 50% or greater: 1274 of 4104 (31%) on duloxetine and milnacipran reported pain relief of 50% or greater compared to 591 of 2814 (21%) participants on placebo (risk difference (RD) 0.09, 95% confidence interval (CI) 0.07 to 0.11; NNTB 11, 95% CI 9 to 14). Duloxetine and milnacipran had a clinically relevant benefit over placebo in patient's global impression to be much or very much improved: 888 of 1710 (52%) on duloxetine and milnacipran (RD 0.19, 95% CI 0.12 to 0.26; NNTB 5, 95% CI 4 to 8) reported to be much or very much improved compared to 354 of 1208 (29%) of participants on placebo. Duloxetine and milnacipran had a clinically relevant benefit compared to placebo for pain relief of 30% or greater. RD was 0.10; 95% CI 0.08 to 0.12; NNTB 10, 95% CI 8 to 12. Duloxetine and milnacipran had no clinically relevant benefit for fatigue (SMD -0.13, 95% CI -0.18 to -0.08; NNTB 18, 95% CI 12 to

Peginterferon alfa-2a and ribavirin in Latino and non-Latino whites with hepatitis C.

PubMed

Rodriguez-Torres, Maribel; Jeffers, Lennox J; Sheikh, Muhammad Y; Rossaro, Lorenzo; Ankoma-Sey, Victor; Hamzeh, Fayez M; Martin, Paul

2009-01-15

Race has been shown to be a factor in the response to therapy for hepatitis C virus (HCV) infection, and limited data suggest that ethnic group may be as well; however, Latinos and other ethnic subpopulations have been underrepresented in clinical trials. We evaluated the effect of Latino ethnic background on the response to treatment with peginterferon alfa-2a and ribavirin in patients infected with HCV genotype 1 who had not been treated previously. In a multicenter, open-label, nonrandomized, prospective study, 269 Latino and 300 non-Latino whites with HCV infection received peginterferon alfa-2a, at a dose of 180 microg per week, and ribavirin, at a dose of 1000 or 1200 mg per day, for 48 weeks, and were followed through 72 weeks. The primary end point was a sustained virologic response. We enrolled Latinos whose parents and grandparents spoke Spanish as their primary language; nonwhite Latinos were excluded. Baseline characteristics were similar in the Latino and non-Latino groups, although higher proportions of Latino patients were 40 years of age or younger, had a body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) of more than 27 or more than 30, and had cirrhosis. The rate of sustained virologic response was higher among non-Latino whites than among Latinos (49% vs. 34%, P<0.001). The absence of HCV RNA in serum was more frequent in non-Latino whites at week 4 (P=0.045) and throughout the treatment period (P<0.001 for all other comparisons). Latino or non-Latino background was an independent predictor of the rate of sustained virologic response in an analysis adjusted for baseline differences in BMI, cirrhosis, and other characteristics. Adherence to treatment did not differ significantly between the two groups. The numbers of patients with adverse events and dose modifications were similar in the two groups, but fewer Latino patients discontinued therapy because of adverse events. Treatment with peginterferon alfa

Safety and efficacy of turoctocog alfa (NovoEight®) during surgery in patients with haemophilia A: results from the multinational guardian™ clinical trials.

PubMed

Santagostino, E; Lentz, S R; Misgav, M; Brand, B; Chowdary, P; Savic, A; Kilinc, Y; Amit, Y; Amendola, A; Solimeno, L P; Saugstrup, T; Matytsina, I

2015-01-01

Recombinant factor VIII (rFVIII) products provide a safe and efficacious replacement therapy for prevention and treatment of bleeding episodes in patients with haemophilia A. The present investigations from the multinational, open-label guardian(™) clinical trials assessed the haemostatic response of turoctocog alfa (NovoEight(®)), a rFVIII product, in patients with severe haemophilia A (FVIII ≤ 1%) undergoing surgery. All patients had a minimum of 50 exposure days to any FVIII product prior to surgery and no history of inhibitors. A total of 41 procedures (13 orthopaedic, 19 dental and 9 general) were performed in 33 patients aged 4-59 years. Of the 41 procedures, 15 were major surgeries in 13 patients and 26 were minor surgeries in 21 patients. The success rate for haemostatic response was 100% (success was defined as 'excellent' or 'good' haemostatic outcome). Turoctocog alfa consumption on the day of surgery ranged from 27 to 153 IU kg(-1). The mean daily dose declined over time, while retaining adequate FVIII coverage as measured by trough levels. Overall, no safety issues were identified. No thrombotic events were observed and none of the patients developed FVIII inhibitors. In conclusion, the present results show that turoctocog alfa was effective in controlling blood loss by obtaining a sufficient haemostatic response in patients with severe haemophilia A undergoing surgery. © 2014 The Authors. Haemophilia Published by John Wiley & Sons Ltd.

Peginterferon alfa-2b in the treatment of Chinese patients with HBeAg-positive chronic hepatitis B: a randomized trial.

PubMed

Cheng, Jun; Wang, Yuming; Hou, Jinlin; Luo, Duande; Xie, Qing; Ning, Qin; Ren, Hong; Ding, Huiguo; Sheng, Jifang; Wei, Lai; Chen, Shijun; Fan, Xiaoling; Huang, Wenxiang; Pan, Chen; Gao, Zhiliang; Zhang, Jiming; Zhou, Boping; Chen, Guofeng; Wan, Mobin; Tang, Hong; Wang, Guiqiang; Yang, Yuxiu; Mohamed, Rosmawati; Guan, Richard; Lee, Tzong-Hsi; Chang, Wen-Hsiung; Zhenfei, Huang; Ye, Zhang; Xu, Daozhen

2014-12-01

In mainland China, peginterferon (PEG-IFN) alfa-2b 1.0μg/kg/wk for 24 weeks is the approved treatment for HBeAg-positive chronic hepatitis B. This multicenter, randomized trial evaluated the safety and efficacy of regimens utilizing increased dose or treatment duration in treatment-naive Chinese patients with chronic hepatitis B. 670 HBeAg-positive patients from China, Malaysia, Taiwan area, Singapore, and Thailand were enrolled. Patients received PEG-IFN alfa-2b 1.0μg/kg/wk (arm A) or 1.5μg/kg/wk (arm B) for 24 weeks, or 1.5μg/kg/wk for 48 weeks (arm C). The primary end point was loss of HBeAg 24 weeks after end of treatment. At the end of follow-up, HBeAg loss was significantly greater in arm C compared with arm A (31.3% vs. 17.3%; P=0.001) and arm B (31.3% vs. 18.1%; P=0.001). No significant difference in the rate of HBeAg loss was observed between arms A and B. The proportions of patients with HBe seroconversion, HBV DNA levels <20,000IU/mL, and ALT normalization at the end of follow-up were significantly higher in arm C compared with arm A and arm B. In arms A, B, and C, rates of early treatment discontinuation were 6.3%, 4.9%, and 8.9%; of discontinuation due to an AE, 2%, 3%, and 3%; and of AEs requiring dose modification, 3%, 6%, and 10%, respectively. In Chinese patients with HBeAg-positive chronic hepatitis B, PEG-IFN alfa-2b 1.5μg/kg/wk for 48 weeks is more efficacious compared with 1.0 and 1.5μg/kg/wk for 24 weeks. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.

Development and Analytical Characterization of Pegunigalsidase Alfa, a Chemically Cross-Linked Plant Recombinant Human α-Galactosidase-A for Treatment of Fabry Disease.

PubMed

Ruderfer, Ilya; Shulman, Avidor; Kizhner, Tali; Azulay, Yaniv; Nataf, Yakir; Tekoah, Yoram; Shaaltiel, Yoseph

2018-05-16

The current treatment of Fabry disease by enzyme replacement therapy with commercially available recombinant human α-Galactosidase A shows a continuous deterioration of the disease patients. Human recombinant α-Galactosidase A is a homodimer with noncovalently bound subunits and is expressed in the ProCellEx plant cell-based protein expression platform to produce pegunigalsidase alfa. The effect of covalent bonding between two α-Galactosidase A subunits by PEG-based cross-linkers of various lengths was evaluated in this study. The results show that cross-linking by a bifunctional PEG polymer of 2000 Da produces a more stable protein with improved pharmacokinetic and biodistribution properties. The chemical modification did not influence the tertiary protein structure but led to an increased thermal stability and showed partial masking of immune epitopes. The developed pegunigalsidase alfa is currently tested in phase III clinical trials and has a potential to show superior efficacy versus the currently used enzyme replacement therapies in the treatment of Fabry disease patients.

HBeAg and hepatitis B virus DNA as outcome predictors during therapy with peginterferon alfa-2a for HBeAg-positive chronic hepatitis B.

PubMed

Fried, Michael W; Piratvisuth, Teerha; Lau, George K K; Marcellin, Patrick; Chow, Wan-Cheng; Cooksley, Graham; Luo, Kang-Xian; Paik, Seung Woon; Liaw, Yun-Fan; Button, Peter; Popescu, Matei

2008-02-01

The aims of this study were to evaluate the usefulness of quantitative hepatitis B e antigen (HBeAg) values for predicting HBeAg seroconversion in patients treated with peginterferon alfa-2a and to assess the dynamic changes in quantitative HBeAg during therapy, compared with conventional measures of serum hepatitis B virus DNA. Data were analyzed from a large, randomized, multinational phase III registration trial involving 271 HBV-infected HBeAg-positive patients who received peginterferon alfa-2a plus oral placebo for 48 weeks. HBeAg levels were measured serially during therapy using a microparticle enzyme immunoassay validated with in-house reference standards obtained from the Paul Ehrlich Institute (PEIU/mL). In patients who achieved HBeAg seroconversion, levels of HBeAg consistently decreased during treatment and remained at their lowest level during the 24 weeks of posttreatment follow-up. After 24 weeks of treatment, 4% of patients with the highest levels of HBeAg (>or=100 PEIU/mL) achieved HBeAg seroconversion, yielding a negative predictive value of 96%, which was greater than that obtained for levels of HBV DNA (86%). Late responders to peginterferon alfa-2a could also be differentiated from nonresponders by continued decrease in HBeAg values, which were not evident by changes in HBV DNA. These analyses suggest quantitative HBeAg is a useful adjunctive measurement for predicting HBeAg seroconversion in patients treated with peginterferon when considering both sensitivity and specificity compared with serum HBV DNA.

Proactive infectious disease approach to dermatologic patients who are taking tumor necrosis factor-alfa antagonists: Part II. Screening for patients on tumor necrosis factor-alfa antagonists.

PubMed

Chirch, Lisa M; Cataline, Philip R; Dieckhaus, Kevin D; Grant-Kels, Jane M

2014-07-01

Tumor necrosis factor-alfa levels are linked to disease severity in patients with inflammatory conditions, such as psoriasis. Inhibitors of this cytokine are commonly used with significant success in the treatment of such inflammatory disorders. Their use, however, can be plagued by infectious complications. An awareness of potential infections associated with these therapies is critical in order to maximize preventive efforts both before and during therapy. This review provides a guide for dermatologists caring for patients in need of this type of biologic therapy to preemptively address the infectious risks. Part II of this continuing medical education article reviews recommended screening methods for patients undergoing evaluations for tumor necrosis factor inhibitor therapy for psoriasis or other dermatologic diseases, and discusses possible prophylactic strategies to use, including the appropriate use of immunizations. Copyright © 2014 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

Serotonin and noradrenaline reuptake inhibitors (Snris) for fibromyalgia

PubMed Central

Welsch, Patrick; Üçeyler, Nurcan; Klose, Petra; Walitt, Brian; Häuser, Winfried

2018-01-01

. For safety we calculated NNTH for serious adverse events. We undertook meta-analysis using a random-effects model. We assessed the evidence using GRADE and created a 'Summary of findings' table. Main results We added eight new studies with 1979 participants for a total of 18 included studies with 7903 participants. Seven studies investigated duloxetine and nine studies investigated milnacipran against placebo. One study compared desvenlafaxine with placebo and pregabalin. One study compared duloxetine with L-carnitine. The majority of studies were at unclear or high risk of bias in three to five domains. The quality of evidence of all comparisons of desvenlafaxine, duloxetine and milnacipran versus placebo in studies with a parallel design was low due to concerns about publication bias and indirectness, and very low for serious adverse events due to concerns about publication bias, imprecision and indirectness. The quality of evidence of all comparisons of duloxetine and desvenlafaxine with other active drugs was very low due to concerns about publication bias, imprecision and indirectness. Duloxetine and milnacipran had no clinically relevant benefit over placebo for pain relief of 50% or greater: 1274 of 4104 (31%) on duloxetine and milnacipran reported pain relief of 50% or greater compared to 591 of 2814 (21%) participants on placebo (risk difference (RD) 0.09, 95% confidence interval (CI) 0.07 to 0.11; NNTB 11, 95% CI 9 to 14). Duloxetine and milnacipran had a clinically relevant benefit over placebo in patient's global impression to be much or very much improved: 888 of 1710 (52%) on duloxetine and milnacipran (RD 0.19, 95% CI 0.12 to 0.26; NNTB 5, 95% CI 4 to 8) reported to be much or very much improved compared to 354 of 1208 (29%) of participants on placebo. Duloxetine and milnacipran had a clinically relevant benefit compared to placebo for pain relief of 30% or greater. RD was 0.10; 95% CI 0.08 to 0.12; NNTB 10, 95% CI 8 to 12. Duloxetine and milnacipran

Properties of Cold HI Emission Clouds in the Inner-Galaxy ALFA Survey

NASA Astrophysics Data System (ADS)

Hughes, James Marcus; Gibson, Steven J.; Noriega-Crespo, Alberto; Newton, Jonathan; Koo, Bon-Chul; Douglas, Kevin A.; Peek, Joshua Eli Goldston; Park, Geumsook; Kang, Ji-hyun; Korpela, Eric J.; Heiles, Carl E.; Dame, Thomas M.

2017-01-01

Star formation, a critical process within galaxies, occurs in the coldest, densest interstellar clouds, whose gas and dust content are observed primarily at radio and infrared wavelengths. The formation of molecular hydrogen (H2) from neutral atomic hydrogen (HI) is an essential early step in the condensation of these clouds from the ambient interstellar medium, but it is not yet completely understood, e.g., what is the predominant trigger? Even more troubling, the abundance of H2 may be severely underestimated by standard tracers like CO, implying significant "dark" H2, and the quantity of HI may also be in error if opacity effects are neglected. We have developed an automated method to account for both HI and H2 in cold, diffuse clouds traced by narrow-line HI 21-cm emission in the Arecibo Inner-Galaxy ALFA (I-GALFA) survey. Our algorithm fits narrow (2-5 km/s), isolated HI line profiles to determine their spin temperature, optical depth, and true column density. We then estimate the "visible" H2 column in the same clouds with CfA and Planck CO data and the total gas column from dust emission measured by Planck, IRAS, and other surveys. Together, these provide constraints on the dark H2 abundance, which we examine in relation to other cloud properties and stages of development. Our aim is to build a database of H2-forming regions with significant dark gas to aid future analyses of coalescing interstellar clouds. We acknowledge support from NSF, NASA, Western Kentucky University, and Williams College. I-GALFA is a GALFA-HI survey observed with the 7-beam ALFA receiver on the 305-meter William E. Gordon Telescope. The Arecibo Observatory is a U.S. National Science Foundation facility operated under sequential cooperative agreements with Cornell University and SRI International, the latter in alliance with the Ana G. Mendez-Universidad Metropolitana and the Universities Space Research Association.

Simeprevir with pegylated interferon alfa 2a or 2b plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-2): a randomised, double-blind, placebo-controlled phase 3 trial.

PubMed

Manns, Michael; Marcellin, Patrick; Poordad, Fred; de Araujo, Evaldo Stanislau Affonso; Buti, Maria; Horsmans, Yves; Janczewska, Ewa; Villamil, Federico; Scott, Jane; Peeters, Monika; Lenz, Oliver; Ouwerkerk-Mahadevan, Sivi; De La Rosa, Guy; Kalmeijer, Ronald; Sinha, Rekha; Beumont-Mauviel, Maria

2014-08-02

Pegylated interferon (peginterferon) alfa 2a or 2b plus ribavirin regimens were the standard of care in patients with hepatitis C virus (HCV) infection, but the sustained virological response can be suboptimum in patients with HCV genotype 1 infection. The efficacy, safety, and tolerability of the combination of simeprevir, a one-pill, once-daily, oral HCV NS3/4A protease inhibitor versus placebo, plus peginterferon alfa 2a or 2b plus ribavirin was assessed in treatment-naive patients with HCV genotype 1 infection. In the QUEST-2, phase 3 study, done at 76 sites in 14 countries (Europe, and North and South Americas), patients with confirmed chronic HCV genotype 1 infection and no history of HCV treatment were randomly assigned with a computer-generated allocation sequence in a ratio of 2:1 and stratified by HCV genotype 1 subtype and host IL28B genotype to receive simeprevir (150 mg once daily, orally), peginterferon alfa 2a (180 μg once weekly, subcutaneous injection) or 2b (according to bodyweight; 50 μg, 80 μg, 100 μg, 120 μg, or 150 μg once weekly, subcutaneous injection), plus ribavirin (1000-1200 mg/day or 800-1400 mg/day, orally; simeprevir group) or placebo (once daily, orally), peginterferon alfa 2a or 2b, plus ribavirin (placebo group) for 12 weeks, followed by just peginterferon alfa 2a or 2b plus ribavirin. Total treatment duration was 24 weeks or 48 weeks (simeprevir group) based on criteria for response-guided therapy (ie, HCV RNA <25 IU/mL undetectable or detectable at week 4 and undetectable week 12) or 48 weeks (placebo). Patients, study personnel, and the sponsor were masked to treatment assignment. The primary efficacy endpoint was sustained virological response at 12 weeks after the planned end of treatment (SVR12). Analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT01290679. Results from the primary (SVR12, week 60) analysis are presented. 209 (81%) of 257 patients in the simeprevir group and

Interferon alfa-2b, colchicine, and benzathine penicillin versus colchicine and benzathine penicillin in Behçet's disease: a randomised trial.

PubMed

Demiroglu, H; Ozcebe, O I; Barista, I; Dündar, S; Eldem, B

2000-02-19

Sight-threatening eye involvement is a serious complication of Behçet's disease. Extraocular complications such as arthritis, vascular occlusive disorders, mucocutaneous lesions, and central-nervous-system disease may lead to morbidity and even death. We designed a prospective study in newly diagnosed patients without previous eye disease to assess whether prevention of eye involvement and extraocular manifestations, and preservation of visual acuity are possible with combination treatments with and without interferon alfa-2b. Patients were randomly assigned 3 million units interferon alfa-2b subcutaneously every other day for the first 6 months plus 1.5 mg colchicine orally daily and 1.2 million units benzathine penicillin intramuscularly every 3 weeks (n=67), or colchicine and benzathine penicillin alone (n=68). The primary endpoint was visual-acuity loss. Analysis was by intention to treat. Significantly fewer patients who were treated with interferon had eye involvement than did patients who did not receive interferon (eight vs 27, relative risk 0.21 [95% CI 0.09-0.50], p<0.001). Ocular attack rate was 0.2 (SD 0.62) per year with interferon therapy and 1.02 (1.13) without interferon therapy (p=0.0001). Visual-acuity loss was significantly lower among patients treated with interferon than in those without interferon (two vs 13, relative risk 0.13 [95% CI 0.03-0.60], p=0.003). Arthritis episodes, vascular events, and mucocutaneous lesions were also less frequent in patients treated with interferon than in those not receiving interferon. No serious side-effects were reported. Therapy with interferon alfa-2b, colchicine, and benzathine penicillin seems to be an effective regimen in Behçet's disease for the prevention of recurrent eye attacks and extraocular complications, and for the protection of vision.

Enzymatic hydrolysis of pretreated Alfa fibers (Stipa tenacissima) using β-d-glucosidase and xylanase of Talaromyces thermophilus from solid-state fermentation.

PubMed

Mallek-Fakhfakh, Hanen; Fakhfakh, Jawhar; Walha, Kamel; Hassairi, Hajer; Gargouri, Ali; Belghith, Hafedh

2017-10-01

This work aims at realizing an optimal hydrolysis of pretreated Alfa fibers (Stipa tenacissima) through the use of enzymes produced from Talaromyces thermophilus AX4, namely β-d-glucosidase and xylanase, by a solid state fermentation process of an agro-industrial waste (wheat bran supplemented with lactose). The carbon source was firstly selected and the optimal values of three other parameters were determined: substrate loading (10g), moisture content (85%) and production time (10days); which led to an optimized enzymatic juice. The outcome was then supplemented with cellulases of T. reesei and used to optimize the enzymatic saccharification of alkali-pretreated Alfa fibers (PAF). The maximum saccharification yield of 83.23% was achieved under optimized conditions (substrate concentration 3.7% (w/v), time 144h and enzyme loading of 0.8 FPU, 15U CMCase, 60U β-d-glucosidase and 125U xylanase).The structural modification of PAF due to enzymatic saccharification was supported by the changes of morphologic and chemical composition observed through macroscopic representation, FTIR and X-Ray analysis. Copyright © 2017 Elsevier B.V. All rights reserved.

Do social functioning and symptoms improve with continuation antidepressant treatment of persistent depressive disorder? An observational study.

PubMed

Hellerstein, David J; Hunnicutt-Ferguson, Kallio; Stewart, Jonathan W; McGrath, Patrick J; Keller, Samantha; Peterson, Bradley S; Chen, Ying

2017-03-01

To determine efficacy of continued treatment with the serotonin norepinephrine reuptake inhibitor duloxetine on symptom reduction and functional improvement in outpatients with dysthymia. Fifty outpatients with DSM-IV-TR diagnosed dysthymia who had participated in a 10 week double-blind, placebo-controlled study of duloxetine received open treatment for three months. Nineteen duloxetine responders continued duloxetine, 24 patients initially treated with placebo started open duloxetine treatment, and 7 duloxetine non-responders were treated with desvenlafaxine or bupropion, selected by clinician choice. Patients continuing duloxetine maintained symptom improvement, 84% meeting response and 63% remission criteria at week 22. Patients initially treated with placebo showed similarly high levels of response (83%) and remission (62%) at week 22, and most duloxetine non-responders subsequently responded to other antidepressants. Duloxetine-continuation patients improved modestly between weeks 10 and 22 on measures of social and cognitive functioning and temperament. Despite this improvement concurrently across several functional domains, 66.7% of patients continuing duloxetine remained in the impaired range of functioning according to the Social Adjustment Scale (SAS). Continued duloxetine treatment appears to be effective in maintaining symptom response in dysthymic disorder, and has positive effects on social functioning. However, the majority of patients do not show normalization of functioning, even when controlling for remission status. Additional treatments should be considered to target residual impairments in social functioning in mood remitted patients with persistent depressive disorder. Copyright © 2016 Elsevier B.V. All rights reserved.

The ALFA (Activity Log Files Aggregation) toolkit: a method for precise observation of the consultation.

PubMed

de Lusignan, Simon; Kumarapeli, Pushpa; Chan, Tom; Pflug, Bernhard; van Vlymen, Jeremy; Jones, Beryl; Freeman, George K

2008-09-08

There is a lack of tools to evaluate and compare Electronic patient record (EPR) systems to inform a rational choice or development agenda. To develop a tool kit to measure the impact of different EPR system features on the consultation. We first developed a specification to overcome the limitations of existing methods. We divided this into work packages: (1) developing a method to display multichannel video of the consultation; (2) code and measure activities, including computer use and verbal interactions; (3) automate the capture of nonverbal interactions; (4) aggregate multiple observations into a single navigable output; and (5) produce an output interpretable by software developers. We piloted this method by filming live consultations (n = 22) by 4 general practitioners (GPs) using different EPR systems. We compared the time taken and variations during coded data entry, prescribing, and blood pressure (BP) recording. We used nonparametric tests to make statistical comparisons. We contrasted methods of BP recording using Unified Modeling Language (UML) sequence diagrams. We found that 4 channels of video were optimal. We identified an existing application for manual coding of video output. We developed in-house tools for capturing use of keyboard and mouse and to time stamp speech. The transcript is then typed within this time stamp. Although we managed to capture body language using pattern recognition software, we were unable to use this data quantitatively. We loaded these observational outputs into our aggregation tool, which allows simultaneous navigation and viewing of multiple files. This also creates a single exportable file in XML format, which we used to develop UML sequence diagrams. In our pilot, the GP using the EMIS LV (Egton Medical Information Systems Limited, Leeds, UK) system took the longest time to code data (mean 11.5 s, 95% CI 8.7-14.2). Nonparametric comparison of EMIS LV with the other systems showed a significant difference, with EMIS

The ALFA (Activity Log Files Aggregation) Toolkit: A Method for Precise Observation of the Consultation

PubMed Central

2008-01-01

Background There is a lack of tools to evaluate and compare Electronic patient record (EPR) systems to inform a rational choice or development agenda. Objective To develop a tool kit to measure the impact of different EPR system features on the consultation. Methods We first developed a specification to overcome the limitations of existing methods. We divided this into work packages: (1) developing a method to display multichannel video of the consultation; (2) code and measure activities, including computer use and verbal interactions; (3) automate the capture of nonverbal interactions; (4) aggregate multiple observations into a single navigable output; and (5) produce an output interpretable by software developers. We piloted this method by filming live consultations (n = 22) by 4 general practitioners (GPs) using different EPR systems. We compared the time taken and variations during coded data entry, prescribing, and blood pressure (BP) recording. We used nonparametric tests to make statistical comparisons. We contrasted methods of BP recording using Unified Modeling Language (UML) sequence diagrams. Results We found that 4 channels of video were optimal. We identified an existing application for manual coding of video output. We developed in-house tools for capturing use of keyboard and mouse and to time stamp speech. The transcript is then typed within this time stamp. Although we managed to capture body language using pattern recognition software, we were unable to use this data quantitatively. We loaded these observational outputs into our aggregation tool, which allows simultaneous navigation and viewing of multiple files. This also creates a single exportable file in XML format, which we used to develop UML sequence diagrams. In our pilot, the GP using the EMIS LV (Egton Medical Information Systems Limited, Leeds, UK) system took the longest time to code data (mean 11.5 s, 95% CI 8.7-14.2). Nonparametric comparison of EMIS LV with the other systems showed

Peginterferon alfa-2a/ribavirin for 48 or 72 weeks in hepatitis C genotypes 1 and 4 patients with slow virologic response.

PubMed

Ferenci, Peter; Laferl, Hermann; Scherzer, Thomas-Matthias; Maieron, Andreas; Hofer, Harald; Stauber, Rudolf; Gschwantler, Michael; Brunner, Harald; Wenisch, Christoph; Bischof, Martin; Strasser, Michael; Datz, Christian; Vogel, Wolfgang; Löschenberger, Karin; Steindl-Munda, Petra

2010-02-01

This randomized multicenter trial evaluated individualization of treatment duration with peginterferon alfa-2a 180 microg/wk plus ribavirin 1000/1200 mg/day in patients with chronic hepatitis C genotype 1/4 based on the rapidity of virologic response (VR). Patients with a rapid VR (RVR; undetectable hepatitis C virus [HCV]-RNA level (<50 IU/mL at week 4) were treated for 24 weeks, those with an early VR (EVR; no RVR but undetectable HCV-RNA level or >or=2-log(10) decrease at week 12) were randomized to 48 (group A) or 72 weeks of treatment (group B; peginterferon alfa-2a was reduced to 135 microg/wk after week 48). Patients without an EVR continued treatment until week 72 if they had undetectable HCV-RNA levels at week 24. The primary end point was relapse; sustained VR (SVR; undetectable HCV-RNA level after 24 weeks of follow-up evaluation) was a secondary end point. Of 551 genotype 1/4 patients starting treatment, 289 were randomized to group A (N = 139) or group B (N = 150). The relapse rate was 33.6% in group A (95% confidence interval [CI], 24.8%-43.4%) and 18.5% in group B (95% CI, 11.9%-27.6%; P = .0115 vs group A) and the SVR rate was 51.1% (95% CI, 42.5%-59.6%) and 58.6% (95% CI, 50.3%-66.6%; P > .1), respectively. The overall SVR rate was 50.4% (278 of 551; 95% CI, 46.2%-54.7%), including 115 of 150 patients with an RVR treated for 24 weeks and 4 of 78 patients without an EVR. Extending therapy with peginterferon alfa-2a/ribavirin to 72 weeks decreases the probability of relapse in patients with an EVR. If they can be maintained on extended-duration therapy, SVR rates also may improve.

A Phase 3, multicenter, open-label, switchover trial to assess the safety and efficacy of taliglucerase alfa, a plant cell-expressed recombinant human glucocerebrosidase, in adult and pediatric patients with Gaucher disease previously treated with imiglucerase.

PubMed

Pastores, Gregory M; Petakov, Milan; Giraldo, Pilar; Rosenbaum, Hanna; Szer, Jeffrey; Deegan, Patrick B; Amato, Dominick J; Mengel, Eugen; Tan, Ee Shien; Chertkoff, Raul; Brill-Almon, Einat; Zimran, Ari

2014-12-01

Taliglucerase alfa is a β-glucosidase enzyme replacement therapy (ERT) approved in the US and other countries for the treatment of Gaucher disease (GD) in adults and is approved in pediatric and adult patients in Australia and Canada. It is the first approved plant cell-expressed recombinant human protein. A Phase 3, multicenter, open-label, 9-month study assessed safety and efficacy of switching to taliglucerase alfa in adult and pediatric patients with GD treated with imiglucerase for at least the previous 2years. Patients with stable disease were offered taliglucerase alfa treatment using the same dose (9-60U/kg body weight) and regimen of administration (every 2weeks) as imiglucerase. This report summarizes results from 26 adult and 5 pediatric patients who participated in the trial. Disease parameters (spleen and liver volumes, hemoglobin concentration, platelet count, and biomarker levels) remained stable through 9months of treatment in adults and children following the switch from imiglucerase. All treatment-related adverse events were mild or moderate in severity and transient in nature. Exploratory parameters of linear growth and development showed positive outcomes in pediatric patients. These findings provide evidence of the efficacy and safety profile of taliglucerase alfa as an ERT for GD in patients previously treated with imiglucerase. This trial was registered at www.clinicaltrials.gov as # NCT00712348. Copyright © 2014 Elsevier Inc. All rights reserved.

Baseline characteristics of patients in the Reduction of Events with Darbepoetin alfa in Heart Failure trial (RED-HF).

PubMed

McMurray, John J V; Anand, Inder S; Diaz, Rafael; Maggioni, Aldo P; O'Connor, Christopher; Pfeffer, Marc A; Solomon, Scott D; Tendera, Michal; van Veldhuisen, Dirk J; Albizem, Moetaz; Cheng, Sunfa; Scarlata, Debra; Swedberg, Karl; Young, James B

2013-03-01

This report describes the baseline characteristics of patients in the Reduction of Events with Darbepoetin alfa in Heart Failure trial (RED-HF) which is testing the hypothesis that anaemia correction with darbepoetin alfa will reduce the composite endpoint of death from any cause or hospital admission for worsening heart failure, and improve other outcomes. Key demographic, clinical, and laboratory findings, along with baseline treatment, are reported and compared with those of patients in other recent clinical trials in heart failure. Compared with other recent trials, RED-HF enrolled more elderly [mean age 70 (SD 11.4) years], female (41%), and black (9%) patients. RED-HF patients more often had diabetes (46%) and renal impairment (72% had an estimated glomerular filtration rate < 60 mL/min/1.73 m2). Patients in RED-HF had heart failure of longer duration [5.3 (5.4) years], worse NYHA class (35% II, 63% III, and 2% IV), and more signs of congestion. Mean EF was 30% (6.8%). RED-HF patients were well treated at randomization, and pharmacological therapy at baseline was broadly similar to that of other recent trials, taking account of study-specific inclusion/exclusion criteria. Median (interquartile range) haemoglobin at baseline was 112 (106-117) g/L. The anaemic patients enrolled in RED-HF were older, moderately to markedly symptomatic, and had extensive co-morbidity.

