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  1. Article ; Online: NGLY1 deficiency: a prospective natural history study.

    Tong, Sandra / Ventola, Pamela / Frater, Christina H / Klotz, Jenna / Phillips, Jennifer M / Muppidi, Srikanth / Dwight, Selina S / Mueller, William F / Beahm, Brendan J / Wilsey, Matt / Lee, Kevin J

    Human molecular genetics

    2023  Volume 32, Issue 18, Page(s) 2787–2796

    Abstract: N-glycanase 1 (NGLY1) deficiency is a debilitating, ultra-rare autosomal recessive disorder caused by loss of function of NGLY1, a cytosolic enzyme that deglycosylates other proteins. It is characterized by severe global developmental delay and/or ... ...

    Abstract N-glycanase 1 (NGLY1) deficiency is a debilitating, ultra-rare autosomal recessive disorder caused by loss of function of NGLY1, a cytosolic enzyme that deglycosylates other proteins. It is characterized by severe global developmental delay and/or intellectual disability, hyperkinetic movement disorder, transient elevation of transaminases, (hypo)alacrima and progressive, diffuse, length-dependent sensorimotor polyneuropathy. A prospective natural history study (NHS) was conducted to elucidate clinical features and disease course. Twenty-nine participants were enrolled (15 onsite, 14 remotely) and followed for up to 32 months, representing ~29% of the ~100 patients identified worldwide. Participants exhibited profound developmental delays, with almost all developmental quotients below 20 on the Mullen Scales of Early Learning, well below the normative score of 100. Increased difficulties with sitting and standing suggested decline in motor function over time. Most patients presented with (hypo)alacrima and reduced sweat response. Pediatric quality of life was poor except for emotional function. Language/communication and motor skill problems including hand use were reported by caregivers as the most bothersome symptoms. Levels of the substrate biomarker, GlcNAc-Asn (aspartylglucosamine; GNA), were consistently elevated in all participants over time, independent of age. Liver enzymes were elevated for some participants but improved especially in younger patients and did not reach levels indicating severe liver disease. Three participants died during the study period. Data from this NHS informs selection of endpoints and assessments for future clinical trials for NGLY1 deficiency interventions. Potential endpoints include GNA biomarker levels, neurocognitive assessments, autonomic and motor function (particularly hand use), (hypo)alacrima and quality of life.
    MeSH term(s) Humans ; Child ; Prospective Studies ; Quality of Life ; Congenital Disorders of Glycosylation ; Biomarkers
    Chemical Substances Biomarkers
    Language English
    Publishing date 2023-06-26
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1108742-0
    ISSN 1460-2083 ; 0964-6906
    ISSN (online) 1460-2083
    ISSN 0964-6906
    DOI 10.1093/hmg/ddad106
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    Zs.A 3469: Show issues Location:
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  2. Article ; Online: Fostamatinib for the treatment of warm antibody autoimmune hemolytic anemia: Phase 2, multicenter, open-label study.

    Kuter, David J / Rogers, Kerry A / Boxer, Michael A / Choi, Michael / Agajanian, Richy / Arnold, Donald M / Broome, Catherine M / Field, Joshua J / Murakhovskaya, Irina / Numerof, Robert / Tong, Sandra

    American journal of hematology

    2022  Volume 97, Issue 6, Page(s) 691–699

    Abstract: Patients with relapsed warm antibody autoimmune hemolytic anemia (wAIHA) have limited treatment options. Fostamatinib is a potent, orally administered spleen tyrosine kinase inhibitor approved in the United States and Europe for the treatment of adults ... ...

