Sapropterin: A New Therapeutic Agent for Phenylketonuria

2009 ◽  
Vol 43 (9) ◽  
pp. 1466-1473 ◽  
Author(s):  
Karly A Hegge ◽  
Kristin K Horning ◽  
Gregory J Peitz ◽  
Kassy Hegge
Keyword(s):  
Safety Profile ◽  
English Language ◽  
Phenylalanine Hydroxylase ◽  
Patient Adherence ◽  
Therapeutic Option ◽  
Phase 2 ◽  
Efficacy Data ◽  
Safety And Efficacy

Objective: To summarize the role of pharmacotherapy in the management of phenylketonuria (PKU) and to review the pharmacology, pharmacokinetics, pharmacodynamics, efficacy data, and safety profile of sapropterin for this indication. Data Sources: A literature search was conducted using MEDLINE (1966–May 2009), International Pharmaceutical Abstracts (1970–May 2009), and Cochrane database (2008) for the following key words: sapropterin, tetrahydrobiopterin, phenylketonurias, and phenylalanine. Study Selection and Data Extraction: English-language studies involving humans examining the role of tetrahydrobiopterin (BH4) in the management of PKU were reviewed to evaluate the pharmacology, pharmacokinetics, pharmacodynamics, efficacy data, and safety profile for sapropterin. All Phase 2 and 3 randomized controlled trials assessing the safety and efficacy of sapropterin were included in this literature evaluation. Data Synthesis: Sapropterin represents the only Food and Drug Administration–approved medication for BH4-responsive PKU, marking an important advance in the treatment of this condition. Among individuals with hyperphenylalaninemia and some residual phenylalanine hydroxylase function, sapropterin can enhance activity of this enzyme to decrease serum phenylalanine concentrations. Sapropterin has been compared with placebo in one Phase 2 and one Phase 3 clinical trial, demonstrating significantly better response rates. Based on available studies, this agent appears to be safe and well tolerated, with adverse event rates similar to those of placebo. However, additional studies are warranted to assess the long-term safety and efficacy of sapropterin therapy. Conclusions: Sapropterin offers a promising therapeutic option for select individuals with BH4-responsive PKU, although long-term data are limited evaluating its safety and efficacy in traditional clinical practice settings. When considering sapropterin therapy, clinicians must consider factors such as cost and patient adherence to drug therapy and/or diet.

scholarly journals Safety and efficacy of panitumumab in combination with trifluridine/tipiracil for pre-treated patients with unresectable, metastatic colorectal cancer with wild-type RAS: The phase 1/2 APOLLON study

2021 ◽  
Author(s):  
Takeshi Kato ◽  
Yoshinori Kagawa ◽  
Yasutoshi Kuboki ◽  
Makio Gamoh ◽  
Yoshito Komatsu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Therapeutic Option ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Phase 2 ◽  
Wild Type ◽  
Open Label ◽  
Safety And Efficacy ◽  
Multicentre Phase

Abstract Background We aimed to assess the safety and efficacy of combination treatment with panitumumab plus trifluridine/tipiracil (FTD/TPI) in patients with wild-type RAS metastatic colorectal cancer (mCRC) who were refractory/intolerant to standard therapies other than anti-epidermal growth factor receptor therapy. Methods APOLLON was an open-label, multicentre, phase 1/2 trial. In the phase 1 part, 3 + 3 de-escalation design was used to investigate the recommended phase 2 dose (RP2D); all patients in the phase 2 part received the RP2D. The primary endpoint was investigator-assessed progression-free survival (PFS) rate at 6 months. Secondary endpoints included PFS, overall survival (OS), overall response rate (ORR), disease control rate (DCR), time to treatment failure (TTF), and safety. Results Fifty-six patients were enrolled (phase 1, n = 7; phase 2, n = 49) at 25 Japanese centres. No dose-limiting toxicities were observed in patients receiving panitumumab (6 mg/kg every 2 weeks) plus FTD/TPI (35 mg/m2 twice daily; days 1–5 and 8–12 in a 28-day cycle), which became RP2D. PFS rate at 6 months was 33.3% (90% confidence interval [CI] 22.8–45.3). Median PFS, OS, ORR, DCR, and TTF were 5.8 months (95% CI 4.5–6.5), 14.1 months (95% CI 12.2–19.3), 37.0% (95% CI 24.3–51.3), 81.5% (95% CI 68.6–90.8), and 5.8 months (95% CI 4.29–6.21), respectively. Neutrophil count decreased (47.3%) was the most common Grade 3/4 treatment-emergent adverse event. No treatment-related deaths occurred. Conclusion Panitumumab plus FTD/TPI exhibited favourable anti-tumour activity with a manageable safety profile and may be a therapeutic option for pre-treated mCRC patients.