Andexanet alfa effectively reverses edoxaban anticoagulation effects and associated bleeding in a rabbit acute hemorrhage model

PubMed Central

Lu, Genmin; Pine, Polly; Leeds, Janet M.; DeGuzman, Francis; Pratikhya, Pratikhya; Lin, Joyce; Malinowski, John; Hollenbach, Stanley J.; Curnutte, John T.

2018-01-01

Introduction Increasing use of factor Xa (FXa) inhibitors necessitates effective reversal agents to manage bleeding. Andexanet alfa, a novel modified recombinant human FXa, rapidly reverses the anticoagulation effects of direct and indirect FXa inhibitors. Objective To evaluate the ability of andexanet to reverse anticoagulation in vitro and reduce bleeding in rabbits administered edoxaban. Materials and methods In vitro studies characterized the interaction of andexanet with edoxaban and its ability to reverse edoxaban-mediated anti-FXa activity. In a rabbit model of surgically induced, acute hemorrhage, animals received edoxaban vehicle+andexanet vehicle (control), edoxaban (1 mg/kg)+andexanet vehicle, edoxaban+andexanet (75 mg, 5-minute infusion, 20 minutes after edoxaban), or edoxaban vehicle+andexanet prior to injury. Results Andexanet bound edoxaban with high affinity similar to FXa. Andexanet rapidly and dose-dependently reversed the effects of edoxaban on FXa activity and coagulation pharmacodynamic parameters in vitro. In edoxaban-anticoagulated rabbits, andexanet reduced anti-FXa activity by 82% (from 548±87 to 100±41 ng/ml; P<0.0001), mean unbound edoxaban plasma concentration by ~80% (from 100±10 to 21±6 ng/ml; P<0.0001), and blood loss by 80% vs. vehicle (adjusted for control, 2.6 vs. 12.9 g; P = 0.003). The reduction in blood loss correlated with the decrease in anti-FXa activity (r = 0.6993, P<0.0001) and unbound edoxaban (r = 0.5951, P = 0.0035). Conclusion These data demonstrate that andexanet rapidly reversed the anticoagulant effects of edoxaban, suggesting it could be clinically valuable for the management of acute and surgery-related bleeding. Correlation of blood loss with anti-FXa activity supports the use of anti-FXa activity as a biomarker for assessing anticoagulation reversal in clinical trials. PMID:29590221

Use of activated protein C has no avail in the early phase of acute pancreatitis

PubMed Central

Ozutemiz, Omer; Yenisey, Cigdem; Genc Simsek, Nilufer; Yuce, Gul; Batur, Yucel

2008-01-01

Objectives. Sepsis and acute pancreatitis have similar pathogenetic mechanisms that have been implicated in the progression of multiple organ failure. Drotrecogin alfa, an analogue of endogenous protein C, reduces mortality in clinical sepsis. Our objective was to evaluate the early therapeutic effects of activated protein C (APC) in a rat model of acute necrotizing pancreatitis. Subjects and method. Acute necrotizing pancreatitis was induced by intraductal injection of 5% Na taurocholate. Hourly bolus injections of saline or recombinant human APC (drotrecogin alfa) was commenced via femoral venous catheter four hours after the induction of acute pancreatitis. The experiment was terminated nine hours after pancratitis induction. Animals in group one (n=20) had a sham operation while animals in group two (n=20) received saline and animals in group three (n=20) received drotrecogin alfa boluses after acute pancreatitis induction. Pancreatic tissue for histopathologic scores and myeloperoxidase, glutathione reductase, glutathione peroxidase, and catalase activites were collected, and blood for serum amylase, urea, creatinine, and inleukin-6 measurements was withdrawn. Results. Serum amylase activity was significantly lower in the APC treated group than the untreated group (17,435±432 U/L vs. 27,426±118 U/L, respectively). While the serum interleukin-6 concentration in the APC untreated group was significantly lower than the treated group (970±323 pg/mL vs. 330±368 pg/mL, respectively). Conclusion. In the early phase of acute pancreatitis, drotrecogin alfa treatment did not result in a significant improvement in oxidative and inflammatory parameters or renal functions. PMID:19088933

Peginterferon Alfa-2a plus Ribavirin in Japanese Patients Infected with Hepatitis C Virus Genotype 2 Who Failed Previous Interferon Therapy

PubMed Central

Kanda, Tatsuo; Nakamoto, Shingo; Nishino, Takayoshi; Takada, Nobuo; Tsubota, Akihito; Kato, Keizo; Miyamura, Tatsuo; Maruoka, Daisuke; Wu, Shuang; Tanaka, Takeshi; Arai, Makoto; Mikami, Shigeru; Fujiwara, Keiichi; Imazeki, Fumio; Yokosuka, Osamu

2013-01-01

Some patients infected with hepatitis C virus (HCV) genotype 2 could be cured with treatment shorter than 24 weeks using peginterferon plus ribavirin, but there are still treatment-refractory patients. Direct-acting antivirals (DAAs) are not currently available for HCV genotype 2 patients, different from genotype 1 patients, in clinical practice. We investigated 29 HCV genotype 2-infected Japanese patients who had been previously treated and failed to clear HCV. We retreated them with peginterferon alfa-2a plus ribavirin and measured HCV RNA level to assess the efficacy and safety of this treatment in patients who had failed previous therapy. We found that retreatment of HCV genotype 2-infected Japanese patients with peginterferon alfa-2a plus ribavirin for 24-48 weeks led to 60 to 66.6% sustained virological response (SVR) in patients previously treated with (peg-)interferon monotherapy and to 69.9% SVR in relapsers previously treated with peginterferon plus ribavirin. Attention should be paid to certain patients with unique features. Selection of patients according to their previous treatment could lead to optimal therapy in HCV genotype 2 treatment-experienced patients. PMID:23289004

Oral sucrosomial iron versus intravenous iron in anemic cancer patients without iron deficiency receiving darbepoetin alfa: a pilot study.

PubMed

Mafodda, Antonino; Giuffrida, D; Prestifilippo, A; Azzarello, D; Giannicola, R; Mare, M; Maisano, R

2017-09-01

Erythropoiesis-stimulating agents (ESAs) are often used in treatment of patients with chemotherapy-induced anemia. Many studies have demonstrated an improved hemoglobin (Hb) response when ESA is combined with intravenous iron supplementation and a higher effectiveness of intravenous iron over traditional oral iron formulations. A new formulation of oral sucrosomial iron featuring an increased bioavailability compared to traditional oral formulations has recently become available and could provide a valid alternative to those by intravenous (IV) route. Our study evaluated the performance of sucrosomial iron versus intravenous iron in increasing hemoglobin in anemic cancer patients receiving chemotherapy and darbepoetin alfa, as well as safety, need of transfusion, and quality of life (QoL). The present study considered a cohort of 64 patients with chemotherapy-related anemia (Hb >8 g/dL <10 g/dL) and no absolute or functional iron deficiency, scheduled to receive chemotherapy and darbepoetin. All patients received darbepoetin alfa 500 mcg once every 3 weeks and were randomly assigned to receive 8 weeks of IV ferric gluconate 125 mg weekly or oral sucrosomial iron 30 mg daily. The primary endpoint was to demonstrate the performance of oral sucrosomial iron in improving Hb response, compared to intravenous iron. The Hb response was defined as the Hb increase ≥2 g/dL from baseline or the attainment Hb ≥ 12 g/dL. There was no difference in the Hb response rate between the two treatment arms. Seventy one percent of patients treated with IV iron achieved an erythropoietic response, compared to 70% of patients treated with oral iron. By conventional criteria, this difference is considered to be not statistically significant. There were also no differences in the proportion of patients requiring red blood cell transfusions and changes in QoL. Sucrosomial oral iron was better tolerated. In cancer patients with chemotherapy-related anemia receiving

Significant and continuous improvement in bone mineral density among type 1 Gaucher disease patients treated with velaglucerase alfa: 69-month experience, including dose reduction.

PubMed

Elstein, Deborah; Foldes, A Joseph; Zahrieh, David; Cohn, Gabriel M; Djordjevic, Maja; Brutaru, Costin; Zimran, Ari

2011-06-15

Since bone pathology is a major concern in type 1 Gaucher disease (GD1), we evaluated bone mineral density (BMD) in adults receiving velaglucerase alfa in the seminal Phase I/II and extension trial. Ten treatment-naïve symptomatic patients with GD1 (four men, six women; median age 35years, range 18-62years) were included; of these, four patients were receiving bisphosphonates at enrollment. Using WHO criteria to classify the lumbar spine (LS) and femoral neck (FN) BMD T-scores, respectively, one (10%) and four (40%) patients had osteoporosis; eight (80%) and five (50%) had osteopenia; and one each (10%) was in the normal range, at baseline. By Month 69, two LS and one FN osteopenic patients normalized and one FN osteoporotic patient became osteopenic; change was seen only in patients not receiving bisphosphonates. Significant improvements in BMD Z-scores were seen at the LS by Month 24 and at the FN by Month 33 and were continuous thereafter. In linear mixed models, Z-scores were significantly lower than the reference population at baseline and improved significantly with treatment (LS and FN both P<0.01); analysis of the subgroup of patients not receiving bisphosphonates showed similar results. In conclusion, in this small cohort, velaglucerase alfa was associated with clinically meaningful and statistically significant LS and FN BMD improvements as early as Month 24 (LS) and 33 (FN), despite dose reduction and significant baseline skeletal pathology. These results suggest that velaglucerase alfa may hold promise in the management of skeletal pathology associated with GD1. Copyright © 2011 Elsevier Inc. All rights reserved.

Extended treatment with pegylated interferon alfa/ribavirin in patients with genotype 2/3 chronic hepatitis C who do not achieve a rapid virological response: final analysis of the randomised N-CORE trial.

PubMed

Shiffman, Mitchell L; Cheinquer, Hugo; Berg, Christoph P; Berg, Thomas; de Figueiredo-Mendes, Cláudio; Dore, Gregory J; Ferraz, Maria Lúcia; Mendes-Corrêa, Maria Cássia; Lima, Maria Patelli; Parise, Edison R; Rios, Alma Minerva Perez; Reuter, Tania; Sanyal, Arun J; Shafran, Stephen D; Hohmann, Marc; Tatsch, Fernando; Bakalos, George; Zeuzem, Stefan

2014-10-01

The combination of pegylated interferon alfa/ribavirin will likely remain the treatment of choice for HCV genotype 2/3 patients in financially constrained countries for the foreseeable future. Patients with poor on-treatment response may benefit from treatment extension. This study examined the effect of 48 versus 24 weeks of peginterferon alfa-2a/ribavirin on the sustained virological response (SVR) in patients with HCV genotype 2/3 who did not achieve rapid virological response (RVR). N-CORE was a multicentre, randomised, phase III study. HCV genotype 2/3 patients receiving peginterferon alfa-2a/ribavirin without a rapid but with an early virological response were randomised at week 24 to stop treatment (Arm A) or continue to 48 weeks (Arm B). The primary efficacy endpoint was SVR. Two hundred thirty-five patients were enrolled. End of treatment response was similar in both treatment arms. SVR24 rates were not significantly greater in the extended treatment arm compared with the standard 24-week treatment in either the intention-to-treat or the per-protocol populations (61 vs. 52 %, p = 0.1934 and 63 vs. 52 %, p = 0.1461, respectively). Serious adverse events occurred more frequently in patients receiving extended treatment duration (12 %) versus 24-week therapy (4 %). It is unclear whether the extension of peginterferon alfa-2a/ribavirin treatment may benefit HCV genotype 2/3 patients who do not achieve RVR. The study was stopped early because recruitment was slower than anticipated, and this may have limited the statistical impact of these findings.

Sustained Responses in Chronic Hepatitis B Patients with Nucleos(t)ide Analogue Drug-resistance after Peg-interferon Alfa-2a Add-on Treatment: A Long-term Cohort Study.

PubMed

Liu, Yunhua; Li, Weikun; Jia, Ting; Peng, Dan; Li, Huimin; Li, Xiaofei; Lv, Songqin

2018-03-28

Background and Aims: The use of additional nucleos(t)ide analogues (NAs) without cross-resistance to previously used NAs as a rescue therapy is recommended by most international guidelines for chronic hepatitis B patients with NA-resistance. We aimed to investigate the efficacy and safety of combination therapy of peg-interferon (PegIFN) alfa-2a and NA in these patients, comparing to those who switch to an alternative NA therapy without cross-resistance. Methods: In this prospective, comparative and cohort study, data were collected from the patients' hospital records. Eligible patients were those with hepatitis B e antigen (HBeAg) positivity and resistance to one or more NAs. All patients were treated with alternative NA alone or in combination with PegIFN alfa-2a for 52 weeks or 72 weeks, respectively. HBeAg seroconversion was measured at the end of follow-up (EOF; more than 104 weeks after the end of treatment). Results: Sixty-three patients were recruited to the cohort study (NA-therapy group = 31 patients; combination therapy group of NA and PegIFN alfa-2a = 32 patients). At the EOF, significantly more patients in the combination therapy group (13/27, 48.2%) achieved primary outcome of HBeAg seroconversion than those in the NA therapy group (4/32, 12.5%) ( p = 0.003). Four patients (14.8%) in the combination therapy group achieved hepatitis B surface antigen (HBsAg) loss and HBsAg seroconversion, but none in the NA therapy group did ( p = 0.039). In the combination therapy group, 16 patients (51.6%) achieved HBeAg seroconversion at the end of treatment, of which, 11 patients (68.8%) maintained the response until EOF. Conclusions: Adding on PegIFN alfa-2a in combination with NA therapy might be an appropriate rescue treatment option for patients who have prior NA resistance. In addition, combination therapy induced sustained off-treatment biochemical responses in these patients.

A review of the clinical utility of duloxetine in the treatment of diabetic peripheral neuropathic pain

PubMed Central

King, Jordan B; Schauerhamer, Marisa B; Bellows, Brandon K

2015-01-01

Diabetes mellitus is a world-wide epidemic with many long-term complications, with neuropathy being the most common. In particular, diabetic peripheral neuropathic pain (DPNP), can be one of the most distressing complications associated with diabetes, leading to decreases in physical and mental quality of life. Despite the availability of many efficient medications, DPNP remains a challenge to treat, and the optimal sequencing of pharmacotherapy remains unknown. Currently, there are only three medications approved by the US Food and Drug Administration specifically for the management of DPNP. Duloxetine (DUL), a selective serotonin-norepinephrine reuptake inhibitor, is one of these. With the goal of optimizing pharmacotherapy use in DPNP population, a review of current literature was conducted, and the clinical utility of DUL described. Along with early clinical trials, recently published observational studies and pharmacoeconomic models may be useful in guiding decision making by clinicians and managed care organizations. In real-world practice settings, DUL is associated with decreased or similar opioid utilization, increased medication adherence, and similar health care costs compared with current standard of care. DUL has consistently been found to be a cost-effective option over short time-horizons. Currently, the long-term cost-effectiveness of DUL is unknown. Evidence derived from randomized clinical trials, real-world observations, and economic models support the use of DUL as a first-line treatment option from the perspective of the patient, clinician, and managed care payer. PMID:26309404

A review of the clinical utility of duloxetine in the treatment of diabetic peripheral neuropathic pain.

PubMed

King, Jordan B; Schauerhamer, Marisa B; Bellows, Brandon K

2015-01-01

Diabetes mellitus is a world-wide epidemic with many long-term complications, with neuropathy being the most common. In particular, diabetic peripheral neuropathic pain (DPNP), can be one of the most distressing complications associated with diabetes, leading to decreases in physical and mental quality of life. Despite the availability of many efficient medications, DPNP remains a challenge to treat, and the optimal sequencing of pharmacotherapy remains unknown. Currently, there are only three medications approved by the US Food and Drug Administration specifically for the management of DPNP. Duloxetine (DUL), a selective serotonin-norepinephrine reuptake inhibitor, is one of these. With the goal of optimizing pharmacotherapy use in DPNP population, a review of current literature was conducted, and the clinical utility of DUL described. Along with early clinical trials, recently published observational studies and pharmacoeconomic models may be useful in guiding decision making by clinicians and managed care organizations. In real-world practice settings, DUL is associated with decreased or similar opioid utilization, increased medication adherence, and similar health care costs compared with current standard of care. DUL has consistently been found to be a cost-effective option over short time-horizons. Currently, the long-term cost-effectiveness of DUL is unknown. Evidence derived from randomized clinical trials, real-world observations, and economic models support the use of DUL as a first-line treatment option from the perspective of the patient, clinician, and managed care payer.

A first-year dornase alfa treatment impact on clinical parameters of patients with cystic fibrosis: the Brazilian cystic fibrosis multicenter study

PubMed Central

Rozov, Tatiana; Silva, Fernando Antônio A. e; Santana, Maria Angélica; Adde, Fabíola Villac; Mendes, Rita Heloisa

2013-01-01

OBJECTIVE: To describe the clinical impact of the first year treatment with dornase alfa, according to age groups, in a cohort of Brazilian Cystic Fibrosis (CF) patients. METHODS: The data on 152 eligible patients, from 16 CF reference centers, that answered the medical questionnaires and performed laboratory tests at baseline (T0), and at six (T2) and 12 (T4) months after dornase alfa initiation, were analyzed. Three age groups were assessed: six to 11, 12 to 13, and >14 years. Pulmonary tests, airway microbiology, emergency room visits, hospitalizations, emergency and routine treatments were evaluated. Student's t-test, chi-square test and analysis of variance were used when appropriated. RESULTS: Routine treatments were based on respiratory physical therapy, regular exercises, pancreatic enzymes, vitamins, bronchodilators, corticosteroids, and antibiotics. In the six months prior the study (T0 phase), hospitalizations for pulmonary exacerbations occurred in 38.0, 10.0 and 61.4% in the three age groups, respectively. After one year of intervention, there was a significant reduction in the number of emergency room visits in the six to 11 years group. There were no significant changes in forced expiratory volume in one second (VEF1), in forced vital capacity (FVC), in oxygen saturation (SpO2), and in Tiffenau index for all age groups. A significant improvement in Shwachman-Kulczychi score was observed in the older group. In the last six months of therapy, chronic or intermittent colonization by P. aeruginosa was detected in 75.0, 71.4 and 62.5% of the studied groups, respectively, while S. aureus colonization was identified in 68.6, 66.6 and 41.9% of the cases. CONCLUSIONS: The treatment with dornase alfa promoted the maintenance of pulmonary function parameters and was associated with a significant reduction of emergency room visits due to pulmonary exacerbations in the six to 11 years age group, with better clinical scores in the >14 age group, one year after the

Population Pharmacokinetic and Pharmacodynamic Model-Based Comparability Assessment of a Recombinant Human Epoetin Alfa and the Biosimilar HX575

PubMed Central

Yan, Xiaoyu; Lowe, Philip J.; Fink, Martin; Berghout, Alexander; Balser, Sigrid; Krzyzanski, Wojciech

2012-01-01

The aim of this study was to develop an integrated pharmacokinetic and pharmacodynamic (PK/PD) model and assess the comparability between epoetin alfa HEXAL/Binocrit (HX575) and a comparator epoetin alfa by a model-based approach. PK/PD data—including serum drug concentrations, reticulocyte counts, red blood cells, and hemoglobin levels—were obtained from 2 clinical studies. In sum, 149 healthy men received multiple intravenous or subcutaneous doses of HX575 (100 IU/kg) and the comparator 3 times a week for 4 weeks. A population model based on pharmacodynamics-mediated drug disposition and cell maturation processes was used to characterize the PK/PD data for the 2 drugs. Simulations showed that due to target amount changes, total clearance may increase up to 2.4-fold as compared with the baseline. Further simulations suggested that once-weekly and thrice-weekly subcutaneous dosing regimens would result in similar efficacy. The findings from the model-based analysis were consistent with previous results using the standard noncompartmental approach demonstrating PK/PD comparability between HX575 and comparator. However, due to complexity of the PK/PD model, control of random effects was not straightforward. Whereas population PK/PD model-based analyses are suited for studying complex biological systems, such models have their limitations (statistical), and their comparability results should be interpreted carefully. PMID:22162538

Guillain-Barre syndrome associated with peginterferon alfa-2a for chronic hepatitis C: A case report

PubMed Central

Niazi, Mumtaz A; Azhar, Ashaur; Tufail, Kashif; Feyssa, Eyob L; Penny, Stephen F; McGregory, Marlene; Araya, Victor; Ortiz, Jorge A

2010-01-01

The recommended therapy for chronic hepatitis C (CHC) infection is the combination of a Pegylated interferon and Ribavirin. Almost all such patients on combination therapy experience one or more adverse events during the course of treatment. Significant neurological side effects are rare. A few cases of Bell’s Palsy, chronic inflammatory demyelinating polyneuropathy and even one case of acute demyelinating polyneuropathy with atypical features for Guillain-Barre syndrome (GBS) associated with Interferon therapy have been reported but no report of GBS with typical features has been published. We present a case report of typical GBS associated with Peginterferon alfa-2a and Ribavirin used for treatment of CHC infection. PMID:21160989

[Cost-effectiveness of drotrecogin alpha [activated] in the treatment of severe sepsis in Spain].

PubMed

Sacristán, José A; Prieto, Luis; Huete, Teresa; Artigas, Antonio; Badia, Xavier; Chinn, Christopher; Hudson, Peter

2004-01-01

The PROWESS clinical trial has shown that treatment with drotrecogin alpha (activated) in patients with severe sepsis is associated with a reduction in the absolute risk of death compared with standard treatment. The aim of the present study was to assess the cost-effectiveness of drotrecogin alpha (activated) versus that of standard care in the treatment of severe sepsis in Spain. A decision analysis model was drawn up to compare costs to hospital discharge and the long-term efficacy of drotrecogin alpha (activated) versus those of standard care in the treatment of severe sepsis in Spain from the perspective of the health care payer. Most of the information for creating the model was obtained from the PROWESS clinical trial. A two-fold baseline analysis was performed: a) for all patients included in the PROWESS clinical trial and b) for the patients with two or more organ failures. The major variables for clinical assessment were the reduction in mortality and years of life gained (YLG). Cost-effectiveness was expressed as cost per YLG. A sensitivity analysis was applied using 3% and 5% discount rates for YLG and by modifying the patterns of health care, intensive care unit costs, and life expectancy by initial co-morbidity and therapeutic efficacy of drotrecogin alpha (activated). Treatment with drotrecogin alfa (activated) was associated with a 6.0% drop in the absolute risk of death (p = 0.005) when all of the patients from the PROWESS trial were included and with a 7.3% reduction (p = 0.005) when the analysis was restricted to patients with two or more organ failures. The cost-effectiveness of drotrecogin alfa (activated) was 13,550 euros per YLG with respect to standard care after analysing all of the patients and 9,800 euros per YLG in the group of patients with two or more organ failures. In the sensitivity analysis, the results ranged from 7,322 to 16,493 euros per YLG. The factors with the greatest impact on the results were the change in the efficacy of

Quantitative Systems Pharmacology Modeling of Acid Sphingomyelinase Deficiency and the Enzyme Replacement Therapy Olipudase Alfa Is an Innovative Tool for Linking Pathophysiology and Pharmacology.

PubMed

Kaddi, Chanchala D; Niesner, Bradley; Baek, Rena; Jasper, Paul; Pappas, John; Tolsma, John; Li, Jing; van Rijn, Zachary; Tao, Mengdi; Ortemann-Renon, Catherine; Easton, Rachael; Tan, Sharon; Puga, Ana Cristina; Schuchman, Edward H; Barrett, Jeffrey S; Azer, Karim

2018-06-19

Acid sphingomyelinase deficiency (ASMD) is a rare lysosomal storage disorder with heterogeneous clinical manifestations, including hepatosplenomegaly and infiltrative pulmonary disease, and is associated with significant morbidity and mortality. Olipudase alfa (recombinant human acid sphingomyelinase) is an enzyme replacement therapy under development for the non-neurological manifestations of ASMD. We present a quantitative systems pharmacology (QSP) model supporting the clinical development of olipudase alfa. The model is multiscale and mechanistic, linking the enzymatic deficiency driving the disease to molecular-level, cellular-level, and organ-level effects. Model development was informed by natural history, and preclinical and clinical studies. By considering patient-specific pharmacokinetic (PK) profiles and indicators of disease severity, the model describes pharmacodynamic (PD) and clinical end points for individual patients. The ASMD QSP model provides a platform for quantitatively assessing systemic pharmacological effects in adult and pediatric patients, and explaining variability within and across these patient populations, thereby supporting the extrapolation of treatment response from adults to pediatrics. © 2018 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Switch to agalsidase alfa after shortage of agalsidase beta in Fabry disease: a systematic review and meta-analysis of the literature.

PubMed

Pisani, Antonio; Bruzzese, Dario; Sabbatini, Massimo; Spinelli, Letizia; Imbriaco, Massimo; Riccio, Eleonora

2017-03-01

In 2009, the agalsidase beta shortage resulted in switching to agalsidase alfa treatment for many Fabry disease patients, offering the unique opportunity to compare the effects of the two drugs. Because single studies describing effects of switching on the disease course are limited and inconclusive, we performed a systematic review and meta-analysis of existing data. Relevant studies were identified in the PubMed, Cochrane, ISI Web, and SCOPUS databases from July 2009 to September 2015. The following parameters were analyzed: clinical events, changes in organ function or structure, disease-related symptoms, lyso-Gb3 plasma levels, and adverse effects. The nine studies (217 patients) included in our systematic review showed only marginal differences in most of the evaluated parameters. Seven of these studies were included in the meta-analysis (176 patients). The pooled incidence rate of major adverse events was reported for five studies (150 patients) and was equal to 0.04 events per person-year. No significant change was observed after the shift in glomerular filtration rate, whereas left ventricular mass index, left ventricular posterior wall dimension, and ejection fraction were significantly reduced over time. Our data showed that the switch to agalsidase alfa was well tolerated and associated with stable clinical conditions.Genet Med 19 3, 275-282.

Development and optimization of enteric coated mucoadhesive microspheres of duloxetine hydrochloride using 3(2) full factorial design.

PubMed

Setia, Anupama; Kansal, Sahil; Goyal, Naveen

2013-07-01

Microspheres constitute an important part of oral drug delivery system by virtue of their small size and efficient carrier capacity. However, the success of these microspheres is limited due to their short residence time at the site of absorption. The objective of the present study was to formulate and systematically evaluate in vitro performance of enteric coated mucoadhesive microspheres of duloxetine hydrochloride (DLX), an acid labile drug. DLX microspheres were prepared by simple emulsification phase separation technique using chitosan as carrier and glutaraldehyde as a cross-linking agent. Microspheres prepared were coated with eudragit L-100 using an oil-in-oil solvent evaporation method. Eudragit L-100was used as enteric coating polymer with the aim to release the drug in small intestine The microspheres prepared were characterized by particle size, entrapment efficiency, swelling index (SI), mucoadhesion time, in vitro drug release and surface morphology. A 3(2) full factorial design was employed to study the effect of independent variables polymer-to-drug ratio (X1) and stirring speed (X2) on dependent variables, particle size, entrapment efficiency, SI, in vitro mucoadhesion and drug release up to 24 h (t24). Microspheres formed were discrete, spherical and free flowing. The microspheres exhibited good mucoadhesive property and also showed high percentage entrapment efficiency. The microspheres were able to sustain the drug release up to 24 h. Thus, the prepared enteric coated mucoadhesive microspheres may prove to be a potential controlled release formulation of DLX for oral administration.

Development and optimization of enteric coated mucoadhesive microspheres of duloxetine hydrochloride using 32 full factorial design

PubMed Central

Setia, Anupama; Kansal, Sahil; Goyal, Naveen

2013-01-01

Background: Microspheres constitute an important part of oral drug delivery system by virtue of their small size and efficient carrier capacity. However, the success of these microspheres is limited due to their short residence time at the site of absorption. Objective: The objective of the present study was to formulate and systematically evaluate in vitro performance of enteric coated mucoadhesive microspheres of duloxetine hydrochloride (DLX), an acid labile drug. Materials and Methods: DLX microspheres were prepared by simple emulsification phase separation technique using chitosan as carrier and glutaraldehyde as a cross-linking agent. Microspheres prepared were coated with eudragit L-100 using an oil-in-oil solvent evaporation method. Eudragit L-100was used as enteric coating polymer with the aim to release the drug in small intestine The microspheres prepared were characterized by particle size, entrapment efficiency, swelling index (SI), mucoadhesion time, in vitro drug release and surface morphology. A 32 full factorial design was employed to study the effect of independent variables polymer-to-drug ratio (X1) and stirring speed (X2) on dependent variables, particle size, entrapment efficiency, SI, in vitro mucoadhesion and drug release up to 24 h (t24). Results: Microspheres formed were discrete, spherical and free flowing. The microspheres exhibited good mucoadhesive property and also showed high percentage entrapment efficiency. The microspheres were able to sustain the drug release up to 24 h. Conclusion: Thus, the prepared enteric coated mucoadhesive microspheres may prove to be a potential controlled release formulation of DLX for oral administration. PMID:24167786

Onset of Type 1 Diabetes Mellitus During Pegylated-interferon Alfa and Ribavirin Therapy for Chronic Hepatitis C Virus Infection

PubMed Central

Ranganathan, Raghini; Janarthanan, Krishnaveni; Rajasekaran, Senthilkumar

2012-01-01

A 16-year-old female was treated with pegylated-interferon (PEG-IFN) alfa (a)-2b and ribavirin combination therapy for chronic hepatitis C virus (HCV) infection. She attained rapid virological response. She presented with diabetic ketoacidosis after 41 weeks of therapy. Anti-glutamic acid decarboxylase antibodies and islet cell antibodies were negative. Her fasting serum C-peptide level was <0.1 ng/mL, and the treatment course was completed. This case underlines the importance of periodic plasma glucose monitoring in patients during and after PEG-IFN and ribavirin therapy. PMID:25755410

Development and Validation of a Stability-Indicating RP-HPLC Method for Duloxetine Hydrochloride in its Bulk and Tablet Dosage Form

PubMed Central

Chhalotiya, Usmangani K.; Bhatt, Kashyap K.; Shah, Dimal A.; Baldania, Sunil L.

2010-01-01

The objective of the present work was to develop a stability-indicating RP-HPLC method for duloxetine hydrochloride (DUL) in the presence of its degradation products generated from forced decomposition studies. The drug substance was found to be susceptible to stress conditions of acid hydrolysis. The drug was found to be stable to dry heat, photodegradation, oxidation and basic condition attempted. Successful separation of the drug from the degradation products formed under acidic stress conditions was achieved on a Hypersil C-18 column (250 mm × 4.6 mm id, 5μm particle size) using acetonitrile: 0.01 M potassium dihydrogen phosphate buffer (pH 5.4 adjusted with orthophosphoric acid) (50:50, v/v) as the mobile phase at a flow rate of 1.0 ml/min. Quantification was achieved with photodiode array detection at 229 nm over the concentration range 1–25 μg/ml with range of recovery 99.8–101.3 % for DUL by the RP-HPLC method. Statistical analysis proved the method to be repeatable, specific, and accurate for estimation of DUL. It can be used as a stability-indicating method due to its effective separation of the drug from its degradation products, PMID:21179321

JAK-inhibitor tofacitinib suppresses interferon alfa production by plasmacytoid dendritic cells and inhibits arthrogenic and antiviral effects of interferon alfa.