    Abstract Patients with relapsed warm antibody autoimmune hemolytic anemia (wAIHA) have limited treatment options. Fostamatinib is a potent, orally administered spleen tyrosine kinase inhibitor approved in the United States and Europe for the treatment of adults with chronic immune thrombocytopenia (ITP). This phase 2 study evaluated the response to fostamatinib, administered at 150 mg BID orally with or without food in adults with wAIHA and active hemolysis with hemoglobin (Hgb) <10 g/dL who had failed at least one prior treatment. Hemoglobin levels and safety assessments were performed at visits every 2 weeks. The primary endpoint was Hgb >10 g/dL with an increase of ≥2 g/dL from baseline by week 24 without rescue therapy or red blood cell transfusion. Eleven of 24 (46%) patients achieved the primary endpoint. Increases in median Hgb were detected at week 2 and sustained over time. Median lactate dehydrogenase levels and reticulocyte counts generally declined over time with little change in median haptoglobin levels. The most common adverse events (AEs) were diarrhea (42%), fatigue (42%), hypertension (27%), dizziness (27%), and insomnia (23%). AEs were manageable and consistent with the fostamatinib safety database of over 3900 patients across multiple diseases (rheumatoid arthritis, B-cell lymphoma, COVID-19, and ITP). No new safety signals were detected. Fostamatinib may be a promising therapeutic option for wAIHA. A randomized, double-blind, phase 3 study is nearing completion.
    MeSH term(s) Adult ; Aminopyridines ; Anemia, Hemolytic, Autoimmune/drug therapy ; COVID-19 ; Humans ; Morpholines ; Oxazines ; Pyridines ; Pyrimidines
    Chemical Substances Aminopyridines ; Morpholines ; Oxazines ; Pyridines ; Pyrimidines ; fostamatinib (SQ8A3S5101)
    Language English
    Publishing date 2022-03-03
    Publishing country United States
    Document type Clinical Trial, Phase II ; Journal Article ; Multicenter Study
    ZDB-ID 196767-8
    ISSN 1096-8652 ; 0361-8609
    ISSN (online) 1096-8652
    ISSN 0361-8609
    DOI 10.1002/ajh.26508
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    Zs.A 1251: Show issues Location:
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  3. Article ; Online: Long-term fostamatinib treatment of adults with immune thrombocytopenia during the phase 3 clinical trial program.

    Bussel, James B / Arnold, Donald M / Boxer, Michael A / Cooper, Nichola / Mayer, Jiri / Zayed, Hany / Tong, Sandra / Duliege, Anne-Marie

    American journal of hematology

    2019  Volume 94, Issue 5, Page(s) 546–553

    Abstract: Two randomized, double-blind, placebo-controlled studies demonstrated responses (≥50 000/μL) to fostamatinib in adults with long-standing immune thrombocytopenia (ITP). The long-term safety and efficacy of fostamatinib were evaluated in a follow-on, open- ...

    Abstract Two randomized, double-blind, placebo-controlled studies demonstrated responses (≥50 000/μL) to fostamatinib in adults with long-standing immune thrombocytopenia (ITP). The long-term safety and efficacy of fostamatinib were evaluated in a follow-on, open-label extension (OLE) study. Patients received double-blind fostamatinib in the randomized trials, and responders continued the same dose, 100 to 150 mg BID, in the OLE study. Nonresponders received 100 mg BID for 4 weeks and could escalate to 150 mg BID at week 4. Endpoints included stable response, platelet count ≥50 000/μL at 4/6 biweekly (randomized trials) or 2/3 monthly visits (OLE), and overall response, ≥1 platelet count ≥50 000/μL during weeks 1 to 12. A total of 146 patients received fostamatinib including 123 in the OLE study. Median treatment duration was 6.7 months. Baseline median ITP duration was 8 years and median platelet count was 16 000/μL; prior treatments included thrombopoietic (TPO) agents (47%), splenectomy (35%), and rituximab (32%). Twenty-seven (18%) patients achieved a stable response with median duration of >28 months and a median platelet count of 89 000/μL. Sixty-four (44%) patients achieved an overall response (including stable responders) with a median platelet count of 63 000/μL and a median response duration of >28 months. Twenty-four of 71 (34%) patients who had failed TPO agents achieved overall responses to fostamatinib. The most common adverse events (AEs) were diarrhea, hypertension, nausea, epistaxis, and abnormal liver function tests. Most AEs were mild/moderate and resolved or were managed with dose reduction, dose interruption, and/or secondary medication. Almost half of the patients achieved an overall response, and most of these maintained their responses for >2 years. No new or increased frequency of AEs was seen at up to 31 months of treatment.
    MeSH term(s) Adult ; Aged ; Aged, 80 and over ; Aminopyridines ; Double-Blind Method ; Female ; Humans ; Male ; Middle Aged ; Morpholines ; Oxazines/administration & dosage ; Oxazines/adverse effects ; Platelet Count ; Purpura, Thrombocytopenic, Idiopathic/blood ; Purpura, Thrombocytopenic, Idiopathic/drug therapy ; Pyridines/administration & dosage ; Pyridines/adverse effects ; Pyrimidines ; Time Factors
    Chemical Substances Aminopyridines ; Morpholines ; Oxazines ; Pyridines ; Pyrimidines ; fostamatinib (SQ8A3S5101)
    Language English
    Publishing date 2019-03-13
    Publishing country United States
    Document type Clinical Trial, Phase III ; Journal Article ; Multicenter Study ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
    ZDB-ID 196767-8
    ISSN 1096-8652 ; 0361-8609
    ISSN (online) 1096-8652
    ISSN 0361-8609
    DOI 10.1002/ajh.25444
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    Zs.A 1251: Show issues Location:
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  4. Article ; Online: Fostamatinib is an effective second-line therapy in patients with immune thrombocytopenia.