Treatment Options for Rheumatoid Arthritis: Celecoxib, Leflunomide, Etanercept, and Infliximab

2000 ◽  
Vol 34 (6) ◽  
pp. 743-760 ◽  
Author(s):  
Brigitte T Luong ◽  
Barbara S Chong ◽  
Dionne M Lowder
Keyword(s):  
Rheumatoid Arthritis ◽  
English Language ◽  
Data Extraction ◽  
Treatment Options ◽  
Nonsteroidal Antiinflammatory Drugs ◽  
Antiinflammatory Drugs ◽  
Safety And Efficacy ◽  
Medline Search ◽  
Pertinent Data

OBJECTIVE: To review new pharmacologic agents approved for use in the management of rheumatoid arthritis (RA). DATA SOURCES: A MEDLINE search (1966–January 2000) was conducted to identify English-language literature available on the pharmacotherapy of RA, focusing on celecoxib, leflunomide, etanercept, and infliximab. These articles, relevant abstracts, and data provided by the manufacturers were used to collect pertinent data. STUDY SELECTION: All controlled and uncontrolled trials were reviewed. DATA EXTRACTION: Agents were reviewed with regard to mechanism of action, efficacy, drug interactions, pharmacokinetics, dosing, precautions/contraindications, adverse effects, and cost. DATA SYNTHESIS: Traditional pharmacologic treatments for RA have been limited by toxicity, loss of efficacy, or both. Increasing discoveries into the mechanisms of inflammation in RA have led to the development of new agents in hopes of addressing these limitations. With the development of celecoxib, a selective cyclooxygenase-2 inhibitor, the potential exists to minimize the gastrotoxicity associated with nonsteroidal antiinflammatory drugs. Leflunomide has been shown to be equal to or less efficacious than methotrexate, and may be beneficial as a second-line disease-modifying antirheumatic drug (DMARD). The biologic response modifiers, etanercept and infliximab, are alternatives that have shown benefit alone or in combination with methotrexate. However, they should be reserved for patients who fail to respond to DMARD therapy. Further studies should be conducted to evaluate the long-term safety and efficacy of these agents as well as their role in combination therapy. CONCLUSIONS: Celecoxib, leflunomide, etanercept, and infliximab are the newest agents approved for RA. Clinical trials have shown that these agents are beneficial in the treatment of RA; however, long-term safety and efficacy data are lacking.

scholarly journals Long-term Safety and Efficacy Data on Botulinum Toxin Type A

2013 ◽  
Vol 139 (2) ◽  
pp. 134 ◽  
Author(s):  
Kenny H. Chan ◽  
Conan Liang ◽  
Pamela Wilson ◽  
David Higgins ◽  
Gregory C. Allen
Keyword(s):  
Botulinum Toxin ◽  
Botulinum Toxin Type A ◽  
Type A ◽  
Botulinum Toxin Type ◽  
Efficacy Data ◽  
Safety And Efficacy

Propofol for the long-term sedation of a critically ill patient

1998 ◽  
Vol 7 (1) ◽  
pp. 73-76 ◽  
Author(s):  
LJ Miller ◽  
R Wiles-Pfeifler
Keyword(s):  
Adverse Effects ◽  
English Language ◽  
Case Reports ◽  
Critically Ill Patient ◽  
Limited Data ◽  
Safety And Efficacy ◽  
Medline Search ◽  
Cardiovascular Depression ◽  
Language Literature