PubMed

Boor, Patrick P C; de Ruiter, Petra E; Asmawidjaja, Patrick S; Lubberts, Erik; van der Laan, Luc J W; Kwekkeboom, Jaap

2017-10-01

Tofacitinib is an oral Janus kinase inhibitor that is effective for the treatment of rheumatoid arthritis and shows encouraging therapeutic effects in several other autoimmune diseases. A prominent adverse effect of tofacitinib therapy is the increased risk of viral infections. Despite its advanced stage of clinical development, the modes of action that mediate the beneficial and adverse effects of tofacitinib in autoimmune diseases remain unclear. Interferon alfa (IFNα) produced by plasmacytoid dendritic cells (PDCs) is critically involved in the pathogenesis of many systemic autoimmune diseases and in immunity to viral infections. Using in vitro culture models with human cells, we studied the effects of tofacitinib on PDC survival and IFNα production, and on arthrogenic and antiviral effects of IFNα. Tofacitinib inhibited the expression of antiapoptotic BCL-A1 and BCL-XL in human PDC and induced PDC apoptosis. TLR7 stimulation upregulated the levels of antiapoptotic Bcl-2 family members and prevented the induction of PDC apoptosis by tofacitinib. However, tofacitinib robustly inhibited the production of IFNα by toll like receptor-stimulated PDC. In addition, tofacitinib profoundly suppressed IFNα-induced upregulation of TLR3 on synovial fibroblasts, thereby inhibiting their cytokine and protease production in response to TLR3 ligation. Finally, tofacitinib counteracted the suppressive effects of IFNα on viral replication. Tofacitinib inhibits PDC survival and IFNα production and suppresses arthrogenic and antiviral effects of IFNα signaling. Inhibition of the IFNα pathway at 2 levels may contribute to the beneficial effects of tofacitinib in autoimmune diseases and explain the increased viral infection rates observed during tofacitinib treatment. Copyright © 2016 Elsevier Inc. All rights reserved.

Ovarian response to 150 µg corifollitropin alfa in a GnRH-antagonist multiple-dose protocol: a prospective cohort study.

PubMed

Lerman, Tamara; Depenbusch, Marion; Schultze-Mosgau, Askan; von Otte, Soeren; Scheinhardt, Markus; Koenig, Inke; Kamischke, Axel; Macek, Milan; Schwennicke, Arne; Segerer, Sabine; Griesinger, Georg

2017-05-01

The incidence of low (<6 oocytes) and high (>18 oocytes) ovarian response to 150 µg corifollitropin alfa in relation to anti-Müllerian hormone (AMH) and other biomarkers was studied in a multi-centre (n = 5), multi-national, prospective, investigator-initiated, observational cohort study. Infertile women (n = 212), body weight >60 kg, underwent controlled ovarian stimulation in a gonadotrophin-releasing hormone-antagonist multiple-dose protocol. Demographic, sonographic and endocrine parameters were prospectively assessed on cycle day 2 or 3 of a spontaneous menstruation before the administration of 150 µg corifollitropin alfa. Serum AMH showed the best correlation with the number of oocytes obtained among all predictor variables. In receiver-operating characteristic analysis, AMH at a threshold of 0.91 ng/ml showed a sensitivity of 82.4%, specificity of 82.4%, positive predictive value 52.9%and negative predictive value 95.1% for predicting low response (area under the curve [AUC], 95% CI; P-value: 0.853, 0.769-0.936; <0.0001). For predicting high response, the optimal threshold for AMH was 2.58 ng/ml, relating to a sensitivity of 80.0%, specificity 82.1%, positive predictive value 42.5% and negative predictive value 96.1% (AUC, 95% CI; P-value: 0.871, 0.787-0.955; <0.0001). In conclusion, patients with serum AMH concentrations between approximately 0.9 and 2.6 ng/ml were unlikely to show extremes of response. Copyright © 2017. Published by Elsevier Ltd.

Protein C: a potential biomarker in severe sepsis and a possible tool for monitoring treatment with drotrecogin alfa (activated)

PubMed Central

Shorr, Andrew F; Nelson, David R; Wyncoll, Duncan LA; Reinhart, Konrad; Brunkhorst, Frank; Vail, George Matthew; Janes, Jonathan

2008-01-01

Introduction Drotrecogin alfa (activated; DrotAA) treatment, a 96-hour infusion, reduces 28-day mortality in severe sepsis to approximately 25%. The question remains whether a longer infusion or higher dose could increase rate of survival. The goal of this study was to identify a dependable, sensitive measure with which to monitor disease progression and response in patients during DrotAA treatment. Methods Data on severe sepsis patients included in PROWESS (placebo-controlled, double-blind, randomized study of 850 DrotAA and 840 placebo individuals) and ENHANCE (single-arm, open-label study of 2,375 DrotAA patients) studies were analyzed. In these studies, DrotAA (24 μg/kg per hour) or placebo was infused for 96 hours and patients were followed for 28 days. Data on six laboratory measures and five organ dysfunctions were systematically analyzed to identify a potential surrogate end-point for monitoring DrotAA therapy and predicting 28-day mortality at the end of therapy. To allow comparison across variables, sensitivity and specificity analyses identified cut-off values for preferred outcome, and relative risks for being above or below cut-offs were calculated, as was the 'proportion of treatment effect explained' (PTEE) to identify biomarkers that contribute to benefit from DrotAA. Results Protein C was the only variable that correlated with outcome across all analyses. Using placebo data, a baseline protein C under 40% was established as a useful predictor of outcome (odds ratio 2.12). Similar odds ratios were associated with cut-off values of other biomarkers, but the treatment benefit associated with DrotAA was significantly greater below the cut-off than above the cut-off only for protein C (relative risk for 28-day mortality 0.66 versus 0.88; P = 0.04). Protein C was the only end-of-infusion biomarker that potentially explained at least 50% of the benefit from DrotAA (PTEE 57.2%). The PTEE was 41% for cardiovascular Sequential Organ Failure Assessment score

Long-term cost-effectiveness of initiating treatment for painful diabetic neuropathy with pregabalin, duloxetine, gabapentin, or desipramine.

PubMed

Bellows, Brandon K; Nelson, Richard E; Oderda, Gary M; LaFleur, Joanne

2016-01-01

Painful diabetic neuropathy (PDN) affects nearly half of patients with diabetes. The objective of this study was to compare the cost-effectiveness of starting patients with PDN on pregabalin (PRE), duloxetine (DUL), gabapentin (GABA), or desipramine (DES) over a 10-year time horizon from the perspective of third-party payers in the United States. A Markov model was used to compare the costs (2013 $US) and effectiveness (quality-adjusted life-years [QALYs]) of first-line PDN treatments in 10,000 patients using microsimulation. Costs and QALYs were discounted at 3% annually. Probabilities and utilities were derived from the published literature. Costs were average wholesale price for drugs and national estimates for office visits and hospitalizations. One-way and probabilistic (PSA) sensitivity analyses were used to examine parameter uncertainty. Starting with PRE was dominated by DUL as DUL cost less and was more effective. Starting with GABA was extendedly dominated by a combination of DES and DUL. DES and DUL cost $23,468 and $25,979, while yielding 3.05 and 3.16 QALYs, respectively. The incremental cost-effectiveness ratio for DUL compared with DES was $22,867/QALY gained. One-way sensitivity analysis showed that the model was most sensitive to the adherence threshold and utility for mild pain. PSA showed that, at a willingness-to-pay (WTP) of $50,000/QALY, DUL was the most cost-effective option in 56.3% of the simulations, DES in 29.2%, GABA in 14.4%, and PRE in 0.1%. Starting with DUL is the most cost-effective option for PDN when WTP is greater than $22,867/QALY. Decision makers may consider starting with DUL for PDN patients.

VizieR Online Data Catalog: UV counterparts in HI clouds using ALFA surveys (Donovan+, 2015)

NASA Astrophysics Data System (ADS)

Donovan Meyer, J.; Peek, J. E. G.; Putman, M.; Grcevich, J.

2017-10-01

GALFA-HI is a survey of Galactic HI conducted with the ALFA seven-beam feed array on the 305 m Arecibo antenna. The survey has both high spatial (FWHM~4') and velocity (0.18 km/s) resolution over 13000 (7520 in DR1) degrees2 of sky between -650 and 650 km/s. Details of the observations and data reduction can be found in Peek et al. (2011ApJS..194...20P). The ALFALFA HI-line survey, now 40% complete, also uses the Arecibo Observatory and its seven-beam feed array to detect potential dwarf galaxies in the vicinity of the Milky Way. The survey, which covers over 7000 (2800 in α.40) deg2 of sky out to 18000 km/s, has the sensitivity to detect 105 Mȯ clouds with 20 km/s linewidths at a distance of 1 Mpc. (2 data files).

Coding of adverse events of suicidality in clinical study reports of duloxetine for the treatment of major depressive disorder: descriptive study.

PubMed

Maund, Emma; Tendal, Britta; Hróbjartsson, Asbjørn; Lundh, Andreas; Gøtzsche, Peter C

2014-06-04

To assess the effects of coding and coding conventions on summaries and tabulations of adverse events data on suicidality within clinical study reports. Systematic electronic search for adverse events of suicidality in tables, narratives, and listings of adverse events in individual patients within clinical study reports. Where possible, for each event we extracted the original term reported by the investigator, the term as coded by the medical coding dictionary, medical coding dictionary used, and the patient's trial identification number. Using the patient's trial identification number, we attempted to reconcile data on the same event between the different formats for presenting data on adverse events within the clinical study report. 9 randomised placebo controlled trials of duloxetine for major depressive disorder submitted to the European Medicines Agency for marketing approval. Clinical study reports obtained from the EMA in 2011. Six trials used the medical coding dictionary COSTART (Coding Symbols for a Thesaurus of Adverse Reaction Terms) and three used MedDRA (Medical Dictionary for Regulatory Activities). Suicides were clearly identifiable in all formats of adverse event data in clinical study reports. Suicide attempts presented in tables included both definitive and provisional diagnoses. Suicidal ideation and preparatory behaviour were obscured in some tables owing to the lack of specificity of the medical coding dictionary, especially COSTART. Furthermore, we found one event of suicidal ideation described in narrative text that was absent from tables and adverse event listings of individual patients. The reason for this is unclear, but may be due to the coding conventions used. Data on adverse events in tables in clinical study reports may not accurately represent the underlying patient data because of the medical dictionaries and coding conventions used. In clinical study reports, the listings of adverse events for individual patients and narratives

Coding of adverse events of suicidality in clinical study reports of duloxetine for the treatment of major depressive disorder: descriptive study

PubMed Central

Tendal, Britta; Hróbjartsson, Asbjørn; Lundh, Andreas; Gøtzsche, Peter C

2014-01-01

Objective To assess the effects of coding and coding conventions on summaries and tabulations of adverse events data on suicidality within clinical study reports. Design Systematic electronic search for adverse events of suicidality in tables, narratives, and listings of adverse events in individual patients within clinical study reports. Where possible, for each event we extracted the original term reported by the investigator, the term as coded by the medical coding dictionary, medical coding dictionary used, and the patient’s trial identification number. Using the patient’s trial identification number, we attempted to reconcile data on the same event between the different formats for presenting data on adverse events within the clinical study report. Setting 9 randomised placebo controlled trials of duloxetine for major depressive disorder submitted to the European Medicines Agency for marketing approval. Data sources Clinical study reports obtained from the EMA in 2011. Results Six trials used the medical coding dictionary COSTART (Coding Symbols for a Thesaurus of Adverse Reaction Terms) and three used MedDRA (Medical Dictionary for Regulatory Activities). Suicides were clearly identifiable in all formats of adverse event data in clinical study reports. Suicide attempts presented in tables included both definitive and provisional diagnoses. Suicidal ideation and preparatory behaviour were obscured in some tables owing to the lack of specificity of the medical coding dictionary, especially COSTART. Furthermore, we found one event of suicidal ideation described in narrative text that was absent from tables and adverse event listings of individual patients. The reason for this is unclear, but may be due to the coding conventions used. Conclusion Data on adverse events in tables in clinical study reports may not accurately represent the underlying patient data because of the medical dictionaries and coding conventions used. In clinical study reports, the

Efficacy and safety of follitropin alfa/lutropin alfa in ART: a randomized controlled trial in poor ovarian responders.

PubMed

Humaidan, P; Chin, W; Rogoff, D; D'Hooghe, T; Longobardi, S; Hubbard, J; Schertz, J

2017-03-01

How does the efficacy and safety of a fixed-ratio combination of recombinant human FSH plus recombinant human LH (follitropin alfa plus lutropin alfa; r-hFSH/r-hLH) compare with that of r-hFSH monotherapy for controlled ovarian stimulation (COS) in patients with poor ovarian response (POR)? The primary and secondary efficacy endpoints were comparable between treatment groups and the safety profile of both treatment regimens was favourable. Although meta-analyses of clinical trials have suggested some beneficial effect on reproductive outcomes with r-hLH supplementation in patients with POR, the definitions of POR were heterogeneous and limit the comparability across studies. Phase III, single-blind, active-comparator, randomized, parallel-group clinical trial. Patients were followed for a single ART cycle. A total of 939 women were randomized (1:1) to receive either r-hFSH/r-hLH or r-hFSH. Randomization, stratified by study site and participant age, was conducted via an interactive voice response system. Women classified as having POR, based on criteria incorporating the ESHRE Bologna criteria, were down-regulated with a long GnRH agonist protocol and following successful down-regulation were randomized (1:1) to COS with r-hFSH/r-hLH or r-hFSH alone. The primary efficacy endpoint was the number of oocytes retrieved following COS. Safety endpoints included the incidence of adverse events, including ovarian hyperstimulation syndrome (OHSS). Post hoc analyses investigated safety outcomes and correlations between live birth and baseline characteristics (age and number of oocytes retrieved in previous ART treatment cycles or serum anti-Müllerian hormone (AMH)). The significance of the treatment effect was tested by generalized linear models (Poisson regression for counts and logistic regression for binary endpoints) adjusting for age and country. Of 949 subjects achieving down-regulation, 939 were randomized to r-hFSH/r-hLH (n = 477) or r-hFSH (n = 462) and received

Corifollitropin alfa followed by highly purified HMG versus recombinant FSH in young poor ovarian responders: a multicentre randomized controlled clinical trial.

PubMed

Drakopoulos, Panagiotis; Vuong, Thi Ngoc Lan; Ho, Ngoc Anh Vu; Vaiarelli, Alberto; Ho, Manh Tuong; Blockeel, Christophe; Camus, Michel; Lam, Anh Tuan; van de Vijver, Arne; Humaidan, Peter; Tournaye, Herman; Polyzos, Nikolaos P

2017-11-01

Does administration of corifollitropin alfa followed by highly purified (hp) HMG result in higher ongoing pregnancy rates compared with daily recombinant FSH (rFSH) in young poor responders? Corifollitropin alfa followed by hp-HMG does not increase ongoing pregnancy rates compared with rFSH in young poor responders, although more supernumerary cryopreserved embryos were obtained with corifollitropin alfa and hp-HMG. Poor ovarian response remains one of the main therapeutic challenges in women undergoing ovarian stimulation, given that very low live birth rates of 6% have been reported in this particular group of infertile patients. Nevertheless, concerns have been raised that a degree of heterogeneity remains, as the prognostic effect of individual factors is still unclear, particularly for the young poor responder group. The rationale for conducting the current randomized trial was based on the results of a previous pilot study demonstrating promising results with the administration of hp-HMG following corifollitropin alpha in women younger than 40 years of age, fulfilling the 'Bologna' criteria. A multicenter, phase III, superiority, randomized trial was conducted using a parallel two-arm design. The study included 152 patients younger than 40 years old and fulfilling the 'Bologna' criteria for poor ovarian response, from one tertiary referral centre in Europe and one tertiary referral centre in Asia. Enrolment was performed from March 2013 to May 2016. Eligible patients were randomized to either administration of 150 μg corifollitropin alfa followed by 300 IU hp-HMG (Group A) or to 300 IU of daily recombinant FSH (Group B) in a fixed GnRH antagonist protocol. The randomization sequence was created using a computer generated randomization list stratified by centre, using 1:1 allocation. The primary outcome was ongoing pregnancy rate (defined as the presence of an intrauterine gestational sac with an embryonic pole demonstrating cardiac activity at 9-10 weeks of

Induction dosing of peginterferon alfa-2a (40 KD) and/or high-dose ribavirin in genotype 1 CHC patients with difficult-to-treat characteristics: pharmacokinetic and viral kinetic (PK/VK) assessment from PROGRESS.

PubMed

Morcos, Peter N; Leong, Ruby; Thommes, James A; DePamphilis, Jean; Grippo, Joseph F; Brennan, Barbara J

2015-01-01

PROGRESS randomized chronic hepatitis C genotype 1 patients with a baseline viral load ≥400,000 IU/mL weighing ≥85 kg to regimens of 180 μg/week for 48 weeks or 360 μg/week for 12 weeks followed by 180 μg/week for 36 weeks peginterferon alfa-2a plus ribavirin. This analysis explored pharmacokinetics and early viral kinetics (VK) and evaluates differences between groups. Blood samples for pharmacokinetic and VK analyses were collected from 51 patients enrolled in the PROGRESS study. Mean peginterferon alfa-2a trough concentration at week 12 was 11.7±4.3 ng/mL for 180 μg and 23.4±11.3 ng/mL for 360 μg. Early VK profiles suggested a trend towards an enhanced viral decline in the 360 μg groups with a mean decrease in HCV RNA at 48 hours post first dose of 1.04 log10 (IU/mL) compared with 0.76 log10 (IU/mL) in the 180 μg groups. Mean beta slope increased with dose, ranging from 0.38±0.26 log10 IU/week at 180 μg to 0.52±0.32 log10 IU/week at 360 μg. Early viral de clines may be enhanced with the 360 μg dose. These data may suggest the utility of high-dose peginterfer on alfa-2a plus direct-acting antivirals (DAA) in select difficult-to-treat populations.

Gateways to clinical trials.

PubMed

Bayés, M; Rabasseda, X; Prous, J R

2005-06-01

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: Abiraterone acetate, acyline, adalimumab, adenosine triphosphate, AEE-788, AIDSVAX gp120 B/B, AK-602, alefacept, alemtuzumab, alendronic acid sodium salt, alicaforsen sodium, alprazolam, amdoxovir, AMG-162, aminolevulinic acid hydrochloride, aminolevulinic acid methyl ester, aminophylline hydrate, anakinra, anecortave acetate, anti-CTLA-4 MAb, APC-8015, aripiprazole, aspirin, atazanavir sulfate, atomoxetine hydrochloride, atorvastatin calcium, atrasentan, AVE-5883, AZD-2171; Betamethasone dipropionate, bevacizumab, bimatoprost, biphasic human insulin (prb), bortezomib, BR-A-657, BRL-55730, budesonide, busulfan; Calcipotriol, calcipotriol/betamethasone dipropionate, calcium folinate, capecitabine, capravirine, carmustine, caspofungin acetate, cefdinir, certolizumab pegol, CG-53135, chlorambucil, ciclesonide, ciclosporin, cisplatin, clofarabine, clopidogrel hydrogensulfate, clozapine, co-trimoxazole, CP-122721, creatine, CY-2301, cyclophosphamide, cypher, cytarabine, cytolin; D0401, darbepoetin alfa, darifenacin hydrobromide, DASB, desipramine hydrochloride, desloratadine, desvenlafaxine succinate, dexamethasone, didanosine, diquafosol tetrasodium, docetaxel, doxorubicin hydrochloride, drotrecogin alfa (activated), duloxetine hydrochloride, dutasteride; Ecallantide, efalizumab, efavirenz, eletriptan, emtricitabine, enfuvirtide, enoxaparin sodium, estramustine phosphate sodium, etanercept, ethinylestradiol, etonogestrel, etonogestrel/ethinylestradiol, etoposide, exenatide; Famciclovir, fampridine, febuxostat, filgrastim, fludarabine phosphate, fluocinolone acetonide, fluorouracil, fluticasone propionate

Comparative efficacy and safety of six antidepressants and anticonvulsants in painful diabetic neuropathy: a network meta-analysis.

PubMed

Rudroju, Neelima; Bansal, Dipika; Talakokkula, Shiva Teja; Gudala, Kapil; Hota, Debasish; Bhansali, Anil; Ghai, Babita

2013-01-01

Anticonvulsants and antidepressants are mostly used in management of painful diabetic neuropathy (PDN). However there are few direct comparisons between drugs of these classes, making evidence-based decision-making in the treatment of painful diabetic neuropathy difficult. This study aimed to perform a network meta-analysis and benefit-risk analysis to evaluate the comparative efficacy and safety of these drugs in PDN treatment. Comparative effectiveness study. Medical Education and Research facility in India. A comprehensive data search was done in PubMed, Cochrane, and Embase up to August 2012. We then systematically reviewed the studies which compared any of 6 drugs for the management of PDN: amitriptyline, duloxetine, gabapentin, pregabalin, valproate, and venlafaxine or any of their combinations. We performed a random-effects network meta-analysis to rank treatments in terms of efficacy and safety. We chose the number of patients experiencing = 50% reduction in pain and number of patient withdrawals due to adverse events (AE) as primary outcomes for efficacy and safety, respectively. We also performed benefit-risk analysis, taking efficacy outcome as benefit and safety outcome as risk. Analysis was intention-to-treat. We included 21 published trials in the analysis. Duloxetine, gabapentin, pregabalin, and venlafaxine were shown to be significantly efficacious compared to placebo with odds ratios (OR) of 2.12, 3.98, 2.78, and 4.43, respectively. Amitriptyline (OR: 7.03, 95% confidence interval [CI]: 1.87, 29.05) and duloxetine (OR: 3.26, 95% CI: 1.04, 9.97) caused more withdrawals than gabapentin. The ranking order of efficacy was gabapentin, venlafaxine, pregabalin, duloxetine/gabapentin, duloxetine, amitriptyline, and placebo and the ranking order of safety was placebo, gabapentin, pregabalin, venlafaxine, duloxetine/gabapentin combination, duloxetine, and amitriptyline. Benefit-risk balance favored the order: gabapentin, venlafaxine, pregabalin, duloxetine

Peginterferon alfa-2a and ribavirin for 24 weeks in hepatitis C type 1 and 4 patients with rapid virological response.

PubMed

Ferenci, Peter; Laferl, Hermann; Scherzer, Thomas-Matthias; Gschwantler, Michael; Maieron, Andreas; Brunner, Harald; Stauber, Rudolf; Bischof, Martin; Bauer, Bernhard; Datz, Christian; Löschenberger, Karin; Formann, Elisabeth; Staufer, Katharina; Steindl-Munda, Petra

2008-08-01

This analysis reports the rate of sustained virological response (SVR) in patients infected with hepatitis C virus (HCV) genotype 1 or 4 who were assigned to 24 weeks of treatment with pegylated interferon (peginterferon) alfa-2a 180 mug/wk plus ribavirin 1000/1200 mg/day after achieving a rapid virological response (RVR; HCV RNA level <50 IU/mL) at week 4 in a prospective trial investigating response-guided therapy. Non-RVR patients with an early virological response were randomized to 48 or 72 weeks of therapy (this is a still-ongoing trial). A total of 150 of 516 patients (29%) had an RVR, 143 of whom completed 24 weeks of treatment. Younger patients, leaner patients, and those with an HCV RNA level alfa-2a plus ribavirin 1000/1200 mg/day is appropriate in genotype 1 and 4 patients with a low baseline HCV RNA level who achieve an RVR by week 4 of therapy.

Acute pancreatitis attributed to the use of interferon alfa-2b.

PubMed

Eland, I A; Rasch, M C; Sturkenboom, M J; Bekkering, F C; Brouwer, J T; Delwaide, J; Belaiche, J; Houbiers, G; Stricker, B H

2000-07-01

Two patients experienced episodes of acute pancreatitis shortly after starting treatment with interferon alfa-2b (IFN-alpha) for a chronic hepatitis C infection. The first patient was a 40-year-old man who developed acute pancreatitis after 15 weeks of treatment with 3 MU IFN-alpha subcutaneously (SC) 3 times weekly and 1200 mg ribavirin. After disappearance of symptoms and normalization of laboratory values, oral intake of solid foods and IFN-alpha therapy were restarted. Within hours, a relapse of acute pancreatitis occurred. A rechallenge with IFN-alpha 4 days later was followed by a prompt increase in serum lipase level, and IFN-alpha therapy was discontinued. The second patient was a 38-year-old man who developed acute pancreatitis 2 hours after SC administration of 5 MU IFN-alpha. Ultrasound endoscopy showed sludge in the gallbladder. The patient was rechallenged 5 weeks later with 3 MU IFN-alpha SC. Although serum amylase and lipase levels increased after readministration of IFN-alpha, treatment was continued. The patient was readmitted 2 weeks later with severe abdominal pain, and IFN-alpha administration was discontinued. Considering the temporal relationship between the start of IFN-alpha treatment and development of acute pancreatitis, the absence of other clear etiologic factors for acute pancreatitis, disappearance of symptoms after discontinuation of IFN-alpha, and positive reactions to rechallenge, IFN-alpha is the most probable cause for development of acute pancreatitis in these patients.

Predictors of pain medication selection among patients diagnosed with fibromyalgia.

PubMed

Boulanger, Luke; Wu, Ning; Chen, Shih-Yin; Nagar, Saurabh; Fraser, Kimberly; Bernauer, Mark J; Zhao, Zhenxiang; Zhao, Yang

2012-04-01

Several pharmacologic therapies have been recommended for managing fibromyalgia. However, the factors associated with each treatment initiation have not been well established. This study assessed factors that were associated with the use of duloxetine vs. other pain medications among patients with fibromyalgia. Administrative claims from a large, U.S. commercially insured population were analyzed using a retrospective cohort design. Patients with fibromyalgia who were 18 to 64 years old and initiated duloxetine vs. selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), venlafaxine, gabapentin, pregabalin, tramadol, or nontramadol opioids between January 1, 2007 and December 12, 2008 were selected. Treatment initiation was defined as no access to the same medication over the previous 90 days, with the most recent initiation date as the index date. All patients selected had at least one fibromyalgia diagnosis (ICD-9-CM: 729.1) in the 12 months prior to initiation of each study medication. Multiple logistic regression models were estimated to assess the predictors of initiating duloxetine vs. each of the other medications. The study included 117,305 patients with fibromyalgia (48 years of age on average; 76% women) who initiated duloxetine (n = 5,827), SSRIs (n = 8,620), TCAs (n = 5,424), venlafaxine (n = 2,038), gabapentin (n = 5,733), pregabalin (n = 11,152), tramadol (n = 7,312), or nontramadol opioids (n = 71,199). Common fibromyalgia-related comorbidities were low back pain (31% to 49%), osteoarthritis (14% to 21%), and sleep disturbance (10% to 15%). Controlling for demographic and clinical characteristics, patients who received pregabalin in the prior 12-month period were more likely to initiate duloxetine. Patients from other treatment cohorts, except for those in the pregabalin and nontramadol opioid cohorts, were more likely to re-initiate the same prior medication than to begin treatment with duloxetine. Other predictors of

Development and validation of a UPLC method for the determination of duloxetine hydrochloride residues on pharmaceutical manufacturing equipment surfaces

PubMed Central

Kumar, Navneet; Sangeetha, D.; Balakrishna, P.

2011-01-01

Background: In pharmaceutical industries, it is very important to remove drug residues from the equipment and areas used. The cleaning procedure must be validated, so special attention must be devoted to the methods used for analysis of trace amounts of drugs. A rapid, sensitive, and specific reverse phase ultra-performance liquid chromatographic (UPLC) method was developed for the quantitative determination of duloxetine in cleaning validation swab samples. Material and Methods: The method was validated using an Acquity UPLC™ HSS T3 (100 × 2.1 mm2) 1.8 μm column with a isocratic mobile phase containing a mixture of 0.01 M potassium dihydrogen orthophosphate, pH adjusted to 3.0 with orthophosphoric acid and acetonitrile (60:40 v/v). The flow rate of the mobile phase was 0.4 ml/min with a column temperature of 40°C and detection wavelength at 230 nm. Cotton swabs, moisten with extraction solution (90% methanol and 10% water), were used to remove any residue of drug from stainless steel, glass and silica surfaces, and give recoveries >80% at four concentration levels. Results: The precision of the results, reported as the relative standard deviation, were below 1.5%. The calibration curve was linear over a concentration range from 0.02 to 5.0 μg/ml with a correlation coefficient of 0.999. The detection limit and quantitation limit were 0.006 and 0.02 μg/ml, respectively. The method was validated over a concentration range of 0.05–5.0 μg/ml. Conclusion: The developed method was validated with respect to specificity, linearity, limit of detection and quantification, accuracy, precision, and robustness. PMID:23781449

FibroTest is an independent predictor of virologic response in chronic hepatitis C patients retreated with pegylated interferon alfa-2b and ribavirin in the EPIC³ program.

PubMed

Poynard, Thierry; Munteanu, Mona; Colombo, Massimo; Bruix, Jordi; Schiff, Eugene; Terg, Ruben; Flamm, Steven; Moreno-Otero, Ricardo; Carrilho, Flair; Schmidt, Warren; Berg, Thomas; McGarrity, Thomas; Heathcote, E Jenny; Gonçales, Fernando; Diago, Moises; Craxi, Antonio; Silva, Marcelo; Boparai, Navdeep; Griffel, Louis; Burroughs, Margaret; Brass, Clifford; Albrecht, Janice

2011-02-01

EPIC-3 is a prospective, international study that has demonstrated the efficacy of PEG-IFN alfa-2b plus weight-based ribavirin in patients with chronic hepatitis C and significant fibrosis who previously failed any interferon-alfa/ribavirin therapy. The aim of the present study was to assess FibroTest (FT), a validated non-invasive marker of fibrosis in treatment-naive patients, as a possible alternative to biopsy as the baseline predictor of subsequent early virologic (EVR) and sustained virologic response (SVR) in previously treated patients. Of 2312 patients enrolled, 1459 had an available baseline FT, biopsy, and complete data. Uni- (UV) and multi-variable (MV) analyses were performed using FT and biopsy. Baseline characteristics were similar as in the overall population; METAVIR stage: 28% F2, 29% F3, and 43% F4, previous relapsers 29%, previous PEG-IFN regimen 41%, high baseline viral load (BVL) 64%. 506 patients (35%) had undetectable HCV-RNA at TW12 (TW12neg), with 58% achieving SVR. The accuracy of FT was similar to that in naive patients: AUROC curve for the diagnosis of F4 vs F2=0.80 (p<0.00001). Five baseline factors were associated (p<0.001) with SVR in UV and MV analyses (odds ratio: UV/MV): fibrosis stage estimated using FT (4.5/5.9) or biopsy (1.5/1.6), genotype 2/3 (4.5/5.1), BVL (1.5/1.3), prior relapse (1.6/1.6), previous treatment with non-PEG-IFN (2.6/2.0). These same factors were associated (p ≤ 0.001) with EVR. Among patients TW12neg, two independent factors remained highly predictive of SVR by MV analysis (p ≤ 0.001): genotype 2/3 (odds ratio=2.9), fibrosis estimated with FT (4.3) or by biopsy (1.5). FibroTest at baseline is a possible non-invasive alternative to biopsy for the prediction of EVR at 12 weeks and SVR, in patients with previous failures and advanced fibrosis, retreated with PEG-IFN alfa-2b and ribavirin. Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Levomilnacipran (F2695), a norepinephrine-preferring SNRI: profile in vitro and in models of depression and anxiety.