    Boccia, Ralph / Cooper, Nichola / Ghanima, Waleed / Boxer, Michael A / Hill, Quentin A / Sholzberg, Michelle / Tarantino, Michael D / Todd, Leslie K / Tong, Sandra / Bussel, James B

    British journal of haematology

    2020  Volume 190, Issue 6, Page(s) 933–938

    Abstract: Fostamatinib demonstrated efficacy in phase 3 trials of adults with immune thrombocytopenia (ITP). Post hoc analysis compared patients who received fostamatinib as second-line therapy (after steroids ± immunoglobulins) versus third-or-later-line therapy ( ...

    Abstract Fostamatinib demonstrated efficacy in phase 3 trials of adults with immune thrombocytopenia (ITP). Post hoc analysis compared patients who received fostamatinib as second-line therapy (after steroids ± immunoglobulins) versus third-or-later-line therapy (after ≥2 prior lines of therapy including a second-line agent). Platelet responses ≥50 000/µl were observed in 25/32 (78%) second-line and 54/113 (48%) third-or-later-line patients. Bleeding events were less frequent in second-line (28%) versus third-or-later-line (45%) patients. Responses once achieved tended to be durable in both groups. The safety profile was similar in both groups. In this post hoc analysis, fostamatinib was more effective as second-line than third-or-later-line therapy for ITP.
    MeSH term(s) Adult ; Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; Oxazines/administration & dosage ; Oxazines/adverse effects ; Platelet Count ; Purpura, Thrombocytopenic, Idiopathic/blood ; Purpura, Thrombocytopenic, Idiopathic/drug therapy ; Pyridines/administration & dosage ; Pyridines/adverse effects
    Chemical Substances Oxazines ; Pyridines ; fostamatinib (SQ8A3S5101)
    Language English
    Publishing date 2020-07-23
    Publishing country England
    Document type Clinical Trial, Phase III ; Comparative Study ; Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
    ZDB-ID 80077-6
    ISSN 1365-2141 ; 0007-1048
    ISSN (online) 1365-2141
    ISSN 0007-1048
    DOI 10.1111/bjh.16959
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    Uh III Zs.182: Show issues Location:
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  5. Article ; Online: The measurement of physical functioning among patients with Tenosynovial Giant Cell Tumor (TGCT) using the Patient-Reported Outcomes Measurement Information System (PROMIS).

    Gelhorn, Heather L / Ye, Xin / Speck, Rebecca M / Tong, Sandra / Healey, John H / Bukata, Susan V / Lackman, Richard D / Murray, Lindsey / Maclaine, Grant / Lenderking, William R / Hsu, Henry H / Lin, Paul S / Tap, William D

    Journal of patient-reported outcomes

    2019  Volume 3, Issue 1, Page(s) 6

    Abstract: Background: Tenosynovial giant cell tumor (TGCT), a rare, locally aggressive neoplasm of the synovium of joints and tendon sheaths, is associated with joint destruction, pain and swelling. Impacts on physical function (PF) vary depending on tumor size ... ...