OBJECTIVE: To report a case in which propofol was used successfully in an intubated patient on a prolonged basis and to review the literature that discusses long-term infusions (> 7 days) of propofol. METHODS: Information was retrieved from a MEDLINE search of the English-language literature. Reports of clinical trials and case reports that compared the safety and efficacy of long-term propofol and midazolam were included in this review. Information about the study design and the efficacy and adverse effects of the drugs was collected, and the data were synthesized. RESULTS: Clinical reports indicate that a long-term infusion of propofol is comparable in safety and efficacy to a long-term infusion of midazolam. The distinct adverse-effect profile of long-term use of propofol, including hypertriglyceridemia, was evaluated and reported as significant. CONCLUSION: The limited data available suggest that long-term infusion of propofol is a practical alternative to use of standard agents for sedation of intubated patients. Adverse effects such as cardiovascular depression, respiratory depression, and hypertriglyceridemia may limit the routine use of propofol.

Six-Year Safety and Efficacy Data from Denosumab Phase 2 Extension Study

2010 ◽  
Vol 13 (1) ◽  
pp. 131-132 ◽  
Author(s):  
Paul D. Miller ◽  
Michael Bolognese ◽  
E. Michael Lewiecki ◽  
Richard L. Weinstein ◽  
Beiying Ding ◽  
...  
Keyword(s):  
Extension Study ◽  
Phase 2 ◽  
Efficacy Data ◽  
Safety And Efficacy

scholarly journals OP27 Long-term safety and efficacy of risankizumab treatment in patients with Crohn’s disease: Final results from the Phase 2 open-label extension study

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S024-S025 ◽  
Author(s):  
M Ferrante ◽  
B G Feagan ◽  
J Panés ◽  
F Baert ◽  
E Louis ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Opportunistic Infections ◽  
Activity Index ◽  
Induction Treatment ◽  
Phase 2 ◽  
Open Label ◽  
Safety And Efficacy ◽  
Open Label Extension

Abstract Background Efficacy and safety of the IL-23 inhibitor risankizumab (RZB) have been assessed in patients with moderate-to-severe Crohn’s disease (CD) following induction/maintenance treatment.1,2 Responders to RZB in a Phase 2 induction/maintenance study2,3 could enrol in an open-label extension (OLE), NCT02513459.4 Final safety and efficacy results from this RZB OLE study are reported here. Methods Patients achieving clinical response (CResp) (decrease from baseline [BL] in CD Activity Index [CDAI] ≥100) without remission (CRem) (CDAI <150) after Period 2 (Week 26) or CResp/CRem after Period 3 (Week 52) of the preceding study1 received open-label 180 mg subcutaneous (SC) RZB every 8 weeks (Q8W) for up to 206 weeks. Patients who lost CResp/CRem at screening of the OLE were re-induced with open-label 600 mg IV RZB at Weeks 0, 4, and 8. Patients receiving re-induction treatment only received subsequent 180 mg SC RZB Q8W if they regained CResp/CRem following re-induction. A centrally read ileocolonoscopy was performed yearly. Treatment-emergent adverse events (AEs) were collected up to 20 weeks after the last RZB dose. CRem and endoscopic remission (ER [CD Endoscopic Index of Severity (CDEIS) ≤4 or CDEIS ≤2 for patients with isolated ileitis at BL]) were reported up to Week 152. Non-responder imputation (NRI) and observed case analysis were used for binary endpoints. Results Sixty-five patients with CD were enrolled in the OLE, with 4 patients re-induced. At BL of the preceding study, median (range) age was 34 (19–67) years and median (range) disease duration was 10 (2–38) years. Sixty patients (92%) were previously exposed to TNF antagonists. In the OLE, median (range) exposure to RZB was 1014.0 (114–1317) days. Twenty-one (32%) patients prematurely discontinued RZB, including 6 (9%) who had developed an AE. AEs were reported in 60 (92%) patients; 23 (35%) experienced serious AEs. The most common AEs were nasopharyngitis (31%), gastroenteritis (23%), and fatigue (20%). Serious infections were reported in 6 (9%) patients and opportunistic infections in 3 (5%) patients. No tuberculosis, malignancies, or deaths occurred. At Week 0 of the current study, 47 (72%) patients were in CRem and 27 (42%) patients had ER. Both CRem and ER were sustained up to Week 152 (Table). Conclusion In this final analysis of patients with CD receiving long-term open-label RZB treatment, the safety profile of RZB remained consistent with previous data² with no new safety signals. Clinical and endoscopic remissions were sustained. References