PubMed

Auclair, A L; Martel, J C; Assié, M B; Bardin, L; Heusler, P; Cussac, D; Marien, M; Newman-Tancredi, A; O'Connor, J A; Depoortère, R

2013-07-01

Levomilnacipran (LVM; F2695) is the more active enantiomer of the serotonin/norepinephrine (5-HT/NE) reuptake inhibitor (SNRI) milnacipran and is currently under development for the treatment of major depressive disorder. LVM was benchmarked against two other SNRIs, duloxetine and venlafaxine, in biochemical, neurochemical and pharmacological assays. LVM exhibited high affinity for human NE (Ki = 92.2 nM) and 5-HT (11.2 nM) transporters, and potently inhibited NE (IC50 = 10.5 nM) and 5-HT (19.0 nM) reuptake (human transporter) in vitro. LVM had 2-fold greater potency for norepinephrine relative to serotonin reuptake inhibition (i.e. NE/5-HT potency ratio: 0.6) and 17 and 27 times higher selectivity for NE reuptake inhibition compared with venlafaxine and duloxetine, respectively. LVM did not exhibit affinity for 23 off-target receptors. LVM (i.p.) increased cortical extracellular levels of 5-HT, and NE (minimal effective doses: MEDs = 20 and 10 mg/kg, respectively). In anti-depressive/anti-stress models, i.p. LVM diminished immobility time in the mouse forced swim (MED = 20 mg/kg) and tail suspension (MED = 2.5 mg/kg) tests, and reduced shock-induced ultrasonic vocalizations in rats (MED = 5 mg/kg). Duloxetine and venlafaxine were less potent (MEDs ≥ 10 mg/kg). At doses active in these three therapeutically-relevant models, LVM (i.p.) did not significantly affect spontaneous locomotor activity. In summary, LVM is a potent, selective inhibitor of NE and 5-HT transporters with preferential activity at the former. It is efficacious in models of anti-depressive/anti-stress activity, with minimal potential for locomotor side effects. Copyright © 2013 Elsevier Ltd. All rights reserved.

Impact of duloxetine and dexamethasone for improving postoperative pain after laparoscopic gynecological surgeries: A randomized clinical trial

PubMed Central

Kassim, Dina Y.; Esmat, Ibrahim M.; Elgendy, Mohammed A.

2018-01-01

Background: Patients’ surgical experiences are influenced by their perception of pain management. Duloxetine (Dulox) and dexamethasone (Dex) are used in multimodal analgesia to reduce opioid use and side effects. Dulox is a selective serotonin and norepinephrine reuptake inhibitor and has efficacy in chronic pain conditions. Dex enhances postoperative (PO) analgesia and reduces PO nausea and vomiting (PONV). Methods: Seventy-five female patients were randomly allocated into one of three equal groups. GI received Dulox 60 mg orally and 100 ml 0.9% sodium chloride (normal saline [NS]) intravenous infusion (IVI) over 15 min, GII: received as GI except Dex 0.1 mg/kg was mixed with NS and GIII received identical placebo for Dulox capsule and Dex IVI, 2 h preoperatively. Patients’ vitals, visual analog scale (VAS), and sedation score were assessed at 30 min, 1 h, 2 h, 6 h, and 12 h postoperatively. Total pethidine requirements, plasma cortisol, PONV, and patients satisfaction were recorded. Results: PO time for 1st rescue analgesic was significantly high in GI and GII compared to GIII and in GII compared to GI. There was a significant less VAS score, heart rate, mean arterial pressure, and a high sedation score in GI and GII compared to GIII at 30 min, 1, 2, and 6 h postoperatively. Total pethidine requirements were significantly less in GI and GII compared to GIII 12 h postoperatively. There was a significant reduction in the 2 h PO serum cortisol (μg/dl) and a significant increase in the PO patients satisfaction score in GI and GII compared to GIII. PONV was decreased significantly in GII compared to GI and GIII. Conclusion: The use of oral Dulox 60 mg combined with Dex 0.1 mg/kg IVI is more effective than oral Dulox 60 mg alone, 2 h preoperatively, for improving PO pain by reducing the requirements for rescue analgesia and PONV. PMID:29416464

Are there different predictors of analgesic response between antidepressants and anticonvulsants in painful diabetic neuropathy?

PubMed

Marchettini, P; Wilhelm, S; Petto, H; Tesfaye, S; Tölle, T; Bouhassira, D; Freynhagen, R; Cruccu, G; Lledó, A; Choy, E; Kosek, E; Micó, J A; Späth, M; Skljarevski, V; Lenox-Smith, A; Perrot, S

2016-03-01

To investigate baseline demographics and disease characteristics as predictors of the analgesic effect of duloxetine and pregabalin on diabetic peripheral neuropathic pain (DPNP). Based on data from the COMBO-DN study, a multinational clinical trial in DPNP, the potential impact of baseline characteristics on pain relief after 8-week monotherapy with 60 mg/day duloxetine or 300 mg/day pregabalin was assessed using analyses of covariance. Subgroups of interest were characterized regarding their baseline characteristics and efficacy outcomes. A total of 804 patients were evaluated at baseline. A significant interaction with treatment was observed in the mood symptom subgroups with a larger pain reduction in duloxetine-treated patients having no mood symptoms [Hospital Anxiety and Depression Scale (HADS) depression or anxiety subscale score <11; -2.33 (duloxetine); -1.52 (pregabalin); p = 0.024]. There were no significant interactions between treatment for subgroups by age (<65 or ≥65 years), gender, baseline pain severity [Brief Pain Inventory Modified Short Form (BPI-MSF) average pain <6 or ≥6], diabetic neuropathy duration (≤2 or >2 years), baseline haemoglobin A1c (HbA1c) (<8% or ≥8%), presence of comorbidities and concomitant medication use. Our analyses suggest that the efficacy of duloxetine and pregabalin for initial 8-week treatment in DPNP was consistent across examined subgroups based on demographics and disease characteristics at baseline except for the presence of mood symptoms. Duloxetine treatment appeared to be particularly beneficial in DPNP patients having no mood symptoms. © 2015 European Pain Federation - EFIC®

Mericitabine and Either Boceprevir or Telaprevir in Combination with Peginterferon Alfa-2a plus Ribavirin for Patients with Chronic Hepatitis C Genotype 1 Infection and Prior Null Response: The Randomized DYNAMO 1 and DYNAMO 2 Studies.

PubMed

Wedemeyer, Heiner; Forns, Xavier; Hézode, Christophe; Lee, Samuel S; Scalori, Astrid; Voulgari, Athina; Le Pogam, Sophie; Nájera, Isabel; Thommes, James A

2016-01-01

Most patients with chronic hepatitis C virus (HCV) genotype 1 infection who have had a previous null response (<2-log10 reduction in HCV RNA by treatment week 12) to peginterferon/ribavirin (PegIFN/RBV) do not achieve a sustained virological response (SVR) when re-treated with a first-generation HCV protease inhibitor (PI) administered in combination with PegIFN/RBV. We studied the incremental benefits associated with adding mericitabine (nucleoside analog inhibitor of HCV polymerase) to PI plus PegIFN alfa-2a/RBV-based therapy in two double-blind randomized multicenter phase 2 trials (with boceprevir in DYNAMO 1, and with telaprevir in DYNAMO 2). The primary endpoint in both trials was SVR, defined as HCV RNA <25 IU/mL 12 weeks after the end of treatment (SVR12). Overall, the addition of mericitabine to PI plus PegIFN alfa-2a/RBV therapy resulted in SVR12 rates of 60-70% in DYNAMO 1 and of 71-96% in DYNAMO 2. SVR12 rates were similar in patients infected with HCV genotype 1a and 1b in both trials. The placebo control arms in both studies were stopped because of high rates of virological failure. Numerically lower relapse rates were associated with longer treatment with mericitabine (24 versus 12 weeks), telaprevir-containing regimens, and regimens that included 48 weeks of PegIFN alfa-2a/RBV therapy. No mericitabine resistance mutations were identified in any patient in either trial. The addition of mericitabine did not add to the safety burden associated with either telaprevir or boceprevir-based regimens. These studies demonstrate increased SVR rates and reduced relapse rates in difficult-to-treat patients when a nucleoside polymerase inhibitor with intermediate antiviral potency is added to regimens containing a first-generation PI. ClinicalTrials.gov NCT01482403 and ClinicalTrials.gov NCT01482390.

Duloxetine

MedlinePlus

... www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/UCM096273.No matter your age, before you take an antidepressant, you, ... abdomen itching yellowing of the skin or eyes dark colored urine loss of appetite extreme tiredness or ...

Effects of centrally acting analgesics on spinal segmental reflexes and wind-up.

PubMed

Mazo, I; Roza, C; Zamanillo, D; Merlos, M; Vela, J M; Lopez-Garcia, J A

2015-08-01

The spinal cord is a prime site of action for analgesia. Here we characterize the effects of established analgesics on segmental spinal reflexes. The aim of the study was to look for the pattern of action or signature of analgesic effects on these reflexes. We used a spinal cord in vitro preparation of neonate mice to record ventral root responses to dorsal root stimulation. Pregabalin, clonidine, morphine and duloxetine and an experimental sigma-1 receptor antagonist (S1RA) were applied to the preparation in a cumulative concentration protocol. Drug effects on the wind-up produced by repetitive stimulation of C-fibres and on responses to single A- and C-fibre intensity stimuli were analysed. All compounds produced a concentration-dependent inhibition of total spikes elicited by repetitive stimulation. Concentrations producing ∼50% reduction in this parameter were (in μM) clonidine (0.01), morphine (0.1), pregabalin (1), duloxetine (10) and S1RA (30). At these concentrations clonidine, pregabalin and S1RA had significant effects on the wind-up index and little depressant effects on responses to single stimuli. Morphine and duloxetine did not depress wind-up index and showed large effects on responses to single stimuli. None of the compounds had strong effects on the amplitude of the non-nociceptive monosynaptic reflex. morphine and duloxetine had general depressant effects on spinal reflexes, whereas the effects of clonidine, pregabalin and S1RA appeared to be restricted to signals originated by strong repetitive activation of C-fibres. Results are discussed in the context of reported behavioural effects of the compounds studied. © 2014 European Pain Federation - EFIC®

Recombinant factor VIIa (eptacog alfa): a review of its use in congenital hemophilia with inhibitors, acquired hemophilia, and other congenital bleeding disorders.

PubMed

Croom, Katherine F; McCormack, Paul L

2008-01-01

Recombinant factor VIIa (NovoSeven; also known as recombinant activated factor VII or eptacog alfa) is structurally similar to human plasma-derived coagulation factor VIIa, but is manufactured using DNA biotechnology. Recombinant factor VIIa interacts with thrombin-activated platelets to produce a thrombin burst leading to accelerated fibrin clot formation localized to the site of vascular injury. It is approved in many countries for use as an intravenous hemostatic agent in patients with congenital hemophilia with inhibitors, and also for acquired hemophilia, factor VII deficiency, and Glanzmann thrombasthenia in some countries. Studies have shown it to be effective and generally well tolerated when used intravenously to treat bleeding episodes or provide hemostatic cover during surgery in patients with congenital hemophilia with inhibitors, acquired hemophilia, factor VII deficiency or Glanzmann thrombasthenia. Based on available data, its efficacy in terms of patient-assessed response may be similar to that of activated prothrombin complex concentrate (aPCC), but treatment with a single 270 microg/kg dose of recombinant factor VIIa might reduce the need for rescue therapy compared with aPCC. Recombinant factor VIIa is not immunogenic in patients with hemophilia, does not produce an anamnestic response in hemophilia patients with inhibitors, and has very low thrombogenicity. It is recommended in guidelines as the treatment of choice for bleeds in patients with hemophilia B with high-responding inhibitors and for patients with factor VII deficiency, and is also a first-line therapeutic option for high-responder hemophilia A patients with inhibitors and those with acquired hemophilia. Cost data from pharmacoeconomic analyses support its use in hemophilia patients with inhibitors. Thus, recombinant factor VIIa is a valuable treatment option for patients with these rare, but potentially serious, bleeding disorders.

Effect and Tolerability of Agalsidase Alfa in Patients with Fabry Disease Who Were Treatment Naïve or Formerly Treated with Agalsidase Beta or Agalsidase Alfa.

PubMed

Goker-Alpan, Ozlem; Nedd, Khan; Shankar, Suma P; Lien, Yeong-Hau H; Weinreb, Neal; Wijatyk, Anna; Chang, Peter; Martin, Rick

2015-01-01

In a multicenter, open-label, treatment protocol (HGT-REP-059; NCT01031173), clinical effects and tolerability of agalsidase alfa (agalα; 0.2 mg/kg every other week) were evaluated in patients with Fabry disease who were treatment naïve or switched from agalsidase beta (switch). Over 24 months, data were collected on the safety profile; renal and cardiac parameters were assessed using estimated glomerular filtration rate (eGFR), left ventricular mass index (LVMI), and midwall fractional shortening (MFS). Enrolled patients included 71 switch (median [range] age, 46.6 [5-84] years; male to female [M:F], 40:31) and 29 treatment naïve (38.7 [12-74] years; M:F, 14:15). Adverse events (AEs) were consistent with the known safety profile of agalα. Two switch patients had hospitalization due to possibly/probably drug-related serious AEs (one with transient ischemic attack, one with infusion-related AEs). One switch and two treatment-naïve patients discontinued treatment because of AEs. Three patients (one each switch, treatment naïve, and previous agalα) died; no deaths were considered drug-related. There was no significant change from baseline in LVMI or MFS in either group. Similarly, eGFR remained stable; mean ± standard error annualized change in eGFR (mL/min/1.73 m(2)) was -2.40 ± 1.04 in switch and -1.68 ± 2.21 in treatment-naïve patients. This is the largest cohort of patients with Fabry disease who were started on or switched to agalα in an FDA-accepted protocol during a worldwide supply shortage of agalsidase beta. Because this protocol was primarily designed to provide access to agalα, there were limitations, including not having stringent selection criteria and the lack of a placebo group.

Pharmacological Characterization of H05, a Novel Serotonin and Noradrenaline Reuptake Inhibitor with Moderate 5-HT2A Antagonist Activity for the Treatment of Depression.

PubMed

Xu, Xiangqing; Wei, Yaqin; Guo, Qiang; Zhao, Song; Liu, Zhiqiang; Xiao, Ting; Liu, Yani; Qiu, Yinli; Hou, Yuanyuan; Zhang, Guisen; Wang, KeWei

2018-06-01

Multitarget antidepressants selectively inhibiting monoaminergic transporters and 5-hydroxytryptamine (5-HT) 2A receptor have demonstrated higher efficacy and fewer side effects than selective serotonin reuptake inhibitors. In the present study, we synthesized a series of novel 3-(benzo[d][1,3]dioxol-4-yloxy)-3-arylpropyl amine derivatives, among which compound H05 was identified as a lead, exhibiting potent inhibitory effects on both serotonin ( K i = 4.81 nM) and norepinephrine (NE) ( K i = 6.72 nM) transporters and moderate 5-HT 2A antagonist activity (IC 50 = 60.37 nM). H05 was able to dose-dependently reduce the immobility duration in mouse forced swimming test and tail suspension test, with the minimal effective doses lower than those of duloxetine, and showed no stimulatory effect on locomotor activity. The administration of H05 (5, 10, and 20 mg/kg, by mouth) significantly shortened the immobility time of adrenocorticotropin-treated rats that serve as a model of treatment-resistant depression, whereas imipramine (30 mg/kg, by mouth) and duloxetine (30 mg/kg, by mouth) showed no obvious effects. Chronic treatment with H05 reversed the depressive-like behaviors in a rat model of chronic unpredictable mild stress and a mouse model of corticosterone-induced depression. Microdialysis analysis revealed that the administration of H05 at either 10 or 20 mg/kg increased the release of 5-HT and NE from the frontal cortex. The pharmacokinetic (PK) and brain penetration analyses suggest that H05 has favorable PK properties with good blood-brain penetration ability. Therefore, it can be concluded that H05, a novel serotonin and NE reuptake inhibitor with 5-HT 2A antagonist activity, possesses efficacious activity in the preclinical models of depression and treatment-resistant depression, and it may warrant further evaluation for clinical development. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

A randomized, prospective trial of ribavirin 400 mg/day versus 800 mg/day in combination with peginterferon alfa-2a in hepatitis C virus genotypes 2 and 3.

PubMed

Ferenci, Peter; Brunner, Harald; Laferl, Hermann; Scherzer, Thomas-Matthias; Maieron, Andreas; Strasser, Michael; Fischer, Gabriele; Hofer, Harald; Bischof, Martin; Stauber, Rudolf; Gschwantler, Michael; Steindl-Munda, Petra; Staufer, Katharina; Löschenberger, Karin

2008-06-01

We compared the efficacy and tolerability of 24 weeks of treatment with ribavirin 800 mg/day (group A) or 400 mg/day (group B) plus peginterferon alfa-2a 180 mug/week in treatment-naive patients infected with hepatitis C virus (HCV) genotype 2 or 3. A total of 97 of 141 patients randomized to group A (68.8%, 95% confidence interval [CI] 60.5%-76.3%) and 90 of 141 patients randomized to group B (63.8; 95% CI 55.3%-71.7%) achieved a sustained virological response, defined as undetectable serum HCV RNA at the end of untreated follow-up (week 48). Among patients infected with genotype 3, the rate of sustained virological response was 67.5% (95% CI 58.4%-75.6%) in group A and 63.9% (95% CI 54.7%-72.4%) in group B, and among patients infected with genotype 2, the rate of sustained virological response was 77.8% (95% CI 54.2%-93.6%) in group A and 55.6% (95% CI 38.4%-83.7%) in group B. Relapse rates in the 2 treatment groups were similar (17% in group A and 20% in group B). The incidence of adverse events, laboratory abnormalities, and dose reductions was similar in the 2 treatment groups. The results suggest that when administered for 24 weeks with peginterferon alfa-2a, ribavirin doses of 400 and 800 mg/day produce equivalent outcomes in patients infected with HCV genotype 3.

Pegylated interferon alfa-2a in patients with essential thrombocythaemia or polycythaemia vera: a post-hoc, median 83 month follow-up of an open-label, phase 2 trial.

PubMed

Masarova, Lucia; Patel, Keyur P; Newberry, Kate J; Cortes, Jorge; Borthakur, Gautam; Konopleva, Marina; Estrov, Zeev; Kantarjian, Hagop; Verstovsek, Srdan

2017-04-01

Pegylated interferon alfa-2a is an immunomodulatory agent used to treat polycythemia vera. The durability of responses and long-term safety of this drug in patients with polycythaemia vera and essential thrombocythaemia have not been reported. Here, we present long-term efficacy and safety data from a single-centre, open-label, phase 2 trial, after a median of 83 months follow up. Patients older than 18 years who were diagnosed with essential thrombocythaemia or polycythaemia vera according to 2001 WHO criteria were eligible to enrol in our study. The initial starting dose of pegylated interferon alfa-2a was 450 μg subcutaneously once per week, but was decreased in a stepwise manner due to toxic effects to a final starting dose of 90 mg per week: three patients were started at a dose of 450 mg per week, three at 360 mg per week, 19 at 270 mg per week, 26 at 180 mg per week, and 32 at 90 mg per week. Treatment was continued for as long as the patients derived clinical benefit with reductions in dose and frequency of administration allowed at the discretion of the treating physician. Haematological responses were assessed every 3-6 months on the basis of blood counts as defined by the European LeukemiaNet critieria. The primary endpoint of the initial study was the proportion of patients with a haematological response. Complete haematological response was defined as normalisation of blood counts (for patients with essential thrombocythaemia, platelets ≤440 × 10 9 per L; for patients with polycythaemia vera, haemoglobin <15·0 g/L without phlebotomy) with complete resolution of palpable splenomegaly or symptoms in the absence of a thrombotic event. Data were analysed with descriptive statistics and in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00452023 and is ongoing but not enrolling new patients. Between May 21, 2005, and Dec 1, 2015, patients were followed up for a median of 83 months (IQR 69-94 months

The Effects of Vortioxetine on Cognitive Function in Patients with Major Depressive Disorder: A Meta-Analysis of Three Randomized Controlled Trials

PubMed Central

Harrison, J; Loft, H; Jacobson, W; Olsen, CK

2016-01-01

Background: Management of cognitive deficits in Major Depressive Disorder (MDD) remains an important unmet need. This meta-analysis evaluated the effects of vortioxetine on cognition in patients with MDD. Methods: Random effects meta-analysis was applied to three randomized, double-blind, placebo-controlled 8-week trials of vortioxetine (5–20mg/day) in MDD, and separately to two duloxetine-referenced trials. The primary outcome measure was change in Digit Symbol Substitution Test (DSST) score. Standardized effect sizes (SES) versus placebo (Cohen’s d) were used as input. Path analysis was employed to determine the extent to which changes in DSST were mediated independently of a change in Montgomery-Åsberg Depression Rating Scale (MADRS) score. Meta-analysis was applied to MADRS-adjusted and -unadjusted SES values. Changes on additional cognitive tests were evaluated (source studies only). Results: Before adjustment for MADRS, vortioxetine separated from placebo on DSST score (SES 0.25–0.48; nominal p < 0.05) in all individual trials, and statistically improved DSST performance versus placebo in meta-analyses of the three trials (SES = 0.35; p < 0.0001) and two duloxetine-referenced trials (SES = 0.26; p = 0.001). After adjustment for MADRS, vortioxetine maintained DSST improvement in one individual trial (p = 0.001) and separation from placebo was maintained in meta-analyses of all three trials (SES = 0.24; p < 0.0001) and both duloxetine-referenced trials (SES 0.19; p = 0.01). Change in DSST with duloxetine failed to separate from placebo in individual trials and both meta-analyses. Change in DSST statistically favored vortioxetine versus duloxetine after MADRS adjustment (SES = 0.16; p = 0.04). Conclusions: Vortioxetine, but not duloxetine, significantly improved cognition, independent of depressive symptoms. Vortioxetine represents an important treatment for MDD-related cognitive dysfunction. PMID:27312740

Multicenter, noninterventional, post-marketing surveillance study to evaluate dosing of recombinant human follicle-stimulating hormone using the redesigned follitropin alfa pen in women undergoing ovulation induction.

PubMed

Nawroth, Frank; Tandler-Schneider, Andreas; Bilger, Wilma

2015-01-01

This prospective, noninterventional, post-marketing surveillance study evaluated doses of recombinant human follicle-stimulating hormone (r-hFSH) using the redesigned follitropin alfa pen in women who were anovulatory or oligomenorrheic and undergoing ovulation induction (OI) alone or OI with intrauterine insemination. The primary endpoint was the proportion of patients who achieved monofollicular or bifollicular development (defined as one or two follicles ≥15 mm). Secondary endpoints included characteristics of ovulation stimulation treatment, such as mean total and mean daily r-hFSH doses. Data were analyzed for 3,193 patients from 30 German fertility centers. The proportion of patients with monofollicular or bifollicular development was 71.1% (n=2,270 of a total of 3,193 patients; intent-to-treat population). The mean±standard deviation total and daily doses of r-hFSH were 696.9±542.5 IU and 61.7±29.4 IU, respectively. The three doses prescribed most frequently were: 37.5 IU (n=703 from N=3,189; 22.0%), 50.0 IU (n=1,056 from N=3,189; 33.1%), and 75.0 IU (n=738 from N=3,189; 23.1%) on the first day of stimulation; and 37.5 IU (n=465 from N=3,189; 14.6%), 50.0 IU (n=922 from N=3,189; 28.9%), and 75.0 IU (n=895 from N=3,189; 28.1%) on the last day of stimulation. This noninterventional, post-marketing surveillance study found that monofollicular or bifollicular development was achieved in 71% of patients studied and the small dose increment (12.5 IU) of the redesigned follitropin alfa pen allowed individualized treatment of women undergoing OI.

Comparative Assessment of the Effect of Hyper-glycosylation on the Pattern and Kinetics of Degradation of Darbepoetin Alfa using a Stability-Indicating Orthogonal Testing Protocol.

PubMed

Moenes, Eman M; Al-Ghobashy, Medhat A; Mohamed, Abeer A; Salem, Maissa Y

2018-01-01

Darbepoetin alfa (DA); hyper-glycosylated Erythropoietin alfa (EPO) is an essential treatment of anemia in patients with chronic kidney failure and cancer. In this study, DA and EPO were subjected to physicochemical stress factors that might be encountered during production, transport and storage (pH, temperature, agitation, repeated freeze-thaw and oxidation). An orthogonal stability-indicating assay protocol comprised of SE-HPLC, RP-HPLC, ELISA and SDS-PAGE was developed and validated to investigate the effect of further glycosylation of DA on the pattern and kinetics of degradation. Results showed a relatively higher stability and lower tendency to form high molecular weight aggregates in the case of DA when compared to EPO, under equivalent stress conditions. Dimers and aggregates were formed for both drugs across the whole pH range and following incubation at temperatures higher than 2-8°C or repeated freeze/thaw. The same observation was noted upon agitation of standard samples prepared in the formulation buffers at high speed and upon oxidation with hydrogen peroxide. The agreement between SE-HPLC, supported with spectral purity data and ELISA confirmed the specificity of both techniques for the intact drugs. Results of RP-HPLC and SDS-PAGE indicated that dimerization occurred through disulfide and bi-tyrosine covalent bonds in the case of pH and oxidation, respectively. It was evident that aggregation was significantly suppressed upon increasing the glycan size and under any of the studied stress factors loss of the glycan has not been observed. These observations supported with the slow kinetics of degradation confirmed the superiority of glyco-engineering over chemical pegylation to enhance the stability of EPO. Formation of such potentially immunogenic product-related impurities at all tested stress factors confirmed the need for orthogonal testing protocols to investigate the complex pattern of degradation of such sensitive products. Copyright © 2017

Mericitabine and Either Boceprevir or Telaprevir in Combination with Peginterferon Alfa-2a plus Ribavirin for Patients with Chronic Hepatitis C Genotype 1 Infection and Prior Null Response: The Randomized DYNAMO 1 and DYNAMO 2 Studies

PubMed Central

Wedemeyer, Heiner; Forns, Xavier; Hézode, Christophe; Lee, Samuel S.; Scalori, Astrid; Voulgari, Athina; Le Pogam, Sophie; Nájera, Isabel; Thommes, James A.

2016-01-01

Most patients with chronic hepatitis C virus (HCV) genotype 1 infection who have had a previous null response (<2-log10 reduction in HCV RNA by treatment week 12) to peginterferon/ribavirin (PegIFN/RBV) do not achieve a sustained virological response (SVR) when re-treated with a first-generation HCV protease inhibitor (PI) administered in combination with PegIFN/RBV. We studied the incremental benefits associated with adding mericitabine (nucleoside analog inhibitor of HCV polymerase) to PI plus PegIFN alfa-2a/RBV-based therapy in two double-blind randomized multicenter phase 2 trials (with boceprevir in DYNAMO 1, and with telaprevir in DYNAMO 2). The primary endpoint in both trials was SVR, defined as HCV RNA <25 IU/mL 12 weeks after the end of treatment (SVR12). Overall, the addition of mericitabine to PI plus PegIFN alfa-2a/RBV therapy resulted in SVR12 rates of 60–70% in DYNAMO 1 and of 71–96% in DYNAMO 2. SVR12 rates were similar in patients infected with HCV genotype 1a and 1b in both trials. The placebo control arms in both studies were stopped because of high rates of virological failure. Numerically lower relapse rates were associated with longer treatment with mericitabine (24 versus 12 weeks), telaprevir-containing regimens, and regimens that included 48 weeks of PegIFN alfa-2a/RBV therapy. No mericitabine resistance mutations were identified in any patient in either trial. The addition of mericitabine did not add to the safety burden associated with either telaprevir or boceprevir-based regimens. These studies demonstrate increased SVR rates and reduced relapse rates in difficult-to-treat patients when a nucleoside polymerase inhibitor with intermediate antiviral potency is added to regimens containing a first-generation PI. Trial Registration: ClinicalTrials.gov NCT01482403 and ClinicalTrials.gov NCT01482390 PMID:26752189

Functionality of a novel follitropin alfa pen injector: results from human factor interactions by patients and nurses.

PubMed

Saunders, Helen; de la Fuente Bitaine, Laura; Eftekhar, Chriss; Howles, Colin M; Glaser, Johanna; Hoja, Tina; Arriagada, Pablo

2018-06-01

The main objective of this user experience testing study was to evaluate the impact of human factors on the use of a disposable pen containing follitropin alfa by patients and nurses with special focus on the convenience, safety and ease of use, in different types of stimulation protocols. Infertile women trying to conceive, and specialist nurses were recruited across 6 European countries. In total 18 patients and 19 nurses took part in the testing, which included both nurse-patient pairings and in-depth interviews. A standardized list of expected and pre-defined critical steps according to the Instructions for Use (IFU), was used to assess the correct handling of the pen. During the user experience testing, no critical errors, related to the use of the pen, which could affect the success of the injection process were identified. In general, both nurses and patients found the pen very easy to learn, use and would be confident using the pen for self-injection. Nurses also found the pen very easy to train the patients. The study provides valuable information on the pen from both patient and nurse perspectives in different simulated scenarios reflecting standard practice.

THE ARECIBO LEGACY FAST ALFA SURVEY. VIII. H I SOURCE CATALOG OF THE ANTI-VIRGO REGION AT {delta} = +25 DEG

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

Martin, Ann M.; Giovanelli, Riccardo; Haynes, Martha P.

We present a fourth catalog of H I sources from the Arecibo Legacy Fast ALFA (ALFALFA) Survey. We report 541 detections over 136 deg{sup 2}, within the region of the sky having 22{sup h} < {alpha} < 03{sup h} and 24 deg. < {delta} < 26 deg. This complements a previous catalog in the region 26 deg. < {delta} < 28 deg. We present here the detections falling into three classes: (1) extragalactic sources with signal-to-noise ratio (S/N)>6.5, where the reliability of the catalog is better than 95%; (2) extragalactic sources 5.0 < S/N < 6.5 and a previously measuredmore » optical redshift that corroborates our detection; or (3) High Velocity Clouds (HVCs), or subcomponents of such clouds, in the periphery of the Milky Way. Of the 541 objects presented here, 90 are associated with HVCs, while the remaining 451 are identified as extragalactic objects. Optical counterparts have been matched with all but one of the extragalactic objects.« less

Safety and usage of darbepoetin alfa in children with chronic kidney disease: prospective registry study.

PubMed

Schaefer, Franz; Hoppe, Bernd; Jungraithmayr, Therese; Klaus, Günter; Pape, Lars; Farouk, Mourad; Addison, Janet; Manamley, Nick; Vondrak, Karel

2016-03-01

Limited prospective data are available on the long-term safety of darbepoetin alfa (DA) for treating anemia in children with chronic kidney disease (CKD). In this prospective, phase IV, observational registry study, children ≤16 years of age with CKD anemia and receiving DA were observed for ≤2 years. Adverse events (AEs), DA dosing, hemoglobin (Hb) concentrations, and transfusions were recorded. A total of 319 patients were included in the analysis (mean age, 9.1 years), 158 (49.5%) of whom were on dialysis at study entry. Of 434 serious AEs reported in 162 children, the most common were peritonitis (10.0%), gastroenteritis (6.0%), and hypertension (4.1%). Six patients (1.9%) died (unrelated to DA). Four patients (1.3%) experienced six serious adverse drug reactions. The geometric mean DA dose range was 1.4-2.0 μg/kg/month. Mean baseline Hb concentration was 11.1 g/dl; mean values for children receiving and not receiving dialysis at baseline ranged between 10.9 and 11.5 g/dl and 11.2-11.7 g/dl, respectively. Overall, 48 patients (15.0%) received ≥1 transfusion. No new safety signals for DA were identified in children receiving DA for CKD anemia for ≤2 years. Based on Hb concentrations and transfusion requirements, DA was effective at managing anemia in these patients.