    Abstract Background: Tenosynovial giant cell tumor (TGCT), a rare, locally aggressive neoplasm of the synovium of joints and tendon sheaths, is associated with joint destruction, pain and swelling. Impacts on physical function (PF) vary depending on tumor size and location. The aim of this study was to identify relevant items, and demonstrate the content validity of custom measures of lower extremity PF from the Patient-Reported Outcomes Measurement Information System Physical Function Physical Function (PROMIS-PF) item bank among patients with TGCT.
    Methods: Patients were recruited for qualitative research interviews to identify predominant TGCT symptoms and impacts. Patients completed a checklist to evaluate the relevance of each PROMIS-PF item. The publicly available PROMIS-PF item response theory (IRT) parameters were used to select items representing the range of the latent PF trait.
    Results: Participants (n = 20) were 75% female, mean age 42.5 years. TGCTs were located in the knee (n = 15), hip (n = 3), and ankle (n = 2). Fifty-four PROMIS-PF items were identified as relevant by ≥20% of the participants. PF concepts discussed by participants during the qualitative interviews were also used to select relevant items. Selected items (n = 13) were used to create a physical function subscale specific to lower extremity tumors.
    Conclusions: We describe a novel method of combining qualitative research and IRT-based item information to select a relevant and content valid subset of PROMIS-PF items to assess heterogeneous impacts on PF in TGCT, a rare disease population.
    Language English
    Publishing date 2019-02-04
    Publishing country Germany
    Document type Journal Article
    ISSN 2509-8020
    ISSN (online) 2509-8020
    DOI 10.1186/s41687-019-0099-0
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  6. Article ; Online: Novel p38α mitogen-activated protein kinase inhibitor shows analgesic efficacy in acute postsurgical dental pain.

    Tong, Sandra E / Daniels, Stephen E / Black, Peter / Chang, Stephen / Protter, Andrew / Desjardins, Paul J

    Journal of clinical pharmacology

    2012  Volume 52, Issue 5, Page(s) 717–728

    Abstract: SCIO-469 is a selective p38α mitogen-activated protein kinase (MAPK) inhibitor for preclinical models of acute pain. This prospective, double-blind, randomized clinical study compared efficacy and safety of oral SCIO-469, ibuprofen, and placebo in ... ...

    Abstract SCIO-469 is a selective p38α mitogen-activated protein kinase (MAPK) inhibitor for preclinical models of acute pain. This prospective, double-blind, randomized clinical study compared efficacy and safety of oral SCIO-469, ibuprofen, and placebo in postsurgical dental pain. Subjects (n = 263) undergoing extraction of 1 or more impacted mandibular third molars received preoperative treatment with SCIO-469 (150, 210, or 300 mg), ibuprofen (400 mg), or placebo; the 210-mg group received 90 mg postoperatively. A 4-point categorical scale and a 100-mm visual analogue scale were used to measure pain intensity. The primary end point was median time from first incision to first rescue medication using the Kaplan-Meier product limit estimator. All SCIO-469 groups had significantly longer times to rescue medication compared with placebo; preoperative and postoperative treatment with 210 + 90 mg SCIO-469 resulted in 8.1 hours versus 4.1 hours to rescue for placebo (P = .003). Ibuprofen also increased time to rescue medication (6.6 hours) versus placebo (P = .04). Dizziness, headache, and nausea were the most frequently reported adverse events. This is the first clinical demonstration of antinociceptive effects in acute pain with preoperative administration of a p38α MAPK inhibitor.
    MeSH term(s) Acute Pain/diagnosis ; Acute Pain/enzymology ; Acute Pain/etiology ; Acute Pain/prevention & control ; Administration, Oral ; Adolescent ; Adult ; Analgesics/administration & dosage ; Analgesics/adverse effects ; Analgesics/pharmacokinetics ; Analgesics/therapeutic use ; Double-Blind Method ; Drug Administration Schedule ; Female ; Humans ; Ibuprofen/therapeutic use ; Indoles/administration & dosage ; Indoles/adverse effects ; Indoles/pharmacokinetics ; Indoles/therapeutic use ; Kaplan-Meier Estimate ; Male ; Mitogen-Activated Protein Kinase 14/antagonists & inhibitors ; Mitogen-Activated Protein Kinase 14/metabolism ; Molar, Third/surgery ; Pain Measurement ; Prospective Studies ; Protein Kinase Inhibitors/adverse effects ; Protein Kinase Inhibitors/pharmacokinetics ; Protein Kinase Inhibitors/therapeutic use ; Time Factors ; Tooth Extraction/adverse effects ; Tooth, Impacted/surgery ; Treatment Outcome ; United States ; Young Adult
    Chemical Substances Analgesics ; Indoles ; Protein Kinase Inhibitors ; SCIO-469 ; Mitogen-Activated Protein Kinase 14 (EC 2.7.11.24) ; Ibuprofen (WK2XYI10QM)
    Language English
    Publishing date 2012-05
    Publishing country England
    Document type Journal Article ; Multicenter Study ; Randomized Controlled Trial
    ZDB-ID 188980-1
    ISSN 1552-4604 ; 0091-2700 ; 0021-9754
    ISSN (online) 1552-4604
    ISSN 0091-2700 ; 0021-9754
    DOI 10.1177/0091270011405496
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    Uf I Zs.176: Show issues Location:
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    ab Jg. 2022: Lesesaal (EG)