scholarly journals P219 Long-term safety of filgotinib in patients with PsA: week 52 safety data from a Phase 2 open-label extension study

Rheumatology ◽  
2020 ◽  
Vol 59 (Supplement_2) ◽  
Author(s):  
Laura Coates ◽  
Philip Mease ◽  
Dafna Gladman ◽  
Filip Van den Bosch ◽  
Anna Rychlewska-Hanczewska ◽  
...  
Keyword(s):  
Interim Analysis ◽  
Safety Data ◽  
Janus Kinase ◽  
Controlled Study ◽  
Stock Ownership ◽  
Phase 2 ◽  
Open Label ◽  
Safety And Efficacy ◽  
Open Label Extension

Abstract Background Filgotinib (FIL) is an orally administered, selective janus kinase 1 (JAK1) inhibitor in development for psoriatic arthritis (PsA). Efficacy and safety of FIL in patients with active PsA were evaluated in a 16-week phase 2 study (EQUATOR, NCT03101670). After 16 weeks, patients could roll-over to an Open Label Extension (OLE) Study (EQUATOR2, NCT03320876) for the purpose of evaluating long-term safety and efficacy. The aim of this analysis was to assess safety and efficacy through 52 weeks of exposure to filgotinib. Methods Patients who completed the randomised, double-blind, placebo-controlled study were eligible for participation in the OLE, during which all patients received once daily (qd) open-label FIL 200mg. In this interim analysis of OLE, for the safety analysis, all data were included from the screening in the core study up to the data cut of 18 April 2019 in the OLE. For the efficacy analysis, all data until OLE Week 52 visit for each patient were included (observed case analysis). Results Of the 131 patients randomised and dosed in EQUATOR, 124 (95%) completed the study and 122 (93%) enrolled in EQUATOR2; 50% were female and mean age was 50. At this interim analysis, 106/122 (87%) remained in the OLE (premature discontinuations during OLE due to: 4 for safety, 11 withdrew consent, and 1 for other reasons). Cumulative patient years of exposure (PYE) on FIL were 160, median time on FIL was 66 weeks. Key safety data are summarised in Table 1. Key ≥Grade 2 treatment-emergent laboratory abnormalities seen with FIL arm (N = 128) compared with PBO (N = 66) were lymphocyte decrease 11.1% vs 4.5%, neutrophil decrease 5.5% vs 0%, ALT increase 1.6% vs 1.5% and creatinine increase 0.8% vs 0%, respectively. At week 52, 34% of the patients fulfilled criteria for minimal disease activity and 81%, 55%, and 33% of patients, respectively, achieved ACR20/50/70 responses. Conclusion FIL 200mg qd was generally well tolerated and the safety profile in PsA was comparable to that observed in the FIL rheumatoid arthritis studies. The data from this interim analysis suggest that further improvement of the patient condition can be expected beyond 16 weeks of treatment. Disclosures L. Coates: Other; Received support from Abbvie, Amgen, Celgene, Galapagos, Janssen, Lilly, Novartis, Pfizer, Prothena, Sun pharma, and UCB. P. Mease: Other; Received support from Abbvie, Amgen, BMS, Celgene, Galapagos, Genentech, Gilead, Janssen, Eli Lilly, Merck, Novartis, Pfizer, SUN, and UCB. D. Gladman: Other; Received support from Abbvie, Amgen, Celgene, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, UCB, BMS, and Galapagos. F. Van den Bosch: Other; Received support from Abbvie, Bristol-Myers Squibb, Eli Lilly, Galapagos, Janssen, Merck, Novartis, Pfizer, and UCB. A. Rychlewska-Hanczewska: Other; Received support from Galapagos and Gilead Sciences. C. Tasset: Corporate appointments; Employee of Galapagos NV. L. Meuleners: Corporate appointments; Employee of Galapagos NV. M. Trivedi: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. Y. Guo: Corporate appointments; Employee of Gilead Sciences, Inc... Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. R. Besuyen: Other; Employee of Galapagos NV. P. Helliwell: Other; Received support from Abbvie, Amgen, Celgene, Galapagos, Janssen, Novartis, Pfizer, and UCB.