Multicenter, noninterventional, post-marketing surveillance study to evaluate dosing of recombinant human follicle-stimulating hormone using the redesigned follitropin alfa pen in women undergoing ovulation induction

PubMed Central

Nawroth, Frank; Tandler-Schneider, Andreas; Bilger, Wilma

2015-01-01

This prospective, noninterventional, post-marketing surveillance study evaluated doses of recombinant human follicle-stimulating hormone (r-hFSH) using the redesigned follitropin alfa pen in women who were anovulatory or oligomenorrheic and undergoing ovulation induction (OI) alone or OI with intrauterine insemination. The primary endpoint was the proportion of patients who achieved monofollicular or bifollicular development (defined as one or two follicles ≥15 mm). Secondary endpoints included characteristics of ovulation stimulation treatment, such as mean total and mean daily r-hFSH doses. Data were analyzed for 3,193 patients from 30 German fertility centers. The proportion of patients with monofollicular or bifollicular development was 71.1% (n=2,270 of a total of 3,193 patients; intent-to-treat population). The mean±standard deviation total and daily doses of r-hFSH were 696.9±542.5 IU and 61.7±29.4 IU, respectively. The three doses prescribed most frequently were: 37.5 IU (n=703 from N=3,189; 22.0%), 50.0 IU (n=1,056 from N=3,189; 33.1%), and 75.0 IU (n=738 from N=3,189; 23.1%) on the first day of stimulation; and 37.5 IU (n=465 from N=3,189; 14.6%), 50.0 IU (n=922 from N=3,189; 28.9%), and 75.0 IU (n=895 from N=3,189; 28.1%) on the last day of stimulation. This noninterventional, post-marketing surveillance study found that monofollicular or bifollicular development was achieved in 71% of patients studied and the small dose increment (12.5 IU) of the redesigned follitropin alfa pen allowed individualized treatment of women undergoing OI. PMID:25926755

Experience and challenges presented by a multicenter crossover study of combination analgesic therapy for the treatment of painful HIV-associated polyneuropathies.

PubMed

Harrison, Taylor; Miyahara, Sachiko; Lee, Anthony; Evans, Scott; Bastow, Barbara; Simpson, David; Gilron, Ian; Dworkin, Robert; Daar, Eric S; Wieclaw, Linda; Clifford, David B

2013-07-01

There is limited evidence for efficacy of analgesics as monotherapy for neuropathic pain associated with HIV-associated polyneuropathies, in spite of demonstrated efficacy in other neuropathic pain conditions. We evaluated the tolerability and analgesic efficacy of duloxetine, methadone, and the combination of duloxetine-methadone compared with placebo. This study was a phase II, randomized, double-blind, placebo-controlled, four-period crossover multicenter study of analgesic therapy for patients with at least moderate neuropathic pain due to HIV-associated polyneuropathy. Duloxetine, methadone, combination duloxetine-methadone, and placebo were administered in four different possible sequences. The primary outcome measure was mean pain intensity (MPI) measured daily in a study-supplied pain diary. A total of 15 patients were enrolled from eight study sites and eight patients completed the entire trial. Study treatments failed to show statistically significant change in MPI compared with placebo. Adverse events were frequent and associated with high rates of drug discontinuation and study dropout. Challenges with participant recruitment and poor retention precluded trial completion to its planned targets, limiting our evaluation of the analgesic efficacy of the study treatments. Challenges to successful completion of this study and lessons learned are discussed. Wiley Periodicals, Inc.

Low molecular weight heparin restores antithrombin III activity from hyperglycemia induced alterations.

PubMed

Ceriello, A; Marchi, E; Palazzni, E; Quatraro, A; Giugliano, D

1990-01-01

Alteration of antithrombin III (ATIII) activity, glycemia level dependent, exists in diabetes mellitus. In this study the ability of a low molecular weight heparin (LMWH) (Fluxum, Alfa-Wassermann S.p.A., Bologna, Italy), as well as unfractioned héparin, to preserve ATIII activity from glucose-induced alterations, both in vitro and in vivo, is reported. The subcutaneous and intravenous LMWH and heparin administration increases basal depressed ATIII activity in diabetic patients. Heparin shows an equivalent effect on both anti-IIa and anti-Xa activity of ATIII, while LMWH is more effective in preserving the anti-Xa activity. Similarity, heparin preserves ATIII activity from hyperglycemia-induced alterations, during hyperglycemic clamp, and LMWH infusion is able to preserve a significant amount of anti-Xa activity from glucose-induced alterations. Since diabetic patients show a high incidence of thrombotic accidents, LMWH appears to be a promising innovation for the prevention of diabetic thrombophylia.

A Randomized, Placebo-Controlled, Active-Reference, Double-Blind, Flexible-Dose Study of the Efficacy of Vortioxetine on Cognitive Function in Major Depressive Disorder

PubMed Central

Mahableshwarkar, Atul R; Zajecka, John; Jacobson, William; Chen, Yinzhong; Keefe, Richard SE

2015-01-01

This multicenter, randomized, double-blind, placebo-controlled, active-referenced (duloxetine 60 mg), parallel-group study evaluated the short-term efficacy and safety of vortioxetine (10–20 mg) on cognitive function in adults (aged 18–65 years) diagnosed with major depressive disorder (MDD) who self-reported cognitive dysfunction. Efficacy was evaluated using ANCOVA for the change from baseline to week 8 in the digit symbol substitution test (DSST)–number of correct symbols as the prespecified primary end point. The patient-reported perceived deficits questionnaire (PDQ) and physician-assessed clinical global impression (CGI) were analyzed in a prespecified hierarchical testing sequence as key secondary end points. Additional predefined end points included the objective performance-based University of San Diego performance-based skills assessment (UPSA) (ANCOVA) to measure functionality, MADRS (MMRM) to assess efficacy in depression, and a prespecified multiple regression analysis (path analysis) to calculate direct vs indirect effects of vortioxetine on cognitive function. Safety and tolerability were assessed at all visits. Vortioxetine was statistically superior to placebo on the DSST (P<0.05), PDQ (P<0.01), CGI-I (P<0.001), MADRS (P<0.05), and UPSA (P<0.001). Path analysis indicated that vortioxetine's cognitive benefit was primarily a direct treatment effect rather than due to alleviation of depressive symptoms. Duloxetine was not significantly different from placebo on the DSST or UPSA, but was superior to placebo on the PDQ, CGI-I, and MADRS. Common adverse events (incidence ⩾5%) for vortioxetine were nausea, headache, and diarrhea. In this study of MDD adults who self-reported cognitive dysfunction, vortioxetine significantly improved cognitive function, depression, and functionality and was generally well tolerated. PMID:25687662

Peginterferon lambda for the treatment of HBeAg-positive chronic hepatitis B: A randomized phase 2b study (LIRA-B).

PubMed

Chan, Henry L Y; Ahn, Sang Hoon; Chang, Ting-Tsung; Peng, Cheng-Yuan; Wong, David; Coffin, Carla S; Lim, Seng Gee; Chen, Pei-Jer; Janssen, Harry L A; Marcellin, Patrick; Serfaty, Lawrence; Zeuzem, Stefan; Cohen, David; Critelli, Linda; Xu, Dong; Wind-Rotolo, Megan; Cooney, Elizabeth

2016-05-01

Peginterferon lambda-1a (lambda) is a Type-III interferon, which, like alfa interferons, has antiviral activity in vitro against hepatitis B virus (HBV) and hepatitis C virus (HCV); however, lambda has a more limited extra-hepatic receptor distribution. This phase 2b study (LIRA-B) evaluated lambda in patients with chronic HBV infection. Adult HBeAg+ interferon-naive patients were randomized (1:1) to weekly lambda (180 μg) or peginterferon alfa-2a (alfa) for 48 weeks. The primary efficacy endpoint was HBeAg seroconversion at week 24 post-treatment; lambda non-inferiority was demonstrated if the 80% confidence interval (80% CI) lower bound was >-15%. Baseline characteristics were balanced across groups (lambda N=80; alfa N=83). Early on-treatment declines in HBV-DNA and qHBsAg through week 24 were greater with lambda. HBeAg seroconversion rates were comparable for lambda and alfa at week 48 (17.5% vs. 16.9%, respectively); however lambda non-inferiority was not met at week 24 post-treatment (13.8% vs. 30.1%, respectively; lambda vs. alfa 80% CI lower bound -24%). Results for other key secondary endpoints (virologic, serologic, biochemical) and post hoc combined endpoints (HBV-DNA <2000 IU/ml plus HBeAg seroconversion or ALT normalization) mostly favored alfa. Overall adverse events (AE), serious AE, and AE-discontinuation rates were comparable between arms but AE-spectra differed (more cytopenias, flu-like, and musculoskeletal symptoms observed with alfa, more ALT flares and bilirubin elevations seen with lambda). Most on-treatment flares occurred early (weeks 4-12), associated with HBV-DNA decline; all post-treatment flares were preceded by HBV-DNA rise. On-treatment, lambda showed greater early effects on HBV-DNA and qHBsAg, and comparable serologic/virologic responses at end-of-treatment. However, post-treatment, alfa-associated HBeAg seroconversion rates were higher, and key secondary results mostly favored alfa. ClinicalTrials.gov number: NCT01204762

Pharmacological modulation of pulvinar resting-state regional oscillations and network dynamics in major depression

PubMed Central

Tadayonnejad, Reza; Ajilore, Olusola; Mickey, Brian J.; Crane, Natania A.; Hsu, David T.; Kumar, Anand; Zubieta, Jon-Kar; Langenecker, Scott A.

2016-01-01

The pulvinar, the largest thalamus nucleus, has rich anatomical connections with several different cortical and subcortical regions suggesting its important involvement in high-level cognitive and emotional functions. Unfortunately, pulvinar dysfunction in psychiatric disorders particularly major depression disorder has not been thoroughly examined to date. In this study we explored the alterations in the baseline regional and network activities of the pulvinar in MDD by applying spectral analysis of resting-state oscillatory activity, functional connectivity and directed (effective) connectivity on resting-state fMRI data acquired from 20 healthy controls and 19 participants with MDD. Furthermore, we tested how pharmacological treatment with duloxetine can modulate the measured local and network variables in ten participants who completed treatment. Our results revealed a frequency-band dependent modulation of power spectrum characteristics of pulvinar regional oscillatory activity. At the network level, we found MDD is associated with aberrant causal interactions between pulvinar and several systems including default-mode and posterior insular networks. It was also shown that duloxetine treatment can correct or overcompensate the pathologic network behavior of the pulvinar. In conclusion, we suggest that pulvinar regional baseline oscillatory activity and its resting-state network dynamics are compromised in MDD and can be modulated therapeutically by pharmacological treatment. PMID:27148894

Outcome of treatment after first relapse in younger adults with acute myeloid leukemia initially treated by the ALFA-9802 trial.

PubMed

Thomas, Xavier; Raffoux, Emmanuel; Renneville, Aline; Pautas, Cécile; de Botton, Stéphane; de Revel, Thierry; Reman, Oumedaly; Terré, Christine; Gardin, Claude; Chelghoum, Youcef; Boissel, Nicolas; Quesnel, Bruno; Cordonnier, Catherine; Bourhis, Jean-Henri; Elhamri, Mohamed; Fenaux, Pierre; Preudhomme, Claude; Socié, Gérard; Michallet, Mauricette; Castaigne, Sylvie; Dombret, Hervé

2012-09-01

Forty-seven percent of adults with acute myeloid leukemia (AML) who entered the ALFA-9802 trial and achieved a first complete remission (CR) experienced a first relapse. We examined the outcome of these 190 adult patients. Eighty-four patients (44%) achieved a second CR. The median overall survival (OS) after relapse was 8.9 months with a 2-year OS at 25%. Factors predicting a better outcome after relapse were stem cell transplant (SCT) performed in second CR and a first CR duration >1 year. Risk groups defined at the time of diagnosis and treatment received in first CR also influenced the outcome after relapse. The best results were obtained in patients with core binding factor (CBF)-AML, while patients initially defined as favorable intermediate risk showed a similar outcome after relapse than those initially entering the poor risk group. We conclude that most adult patients with recurring AML could not be rescued using current available therapies, although allogeneic SCT remains the best therapeutic option at this stage of the disease. Copyright © 2012 Elsevier Ltd. All rights reserved.

Experience and challenges presented by a multicenter crossover study of combination analgesic therapy for the treatment of painful HIV-associated polyneuropathies

PubMed Central

Harrison, Taylor; Miyahara, Sachiko; Lee, Anthony; Evans, Scott; Bastow, Barbara; Simpson, David; Gilron, Ian; Dworkin, Robert; Daar, Eric S.; Wieclaw, Linda; Clifford, David B.

2014-01-01

Objective There is limited evidence for efficacy of analgesics as monotherapy for neuropathic pain associated with HIV-associated polyneuropathies, in spite of demonstrated efficacy in other neuropathic pain conditions. We evaluated the tolerability and analgesic efficacy of duloxetine, methadone, and the combination of duloxetine-methadone compared to placebo. Design This study was a phase II, randomized, double blind, placebo-controlled, four-period crossover multi-center study of analgesic therapy for patients with at least moderate neuropathic pain due to HIV-associated polyneuropathy. Duloxetine, methadone, combination duloxetine-methadone, and placebo were administered in four different possible sequences. The primary outcome measure was mean pain intensity (MPI) measured daily in a study-supplied pain diary. Results A total of 15 patients were enrolled from 8 study sites and 8 patients completed the entire trial. Study treatments failed to show statistically significant change in MPI compared to placebo. Adverse events were frequent and associated with high rates of drug discontinuation and study drop-out. Conclusions Challenges with participant recruitment and poor retention precluded trial completion to its planned targets, limiting our evaluation of the analgesic efficacy of the study treatments. Challenges to successful completion of this study and lessons learned are discussed. PMID:23565581

[Effects of traditional cooking on antinutritional factors of the black beans (Phaseolus vulgaris) of Costa Rica].

PubMed

Bonilla, A R; Calzada, C; Cooke, R

1991-12-01

Trypsin inhibitors, alfa amylase inhibitors and hemagglutinins were determined in black beans (P. vulgaris) produced in Costa Rica. The effect of the traditional cooking on such antinutritional factors was also studied. The antinutritional factors were analyzed spectrophotometrically in the raw beans, as well as after several cooking periods of time. The results showed that alfa-amylase inhibitors were the most thermoresistant. After 30 min of cooking time there was a 33% of activity left from the initial activity of the raw beans. Approximately 80% of the antitryptic activity was destroyed at 9 min of cooking time. After 10 min of cooking time, only 1% of hemagglutinin activity was present.

Large randomized study of thymosin alpha 1, interferon alfa, or both in combination with dacarbazine in patients with metastatic melanoma.

PubMed

Maio, Michele; Mackiewicz, Andrzej; Testori, Alessandro; Trefzer, Uwe; Ferraresi, Virginia; Jassem, Jacek; Garbe, Claus; Lesimple, Thierry; Guillot, Bernard; Gascon, Pere; Gilde, Katalin; Camerini, Roberto; Cognetti, Francesco

2010-04-01

Thymosin alpha 1 (Talpha1) is an immunomodulatory polypeptide that enhances effector T-cell responses. In this large randomized study, we evaluated the efficacy and safety of combining Talpha1 with dacarbazine (DTIC) and interferon alfa (IFN-alpha) in patients with metastatic melanoma. Four hundred eighty-eight patients were randomly assigned to five treatment groups: DTIC+IFN-alpha+Talpha1 (1.6 mg); DTIC+IFN-alpha+Talpha1 (3.2 mg); DTIC+IFN-alpha+Talpha1 (6.4 mg); DTIC+Talpha1 (3.2 mg); DTIC+IFN-alpha (control group). The primary end point was best overall response at study end (12 months). Secondary end points included duration of response, overall survival (OS), and progression-free survival (PFS). Patients were observed for up to 24 months. Ten and 12 tumor responses were observed in the DTIC+IFN-alpha+Talpha1 (3.2 mg) and DTIC+Talpha1 (3.2 mg) groups, respectively, versus four in the control group, which was sufficient to reject the null hypothesis that P(0) < or = .05 (expected response rate of standard therapy) in these two arms. Duration of response ranged from 1.9 to 23.2 months in patients given Talpha1 and from 4.4 to 8.4 months in the control group. Median OS was 9.4 months in patients given Talpha1 versus 6.6 months in the control group (hazard ratio = 0.80; 9% CI, 0.63 to 1.02; P = .08). An increase in PFS was observed in patients given Talpha1 versus the control group (hazard ratio = 0.80; 95% CI, 0.63 to 1.01; P = .06). Addition of Talpha1 to DTIC and IFN-alpha did not lead to any additional toxicity. These results suggest Talpha1 has activity in patients with metastatic melanoma and provide rationale for further clinical evaluation of this agent.

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.

Arecibo pulsar survey using ALFA. III. Precursor survey and population synthesis

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

Swiggum, J. K.; Lorimer, D. R.; McLaughlin, M. A.

The Pulsar Arecibo L-band Feed Array (PALFA) Survey uses the ALFA 7-beam receiver to search both inner and outer Galactic sectors visible from Arecibo (32° ≲ ℓ ≲ 77° and 168° ≲ ℓ ≲ 214°) close to the Galactic plane (|b| ≲ 5°) for pulsars. The PALFA survey is sensitive to sources fainter and more distant than have previously been seen because of Arecibo's unrivaled sensitivity. In this paper we detail a precursor survey of this region with PALFA, which observed a subset of the full region (slightly more restrictive in ℓ and |b| ≲ 1°) and detected 45 pulsars.more » Detections included 1 known millisecond pulsar and 11 previously unknown, long-period pulsars. In the surveyed part of the sky that overlaps with the Parkes Multibeam Pulsar Survey (36° ≲ ℓ ≲ 50°), PALFA is probing deeper than the Parkes survey, with four discoveries in this region. For both Galactic millisecond and normal pulsar populations, we compare the survey's detections with simulations to model these populations and, in particular, to estimate the number of observable pulsars in the Galaxy. We place 95% confidence intervals of 82,000 to 143,000 on the number of detectable normal pulsars and 9000 to 100,000 on the number of detectable millisecond pulsars in the Galactic disk. These are consistent with previous estimates. Given the most likely population size in each case (107,000 and 15,000 for normal and millisecond pulsars, respectively), we extend survey detection simulations to predict that, when complete, the full PALFA survey should have detected 1000{sub −230}{sup +330} normal pulsars and 30{sub −20}{sup +200} millisecond pulsars. Identical estimation techniques predict that 490{sub −115}{sup +160} normal pulsars and 12{sub −5}{sup +70} millisecond pulsars would be detected by the beginning of 2014; at the time, the PALFA survey had detected 283 normal pulsars and 31 millisecond pulsars, respectively. We attribute the deficiency in normal pulsar

PRIORITIZING FUTURE RESEACH ON OFF-LABEL PRESCRIBING: RESULTS OF A QUANTITATIVE EVALUATION

PubMed Central

Walton, Surrey M.; Schumock, Glen T.; Lee, Ky-Van; Alexander, G. Caleb; Meltzer, David; Stafford, Randall S.

2015-01-01

Background Drug use for indications not approved by the Food and Drug Administration exceeds 20% of prescribing. Available compendia indicate that a minority of off-label uses are well supported by evidence. Policy makers, however, lack information to identify where systematic reviews of the evidence or other research would be most valuable. Methods We developed a quantitative model for prioritizing individual drugs for future research on off-label uses. The base model incorporated three key factors, 1) the volume of off-label use with inadequate evidence, 2) safety, and 3) cost and market considerations. Nationally representative prescribing data were used to estimate the number of off-label drug uses by indication from 1/2005 through 6/2007 in the United States, and these indications were then categorized according to the adequacy of scientific support. Black box warnings and safety alerts were used to quantify drug safety. Drug cost, date of market entry, and marketing expenditures were used to quantify cost and market considerations. Each drug was assigned a relative value for each factor, and the factors were then weighted in the final model to produce a priority score. Sensitivity analyses were conducted by varying the weightings and model parameters. Results Drugs that were consistently ranked highly in both our base model and sensitivity analyses included quetiapine, warfarin, escitalopram, risperidone, montelukast, bupropion, sertraline, venlafaxine, celecoxib, lisinopril, duloxetine, trazodone, olanzapine, and epoetin alfa. Conclusion Future research into off-label drug use should focus on drugs used frequently with inadequate supporting evidence, particularly if further concerns are raised by known safety issues, high drug cost, recent market entry, and extensive marketing. Based on quantitative measures of these factors, we have prioritized drugs where targeted research and policy activities have high potential value. PMID:19025425

49 CFR Appendix A to Part 593 - List of Vehicles Determined To Be Eligible for Importation

Code of Federal Regulations, 2010 CFR

2010-10-01

... Legend 1990-1992 305 AL-Spaw EMA Mobile Stage Trailer 2009 42 Alfa Romeo 164 1989 196 Alfa Romeo 164 1991 76 Alfa Romeo 164 1994 156 Alfa Romeo Spider 1987 70 Alfa Romeo Spyder 1992 503 Alpina B12 5.0 Sedan...

49 CFR Appendix A to Part 593 - List of Vehicles Determined To Be Eligible for Importation

Code of Federal Regulations, 2011 CFR

2011-10-01

...-Spaw EMA Mobile Stage Trailer 2009 42 Alfa Romeo 164 1989 196 Alfa Romeo 164 1991 76 Alfa Romeo 164 1994 156 Alfa Romeo Spider 1987 70 Alfa Romeo Spyder 1992 503 Alpina B12 5.0 Sedan 1988-1994 41 Alpina...

Pelvic floor muscle training added to another active treatment versus the same active treatment alone for urinary incontinence in women.

PubMed

Ayeleke, Reuben Olugbenga; Hay-Smith, E Jean C; Omar, Muhammad Imran

2015-11-03

Pelvic floor muscle training (PFMT) is a first-line conservative treatment for urinary incontinence in women. Other active treatments include: physical therapies (e.g. vaginal cones); behavioural therapies (e.g. bladder training); electrical or magnetic stimulation; mechanical devices (e.g. continence pessaries); drug therapies (e.g. anticholinergics (solifenacin, oxybutynin, etc.) and duloxetine); and surgical interventions including sling procedures and colposuspension. This systematic review evaluated the effects of adding PFMT to any other active treatment for urinary incontinence in women To compare the effects of pelvic floor muscle training combined with another active treatment versus the same active treatment alone in the management of women with urinary incontinence. We searched the Cochrane Incontinence Group Specialised Register, which contains trials identified from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE in process, ClinicalTrials.gov, WHO ICTRP and handsearching of journals and conference proceedings (searched 5 May 2015), and CINAHL (January 1982 to 6 May 2015), and the reference lists of relevant articles. We included randomised or quasi-randomised trials with two or more arms, of women with clinical or urodynamic evidence of stress urinary incontinence, urgency urinary incontinence or mixed urinary incontinence. One arm of the trial included PFMT added to another active treatment; the other arm included the same active treatment alone. Two review authors independently assessed trials for eligibility and methodological quality and resolved any disagreement by discussion or consultation with a third party. We extracted and processed data in accordance with the Cochrane Handbook for Systematic Reviews of Interventions. Other potential sources of bias we incorporated into the 'Risk of bias' tables were ethical approval, conflict of interest and funding source. Thirteen trials met the inclusion criteria

Effects of switching from a reduced dose imiglucerase to velaglucerase in type 1 Gaucher disease: clinical and biochemical outcomes

PubMed Central

van Dussen, Laura; Cox, Timothy M.; Hendriks, Erik J.; Morris, Elizabeth; Akkerman, Erik M.; Maas, Mario; Groener, Johanna E. M.; Aerts, Johannes M.F.G.; Deegan, Patrick B.; Hollak, Carla E. M.

2012-01-01

This paper describes the effects of a switch to velaglucerase alfa in a group of adult patients with type 1 Gaucher disease, all of whom had previously had their dose reduced as a consequence of the worldwide imiglucerase shortage. Thirty-two patients from two large European Gaucher centers switched to treatment with velaglucerase alfa after 1-8.5 months of dose reduction. The course of important Gaucher disease parameters was studied at four time points: one year before the shortage, just before the shortage, before a switch to velaglucerase and after up to one year of treatment with velaglucerase. These parameters included hemoglobin concentration, platelet count, plasma chitotriosidase activity in all patients, and spleen and liver volumes (as well as bone marrow fat fraction images) in 10 patients. Decreases in platelet counts as a result of reduced treatment with imiglucerase were quickly restored on treatment with velaglucerase alfa. Chitotriosidase activity declined overall after switching. Five out of 10 patients had an increase in liver volume of at least 10% after six months of velaglucerase treatment, which was reversible in 3. Most patients received infusions at home and no important side effects were observed. Velaglucerase alfa appears to be a safe and effective alternative for imiglucerase. PMID:22773601

Hospital inpatient prospective payment system: incorporating new technology.

PubMed

Durthaler, Jeffrey M; Miller, Alicia

2003-11-01

New technologies in the impatient prospective payment system are discussed. On December 21, 2000, Congress passed Public Law 106-554 that includes a requirement to establish a mechanism to more expeditiously incorporate the costs and establish qualifying criteria for payment of new services and technologies into the hospital inpatient prospective payment system. The final ruling of this law states that a new service or technology must demonstrate substantial improvement, be inadequately paid under the DRG system, and be "new." The intent of these criteria is to identify new technologies that offer substantial improvement over existing technologies and to provide supplemental payment that encourages physicians and hospitals to utilize the new technology. In November 2001, drotrecogin alfa (activated) received fast-track FDA approval because of the robust findings from the PROWESS trial. Drotrecogin alfa (activated) is the first agent proven to reduce mortality in patients suffering from severe sepsis associated with acute organ dysfunction who are at a high risk of death (i.e., APACHE II score > 24). In August 2002, drotrecogin alfa (activated) was one of four such new technologies and the first agent approved for new technology payment under the prospective payment system (PPS). This decision offers confidence that the PPS is effectively striving to incorporate new medical services and technologies at a pace similar to that of innovation. Providers may receive up to $3400 in additional reimbursement when drotrecogin alfa (activated) is administered in the Medicare population. Pharmacy and patient accounting personnel should develop a collaborative process to identify, document, and capture this new source of payment.

Comparison of corifollitropin alfa and daily recombinant follicle-stimulating hormone in poor responder patients undergoing in vitro fertilization cycles.

PubMed

Akarsu, Süleyman; Demir, Sibel; Gode, Funda; Işık, Ahmet Zeki

2017-12-01

The aim of this study was to compare the effect of corifollitropin alfa (CFA) and recombinant follicle-stimulating hormone (rFSH) in poor-responder patients undergoing antagonist cycles. The study was a retrospective analysis of the treatment results of 214 poor responder patients who had been admitted to the In Vitro Fertilization Unit of İzmir Medical Park Hospital between November 2014 and November 2016. Intracytoplasmic sperm injections were performed in 38 patients (group 1) with CFA, and the remaining 176 (group 2) with rFSH for controlled ovarian hyperstimulation. The age, body mass index, anti-müllerian hormone level, duration of infertility, duration of induction and antral follicle number were similar in the two groups. There was no difference in the total aspirated oocyte counts, mature oocyte ratio, fertilization rate, implantation rate, and clinical pregnancy rates between the two groups. The implantation rate was 9/38 (23.6%) in group 1 and 42/176 (23.8%) in group 2, whereas the clinical pregnancy rates were 16.3% and 17.2%, respectively. No difference was found in terms of oocyte count, fertilization rate, implantation rate, and clinical pregnancy rates of CFA or rFSH use in the antagonist cycles in poor-responder patients.

Pharmacokinetic properties of IB1001, an investigational recombinant factor IX, in patients with haemophilia B: repeat pharmacokinetic evaluation and sialylation analysis.

PubMed

Martinowitz, U; Shapiro, A; Quon, D V; Escobar, M; Kempton, C; Collins, P W; Chowdary, P; Makris, M; Mannucci, P M; Morfini, M; Valentino, L A; Gomperts, E; Lee, M

2012-11-01

IB1001 trenacog alfa is an investigational recombinant factor IX (FIX) for the treatment and prevention of bleeding in individuals with haemophilia B. To compare the pharmacokinetics (PK) of IB1001 with nonacog alfa in individuals with haemophilia B and to assess the relationship between sialylation and PK of IB1001 (NCT00768287). A randomized, double-blind, non-inferiority, cross-over study conducted in participants aged ≥ 12 years weighing ≥ 40 kg, with severe or moderately severe haemophilia B (FIX activity ≤ 2 IU dL (-1) ). PK parameters were derived using observed FIX concentration levels and actual PK sampling times, and repeated in a subset of participants who had received IB1001 prophylaxis for 4-18 months. A retrospective analysis was conducted in subgroups according to the sialylation levels of IB1001 (50.8, 57.8-59.0%, or 71.7%). In the 32 adolescent and adult males evaluated, there were no clinically meaningful differences in PK parameters between those receiving IB1001 75 IU kg(-1) or nonacog alfa. The lower limit of the one-sided 95% confidence interval for the ratio of AUC(0-t) and AUC(0-∞) (IB1001/nonacog alfa) was 0.90, establishing non-inferiority. Terminal phase half-lives were similar (29.7 ± 18.2 h for IB1001 and 33.4 ± 21.2 h for nonacog alfa). The PK results were stable for up to 18 months of IB1001 exposure; the impact of sialylation levels was not clinically meaningful. There were no clinically meaningful PK differences between IB1001 and nonacog alfa. IB1001 was well tolerated and without safety concerns. The non-inferiority of IB1001 to nonacog alfa supports IB1001 becoming a useful alternative recombinant agent for the management of haemophilia B. © 2012 Blackwell Publishing Ltd.

Clinical Experience of Interferon Alfa-2a Treatment for Refractory Uveitis in Behçet's Disease.

PubMed

Park, Ji-Youn; Chung, Yoo-Ri; Lee, Kihwang; Song, Ji Hun; Lee, Eun-So

2015-07-01

Behçet's disease (BD) involves multisystem vasculitis of unknown origin. Ocular manifestations of BD mostly include bilateral panuveitis and retinal vasculitis, which are very challenging to treat. Interferon alfa-2a (IFN) has been recently introduced for treating refractory Behçet uveitis, mainly in Germany and Turkey. Nonetheless, there is so far no consensus about the ideal treatment regimen of IFN for Behçet uveitis. We report our experience of IFN treatment in five Korean BD patients with refractory uveitis. All patients complained of oral ulcers; one patient had a positive pathergy test and 2 showed the presence of HLA-B51. Immunosuppressive agents used prior to IFN treatment included cyclosporine and methotrexate. The IFN treatment was commenced with a dose of 6-9 MIU/day for 7 days, adjusted according to individual ocular manifestations, tapered down to 3 MIU three times in a week, and then discontinued. All patients showed positive response to IFN treatment; 50% of them showed complete response without additional major ocular inflammation during the follow-up period. Other BD symptoms also improved after IFN treatment in most cases. After treatment, the relapse rate and the required dose of oral corticosteroid were decreased in most cases, showing a significant steroid-sparing effect. However, the visual acuity was not improved in most cases due to irreversible macular sequelae. Despite the small sample size of this study, we suggest that, in Korean patients, IFN is an effective treatment modality for BD uveitis as was observed in German and Turkish patients.

49 CFR Appendix A to Part 593 - List of Vehicles Determined To Be Eligible for Importation

Code of Federal Regulations, 2013 CFR

2013-10-01

... 1989 77 Acura Legend 1990-1992 305 Alfa Romeo 164 1989 196 Alfa Romeo 164 1991 76 Alfa Romeo 164 1994 156 Alfa Romeo Spider 1992 503 Alpina B11 Sedan 1989-1994 48 Alpina B12 Coupe 1989-1996 43 Alpina B12...