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  7. Article ; Online: Patient-reported Symptoms of Tenosynovial Giant Cell Tumors.

    Gelhorn, Heather L / Tong, Sandra / McQuarrie, Kelly / Vernon, Christina / Hanlon, Jennifer / Maclaine, Grant / Lenderking, William / Ye, Xin / Speck, Rebecca M / Lackman, Richard D / Bukata, Susan V / Healey, John H / Keedy, Vicki L / Anthony, Stephen P / Wagner, Andrew J / Von Hoff, Daniel D / Singh, Arun S / Becerra, Carlos R / Hsu, Henry H /
    Lin, Paul S / Tap, William D

    Clinical therapeutics

    2016  Volume 38, Issue 4, Page(s) 778–793

    Abstract: Purpose: Tenosynovial giant cell tumor (TGCT), a rare locally aggressive neoplasm of the synovium of joints and tendon sheaths, is associated with joint destruction, inflammation, pain, and swelling, in part due to colony-stimulating factor 1 receptor- ... ...

    Abstract Purpose: Tenosynovial giant cell tumor (TGCT), a rare locally aggressive neoplasm of the synovium of joints and tendon sheaths, is associated with joint destruction, inflammation, pain, and swelling, in part due to colony-stimulating factor 1 receptor-bearing macrophages recruited to the tumor by genetic elevation of colony-stimulating factor 1 activity. The most common treatment is surgery, although promising pharmacologic treatments are in development. Patient-reported outcome (PRO) instruments are critical end points in demonstrating the clinical relevance of standard oncologic outcome measures and the overall impact of novel pharmacologic therapies in nonmalignant neoplastic conditions such as TGCT. The content validity of PROs relevant to patients with TGCT has not been formally investigated, and instruments to evaluate such outcomes do not exist for this condition.
    Methods: PRO instruments of potential relevance were evaluated by using a literature review and by clinical and PRO experts. Patients with TGCT were recruited through clinical sites and the Internet for participation in qualitative research interviews to identify predominant symptoms and to test the relevance and content validity of several PRO measures. Select PRO measures were included in a Phase I clinical trial, and preliminary results of the PRO end points are reported descriptively.
    Findings: Of the 22 subjects who participated in qualitative interviews, 73% were female, and their mean age was 42.5 years (range, 27-56 years). The TGCTs (19 diffuse and 3 localized) were located in the knee (n = 15), hip (n = 3), ankle (n = 2), elbow (n = 1), and forearm (n = 1). The most common symptoms cited were pain (82%), swelling (86%), stiffness (73%), reduced range of motion (64%), and joint instability (64%), which were consistent with clinical expert input and with the content of instruments chosen by PRO experts. The worst pain numeric rating scale, Patient Reported Outcomes Measurement Information System physical functioning items, and the Western Ontario and McMaster Universities Osteoarthritis Index, as well as a worst stiffness numeric rating scale developed for TGCT, were confirmed as meaningful measures of TGCT patient symptoms and were well understood in qualitative interviews. Results from the Phase I trial showed trends of improvement in both pain and stiffness over time.
    Implications: This study is the first to gather information directly from patients with TGCT regarding their symptom experiences. Pain, stiffness, and physical functioning are important treatment outcomes in patients with TGCT. We have identified content-valid PRO measures of these concepts, which are included in an ongoing Phase III TGCT clinical trial with pexidartinib (PLX3397) (NCT02371369).
    MeSH term(s) Adult ; Female ; Giant Cell Tumor of Tendon Sheath ; Humans ; Male ; Middle Aged ; Patient Reported Outcome Measures ; Treatment Outcome
    Language English
    Publishing date 2016
    Publishing country United States
    Document type Clinical Trial, Phase I ; Journal Article
    ZDB-ID 603113-4
    ISSN 1879-114X ; 0149-2918
    ISSN (online) 1879-114X
    ISSN 0149-2918
    DOI 10.1016/j.clinthera.2016.03.008
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    Zs.A 1435: Show issues Location:
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    Zs.MO 404: Show issues