scholarly journals The Use of Sodium Bicarbonate in the Treatment of Acidosis in Sepsis: A Literature Update on a Long Term Debate

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Dimitrios Velissaris ◽  
Vasilios Karamouzos ◽  
Nikolaos Ktenopoulos ◽  
Charalampos Pierrakos ◽  
Menelaos Karanikolas
Keyword(s):  
Metabolic Acidosis ◽  
Sodium Bicarbonate ◽  
Therapeutic Option ◽  
Ongoing Debate ◽  
Arterial Blood Gas ◽  
Arterial Blood ◽  
Bicarbonate Therapy ◽  
Reasonable Approach

Introduction. Sepsis and its consequences such as metabolic acidosis are resulting in increased mortality. Although correction of metabolic acidosis with sodium bicarbonate seems a reasonable approach, there is ongoing debate regarding the role of bicarbonates as a therapeutic option.Methods. We conducted a PubMed literature search in order to identify published literature related to the effects of sodium bicarbonate treatment on metabolic acidosis due to sepsis. The search included all articles published in English in the last 35 years.Results. There is ongoing debate regarding the use of bicarbonates for the treatment of acidosis in sepsis, but there is a trend towards not using bicarbonate in sepsis patients with arterial blood gaspH>7.15.Conclusions. Routine use of bicarbonate for treatment of severe acidemia and lactic acidosis due to sepsis is subject of controversy, and current opinion does not favor routine use of bicarbonates. However, available evidence is inconclusive, and more studies are required to determine the potential benefit, if any, of bicarbonate therapy in the sepsis patient with acidosis.

scholarly journals Effects of a physiotherapist-led approach based on a biopsychosocial model for spinal disorders: protocol for a systematic review

BMJ Open ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. e055144
Author(s):  
Takahiro Miki ◽  
Yu Kondo ◽  
Hiroshi Kurakata ◽  
Tsuneo Takebayashi ◽  
Mina Samukawa
Keyword(s):  
English Language ◽  
Long Term Effects ◽  
Short Term ◽  
Spinal Disorders ◽  
Ethical Approval ◽  
Registration Number ◽  
Randomised Controlled ◽  
Cause Of Pain

IntroductionLow back pain and neck pain are among the most common musculoskeletal disorders, and their related medical costs are rising every year. Many interventions are based on the biopsychosocial (BPS) model since the cause of pain is more multifaceted. Physiotherapists have increased opportunities to perform multidisciplinary interventions alone in clinical practice due to a lack of understanding of the model and its cost. Therefore, physiotherapist-led interventions using the BPS model are important and require an updated report summarising their effectiveness. Thus, the purpose of this study will be to summarise and synthesise the effects of physiotherapist-led interventions using the BPS model for spinal disorders.Methods and analysisWe will search the Web of Science, CENTRAL, MEDLINE, PsycINFO, CINAHL and PEDro electronic databases, using a date range from inception to September 2021. We will include only randomised controlled trials for patients diagnosed with spinal disorders who received physiotherapist-led interventions based on the BPS model. The search will be limited to English-language publications. Pain intensity and disability are the primary outcomes. Secondary outcomes are any psychological factors. We will examine the short-term, medium-term and long-term effects, and a subgroup analysis will be conducted, if possible, to investigate the role of additional physiotherapist training.Ethics and disseminationThis study is exempt from ethical approval because it involves publicly available documents. The findings will be submitted for publication in a relevant peer-reviewed journal.PROSPERO registration numberCRD42021258071.

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