Effect of photo-selective nettings on post-harvest quality and bioactive compounds in selected tomato cultivars.

PubMed

Selahle, Maphoko Kamogelo; Sivakumar, Dharini; Soundy, Puffy

2014-08-01

Photo-selective coloured netting is referred to as a 'new agro-technological' concept adopted to manipulate light quality changes that can induce favourable responses in plants. Tomato (Solanum lycopersicum L.) cultivars AlvaV, Irit and SCX 248 grown under the black net (commercial net, 25% shading) showed higher weight loss, loss of firmness, ascorbic acid content and decline in the ratio of soluble solids content/titrable acidity during post-harvest storage (low-temperature storage at 10°C and 90% relative humidity for 21 days followed by market shelf conditions at 25°C for 2 days). During post-harvest storage, lycopene, β-carotene, total phenolic content and antioxidant scavenging activity were higher in cvs AlfaV and Irit grown under the black or pearl nets. However, the β-carotene, total phenolic content and antioxidant scavenging activity were higher in SCX 248 grown under the red net during post-harvest storage. Cultivar AlfaV grown under the red and pearl nets had a higher number of odour active aroma compounds during post-harvest storage. Panellists preferred cv. AlfaV grown under the pearl nets after storage based on taste, overall appearance and firm textured fruits. Pearl photo-selective nets retained the overall fruit quality and bioactive components in cvs AlfaV and Irit during post-harvest storage. Red photo-selective nets, however, showed greater influence on retention of overall fruit quality and bioactive compounds in cv. SCX 248 during post-harvest storage. © 2013 Society of Chemical Industry.

Impact of severe haemophilia A on patients' health status: results from the guardian(™) 1 clinical trial of turoctocog alfa (NovoEight(®) ).

PubMed

Ozelo, M; Chowdary, P; Regnault, A; Busk, A K

2015-07-01

Haemophilia and its treatment interfere with patients' life and may affect adherence to treatment. This study explored the impact of severe haemophilia A on patients' health status, especially in young adults (YA), using data from guardian(™) 1, a multinational, open-label, non-controlled phase 3 trial investigating safety and efficacy of turoctocog alfa (NovoEight(®) ) in previously treated patients aged 12 years and older with severe haemophilia A (FVIII ≤ 1%). Health status was assessed using the EuroQoL-5 dimensions (EQ-5D-3L), covering 5 dimensions of health (mobility, self-care, usual activities, pain/discomfort and anxiety/depression), and a visual analogue scale (VAS) measuring self-rated overall health status. EQ-5D was administered pretreatment (screening/baseline) and posttreatment (end-of-trial). Baseline responses to the EQ-5D dimensions and VAS were described overall and by age and compared to reference values from UK general population. Guardian(™) 1 included 150 patients (16 adolescents, 83 YA aged 16-29 and 51 adults aged 30+). All five dimensions of patients' health status were impacted at baseline. The percentage of haemophilia patients reporting problems was consistently significantly greater than age-matched general population reference values. Likewise, for all age groups mean baseline EQ-5D VAS score was significantly lower for haemophilia patients (YA: 78.0) than for the general population (YA aged 18-29: 87.3). The health status of patients with severe haemophilia A entering guardian(™) 1 was markedly poorer than that of the general population, particularly regarding mobility and pain. YA patients reported better health status than older patients, but considerably lower than that of the general YA population. © 2015 The Authors. Haemophilia Published by John Wiley & Sons Ltd.

Pharmacokinetic study of darbepoetin alfa: absorption, distribution, and excretion after a single intravenous and subcutaneous administration to rats.

PubMed

Yoshioka, E; Kato, K; Shindo, H; Mitsuoka, C; Kitajima, S-I; Ogata, H; Misaizu, T

2007-01-01

KRN321 is a hyperglycosylated analogue of recombinant human erythropoietin (rHuEPO, epoetin alfa), and its absorption, distribution, and excretion have been studied after a single intravenous and subcutaneous administration of 125I-KRN321 at a dose of 0.5 microg kg-1 to male rats. The half-lives of immunoreactive radioactivity in the terminal phase after intravenous and subcutaneous administration were 14.05 and 14.36 h, respectively, and the bioavailability rate after subcutaneous administration was 47%. The total radioactivity in tissues was lower than that in the serum in all tissues excluding the thyroid gland and skin at the injection site (subcutaneous administration). The maximum concentrations were observed in the bone marrow or skin at the injection site followed by the thyroid gland, kidneys, adrenal glands, spleen, lungs, stomach and bladder. The radioactivity found in trichloroacetic acid-precipitated fractions suggested that a high-molecular weight compound, unchanged or mixed with endogenous protein, distributed to the tissues after administration. The whole-body autoradiographic findings in both groups were in agreement with the tissue distribution mentioned above. The blood cell uptake of KRN321 was low for both groups. The excretion ratios of radioactivity into urine and faeces up to 168 h were 71.4 and 14.1% after the intravenous administration and 74.9 and 12.0% after the subcutaneous administration. There was no difference in the excretion profile of radioactivity between the two groups.

Successful treatment of a chronic-phase T-315I-mutated chronic myelogenous leukemia patient with a combination of imatinib and interferon-alfa.

PubMed

Itonaga, Hidehiro; Tsushima, Hideki; Hata, Tomoko; Matsuo, Emi; Imanishi, Daisuke; Imaizumi, Yoshitaka; Kawaguchi, Yasuhisa; Fukushima, Takuya; Doi, Yuko; Mori, Sayaka; Kamihira, Shimeru; Tomonaga, Masao; Miyazaki, Yasushi

2012-02-01

The T315I BCR-ABL mutation in chronic myelogenous leukemia (CML) patients is responsible for up to 20% of all clinically observed resistance. This mutation confers resistance not only to imatinib, but also to second-generation BCR-ABL tyrosine kinases, such as nilotinib and dasatinib. A number of strategies have been implemented to overcome this resistance, but allogeneic stem cell transplantation remains the only established therapeutic option for a cure. A 61-year-old male was diagnosed with Philadelphia chromosome-positive chronic-phase CML in 2002. He was initially treated with imatinib and complete cytogenetic response (CCyR) was achieved 12 months later. However, after 18 months, a loss of CCyR was observed and a molecular study at 24 months revealed a T315I mutation of the BCR-ABL gene. At 30 months, imatinib/interferon-alfa (IFNα) combination therapy was initiated in an effort to overcome the resistance. Thirty months later, he re-achieved CCyR, and the T315I BCR-ABL mutation disappeared at 51 months. To our knowledge, this is the first case report showing the effectiveness of imatinib/IFNα combination therapy for CML patients bearing the T315I BCR-ABL mutation.

Sustaining the Drone Enterprise: How Manpower Analysis Engendered Policy Reform in the United States Air Force

DTIC Science & Technology

2016-01-17

permanently transitioned to the RPA community. (E.g., an F-16 pilot who permanently becomes an RPA pilot). “Borrowed” pilots, officially called “ ALFAs ...initiative as of October 2015. 2) Hold ALFA pilots an additional 3 “Vulnerable to Move List” (VML) cycles. The standard ALFA tour for pilots of manned...Given this policy to hold the ALFAs for an additional three VML cycles, the RPA enterprise will retain approximately 60 ALFA pilots for an additional

Functional Impairment and Painful Physical Symptoms in Patients with Major Depressive Disorder Treated with Antidepressants: Real-World Evidence from the Middle East.

PubMed

Hong, Jihyung; Novick, Diego; Moneta, Maria Victoria; El-Shafei, Ahmed; Dueñas, Héctor; Haro, Josep Maria

2017-01-01

The Global Burden of Disease 2010 study reported the relative size of major depressive disorder (MDD) burden to be greater in the Middle East and North Africa than anywhere else. However, little research has been carried out to examine the comparative effectiveness of antidepressants in this region. To assess and compare functioning levels in Middle Eastern patients with MDD treated with either duloxetine or a selective serotonin reuptake inhibitor (SSRI), and to examine the impacts of depression-related pain on functioning by the type of treatment. This post-hoc analysis, which focused on Middle Eastern patients, used data from a 6-month prospective observational study that included 1,549 MDD patients without sexual dysfunction. Levels of functional impairment and depression-related pain were assessed using the Sheehan Disability Scale (SDS) and the modified Somatic Symptom Inventory, respectively. A mixed model with repeated measures (MMRM) was employed. The mean age of the patients was 37.3 (SD=8.4) years, and 34.6% were female. Patient functioning was, on average, moderately impaired at baseline, but improved substantially during follow-up in both the duloxetine (n=152) and the SSRI (n=123) cohorts. The MMRM results showed a lower level of functional impairment at 24 weeks in the duloxetine cohort than in the SSRI cohort (p<0.001). Pain severity at baseline was positively associated with functional impairment during follow-up only in the SSRI cohort (p=0.003). Duloxetine-treated MDD patients achieved better functioning than SSRI-treated patients. This treatment difference was partly driven by depression-related pain.

Comparative efficacy and safety of selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors in older adults: a network meta-analysis.

PubMed

Thorlund, Kristian; Druyts, Eric; Wu, Ping; Balijepalli, Chakrapani; Keohane, Denis; Mills, Edward

2015-05-01

To establish the comparative efficacy and safety of selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors in older adults using the network meta-analysis approach. Systematic review and network meta-analysis. Individuals aged 60 and older. Data on partial response (defined as at least 50% reduction in depression score from baseline) and safety (dizziness, vertigo, syncope, falls, loss of consciousness) were extracted. A Bayesian network meta-analysis was performed on the efficacy and safety outcomes, and relative risks (RRs) with 95% credible intervals (CrIs) were produced. Fifteen randomized controlled trials were eligible for inclusion in the analysis. Citalopram, escitalopram, paroxetine, duloxetine, venlafaxine, fluoxetine, and sertraline were represented. Reporting on partial response and dizziness was sufficient to conduct a network meta-analysis. Reporting on other outcomes was sparse. For partial response, sertraline (RR=1.28), paroxetine (RR=1.48), and duloxetine (RR=1.62) were significantly better than placebo. The remaining interventions yielded RRs lower than 1.20. For dizziness, duloxetine (RR=3.18) and venlafaxine (RR=2.94) were statistically significantly worse than placebo. Compared with placebo, sertraline had the lowest RR for dizziness (1.14) and fluoxetine the second lowest (1.31). Citalopram, escitalopram, and paroxetine all had RRs between 1.4 and 1.7. There was clear evidence of the effectiveness of sertraline, paroxetine, and duloxetine. There also appears to be a hierarchy of safety associated with the different antidepressants, although there appears to be a dearth of reporting of safety outcomes. © 2015, Copyright the Authors Journal compilation © 2015, The American Geriatrics Society.

Entropy-Stabilized Oxides

DTIC Science & Technology

2015-09-29

discovery and exploitation. Methods Solid-state synthesis of bulk materials. MgO ( Alfa Aesar, 99.99%), NiO (Sigma Aldrich, 99%), CuO ( Alfa Aesar, 99.9...CoO ( Alfa Aesar, 99%) and ZnO ( Alfa Aesar 99.9%) are massed and combined using a shaker mill and 3-mm diameter yttrium-stabilized zirconia milling

Antidepressants normalize the default mode network in patients with dysthymia.

PubMed

Posner, Jonathan; Hellerstein, David J; Gat, Inbal; Mechling, Anna; Klahr, Kristin; Wang, Zhishun; McGrath, Patrick J; Stewart, Jonathan W; Peterson, Bradley S

2013-04-01

The default mode network (DMN) is a collection of brain regions that reliably deactivate during goal-directed behaviors and is more active during a baseline, or so-called resting, condition. Coherence of neural activity, or functional connectivity, within the brain's DMN is increased in major depressive disorder relative to healthy control (HC) subjects; however, whether similar abnormalities are present in persons with dysthymic disorder (DD) is unknown. Moreover, the effect of antidepressant medications on DMN connectivity in patients with DD is also unknown. To use resting-state functional-connectivity magnetic resonance imaging (MRI) to study (1) the functional connectivity of the DMN in subjects with DD vs HC participants and (2) the effects of antidepressant therapy on DMN connectivity. After collecting baseline MRI scans from subjects with DD and HC participants, we enrolled the participants with DD into a 10-week prospective, double-blind, placebo-controlled trial of duloxetine and collected MRI scans again at the conclusion of the study. Enrollment occurred between 2007 and 2011. University research institute. Volunteer sample of 41 subjects with DD and 25 HC participants aged 18 to 53 years. Control subjects were group matched to patients with DD by age and sex. We used resting-state functional-connectivity MRI to measure the functional connectivity of the brain's DMN in persons with DD compared with HC subjects, and we examined the effects of treatment with duloxetine vs placebo on DMN connectivity. Of the 41 subjects with DD, 32 completed the clinical trial and MRI scans, along with the 25 HC participants. At baseline, we found that the coherence of neural activity within the brain's DMN was greater in persons with DD compared with HC subjects. Following a 10-week clinical trial, we found that treatment with duloxetine, but not placebo, normalized DMN connectivity. The baseline imaging findings are consistent with those found in patients with major

Antidepressants Normalize the Default Mode Network in Patients With Dysthymia

PubMed Central

Posner, Jonathan; Hellerstein, David J.; Gat, Inbal; Mechling, Anna; Klahr, Kristin; Wang, Zhishun; McGrath, Patrick J.; Stewart, Jonathan W.; Peterson, Bradley S.

2014-01-01

Importance The default mode network (DMN) is a collection of brain regions that reliably deactivate during goal-directed behaviors and is more active during a baseline, or so-called resting, condition. Coherence of neural activity, or functional connectivity, within the brain’s DMN is increased in major depressive disorder relative to healthy control (HC) subjects; however, whether similar abnormalities are present in persons with dysthymic disorder (DD) is unknown. Moreover, the effect of antidepressant medications on DMN connectivity in patients with DD is also unknown. Objective To use resting-state functional-connectivity magnetic resonance imaging (MRI) to study (1) the functional connectivity of the DMN in subjects with DD vs HC participants and (2) the effects of antidepressant therapy on DMN connectivity. Design After collecting baseline MRI scans from subjects with DD and HC participants, we enrolled the participants with DD into a 10-week prospective, double-blind, placebo-controlled trial of duloxetine and collected MRI scans again at the conclusion of the study. Enrollment occurred between 2007 and 2011. Setting University research institute. Participants Volunteer sample of 41 subjects with DD and 25 HC participants aged 18 to 53 years. Control subjects were group matched to patients with DD by age and sex. Main Outcome Measures We used resting-state functional-connectivity MRI to measure the functional connectivity of the brain’s DMN in persons with DD compared with HC subjects, and we examined the effects of treatment with duloxetine vs placebo on DMN connectivity. Results Of the 41 subjects with DD, 32 completed the clinical trial and MRI scans, along with the 25 HC participants. At baseline, we found that the coherence of neural activity within the brain’s DMN was greater in persons with DD compared with HC subjects. Following a 10-week clinical trial, we found that treatment with duloxetine, but not placebo, normalized DMN connectivity

A comparison of menotropin, highly-purified menotropin and follitropin alfa in cycles of intracytoplasmic sperm injection

PubMed Central

Esteves, Sandro C; Schertz, Joan C; Verza, Sidney; Schneider, Danielle T; Zabaglia, Silval FC

2009-01-01

Background Over the last several decades, as a result of an evolution in manufacturing processes, a marked development has been made in the field of gonadotropins for ovarian stimulation. Initially, therapeutic gonadotropins were produced from a simple process of urine extraction and purification; now they are produced via a complex system involving recombinant technology, which yields gonadotropins with high levels of purity, quality, and consistency. Methods A retrospective analysis of 865 consecutive intracytoplasmic sperm injection (ICSI) cycles of controlled ovarian hyperstimulation (COH) compared the clinical efficacy of three gonadotropins (menotropin [hMG; n = 299], highly-purified hMG [HP-hMG; n = 330] and follitropin alfa [r-hFSH; n = 236]) for ovarian stimulation after pituitary down-regulation. The endpoints were live birth rates and total doses of gonadotropin per cycle and per pregnancy. Results Laboratory and clinical protocols remained unchanged over time, except for the type of gonadotropin used, which was introduced sequentially (hMG, then HP-hMG, and finally r-hFSH). Live birth rates were not significantly different for hMG (24.4%), HP-hMG (32.4%) and r-hFSH (30.1%; p = 0.09) groups. Total dose of gonadotropin per cycle was significantly higher in the hMG (2685 +/- 720 IU) and HP-hMG (2903 +/- 867 IU) groups compared with the r-hFSH-group (2268 +/- 747 IU; p < 0.001). Total dose of gonadotropin required to achieve clinical pregnancy was 15.7% and 11.0% higher for the hMG and HP-hMG groups, respectively, compared with the r-hFSH group, and for live births, the differences observed were 45.3% and 19.8%, respectively. Conclusion Although similar live birth rates were achieved, markedly lower doses of r-hFSH were required compared with hMG or HP-hMG. PMID:19828024

What makes patients with fibromyalgia feel better? Correlations between Patient Global Impression of Improvement and changes in clinical symptoms and function: a pooled analysis of 4 randomized placebo-controlled trials of duloxetine.

PubMed

Hudson, James I; Arnold, Lesley M; Bradley, Laurence A; Choy, Ernest H S; Mease, Philip J; Wang, Fujun; Ahl, Jonna; Wohlreich, Madelaine M

2009-11-01

To investigate the relationship between changes in clinical rating scale items and endpoint Patient Global Impression of Improvement (PGI-I). Data were pooled from 4 randomized, double-blind, placebo-controlled studies of duloxetine in patients with fibromyalgia (FM). Variables included in the analyses were those that assessed symptoms in FM domains of pain, fatigue, sleep, cognitive difficulties, emotional well-being, physical function, and impact on daily living. The association of endpoint PGI-I with changes from baseline in individual variables was assessed using Pearson product-moment correlations (r). Stepwise linear regression was used to identify those variables for which changes from baseline were statistically significant independent predictors of the endpoint PGI-I ratings. Changes in pain variables and interference of symptoms with the ability to work were highly correlated (r >or= 0.5 or r

TSAT is a better predictor than ferritin of hemoglobin response to Epoetin alfa in US dialysis patients

PubMed Central

Gaweda, Adam E; Bhat, Premila; Maglinte, Gregory A; Chang, Chun-Lan; Hill, Jerrold; Park, Grace S; Ashfaq, Akhtar; Gitlin, Matthew

2014-01-01

Clinical guidelines recommend concurrent treatment of anemia in end-stage renal disease with erythropoiesis-stimulating agents (ESAs) and iron. However, there are mixed data about optimal iron supplementation. To help address this gap, the relationship between iron markers and hemoglobin (Hb) response to ESA (Epoetin alfa) dose was examined. Electronic medical records of 1902 US chronic hemodialysis patients were analyzed over a 12-month period between June 2009 and June 2010. The analysis included patients who had at least one Hb value during each 4-week interval for four consecutive intervals (k − 2, k − 1, k, and k + 1; k is the index interval), received at least one ESA dose during intervals k − 1 or k, had at least one transferrin saturation (TSAT) value at interval k, and at least one ferritin value during intervals k − 2, k − 1, or k. Effect modification by TSAT and ferritin on Hb response was evaluated using the generalized estimating equations approach. Patients had a mean (standard deviation) age of 62 (15) years; 41% were Caucasian, 34% African American, 65% had hypertension, and 39% diabetes. Transferrin saturation, but not ferritin, had a statistically significant (P < 0.05) modifying effect on Hb response. Maximum Hb response was achieved when TSAT was 34%, with minimal incremental effect beyond these levels. Of the two standard clinical iron markers, TSAT should be used as the primary marker of the modifying effect of iron on Hb response to ESA. Long-term safety of iron use to improve Hb response to ESA warrants further study. PMID:23968235

Rapid and high-precision measurement of sulfur isotope and sulfur concentration in sediment pore water by multi-collector inductively coupled plasma mass spectrometry.

PubMed

Bian, Xiao-Peng; Yang, Tao; Lin, An-Jun; Jiang, Shao-Yong

2015-01-01

We have developed a technique for the rapid, precise and accurate determination of sulfur isotopes (δ(34)S) by MC-ICP-MS applicable to a range of sulfur-bearing solutions of different sulfur content. The 10 ppm Alfa-S solution (ammonium sulfate solution, working standard of the lab of the authors) was used to bracket other Alfa-S solutions of different concentrations and the measured δ(34)SV-CDT values of Alfa-S solutions deviate from the reference value to varying degrees (concentration effect). The stability of concentration effect has been verified and a correction curve has been constructed based on Alfa-S solutions to correct measured δ(34)SV-CDT values. The curve has been applied to AS solutions (dissolved ammonium sulfate from the lab of the authors) and pore water samples successfully, validating the reliability of our analytical method. This method also enables us to measure the sulfur concentration simultaneously when analyzing the sulfur isotope composition. There is a strong linear correlation (R(2)>0.999) between the sulfur concentrations and the intensity ratios of samples and the standard. We have constructed a regression curve based on Alfa-S solutions and this curve has been successfully used to determine sulfur concentrations of AS solutions and pore water samples. The analytical technique presented here enable rapid, precise and accurate S isotope measurement for a wide range of sulfur-bearing solutions - in particular for pore water samples with complex matrix and varying sulfur concentrations. Also, simultaneous measurement of sulfur concentrations is available. Copyright © 2014 Elsevier B.V. All rights reserved.

The clinical importance of changes in the 0 to 10 numeric rating scale for worst, least, and average pain intensity: analyses of data from clinical trials of duloxetine in pain disorders.

PubMed

Farrar, John T; Pritchett, Yili L; Robinson, Michael; Prakash, Apurva; Chappell, Amy

2010-02-01

Data on 1,700 patients pooled from 5 randomized, placebo-controlled duloxetine studies (3 in diabetic peripheral neuropathic pain and 2 in fibromyalgia) were analyzed to determine clinically important differences (CIDs) in the 0 to 10 Numeric Rating Scale-Pain Intensity (NRS-PI) for patient-reported "worst" and "least" pain intensity while validating the previously published level for "average" pain. The correspondence between the baseline-to-endpoint raw and percentage change in the NRS-PI for the worst, least, and average pain were compared to patients' perceived improvements at endpoint as measured by the 7-point Patient Global Impression of Improvement (PGI-I) scales. Stratification by baseline pain separated the raw but not the percent change scores. The PGI-I category of "much better" or above was our a priori definition of a CID. Cutoff points for the NRS-PI change scores were determined using a receiver operator curve analysis. A consistent relationship between the worst and average NRS-PI percent change and the PGI-I was demonstrated regardless of the study, pain type, age, sex, or treatment group with a reduction of approximately 34%. The least pain item CID was slightly higher at 41%. Raw change CID cutoff points were approximately -2, -2.5 and -3 for least, average, and worst pain respectively. We determined an anchor-based value for the change in the worst, least, and average pain intensity items of the Brief Pain Inventory that best represents a clinically important difference. Our findings support a standard definition of a clinically important difference in clinical trials of chronic-pain therapies. Copyright 2010 American Pain Society. Published by Elsevier Inc. All rights reserved.

Pharmacokinetics, safety and efficacy of a recombinant factor IX product, trenonacog alfa in previously treated haemophilia B patients.

PubMed

Collins, P W; Quon, D V K; Makris, M; Chowdary, P; Kempton, C L; Apte, S J; Ramanan, M V; Hay, C R M; Drobic, B; Hua, Y; Babinchak, T J; Gomperts, E D

2018-01-01

Trenonacog alfa (IB1001) is a recombinant factor IX (rFIX) manufactured in Chinese hamster ovary (CHO) cells. IB1001 was evaluated in a multicentre clinical trial with haemophilia B patients. The aim was to establish IB1001 pharmacokinetic non-inferiority to comparator rFIX, safety and efficacy in previously treated patients (PTPs) with haemophilia B. Subjects were severe or moderately severe haemophilia B adult and adolescent PTPs with no history of FIX inhibitors. IB1001 PK non-inferiority to comparator rFIX was demonstrated through ratio of AUC 0-∞ in 32 subjects. IB1001 was well tolerated in all 76 treated subjects; the most common adverse drug reaction was headache (2.6% of subjects) and there were no reports of FIX inhibitors. Transient non-inhibitory binding FIX antibodies and anti-CHO cell protein antibodies developed in 21% and 29% of subjects respectively; no safety concerns were associated with development of these antibodies. Prophylaxis (mean duration ± SD: 17.9 ± 9.6 months, mean dose: 55.5 ± 12.9 IU/kg, median 1.0 infusion per week) was effective in preventing bleeds (median annual bleed rate: 1.52, interquartile range: 0.0-3.46). One or two IB1001 infusions resolved 84% of the bleeds, while for 84% of treatments haemostatic efficacy of IB1001 was rated excellent or good. IB1001 haemostatic efficacy for all 19 major surgeries was rated adequate or better than adequate. IB1001 is safe and efficacious for treatment of bleeds, routine prophylaxis and perioperative management in haemophilia B patients. © 2017 The Authors. Haemophilia Published by John Wiley & Sons Ltd.

Arecibo Pulsar Survey Using ALFA. IV. Mock Spectrometer Data Analysis, Survey Sensitivity, and the Discovery of 40 Pulsars

NASA Astrophysics Data System (ADS)

Lazarus, P.; Brazier, A.; Hessels, J. W. T.; Karako-Argaman, C.; Kaspi, V. M.; Lynch, R.; Madsen, E.; Patel, C.; Ransom, S. M.; Scholz, P.; Swiggum, J.; Zhu, W. W.; Allen, B.; Bogdanov, S.; Camilo, F.; Cardoso, F.; Chatterjee, S.; Cordes, J. M.; Crawford, F.; Deneva, J. S.; Ferdman, R.; Freire, P. C. C.; Jenet, F. A.; Knispel, B.; Lee, K. J.; van Leeuwen, J.; Lorimer, D. R.; Lyne, A. G.; McLaughlin, M. A.; Siemens, X.; Spitler, L. G.; Stairs, I. H.; Stovall, K.; Venkataraman, A.

2015-10-01

The on-going Arecibo Pulsar-ALFA (PALFA) survey began in 2004 and is searching for radio pulsars in the Galactic plane at 1.4 GHz. Here we present a comprehensive description of one of its main data reduction pipelines that is based on the PRESTO software and includes new interference-excision algorithms and candidate selection heuristics. This pipeline has been used to discover 40 pulsars, bringing the survey’s discovery total to 144 pulsars. Of the new discoveries, eight are millisecond pulsars (MSPs; P\\lt 10 ms) and one is a Fast Radio Burst (FRB). This pipeline has also re-detected 188 previously known pulsars, 60 of them previously discovered by the other PALFA pipelines. We present a novel method for determining the survey sensitivity that accurately takes into account the effects of interference and red noise: we inject synthetic pulsar signals with various parameters into real survey observations and then attempt to recover them with our pipeline. We find that the PALFA survey achieves the sensitivity to MSPs predicted by theoretical models but suffers a degradation for P≳ 100 ms that gradually becomes up to ˜10 times worse for P\\gt 4 {{s}} at {DM}\\lt 150 pc cm-3. We estimate 33 ± 3% of the slower pulsars are missed, largely due to red noise. A population synthesis analysis using the sensitivity limits we measured suggests the PALFA survey should have found 224 ± 16 un-recycled pulsars in the data set analyzed, in agreement with the 241 actually detected. The reduced sensitivity could have implications on estimates of the number of long-period pulsars in the Galaxy.

Antidepressants but not antipsychotics have antiepileptogenic effects with limited effects on comorbid depressive-like behaviour in the WAG/Rij rat model of absence epilepsy

PubMed Central

Citraro, Rita; Leo, Antonio; De Fazio, Pasquale; De Sarro, Giovambattista; Russo, Emilio

2015-01-01

Background and Purpose Two of the most relevant unmet needs in epilepsy are represented by the development of disease-modifying drugs able to affect epileptogenesis and/or the study of related neuropsychiatric comorbidities. No systematic study has investigated the effects of chronic treatment with antipsychotics or antidepressants on epileptogenesis. However, such drugs are known to influence seizure threshold. Experimental Approach We evaluated the effects of an early long-term treatment (ELTT; 17 weeks), started before seizure onset (P45), with fluoxetine (selective 5-HT-reuptake inhibitor), duloxetine (dual-acting 5-HT-noradrenaline reuptake inhibitor), haloperidol (typical antipsychotic drug), risperidone and quetiapine (atypical antipsychotic drugs) on the development of absence seizures and comorbid depressive-like behaviour in the WAG/Rij rat model. Furthermore, we studied the effects of these drugs on established absence seizures in adult (6-month-old) rats after a chronic 7 weeks treatment. Key Results ELTT with all antipsychotics did not affect the development of seizures, whereas, both ELTT haloperidol (1 mg·kg−1 day−1) and risperidone (0.5 mg·kg−1 day−1) increased immobility time in the forced swimming test and increased absence seizures only in adult rats (7 weeks treatment). In contrast, both fluoxetine (30 mg·kg−1 day−1) and duloxetine (10–30 mg·kg−1 day−1) exhibited clear antiepileptogenic effects. Duloxetine decreased and fluoxetine increased absence seizures in adult rats. Duloxetine did not affect immobility time; fluoxetine 30 mg·kg−1 day−1 reduced immobility time while at 10 mg·kg−1 day−1 an increase was observed. Conclusions and Implications In this animal model, antipsychotics had no antiepileptogenic effects and might worsen depressive-like comorbidity, while antidepressants have potential antiepileptogenic effects even though they have limited effects on comorbid depressive-like behaviour. PMID

Antidepressant-selective gynecomastia.

PubMed

Kaufman, Kenneth R; Podolsky, Dina; Greenman, Danielle; Madraswala, Rehman

2013-01-01

To describe what we believe is the first reported case of synergistic gynecomastia during treatment of depressive and anxiety disorders when sertraline was added to a stable medication regimen including duloxetine, rosuvastatin, and amlodipine. A 67-year-old male with major depression, dysthymia, obsessive-compulsive disorder, social anxiety, hypertension, diabetes, and hyperlipidemia presented with new-onset gynecomastia and breast tenderness. Mammography revealed bilateral gynecomastia (fibroglandular tissue posterior to the nipples bilaterally) without suspicious mass, calcification, or other abnormalities. These new symptoms developed after sertraline was added to his stable medication regimen (duloxetine, alprazolam, rosuvastatin, metoprolol, amlodipine, hydrochlorothiazide/triamterene, metformin, and sitagliptin). These symptoms were dose-dependent, with gynecomastia and breast tenderness more severe as sertraline was titrated from 25 mg/day to 50 mg/day and then to 75 mg/day. When sertraline was discontinued, gynecomastia and breast tenderness rapidly resolved. Mammoplasia and gynecomastia are associated with altered dopamine neurotransmission and/or perturbations in sexual hormones. These adverse effects may be medication induced. Selective serotonin reuptake inhibitors (sertraline), serotonin-norepinephrine reuptake inhibitors (duloxetine), rosuvastatin, and amlodipine have been reported to cause these adverse effects. This case was unique, since the patient had been on both sertraline and duloxetine previously as independent psychotropics without the development of gynecomastia. In the context of an additive drug adverse effect, the probability of sertraline as the precipitant drug was determined by both the Naranjo probability scale and the Horn drug interaction probability scale as probable. Gynecomastia is associated with antidepressants and other medications but is rarely addressed. Gynecomastia may be antidepressant selective or may be the result of

Treatment-naïve Gaucher disease patients achieve therapeutic goals and normalization with velaglucerase alfa by 4years in phase 3 trials.