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  8. Article: A 24-week, randomized, double-blind, placebo-controlled, parallel group study of the efficacy of oral SCIO-469, a p38 mitogen-activated protein kinase inhibitor, in patients with active rheumatoid arthritis.

    Genovese, Mark C / Cohen, Stanley B / Wofsy, David / Weinblatt, Michael E / Firestein, Gary S / Brahn, Ernest / Strand, Vibeke / Baker, Daniel G / Tong, Sandra E

    The Journal of rheumatology

    2011  Volume 38, Issue 5, Page(s) 846–854

    Abstract: Objective: To evaluate the efficacy, safety, and tolerability of oral SCIO-469, a p38 MAPK inhibitor that blocks tumor necrosis factor-α, interleukin-1ß, and cyclooxygenase-2 synthesis in patients with active rheumatoid arthritis (RA).: Methods: ... ...

    Abstract Objective: To evaluate the efficacy, safety, and tolerability of oral SCIO-469, a p38 MAPK inhibitor that blocks tumor necrosis factor-α, interleukin-1ß, and cyclooxygenase-2 synthesis in patients with active rheumatoid arthritis (RA).
    Methods: Patients were randomized to receive SCIO-469 at either 30 or 60 mg three times daily in an immediate-release (IR) formulation or at 100 mg once daily in an extended-release (ER) formulation, or placebo for 24 weeks. The primary endpoint was American College of Rheumatology (ACR)20 response at Week 12. Safety was monitored through Week 26.
    Results: Overall, 302 patients were randomized: 76 to placebo, 75 to 30 mg IR, 73 to 60 mg IR, and 78 to 100 mg ER. There were no significant differences in ACR20 responses at Week 12 between SCIO-469 and placebo. Declines in C-reactive protein and erythrocyte sedimentation rate during early treatment did not persist to Week 12 and were not a consequence of decreased SCIO-469 plasma levels. The 60 mg IR regimen showed a dose-limiting toxicity manifested by elevations in alanine aminotransferase. Adverse events were common in all groups (79.7% and 86.7% through 13 and 26 weeks, respectively). Twenty-one patients reported 28 serious adverse events (SAE). SAE were more common with IR SCIO-469 than with placebo (7% vs 4%) but were not reported with ER SCIO-469.
    Conclusion: In all regimens tested, SCIO-469 showed no greater efficacy compared to placebo in patients with RA. The transient effect of SCIO-469 on acute-phase reactants suggests a complex role of p38 MAPK in inflammation.
    MeSH term(s) Administration, Oral ; Adult ; Aged ; Arthritis, Rheumatoid/drug therapy ; Arthritis, Rheumatoid/physiopathology ; Blood Sedimentation ; C-Reactive Protein/metabolism ; Double-Blind Method ; Female ; Humans ; Indoles/administration & dosage ; Indoles/adverse effects ; Male ; Middle Aged ; Severity of Illness Index ; Treatment Outcome ; p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors
    Chemical Substances Indoles ; SCIO-469 ; C-Reactive Protein (9007-41-4) ; p38 Mitogen-Activated Protein Kinases (EC 2.7.11.24)
    Language English
    Publishing date 2011-05
    Publishing country Canada
    Document type Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
    ZDB-ID 194928-7
    ISSN 1499-2752 ; 0315-162X
    ISSN (online) 1499-2752
    ISSN 0315-162X
    DOI 10.3899/jrheum.100602
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