PubMed

Zimran, Ari; Elstein, Deborah; Gonzalez, Derlis E; Lukina, Elena A; Qin, Yulin; Dinh, Quinn; Turkia, Hadhami Ben

2018-02-01

Gaucher disease is an inherited metabolic disease characterized by β-glucocerebrosidase deficiency and commonly treated with enzyme replacement therapy (ERT). The efficacy of ERT with velaglucerase alfa was assessed based on the achievement of published therapeutic goals and the normalization of disease parameters in 39 treatment-naïve patients with type 1 Gaucher disease, 6 to 62years of age, enrolled in phase 3 clinical trials. After 4years of ERT, therapeutic goals for thrombocytopenia and splenomegaly had been achieved in 100% of patients; goals for anemia and hepatomegaly had been achieved in 95% and 94% of patients, respectively. Consistent with the goal for bone mineral density, lumbar spine bone density improved in 87% of patients ≥18years of age. At year 4, compared with clinical ranges for healthy individuals, 86% of patients with a low baseline hemoglobin concentration had normalized, 60% with a low baseline platelet count had normalized, 67% with baseline splenomegaly had normalized, 58% with hepatomegaly had normalized, and lumbar spine bone density had normalized in 53% of adults. The decade-old therapeutic goals do not reflect the potential for normalization of clinical parameters in ERT-treated patients. Goals consistent with normalization or near-normalization should be considered. ClinicalTrials.gov identifiers: NCT00430625, NCT00553631, NCT00635427. Copyright © 2016 Shire Human Genetic Therapies, Inc. Published by Elsevier Inc. All rights reserved.

77 FR 43429 - Unblocking of 1 Individual and 2 Entities Designated Pursuant to Executive Order 13315

Federal Register 2010, 2011, 2012, 2013, 2014

2012-07-24

.... The following designations are removed from the SDN List: Individual 1. KARAM, Nabil Victor, c/o ALFA COMPANY LIMITED FOR INTERNATIONAL TRADING AND MARKETING, P.O. Box 212953, Amman 11121, Jordan; c/o ALFA... 910606, Amman 11191, Jordan; DOB 1954; nationality Lebanon (individual) [IRAQ2]. Entities 1. ALFA COMPANY...

Quantification of EVI1 transcript levels in acute myeloid leukemia by RT-qPCR analysis: A study by the ALFA Group.

PubMed

Smol, Thomas; Nibourel, Olivier; Marceau-Renaut, Alice; Celli-Lebras, Karine; Berthon, Céline; Quesnel, Bruno; Boissel, Nicolas; Terré, Christine; Thomas, Xavier; Castaigne, Sylvie; Dombret, Hervé; Preudhomme, Claude; Renneville, Aline

2015-12-01

EVI1 overexpression confers poor prognosis in acute myeloid leukemia (AML). Quantification of EVI1 expression has been mainly assessed by real-time quantitative PCR (RT-qPCR) based on relative quantification of EVI1-1D splice variant. In this study, we developed a RT-qPCR assay to perform quantification of EVI1 expression covering the different splice variants. A sequence localized in EVI1 exons 14 and 15 was cloned into plasmids that were used to establish RT-qPCR standard curves. Threshold values to define EVI1 overexpression were determined using 17 bone marrow (BM) and 31 peripheral blood (PB) control samples and were set at 1% in BM and 0.5% in PB. Samples from 64 AML patients overexpressing EVI1 included in the ALFA-0701 or -0702 trials were collected at diagnosis and during follow-up (n=152). Median EVI1 expression at AML diagnosis was 23.3% in BM and 3.6% in PB. EVI1 expression levels significantly decreased between diagnostic and post-induction samples, with an average variation from 21.6% to 3.56% in BM and from 4.0% to 0.22% in PB, but did not exceed 1 log10 reduction. Our study demonstrates that the magnitude of reduction in EVI1 expression levels between AML diagnosis and follow-up is not sufficient to allow sensitive detection of minimal residual disease. Copyright © 2015 Elsevier Ltd. All rights reserved.

Free-surface phenomena under low- and zero-gravity conditions

NASA Technical Reports Server (NTRS)

Coles, D.

1985-01-01

An apparatus to measure contact angle was constructed to exploit the proposed internal-corner criterion. If 2 alfa is the internal angle between two intersecting vertical planes and gamma is the contact angle, a meniscus at the corner rises to a finite height if alfa + gamma pi/2 and to an infinite height if alfa + gamma pi/2. The apparatus operates by decreasing the angle alfa from pi/2 until the meniscus height changes abruptly. A number of liquids are tested on glass and plexiglas.

Gateways to clinical trials.

PubMed

Bayes, M; Rabasseda, X; Prous, J R

2003-06-01

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies knowledge area of Prous Science Integrity(R), the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: AdGVVEGF121.10, anakinra, andolast, anidulafungin, APC-2059, l-arginine hydrochloride, aripiprazole, arzoxifene hydrochloride, asimadoline; Bexarotene, bimatoprost, bimosiamose, bizelesin, BMS-188667, botulinum toxin type B, bromfenac sodium, bryostatin 1; Cannabidiol, cariporide mesilate, CCI-1004, CDP-571, cerivastatin sodium, clevudine; Dalbavancin, darbepoetin alfa, decitabine, deligoparin sodium, diethylnorspermine, drotrecogin alfa (activated), DTaP-HBV-IPV/Hib-vaccine; E-5564, eculizumab, edodekin alfa, emtricitabine, enfuvirtide, (-)-epigallocatechin gallate, eplerenone, esomeprazole magnesium, etaquine, etoricoxib, ezetimibe; Fesoterodine, fipamezole hydrochloride, fondaparinux sodium, fosamprenavir calcium, frovatriptan, fulvestrant; Gadofosveset sodium, galiximab, ghrelin (human), glufosfamide; Homoharringtonine; Idraparinux sodium, imatinib mesylate, INS-37217; KRN-7000; L-651582, lafutidine, lanthanum carbonate, lenercept, levetiracetam, lusupultide; Magnesium sulfate, melatonin, mepolizumab, midostaurin, morphine hydrochloride, mozavaptan; Natalizumab, nesiritide; OPC-51803, oregovomab, oritavancin; Peginterferon alfa-2(a), pleconaril, plevitrexed, prasterone, pregabalin; Ranibizumab, Ro-31-7453, roxifiban acetate, rubitecan; SCV-07, SHL-749, sho-saiko-to, soblidotin, solifenacin succinate; Tegaserod maleate, telithromycin, tenecteplase, theraCIM, tipifarnib, travoprost; Valdecoxib, vardenafil hydrochloride hydrate, voriconazole; Ximelagatran; Ziprasidone hydrochloride, ZYC-00101. (c) 2003 Prous Science. All rights reserved.

Overall Survival and Updated Results for Sunitinib Compared With Interferon Alfa in Patients With Metastatic Renal Cell Carcinoma

PubMed Central

Motzer, Robert J.; Hutson, Thomas E.; Tomczak, Piotr; Michaelson, M. Dror; Bukowski, Ronald M.; Oudard, Stéphane; Negrier, Sylvie; Szczylik, Cezary; Pili, Roberto; Bjarnason, Georg A.; Garcia-del-Muro, Xavier; Sosman, Jeffrey A.; Solska, Ewa; Wilding, George; Thompson, John A.; Kim, Sindy T.; Chen, Isan; Huang, Xin; Figlin, Robert A.

2009-01-01

Purpose A randomized, phase III trial demonstrated superiority of sunitinib over interferon alfa (IFN-α) in progression-free survival (primary end point) as first-line treatment for metastatic renal cell carcinoma (RCC). Final survival analyses and updated results are reported. Patients and Methods Seven hundred fifty treatment-naïve patients with metastatic clear cell RCC were randomly assigned to sunitinib 50 mg orally once daily on a 4 weeks on, 2 weeks off dosing schedule or to IFN-α 9 MU subcutaneously thrice weekly. Overall survival was compared by two-sided log-rank and Wilcoxon tests. Progression-free survival, response, and safety end points were assessed with updated follow-up. Results Median overall survival was greater in the sunitinib group than in the IFN-α group (26.4 v 21.8 months, respectively; hazard ratio [HR] = 0.821; 95% CI, 0.673 to 1.001; P = .051) per the primary analysis of unstratified log-rank test (P = .013 per unstratified Wilcoxon test). By stratified log-rank test, the HR was 0.818 (95% CI, 0.669 to 0.999; P = .049). Within the IFN-α group, 33% of patients received sunitinib, and 32% received other vascular endothelial growth factor–signaling inhibitors after discontinuation from the trial. Median progression-free survival was 11 months for sunitinib compared with 5 months for IFN-α (P < .001). Objective response rate was 47% for sunitinib compared with 12% for IFN-α (P < .001). The most commonly reported sunitinib-related grade 3 adverse events included hypertension (12%), fatigue (11%), diarrhea (9%), and hand-foot syndrome (9%). Conclusion Sunitinib demonstrates longer overall survival compared with IFN-α plus improvement in response and progression-free survival in the first-line treatment of patients with metastatic RCC. The overall survival highlights an improved prognosis in patients with RCC in the era of targeted therapy. PMID:19487381

Peginterferon Lambda-1a Is Associated with a Low Incidence of Autoimmune Thyroid Disease in Chronic Hepatitis C.

PubMed

Fredlund, Paul; Hillson, Jan; Gray, Todd; Shemanski, Lynn; Dimitrova, Dessislava; Srinivasan, Subasree

2015-11-01

Peginterferon alfa (alfa) increases the risk of autoimmune disease. Peginterferon lambda-1a (Lambda) acts through a receptor with a more liver-specific distribution compared to the alfa receptor. In a phase-2b study, 525 treatment-naive patients with chronic hepatitis C virus (HCV) infection received ribavirin and Lambda interferon (120, 180, or 240 μg) or alfa interferon (180 μg) for 24 (genotypes 2 and 3) or 48 (genotypes 1 and 4) weeks. Retrospective analysis found that adverse events of MedDRA-coded thyroid dysfunction and abnormal levels of thyroid-stimulating hormone (TSH) were significantly more frequent with alfa versus Lambda (12% versus 2.6% and 15.2% versus 3.4%, respectively, both P<0.0001). Most Lambda recipients with abnormal TSH had levels below the lower limit of normal; the frequency of low and high TSH was similar in alfa recipients with abnormal TSH. Blinded review by an endocrinologist found that new-onset primary hypothyroidism or painless thyroiditis was less frequent with Lambda versus alfa (0.5% and 1.8% versus 5.3% and 7.5%, respectively, P<0.0001). Most TSH elevations reflected new-onset hypothyroidism requiring treatment, while most markedly suppressed TSH values reflected probable painless thyroiditis and resolved without sequelae. In conclusion, HCV-infected patients treated with Lambda/ribavirin experienced fewer adverse events of thyroid dysfunction compared with patients treated with alfa/ribavirin.

Theoretical Design and Experimental Evaluation of Molten Carbonate Modified LSM Cathode for Low Temperature Solid Oxide Fuel Cells

DTIC Science & Technology

2012-01-01

Li-K binary eutectic salts were prepared for infiltration. Li2CO3 (99%, Alfa Aesar) and K2CO3 (99%, Alfa Aesar) were mixed with a molar ratio of 62:38...99.9%, Alfa Aesar) were also prepared. For infiltration, the eutectic melt was ultrasonic dispersed in ethanol. A few drops of the salt suspension...and heated at 650 oC for 2 h to form a eutectic melt. In addition, eutectic melts containing 0.5 mol % La2O3 (99.9%, Alfa Aesar) or 0.5 mol % Gd2O3

The use of recombinant human LH (lutropin alfa) in the late stimulation phase of assisted reproduction cycles: a double-blind, randomized, prospective study.

PubMed

Tarlatzis, B; Tavmergen, E; Szamatowicz, M; Barash, A; Amit, A; Levitas, E; Shoham, Z

2006-01-01

The effect of recombinant human LH (r-hLH; lutropin alfa) in women undergoing controlled ovarian stimulation with recombinant human FSH (r-hFSH) prior to IVF was investigated. After down-regulation with the GnRH agonist, buserelin, 114 normo-ovulatory women (aged 18-37 years) received r-hFSH alone until the lead follicle reached a diameter of 14 mm. Patients were then randomized in a double-blind fashion to receive r-hFSH in addition to r-hLH, 75 IU s.c., or placebo daily for a maximum of 10 days prior to oocyte retrieval and IVF. The primary end-point was the number of metaphase II oocytes. There were no significant differences between treatment groups for the primary end-point. Serum estradiol concentrations on the day of HCG administration were significantly higher in the group receiving r-hLH plus r-hFSH than in the group receiving r-hFSH alone (P = 0.0001), but there were no significant differences between the groups in dose and duration of r-hFSH treatment required, oocyte maturation, fertilization rate, pregnancy rate and live birth rate. In this patient population, the addition of r-hLH during the late follicular phase of a long GnRH agonist and r-hFSH stimulation cycle provides no further benefit in terms of oocyte maturation or other end-points.

Post-marketing surveillance data of thrombomodulin alfa: sub-analysis in patients with sepsis-induced disseminated intravascular coagulation.

PubMed

Eguchi, Yutaka; Gando, Satoshi; Ishikura, Hiroyasu; Saitoh, Daizoh; Mimuro, Jun; Takahashi, Hoyu; Kitajima, Isao; Tsuji, Hajime; Matsushita, Tadashi; Tsujita, Ryuichi; Nagao, Osamu; Sakata, Yoichi

2014-01-01

Thrombomodulin alfa (TM-α, recombinant thrombomodulin) significantly improved disseminated intravascular coagulation (DIC) when compared with heparin therapy in a phase III study. Post-marketing surveillance of TM-α was performed to evaluate the effects and safety in patients with sepsis-induced DIC. From May 2008 to April 2010, a total of 1,787 patients with sepsis-induced DIC treated with TM-α were registered. DIC was diagnosed based on the Japanese Association for Acute Medicine (JAAM) criteria. The DIC resolution and survival rates on day 28 after the last TM-α administration, and changes in DIC, systemic inflammatory response syndrome (SIRS), and sequential organ failure assessment (SOFA) scores and coagulation and inflammation markers were evaluated. The most frequent underlying disease was infectious focus-unknown sepsis (29.8%). The mean ± SD values of age, dose, and the duration of TM-α administration were 64.7 ± 20.3 years, 297.3 ± 111.4 U/kg/day, and 5.6 ± 3.4 days, respectively. A total of 1,320 subjects (73.9%) received combined administration with other anticoagulants. Both coagulation and inflammation markers, such as fibrin/fibrinogen degradation products, prothrombin time ratio, thrombin-antithrombin complex, and C-reactive protein, as well as JAAM DIC, SIRS, and SOFA scores, significantly and simultaneously decreased after TM-α administration (p < 0.001). DIC resolution and 28-day survival rates were 44.4% and 66.0%, respectively. The 28-day survival rate decreased significantly according to the duration of DIC before TM-α administration (p < 0.001). Total adverse drug reactions (ADRs), bleeding ADRs, and serious bleeding adverse events occurred in 126 (7.1%), 98 (5.5%), and 121 (6.8%) subjects, respectively. On day 28, after the last TM-α administration available for an antibody test, only one patient was positive for anti-TM-α antibodies (0.11%). Our results suggest that TM-α is most effective for treating

Drug Reduces Cancer Treatment-Related Joint Pain

Cancer.gov

A Cancer Currents blog post about a clinical trial demonstrating that duloxetine (Cymbalta®) may reduce joint pain caused by aromatase inhibitors in women being treated for early-stage breast cancer.

Dose conversion ratio in hemodialysis patients switched from darbepoetin alfa to PEG-epoetin beta: AFFIRM study.

PubMed

Choi, Peter; Farouk, Mourad; Manamley, Nick; Addison, Janet

2013-11-01

There is limited information published on switching erythropoiesis-stimulating agent (ESA) treatment for anemia associated with chronic kidney disease (CKD) from darbepoetin alfa (DA) to methoxy polyethylene glycol-epoetin beta (PEG-Epo) outside the protocol of interventional clinical studies. AFFIRM (Aranesp Efficiency Relative to Mircera) was a retrospective, multi-site, observational study designed to estimate the population mean maintenance dose conversion ratio [DCR; dose ratio achieving comparable hemoglobin level (Hb) between two evaluation periods] in European hemodialysis patients whose treatment was switched from DA to PEG-Epo. Eligible patients had received hemodialysis for ≥ 12 months and DA for ≥ 7 months. Data were collected from 7 months before until 7 months after switching treatment. DCR was calculated for patients with Hb and ESA data available in both evaluation periods (EP; Months 1 and 2 were defined as the pre-switch EP, and Months 6 and 7 as the post-switch EP). Red blood cell transfusions pre- and post-switch were quantified. Of 302 patients enrolled, 206 had data available for DCR analysis. The geometric mean DCR was 1.17 (95% CI 1.05, 1.29). Regression analysis indicated a non-linear relationship between pre- and post-switch ESA doses; DCR decreased with increasing pre-switch DA dose. The geometric mean weekly ESA doses were 24.1 μg DA in the pre-switch EP and 28.6 μg PEG-Epo in the post-switch EP. Mean Hb was 11.5 g/dL in the pre-switch EP and 11.4 g/dL in the post-switch EP. There were 16 transfusions and 34 units transfused in the pre-switch period, versus 48 transfusions and 95 units transfused post-switch. Excluding patients receiving a transfusion within 90 days of or during either EP, the DCR was 1.21 (95% CI 1.09, 1.35). In these hemodialysis patients switched from DA to PEG-Epo the DCR was 1.17 and 1.21 after accounting for the effect of transfusions. The number of transfusions and units transfused increased approximately

Impact of Age and Polytherapy on Fingolimod Induced Bradycardia: a Preclinical Study.

PubMed

Ritter, Christian; Svačina, Martin K R; Bobylev, Ilja; Joshi, Abhijeet; Schneider, Toni; Lehmann, Helmar C

2017-03-01

Fingolimod is a an oral disease modifying drug for relapsing remitting multiple sclerosis (MS) preventing egress of B and T cells from lymph nodes. Relevant first dose adverse events include bradycardia and atrioventricular conduction slowing. Cardiac side effects of fingolimod and combinational pharmacotherapy including duloxetine and tolterodine were monitored in mice of different age using implantable ECG telemetric systems. Cardiac tissue was assessed for S1P-receptor subtype (1 and 3), and for GIRK1 expression. Fingolimod led to a significant heart rate reduction within 60 min, which returned to baseline values within 24 h. In older mice bradycardia was more pronounced compared to younger mice. Atrioventricular conduction was not affected. Older mice showed a higher S1PR3 expression in a naïve state and receptor expression was reduced after fingolimod administration. Combination with duloxetine or tolterodine alleviated fingolimod induced heart rate decrease. Our data provide preclinical evidence that negative chronotropic effects of fingolimod might be age dependent, possibly due to an altered expression and internalization of cardiac S1PR3 in older animals. This data could be relevant for future clinical monitoring and patient selection in the aging MS population. Combinational therapies of fingolimod and duloxetine or tolterodine are well tolerated and safe without an increased risk for pronounced bradycardia or arrhythmia.

Cost-effectiveness analysis of a new 8% capsaicin patch compared to existing therapies for postherpetic neuralgia.

PubMed

Armstrong, Edward P; Malone, Daniel C; McCarberg, Bill; Panarites, Christopher J; Pham, Sissi V

2011-05-01

The purpose of this study was to compare the cost effectiveness of a new 8% capsaicin patch, compared to the current treatments for postherpetic neuralgia (PHN), including tricyclic antidepressants (TCAs), topical lidocaine patches, duloxetine, gabapentin, and pregabalin. A 1-year Markov model was constructed for PHN with monthly cycles, including dose titration and management of adverse events. The perspective of the analysis was from a payer perspective, managed-care organization. Clinical trials were used to determine the proportion of patients achieving at least a 30% improvement in PHN pain, the efficacy parameter. The outcome was cost per quality-adjusted life-year (QALY); second-order probabilistic sensitivity analyses were conducted. The effectiveness results indicated that 8% capsaicin patch and topical lidocaine patch were significantly more effective than the oral PHN products. TCAs were least costly and significantly less costly than duloxetine, pregabalin, topical lidocaine patch, 8% capsaicin patch, but not gabapentin. The incremental cost-effectiveness ratio for the 8% capsaicin patch overlapped with the topical lidocaine patch and was within the accepted threshold of cost per QALY gained compared to TCAs, duloxetine, gabapentin, and pregablin. The frequency of the 8% capsaicin patch retreatment assumption significantly impacts its cost-effectiveness results. There are several limitations to this analysis. Since no head-to-head studies were identified, this model used inputs from multiple clinical trials. Also, a last observation carried forward process was assumed to have continued for the duration of the model. Additionally, the trials with duloxetine may have over-predicted its efficacy in PHN. Although a 30% improvement in pain is often an endpoint in clinical trials, some patients may require greater or less improvement in pain to be considered a clinical success. The effectiveness results demonstrated that 8% capsaicin and topical lidocaine

A randomized, controlled study of peginterferon lambda-1a/ribavirin ± daclatasvir for hepatitis C virus genotype 2 or 3.

PubMed

Foster, Graham R; Chayama, Kazuaki; Chuang, Wan-Long; Fainboim, Hugo; Farkkila, Martti; Gadano, Adrian; Gaeta, Giovanni B; Hézode, Christophe; Inada, Yukiko; Heo, Jeong; Kumada, Hiromitsu; Lu, Sheng-Nan; Marcellin, Patrick; Moreno, Christophe; Roberts, Stuart K; Strasser, Simone I; Thompson, Alexander J; Toyota, Joji; Paik, Seung Woon; Vierling, John M; Zignego, Anna L; Cohen, David; McPhee, Fiona; Wind-Rotolo, Megan; Srinivasan, Subasree; Hruska, Matthew; Myler, Heather; Portsmouth, Simon D

2016-01-01

Peginterferon Lambda was being developed as an alternative to alfa interferon for the treatment of chronic hepatitis C virus (HCV) infection. We compared peginterferon Lambda-1a plus ribavirin (Lambda/RBV) and Lambda/RBV plus daclatasvir (DCV; pangenotypic NS5A inhibitor) with peginterferon alfa-2a plus RBV (alfa/RBV) in treatment-naive patients with HCV genotype 2 or 3 infection. In this multicenter, double-blind, phase 3 randomized controlled trial, patients were assigned 2:2:1 to receive 24 weeks of Lambda/RBV, 12 weeks of Lambda/RBV + DCV, or 24 weeks of alfa/RBV. The primary outcome measure was sustained virologic response at post-treatment Week 12 (SVR12). Overall, 874 patients were treated: Lambda/RBV, n = 353; Lambda/RBV + DCV, n = 349; alfa/RBV, n = 172. Patients were 65 % white and 33 % Asian, 57 % male, with a mean age of 47 years; 52 % were infected with genotype 2 (6 % cirrhotic) and 48 % with genotype 3 (9 % cirrhotic). In the Lambda/RBV + DCV group, 83 % (95 % confidence interval [CI] 78.5, 86.5) achieved SVR12 (90 % genotype 2, 75 % genotype 3) whereas SVR12 was achieved by 68 % (95 % CI 63.1, 72.9) with Lambda/RBV (72 % genotype 2, 64 % genotype 3) and 73 % (95 % CI 66.6, 79.9) with peginterferon alfa/RBV (74 % genotype 2, 73 % genotype 3). Lambda/RBV + DCV was associated with lower incidences of flu-like symptoms, hematological abnormalities, and discontinuations due to adverse events compared with alfa/RBV. The 12-week regimen of Lambda/RBV + DCV was superior to peginterferon alfa/RBV in the combined population of treatment-naive patients with genotype 2 or 3 infection, with an improved tolerability and safety profile compared with alfa/RBV.

Post-marketing surveillance of thrombomodulin alfa, a novel treatment of disseminated intravascular coagulation - safety and efficacy in 1,032 patients with hematologic malignancy.

PubMed

Asakura, Hidesaku; Takahashi, Hoyu; Tsuji, Hajime; Matsushita, Tadashi; Ninomiya, Hideyuki; Honda, Goichi; Mimuro, Jun; Eguchi, Yutaka; Kitajima, Isao; Sakata, Yoichi

2014-03-01

Post-marketing surveillance of thrombomodulin alfa (TM-α) was performed to evaluate safety and efficacy in patients with disseminated intravascular coagulation (DIC) with hematologic malignancy. All patients treated with TM-α from May 2008 to April 2010 in Japan were included. Information about baseline characteristics, safety, and efficacy were collected. The DIC resolution rate, survival rate on Day 28 after the last TM-α administration, and changes in DIC score and coagulation tests were evaluated. The underlying diseases associated with DIC were acute myeloid leukemia (except for acute promyelocytic leukemia, n=350), lymphoma (n=199), acute promyelocytic leukemia (n=172), acute lymphoblastic leukemia (n=156), myelodysplastic syndromes (n=61), and other (n=94). The incidence rates of bleeding-related adverse events and adverse drug reactions were 17.8% and 4.6%, respectively. In subjects with bleeding symptoms at baseline, 55.0% were assessed as disappeared or improved based on symptoms after TM-α treatment. The DIC resolution and survival rates were 55.9% and 70.7%, respectively. The DIC score and coagulation tests including thrombin-antithrombin complex (TAT) were significantly improved. Coagulation tests were significantly improved after TM-α treatment even in subjects whose clinical course of underlying disease was assessed as unchanged or exacerbated. This surveillance confirmed the safety and efficacy of TM-α in clinical practice, thus TM-α may be an ideal treatment for patients with DIC based upon hematologic malignancy. Copyright © 2014 Elsevier Ltd. All rights reserved.

Efficacy of sofosbuvir plus ribavirin with or without peginterferon-alfa in patients with hepatitis C virus genotype 3 infection and treatment-experienced patients with cirrhosis and hepatitis C virus genotype 2 infection.

PubMed

Foster, Graham R; Pianko, Stephen; Brown, Ashley; Forton, Daniel; Nahass, Ronald G; George, Jacob; Barnes, Eleanor; Brainard, Diana M; Massetto, Benedetta; Lin, Ming; Han, Bin; McHutchison, John G; Subramanian, G Mani; Cooper, Curtis; Agarwal, Kosh

2015-11-01

We conducted an open-label, randomized, phase 3 trial to determine the efficacy and safety of sofosbuvir and ribavirin, with and without peginterferon-alfa, in treatment-experienced patients with cirrhosis and hepatitis C virus (HCV) genotype 2 infection and treatment-naïve or treatment-experienced patients with HCV genotype 3 infection. The study was conducted at 80 sites in Europe, North America, Australia, and New Zealand Patients were randomly assigned (1:1:1) to groups given sofosbuvir and ribavirin for 16 weeks (n = 196); sofosbuvir and ribavirin for 24 weeks (n = 199); or sofosbuvir, peginterferon-alfa, and ribavirin for 12 weeks (n = 197). The primary end point was the percentage of patients with HCV RNA <15 IU/mL 12 weeks after stopping therapy (sustained virologic response [SVR12]). From October 2013 until April 2014, we enrolled and treated 592 patients-48 with genotype 2 HCV and compensated cirrhosis who had not achieved SVR with previous treatments and 544 with genotype 3 HCV (279 treatment-naïve and 265 previously treated). Overall, 219 patients (37%) had compensated cirrhosis. The last post-treatment week 12 patient visit was in January 2015. Rates of SVR12 among patients with genotype 2 HCV were 87% and 100%, for those receiving 16 and 24 weeks of sofosbuvir and ribavirin, respectively, and 94% for those receiving sofosbuvir, peginterferon, and ribavirin for 12 weeks. Rates of SVR12 among patients with genotype 3 HCV were 71% and 84% in those receiving 16 and 24 weeks of sofosbuvir and ribavirin, respectively, and 93% in those receiving sofosbuvir, peginterferon, and ribavirin. On-treatment virologic failure occurred in 3 patients with HCV genotype 3a receiving sofosbuvir and ribavirin for 24 weeks. The most common adverse events were fatigue, headache, insomnia, and nausea. Overall, 1% of patients discontinued treatment due to adverse events. Among patients with genotype 3 HCV infection, including a large proportion of treatment

Economic Evaluation of First-Line Treatments for Metastatic Renal Cell Carcinoma: A Cost-Effectiveness Analysis in A Health Resource–Limited Setting

PubMed Central

Wu, Bin; Dong, Baijun; Xu, Yuejuan; Zhang, Qiang; Shen, Jinfang; Chen, Huafeng; Xue, Wei

2012-01-01

Background To estimate, from the perspective of the Chinese healthcare system, the economic outcomes of five different first-line strategies among patients with metastatic renal cell carcinoma (mRCC). Methods and Findings A decision-analytic model was developed to simulate the lifetime disease course associated with renal cell carcinoma. The health and economic outcomes of five first-line strategies (interferon-alfa, interleukin-2, interleukin-2 plus interferon-alfa, sunitinib and bevacizumab plus interferon-alfa) were estimated and assessed by indirect comparison. The clinical and utility data were taken from published studies. The cost data were estimated from local charge data and current Chinese practices. Sensitivity analyses were used to explore the impact of uncertainty regarding the results. The impact of the sunitinib patient assistant program (SPAP) was evaluated via scenario analysis. The base-case analysis showed that the sunitinib strategy yielded the maximum health benefits: 2.71 life years and 1.40 quality-adjusted life-years (QALY). The marginal cost-effectiveness (cost per additional QALY) gained via the sunitinib strategy compared with the conventional strategy was $220,384 (without SPAP, interleukin-2 plus interferon-alfa and bevacizumab plus interferon-alfa were dominated) and $16,993 (with SPAP, interferon-alfa, interleukin-2 plus interferon-alfa and bevacizumab plus interferon-alfa were dominated). In general, the results were sensitive to the hazard ratio of progression-free survival. The probabilistic sensitivity analysis demonstrated that the sunitinib strategy with SPAP was the most cost-effective approach when the willingness-to-pay threshold was over $16,000. Conclusions Our analysis suggests that traditional cytokine therapy is the cost-effective option in the Chinese healthcare setting. In some relatively developed regions, sunitinib with SPAP may be a favorable cost-effective alternative for mRCC. PMID:22412884

Economic evaluation of first-line treatments for metastatic renal cell carcinoma: a cost-effectiveness analysis in a health resource-limited setting.

PubMed

Wu, Bin; Dong, Baijun; Xu, Yuejuan; Zhang, Qiang; Shen, Jinfang; Chen, Huafeng; Xue, Wei

2012-01-01

To estimate, from the perspective of the Chinese healthcare system, the economic outcomes of five different first-line strategies among patients with metastatic renal cell carcinoma (mRCC). A decision-analytic model was developed to simulate the lifetime disease course associated with renal cell carcinoma. The health and economic outcomes of five first-line strategies (interferon-alfa, interleukin-2, interleukin-2 plus interferon-alfa, sunitinib and bevacizumab plus interferon-alfa) were estimated and assessed by indirect comparison. The clinical and utility data were taken from published studies. The cost data were estimated from local charge data and current Chinese practices. Sensitivity analyses were used to explore the impact of uncertainty regarding the results. The impact of the sunitinib patient assistant program (SPAP) was evaluated via scenario analysis. The base-case analysis showed that the sunitinib strategy yielded the maximum health benefits: 2.71 life years and 1.40 quality-adjusted life-years (QALY). The marginal cost-effectiveness (cost per additional QALY) gained via the sunitinib strategy compared with the conventional strategy was $220,384 (without SPAP, interleukin-2 plus interferon-alfa and bevacizumab plus interferon-alfa were dominated) and $16,993 (with SPAP, interferon-alfa, interleukin-2 plus interferon-alfa and bevacizumab plus interferon-alfa were dominated). In general, the results were sensitive to the hazard ratio of progression-free survival. The probabilistic sensitivity analysis demonstrated that the sunitinib strategy with SPAP was the most cost-effective approach when the willingness-to-pay threshold was over $16,000. Our analysis suggests that traditional cytokine therapy is the cost-effective option in the Chinese healthcare setting. In some relatively developed regions, sunitinib with SPAP may be a favorable cost-effective alternative for mRCC.

Pain management discussion forum: serious interaction among frequently used drugs for chronic pain.

PubMed

Breivik, Harald

2014-06-01

A query and response regarding a patient who was taking high-dose tramadol and duloxetine is presented. The patient developed serotonin syndrome. Risks for this clinically important drug interaction and management of the syndrome are discussed.

76 FR 80332 - Foreign-Trade Zone 7-Mayaguez, PR, Expansion of Manufacturing Authority; Amgen Manufacturing...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-12-23

... approved by the Board in 2008 for the manufacture of epogen[reg] (epoetin alfa), neupogen[reg] (filgrastim), aransep[reg] (darbepoetin alfa), enbrel[reg] (etanercept), kineret[reg] (anakinra), and neulasta[reg...

Recombinant factor VIIa (eptacog alfa): a pharmacoeconomic review of its use in haemophilia in patients with inhibitors to clotting factors VIII or IX.

PubMed

Lyseng-Williamson, Katherine A; Plosker, Greg L

2007-01-01

Recombinant factor VIIa (NovoSeven; also known as recombinant activated factor VII or eptacog alfa) is indicated as an intravenous haemostatic agent in haemophilia patients with inhibitors to clotting factors VIII or IX. In noncomparative trials in haemophilia patients with inhibitors, on-demand home treatment with recombinant factor VIIa was effective in controlling episodes of mild to moderate bleeding and well tolerated, with early treatment being associated with a greater rate of success and the need for fewer doses than delayed treatment. Prophylactic treatment with recombinant factor VIIa was also effective in maintaining haemostasis in patients with this indication undergoing surgery. Relative to prior treatment with plasma-derived agents, treatment with recombinant factor VIIa was associated with improvements in health-related quality of life in a cost-utility study in haemophilia patients with inhibitors in Australia. In well designed decision-model cost analyses conducted from a healthcare payer perspective in several countries, on-demand treatment with recombinant factor VIIa to control mild to moderate bleeding episodes in this patient population was predicted to be cost saving or cost neutral relative to on-demand treatment with intravenous activated prothrombin complex concentrate (aPCC). Although the acquisition cost of recombinant factor VIIa was greater than that of aPCC in some studies, the greater initial efficacy of recombinant factor VIIa than aPCC resulted in lower predicted total medical costs. Results were generally robust to plausible changes in key parameters. Orthopaedic surgery with recombinant factor VIIa to maintain haemostasis in haemophilia patients with inhibitors was generally predicted to be cost saving, relative to not having surgery, over the medium to long term in modelled cost analyses from a healthcare payer perspective in the UK and US. The initial cost of surgery was high, but the difference in costs between patients

Coculture-inducible bacteriocin activity of Lactobacillus plantarum strain J23 isolated from grape must.

PubMed

Rojo-Bezares, Beatriz; Sáenz, Yolanda; Navarro, Laura; Zarazaga, Myriam; Ruiz-Larrea, Fernanda; Torres, Carmen

2007-08-01

Detection and characterization of bacteriocin production by Lactobacillus plantarum strain J23, recovered from a grape must sample in Spain, have been carried out. Bacteriocin activity was degraded by proteolytic enzymes (trypsin, alfa-chymotrypsin, papaine, protease, proteinase K and acid proteases), and it was stable at high temperatures (121 degrees C, 20min), in a wide range of pH (1-12), and after treatment with organic solvents. L. plantarum J23 showed antimicrobial activity against Oenococcus oeni, and a range of Lactobacillus and Pediococcus species. Bacteriocin production was detected in liquid media only when J23 was cocultivated with some inducing bacteria, and induction took place when intact cells or 55 degrees C heated cells of the inducer were cocultivated with J23, but not with their autoclaved cells. Bacteriocin activity of J23 was not induced by high initial J23 inocula, and it was detected in cocultures during the exponential phase. The presence of ethanol or acidic pH in the media reduced bacteriocin production in the cocultures of J23 with the inducing bacteria. The presence of plantaricin-related plnEF and plnJ genes was detected by PCR and sequencing. Nevertheless, negative results were obtained for plnA, plnK, plNC8, plS and plW genes.

Baker's asthma in a child.

PubMed

Alonso, E; Ausín, A; Elices, A; Moreno-Escobosa, M; Ibáñez, M; Laso, M

2001-01-01

baker's asthma is a well-known occupational lung disease which usually develops in adults. We report the case of a two years old boy who suffered from asthma, urticaria and atopic dermatitis for twelve months, whose symptoms were associated to visits to his grandfather's bakery. skin prick tests (SPT) were made to dust mites, moulds, flours, alfa-amylase and egg. It was also determined total IgE and specific IgE antibodies to alfa-amylase and flours. Subsequently, a challenge test was carried out with wheat flour. The SPTs were positive to flours, alfa-amylase and egg. The determination of specific IgE antibodies showed 2.64 kU/L to wheat, 0.79 kU/L to glyadin and 2.98 kU/L to alfa-amylase. The patient developed asthma and rhinitis after manipulating wheat flour for 10 min. we demonstrated a type I hypersensitivity to wheat flour and alfa-amylase in a two years old child by SPT, specific IgE antibodies and challenge test. This case in the childhood equivalent of occupational baker's asthma.

49 CFR Appendix B- to Part 544... - Appendix B- to Part 544 Issuers of Motor Vehicle Insurance Policies Subject to the Reporting...

Code of Federal Regulations, 2010 CFR

2010-10-01

... Only in Designated States Link to an amendment published at 75 FR 54044, Sept. 3, 2010. Alfa Insurance... Alfa Insurance Group (Alabama) Auto Club (Michigan) Balboa Insurance Group (South Dakota) 1 Commerce...

Randomized equivalence study evaluating the possibility of switching hemodialysis patients receiving subcutaneous human erythropoietin directly to intravenous darbepoetin alfa.

PubMed

Chazot, Charles; Terrat, Jean Claude; Dumoulin, Alexandre; Ang, Kim-Seng; Gassia, Jean Paul; Chedid, Khalil; Maurice, Francois; Canaud, Bernard

2009-02-01

Darbepoetin alfa is an erythropoiesis-stimulating agent (ESA) used either intravenously or subcutaneously with no dose penalty; however, the direct switch from subcutaneous recombinant human erythropoietin (rHuEPO) to intravenous darbepoetin has barely been studied. To establish the equivalence of a direct switch from subcutaneous rHuEPO to intravenous darbepoetin versus an indirect switch from subcutaneous rHuEPO to intravenous darbepoetin after 2 months of subcutaneous darbepoetin in patients undergoing hemodialysis. In this open, randomized, 6-month, prospective study, patients with end-stage kidney disease who were on hemodialysis were randomized into 2 groups: direct switch from subcutaneous rHuEPO to intravenous darbepoetin (group 1) and indirect switch from subcutaneous rHuEPO to intravenous darbepoetin after 2 months of subcutaneous darbepoetin (group 2). A third, nonrandomized group (control), consisting of patients treated with intravenous rHuEPO who were switched to intravenous darbepoetin, was also studied to reflect possible variations of hemoglobin (Hb) levels due to change from one type of ESA to the other. The primary outcome was the proportion of patients with stable Hb levels at month 6. Secondary endpoints included Hb stability at month 3, dosage requirements for darbepoetin, and safety of the administration route. Among 154 randomized patients, the percentages with stable Hb levels were equivalent in groups 1 and 2, respectively, at month 3 (86.0% vs 91.3%) and month 6 (82.1% vs 81.6%; difference -0.5 [90% CI -12.8 to 11.8]). Mean Hb levels between baseline and month 6 remained stable in both groups, with no variation in mean darbepoetin dose. Mean ferritin levels remained above 100 microg/L in the 3 groups during the whole study, and darbepoetin was well tolerated. This study has shown equivalent efficacy on Hb stability without the need for dosage increase in patients switched directly from subcutaneous rHuEPO to intravenous darbepoetin.

Mechanisms of Hyperbilirubinemia During Peginterferon Lambda-1a Therapy for Chronic Hepatitis C Infection: A Retrospective Investigation.

PubMed

Zwirtes, Ricardo; Narasimhan, Premkumar; Wind-Rotolo, Megan M; Xu, Dong; Hruska, Matthew W; Kishnani, Narendra; Colston, Elizabeth M; Srinivasan, Subasree

2016-11-01

The phase 2b EMERGE study compared the efficacy/safety of peginterferon lambda-1a (Lambda) and peginterferon alfa-2a (Alfa), both with ribavirin (RBV), for treatment of chronic hepatitis C virus (HCV) infection. A key safety finding was a higher frequency of hyperbilirubinemia with Lambda/RBV versus Alfa/RBV. To characterize mechanisms of hyperbilirubinemia associated with Lambda/RBV, we conducted a retrospective analysis of safety data from the HCV genotype 1 and genotype 4 cohort of the EMERGE study. Subjects were randomized to once-weekly Lambda (120/180/240 μg) or Alfa (180 μg), with daily RBV, for 48 weeks. Early-onset Lambda/RBV-related hyperbilirubinemia events (6-12 weeks) resulted mostly from RBV-induced hemolysis evidenced by sustained reticulocytosis and a predominantly unconjugated pattern of hyperbilirubinemia. The higher hyperbilirubinemia frequency with Lambda/RBV versus Alfa/RBV was attributed to bone marrow suppression known to occur with Alfa but not Lambda. Late-onset (>12 weeks) Lambda/RBV-related hyperbilirubinemia events occurred most frequently with higher Lambda doses and were associated with increased levels of hepatic transaminase and direct bilirubin fractions compared with early events. This dual pattern of hyperbilirubinemia observed while on Lambda/RBV treatment is thought to be caused by exaggerated RBV-induced hemolysis in early-onset events compared with possible direct Lambda-induced hepatocellular toxicity in late-onset events.

THE ARECIBO LEGACY FAST ALFA SURVEY. V. THE H I SOURCE CATALOG OF THE ANTI-VIRGO REGION AT {delta} = +27{sup 0}

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

Saintonge, Amelie; Giovanelli, Riccardo; Haynes, Martha P.

We present a second catalog of H I sources detected in the Arecibo Legacy Fast ALFA Survey. We report 488 detections over 135 deg{sup 2}, within the region of the sky having 22 h < {alpha} < 03 h and +26{sup 0} < {delta} < +28{sup 0}. We present here the detections that have either (a) S/N>6.5, where the reliability of the catalog is better than 95% or (b) 5.0 < S/N < 6.5 and a previously measured redshift that corroborates our detection. Of the 488 objects presented here, 49 are high-velocity clouds or clumps thereof with negative heliocentric recessionmore » velocities. These clouds are mostly very compact and isolated, while some of them are associated with large features such as Wright's Cloud or the northern extension of the Magellanic Stream. The remaining 439 candidate detections are identified as extragalactic objects and have all been matched with optical counterparts. Five of the six galaxies detected with M{sub Hi}<10{sup 7.5} M{sub sun} are satellites of either the NGC672/IC1727 nearby galaxy pair or their neighboring dwarf irregular galaxy NGC784. The data of this catalog release include a slice through the Pisces-Perseus foreground void, a large nearby underdensity of galaxies. We report no detections within the void, where our catalog is complete for systems with H i masses of 10{sup 8} M{sub sun}. Gas-rich, optically-dark galaxies do not seem to constitute an important void population, and therefore do not suffice for producing a viable solution to the void phenomenon.« less

77 FR 14593 - Unblocking of Specially Designated Nationals and Blocked Persons Pursuant to Executive Order 12978

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-12

..., Orlando, c/o ALFA PHARMA S.A., Bogota, Colombia; c/o LABORATORIOS GENERICOS VETERINARIOS, Bogota, Colombia.../o DISTRIBUIDORA DE DROGAS CONDOR LTDA., Bogota, Colombia; c/o ALFA PHARMA S.A., Bogota, Colombia; c...

Prognostic value of plasma N-terminal pro-brain natriuretic peptide in patients with severe sepsis.

PubMed

Brueckmann, Martina; Huhle, Guenter; Lang, Siegfried; Haase, Karl K; Bertsch, Thomas; Weiss, Christel; Kaden, Jens J; Putensen, Christian; Borggrefe, Martin; Hoffmann, Ursula

2005-07-26

Increased plasma levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) have been identified as predictors of cardiac dysfunction and prognosis in congestive heart failure and ischemic heart disease. In severe sepsis patients, however, no information is available yet about the prognostic value of natriuretic peptides. Therefore, the aim of the present study was to determine the role of the N-terminal prohormone forms of ANP (NT-proANP) and BNP (NT-proBNP) in the context of outcome of septic patients. Furthermore, the effect of treatment with recombinant human activated protein C [drotrecogin alfa (activated)] on plasma levels of natriuretic peptides in severe sepsis was evaluated. Fifty-seven patients with severe sepsis were included. Levels of NT-proANP and NT-proBNP were measured on the second day of sepsis by ELISA. Septic patients with NT-proBNP levels >1400 pmol/L were 3.9 times more likely (relative risk [RR], 3.9; 95% CI, 1.6 to 9.7) to die from sepsis than patients with lower NT-proBNP values (P<0.01). NT-proANP levels, however, were not predictive of survival in our patient population. A highly significant correlation was found between troponin I levels and plasma concentrations of NT-proBNP in septic patients (r=0.68, P<0.0001). In addition, troponin I significantly accounted for the variation in NT-proBNP levels (P<0.0001), suggesting an important role for NT-proBNP in the context of cardiac injury and dysfunction in septic patients. Twenty-three septic patients who received treatment with drotrecogin alfa (activated) presented with significantly lower concentrations of NT-proANP, NT-proBNP, and troponin I compared with patients not receiving drotrecogin alfa (activated). NT-proBNP may serve as useful laboratory marker to predict survival in patients presenting with severe sepsis.

Simeprevir

MedlinePlus

... used along with ribavirin (Copegus, Rebetol) and peginterferon alfa (Pegasys) to treat chronic hepatitis C (an ongoing ... crush them.You will take simeprevir with peginterferon alfa and ribavirin for 12 weeks. Then you will ...

Abacavir, Dolutegravir, and Lamivudine

MedlinePlus

... If you have HCV and are taking interferon alfa with or without ribavirin (Copegus, Rebetol, Ribasphere) and ... are taking abacavir, dolutegravir, and lamivudine and interferon alfa with or without ribavirin, tell your doctor if ...

Sofosbuvir

MedlinePlus

... Rebetol, Ribasphere, others) and sometimes another medication (peginterferon alfa [Pegasys] to treat certain types of chronic hepatitis ... Sofosbuvir must be taken in combination with peginterferon alfa and ribavirin or in combination with ribavirin alone. ...

Telaprevir

MedlinePlus

... two other medications (ribavirin [Copegus, Rebetol] and peginterferon alfa [Pegasys]) to treat chronic hepatitis C (an ongoing ... not successfully be treated with ribavirin and peginterferon alfa alone. Telaprevir is in a class of medications ...

Boceprevir

MedlinePlus

... two other medications (ribavirin [Copegus, Rebetol] and peginterferon alfa [Pegasys]) to treat chronic hepatitis C (an ongoing ... when they were treated with ribavirin and peginterferon alfa alone. Boceprevir is in a class of medications ...

Batten Disease

MedlinePlus

... Drug Administration has approved the use of cerliponase alfa to slow the progression of symptoms in children ... Drug Administration has approved the use of cerliponase alfa to slow the progression of symptoms in children ...

Effectiveness of treatments for severe sepsis: a prospective, multicenter, observational study.

PubMed

Ferrer, Ricard; Artigas, Antonio; Suarez, David; Palencia, Eduardo; Levy, Mitchell M; Arenzana, Angel; Pérez, Xose Luis; Sirvent, Josep-Maria

2009-11-01

Several Surviving Sepsis Campaign Guidelines recommendations are reevaluated. To analyze the effectiveness of treatments recommended in the sepsis guidelines. In a prospective observational study, we studied all adult patients with severe sepsis from 77 intensive care units. We recorded compliance with four therapeutic goals (central venous pressure 8 mm Hg or greater for persistent hypotension despite fluid resuscitation and/or lactate greater than 36 mg/dl, central venous oxygen saturation 70% or greater for persistent hypotension despite fluid resuscitation and/or lactate greater than 36 mg/dl, blood glucose greater than or equal to the lower limit of normal but less than 150 mg/dl, and inspiratory plateau pressure less than 30 cm H(2)O for mechanically ventilated patients) and four treatments (early broad-spectrum antibiotics, fluid challenge in the event of hypotension and/or lactate greater than 36 mg/dl, low-dose steroids for septic shock, drotrecogin alfa [activated] for multiorgan failure). The primary outcome measure was hospital mortality. The effectiveness of each treatment was estimated using propensity scores. Of 2,796 patients, 41.6% died before hospital discharge. Treatments associated with lower hospital mortality were early broad-spectrum antibiotic treatment (treatment within 1 hour vs. no treatment within first 6 hours of diagnosis; odds ratio, 0.67; 95% confidence interval, 0.50-0.90; P = 0.008) and drotrecogin alfa (activated) (odds ratio, 0.59; 95% confidence interval, 0.41-0.84; P = 0.004). Fluid challenge and low-dose steroids showed no benefits. In severe sepsis, early administration of broad-spectrum antibiotics in all patients and administration of drotrecogin alfa (activated) in the most severe patients reduce mortality.

Impact of patient selection and study characteristics on signal detection in placebo-controlled trials with antidepressants.

PubMed

Mancini, Michele; Wade, Alan G; Perugi, Giulio; Lenox-Smith, Alan; Schacht, Alexander

2014-04-01

An increasing rate of antidepressant trials fail due to large placebo responses. This analysis aimed to identify variables influencing signal detection in clinical trials of major depressive disorder. Patient-level data of randomized patients with a duloxetine dose ≥ 60 mg/day were obtained from Lilly. Total scores of the Hamilton Depression Rating scale (HAM-D) were used as efficacy endpoints. In total, 4661 patients from 14 studies were included in the analysis. The overall effect size (ES), based on the HAM-D total score at endpoint, between duloxetine and placebo was -0.272. Although no statistically significant interactions were found, the following results for factors influencing ES were seen: a very low ES (-0.157) in patients in the lowest baseline HAM-D category and in patients recruited in the last category of the recruitment period (-0.122). A higher ES in patients recruited in centers with a site-size at but not more than 2.5 times the average site-size for the study (-0.345). Study characteristics that resulted in low signal detection in our database were: <80% study completers, a HAM-D placebo response >5 points, a high variability of placebo response (SD > 7 points HAM-D), >6 post baseline visits per study, and use of an active control drug. Simpler trial designs, more homogeneous and mid-sized study sites, a primary analysis based on a higher cutoff blinded to investigators to avoid the influence of score inflation in mild patients and, if possible, studies without an active control group could lead to a better signal detection of antidepressive efficacy. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Investigation of the predictive validity of laser-EPs in normal, UVB-inflamed and capsaicin-irritated skin with four analgesic compounds in healthy volunteers.

PubMed

Schaffler, Klaus; Nicolas, Laurent B; Borta, Andreas; Brand, Tobias; Reitmeir, Peter; Roebling, Robert; Scholpp, Joachim

2017-07-01

The aim of the present study was to assess the predictivity of laser-(radiant-heat)-evoked potentials (LEPs) from the vertex electroencephalogram, using an algesimetric procedure, testing the anti-nociceptive/anti-hyperalgesic effects of single oral doses of four marketed analgesics (of different compound classes) vs. placebo, in healthy volunteers with three skin types. This was a randomized, placebo-controlled, single-blind, five-way-crossover trial. Twenty-five healthy male/female Caucasians were included (receiving celecoxib 200 mg, pregabalin 150 mg, duloxetine 60 mg, lacosamide 100 mg or placebo) in a Williams design, with CO 2 laser-induced painful stimuli to normal, ultraviolet (UV) B-inflamed and capsaicin-irritated skin. LEPs and visual analogue scale ratings were taken at baseline and hourly for 6 h postdose from all three skin types. In normal skin, the averaged postdose LEP peak-to-peak-(PtP)-amplitudes were reduced by pregabalin (-2.68 μV; 95% confidence interval (CI) -4.16, 1.19) and duloxetine (-1.73 μV; 95% CI -3.21, -0.26) but not by lacosamide and celecoxib vs. placebo. On UVB-irradiated skin, reflecting inflammatory pain, celecoxib induced a pronounced reduction in LEP PtP amplitudes vs. placebo (-6.2 μV; 95% CI -7.88, -4.51), with a smaller reduction by duloxetine (-4.54 μV; 95% CI -6.21, -2.87) and pregabalin (-3.72 μV; 95% CI -5.40, -2.04), whereas lacosamide was inactive. LEP PtP amplitudes on capsaicin-irritated skin, reflecting peripheral/spinal sensitization, as in neuropathic pain, were reduced by pregabalin (-3.78 μV; 95% CI -5.31, -2.25) and duloxetine (-2.32 μV; 95% CI -3.82, -0.82) but not by celecoxib or lacosamide vs. placebo, which was in agreement with known clinical profiles. Overall, PtP amplitude reductions were in agreement with subjective ratings. LEP algesimetry is sensitive to analgesics with different modes of action and may enable the effects of novel analgesics to be assessed during early clinical

An Integrated Approach for a Structural and Functional Evaluation of Biosimilars: Implications for Erythropoietin.

PubMed

Gianoncelli, Alessandra; Bonini, Sara A; Bertuzzi, Michela; Guarienti, Michela; Vezzoli, Sara; Kumar, Rajesh; Delbarba, Andrea; Mastinu, Andrea; Sigala, Sandra; Spano, Pierfranco; Pani, Luca; Pecorelli, Sergio; Memo, Maurizio

2015-08-01

Authorization to market a biosimilar product by the appropriate institutions is expected based on biosimilarity with its originator product. The analogy between the originator and its biosimilar(s) is assessed through safety, purity, and potency analyses. In this study, we proposed a useful quality control system for rapid and economic primary screening of potential biosimilar drugs. For this purpose, chemical and functional characterization of the originator rhEPO alfa and two of its biosimilars was discussed. Qualitative and quantitative analyses of the originator rhEPO alfa and its biosimilars were performed using reversed-phase high-performance liquid chromatography (RP-HPLC). The identification of proteins and the separation of isoforms were studied using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and two-dimensional gel electrophoresis (2D-PAGE), respectively. Furthermore, the biological activity of these drugs was measured both in vitro, evaluating the TF-1 cell proliferation rate, and in vivo, using the innovative experimental animal model of the zebrafish embryos. Chemical analyses showed that the quantitative concentrations of rhEPO alfa were in agreement with the labeled claims by the corresponding manufacturers. The qualitative analyses performed demonstrated that the three drugs were pure and that they had the same amino acid sequence. Chemical differences were found only at the level of isoforms containing N-glycosylation; however, functional in vitro and in vivo studies did not show any significant differences from a biosimilar point of view. These rapid and economic structural and functional analyses were effective in the evaluation of the biosimilarity between the originator rhEPO alfa and the biosimilars analyzed.

77 FR 74916 - Unblocking of Specially Designated Nationals and Blocked Persons Pursuant to the Foreign...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-12-18

... BUITRAGO, Mesias, c/o GESTION ALFA LTDA., Bogota, Colombia; Calle 62 No. 9A-82 of. 616, Bogota, Colombia.... GESTION ALFA LTDA., Calle 62 No. 9A-82 of. 810, Bogota, Colombia; NIT 830095836-9 (Colombia) [SDNTK]. In...

77 FR 35387 - Granting of Request for Early Termination of the Waiting Period Under The Premerger Notification...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-13

... UnitedHealth Group, Inc.; Preferred Care Partners Holding Corp.; UnitedHealth Group, Inc. 20120790 G Alfa, S.A.B. de C.V.; J.L. French Automotive Castings, Inc.; Alfa, S.A.B. de C.V. 05/17/2012 20120809 G...

Erythropoiesis stimulating agents and techniques: a challenge for doping analysts.

PubMed

Jelkmann, W

2009-01-01

Recombinant human erythropoietin (rHuEPO) engineered in Chinese hamster ovary (CHO) cell cultures (Epoetin alfa and Epoetin beta) and its hyperglycosylated analogue Darbepoetin alfa are known to be misused by athletes. The drugs can be detected by isoelectric focusing (IEF) and immunoblotting of urine samples, because "EPO" is in reality a mixture of isoforms and the N-glycans of the recombinant products differ from those of the endogenous hormone. However, there is a plethora of novel erythropoiesis stimulating agents (ESAs). Since the originator Epoetins alfa and beta are no longer protected by patent in the European Union, rHuEPO biosimilars have entered the market. In addition, several companies in Asia, Africa and Latin America produce copied rHuEPOs for clinical purposes. While the amino acid sequence of all Epoetins is identical, the structure of their glycans differs depending on the mode of production. Some products contain more acidic and others more basic EPO isoforms. Epoetin delta is special, as it was engineered by homologous recombination in human fibrosarcoma cells (HT-1080), thus lacking N-glycolylneuraminic acid like native human EPO. ESAs under development include EPO fusion proteins, synthetic erythropoiesis stimulating protein (SEP) and peptidic (Hematide(), CNTO 528) as well as non-peptidic EPO mimetics. Furthermore, preclinical respectively clinical trials have been performed with small orally active drugs that stimulate endogenous EPO production by activating the EPO promoter ("GATA-inhibitors": diazepane derivatives) or enhancer ("HIF-stabilizers": 2-oxoglutarate analogues). The prohibited direct EPO gene transfer may become a problem in sports only in the future.

Accessory factors promote AlfA-dependent plasmid segregation by regulating filament nucleation, disassembly, and bundling

PubMed Central

Polka, Jessica K.; Kollman, Justin M.; Mullins, R. Dyche

2014-01-01

In bacteria, some plasmids are partitioned to daughter cells by assembly of actin-like proteins (ALPs). The best understood ALP, ParM, has a core set of biochemical properties that contributes to its function, including dynamic instability, spontaneous nucleation, and bidirectional elongation. AlfA, an ALP that pushes plasmids apart in Bacillus, relies on a different set of underlying properties to segregate DNA. AlfA elongates unidirectionally and is not dynamically unstable; its assembly and disassembly are regulated by a cofactor, AlfB. Free AlfB breaks up AlfA bundles and promotes filament turnover. However, when AlfB is bound to the centromeric DNA sequence, parN, it forms a segrosome complex that nucleates and stabilizes AlfA filaments. When reconstituted in vitro, this system creates polarized, motile comet tails that associate by antiparallel filament bundling to form bipolar, DNA-segregating spindles. PMID:24481252

Umbilical Cord Blood Use for Admission Blood Tests of VLBW (Very Low Birth Weight) Preterm Neonates: A Multi-center Randomized Clinical Trial

DTIC Science & Technology

2016-09-12

agents (erythropoietin and darbepoetin alfa ), and limiting phlebotomy via use of point-of-care testing devices, benchtop laboratory analyzers, and...Manual, 2014. 18: p. 571-592. 6. Ohls, R.K., et al., A randomized, masked, placebo-controlled study of darbepoetin alfa in preterm infants. Pediatrics

Clinical relevance of IDH1/2 mutant allele burden during follow-up in acute myeloid leukemia. A study by the French ALFA group

PubMed Central

Ferret, Yann; Boissel, Nicolas; Helevaut, Nathalie; Madic, Jordan; Nibourel, Olivier; Marceau-Renaut, Alice; Bucci, Maxime; Geffroy, Sandrine; Celli-Lebras, Karine; Castaigne, Sylvie; Thomas, Xavier; Terré, Christine; Dombret, Hervé; Preudhomme, Claude; Renneville, Aline

2018-01-01

Assessment of minimal residual disease has emerged as a powerful prognostic factor in acute myeloid leukemia. In this study, we investigated the potential of IDH1/2 mutations as targets for minimal residual disease assessment in acute myeloid leukemia, since these mutations collectively occur in 15–20% of cases of acute myeloid leukemia and now represent druggable targets. We employed droplet digital polymerase chain reaction assays to quantify IDH1R132, IDH2R140, and IDH2R172 mutations on genomic DNA in 322 samples from 103 adult patients with primary IDH1/2 mutant acute myeloid leukemia and enrolled on Acute Leukemia French Association (ALFA) - 0701 or -0702 clinical trials. The median IDH1/2 mutant allele fraction in bone marrow samples was 42.3% (range, 8.2 – 49.9%) at diagnosis of acute myeloid leukemia, and below the detection limit of 0.2% (range, <0.2 – 39.3%) in complete remission after induction therapy. In univariate analysis, the presence of a normal karyotype, a NPM1 mutation, and an IDH1/2 mutant allele fraction <0.2% in bone marrow after induction therapy were statistically significant predictors of longer disease-free survival. In multivariate analysis, these three variables remained significantly predictive of disease-free survival. In 7/103 (7%) patients, IDH1/2 mutations persisted at high levels in complete remission, consistent with the presence of an IDH1/2 mutation in pre-leukemic hematopoietic stem cells. Five out of these seven patients subsequently relapsed or progressed toward myelodysplastic syndrome, suggesting that patients carrying the IDH1/2 mutation in a pre-leukemic clone may be at high risk of hematologic evolution. PMID:29472349

Clinical relevance of IDH1/2 mutant allele burden during follow-up in acute myeloid leukemia. A study by the French ALFA group.

PubMed

Ferret, Yann; Boissel, Nicolas; Helevaut, Nathalie; Madic, Jordan; Nibourel, Olivier; Marceau-Renaut, Alice; Bucci, Maxime; Geffroy, Sandrine; Celli-Lebras, Karine; Castaigne, Sylvie; Thomas, Xavier; Terré, Christine; Dombret, Hervé; Preudhomme, Claude; Renneville, Aline

2018-05-01

Assessment of minimal residual disease has emerged as a powerful prognostic factor in acute myeloid leukemia. In this study, we investigated the potential of IDH1/2 mutations as targets for minimal residual disease assessment in acute myeloid leukemia, since these mutations collectively occur in 15-20% of cases of acute myeloid leukemia and now represent druggable targets. We employed droplet digital polymerase chain reaction assays to quantify IDH1R132 , IDH2R140 , and IDH2R172 mutations on genomic DNA in 322 samples from 103 adult patients with primary IDH1/2 mutant acute myeloid leukemia and enrolled on Acute Leukemia French Association (ALFA) - 0701 or -0702 clinical trials. The median IDH1/2 mutant allele fraction in bone marrow samples was 42.3% (range, 8.2 - 49.9%) at diagnosis of acute myeloid leukemia, and below the detection limit of 0.2% (range, <0.2 - 39.3%) in complete remission after induction therapy. In univariate analysis, the presence of a normal karyotype, a NPM1 mutation, and an IDH1/2 mutant allele fraction <0.2% in bone marrow after induction therapy were statistically significant predictors of longer disease-free survival. In multivariate analysis, these three variables remained significantly predictive of disease-free survival. In 7/103 (7%) patients, IDH1/2 mutations persisted at high levels in complete remission, consistent with the presence of an IDH1/2 mutation in pre-leukemic hematopoietic stem cells. Five out of these seven patients subsequently relapsed or progressed toward myelodysplastic syndrome, suggesting that patients carrying the IDH1/2 mutation in a pre-leukemic clone may be at high risk of hematologic evolution. Copyright © 2018 Ferrata Storti Foundation.

Toxicity Assessment of Six Titanium Dioxide Nanoparticles in Human Epidermal Keratinocytes