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  1. Article ; Online: Sub-analysis of geographical variations in the 2-year observational COPTIMIZE trial of patients with relapsing-remitting multiple sclerosis converting to glatiramer acetate.

    Ziemssen, Tjalf / Gilgun-Sherki, Yossi

    BMC neurology

    2015  Volume 15, Page(s) 189

    Abstract: Background: Studies suggest that patients with relapsing-remitting multiple sclerosis (RRMS) who fail to benefit from a disease-modifying treatment (DMT) may benefit from converting to another DMT class. COPTIMIZE was a 24-month observational study ... ...

    Abstract Background: Studies suggest that patients with relapsing-remitting multiple sclerosis (RRMS) who fail to benefit from a disease-modifying treatment (DMT) may benefit from converting to another DMT class. COPTIMIZE was a 24-month observational study designed to assess the disease course of patients converting to glatiramer acetate (GA) 20 mg daily from another DMT and the association of disease characteristics and reasons for converting. This sub-analysis was to determine if any findings varied by three geographic locations: Latin America (LA), Canada and Western Europe (CWE), and Eastern Europe (EE).
    Methods: A total of 668 patients were included (263 LA, 248 CWE, 157 EE) in an analysis of annualized relapse rate (ARR) and annualized rate of deterioration (ARD), as well as secondary endpoints including reason for DMT switch and changes in disability and fatigue scores. Repeated-measures analysis of variance and log transformation were used to analyze ARR and ARD, whereas the Wilcoxon signed rank test was used for secondary endpoints.
    Results: The sub-analysis of treatment outcomes stratified by region showed that Latin American patients had higher ARR before conversion to GA compared with patients from the other two areas and subsequently experienced the largest reduction in ARR. Latin American patients also had higher baseline rates of comorbidities and relapses with incomplete remissions and improved more than those in the other two regions based on measures of fatigue, quality of life, depression, and cognition scores. Latin American patients also generally had a better perception of the benefits associated with their conversion to GA in terms of efficacy and adverse events.
    Conclusions: These findings indicate that, in RRMS patients, converting to GA is associated with positive treatment outcomes regardless of geographic location. However, the reasons for converting and the type and degree of any associated benefits appear to vary depending on various factors, including patients' geographical location.
    MeSH term(s) Adult ; Canada/epidemiology ; Cognition ; Depression/epidemiology ; Europe/epidemiology ; Fatigue/epidemiology ; Female ; Glatiramer Acetate/therapeutic use ; Humans ; Immunosuppressive Agents/therapeutic use ; Latin America/epidemiology ; Male ; Multiple Sclerosis, Relapsing-Remitting/drug therapy ; Multiple Sclerosis, Relapsing-Remitting/epidemiology ; Quality of Life
    Chemical Substances Immunosuppressive Agents ; Glatiramer Acetate (5M691HL4BO)
    Language English
    Publishing date 2015-10-08
    Publishing country England
    Document type Journal Article ; Multicenter Study ; Observational Study ; Research Support, Non-U.S. Gov't
    ISSN 1471-2377
    ISSN (online) 1471-2377
    DOI 10.1186/s12883-015-0448-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: MPOWERED Trial Open-Label Extension: Long-term Efficacy and Safety Data for Oral Octreotide Capsules in Acromegaly.

    Fleseriu, Maria / Molitch, Mark / Dreval, Alexander / Pokramovich, Yulia / Bondar, Irina / Poteshkin, Yury / Macut, Djuro / Obermayer-Pietsch, Barbara / Gilgun-Sherki, Yossi / Haviv, Asi / Biermasz, Nienke / Strasburger, Christian J

    The Journal of clinical endocrinology and metabolism

    2023  Volume 108, Issue 12, Page(s) 3214–3222

    Abstract: Context: The MPOWERED core trial (NCT02685709) and open-label extension (OLE) phase investigated long-term efficacy and safety of oral octreotide capsules (OOC) in patients with acromegaly. Core trial primary endpoint data demonstrated noninferiority to ...

    Abstract Context: The MPOWERED core trial (NCT02685709) and open-label extension (OLE) phase investigated long-term efficacy and safety of oral octreotide capsules (OOC) in patients with acromegaly. Core trial primary endpoint data demonstrated noninferiority to injectable somatostatin receptor ligands (iSRLs). Core trial completers were invited to participate in the OLE phase.
    Objective: To assess long-term efficacy and safety of OOC in patients with acromegaly who previously responded to and tolerated both OOC and injectable octreotide/lanreotide and completed the core phase.
    Methods: The unique study design of transitioning between OOC and iSRLs allowed within-patient evaluations. The proportion of biochemical responders (insulin-like growth factor I < 1.3 × upper limit of normal) at end of each extension year who entered that year as responders was the main outcome measure.
    Results: At year 1 extension end, 52/58 patients from both the monotherapy and the combination therapy groups were responders (89.7%; 95% CI 78.8-96.1), 36/41 (87.8%; 95% CI 73.8-95.9) in year 2, and 29/31 (93.5%; 95% CI 78.6-99.2) in year 3. No new or unexpected safety signals were detected; 1 patient withdrew owing to treatment failure. Patients who transitioned from iSRLs in the core trial to OOC in the OLE phase reported improved treatment convenience/satisfaction and symptom control.
    Conclusion: Patient-reported outcome data support for the first time that transitioning patients randomized to iSRL (who previously responded to both OOC and iSRLs) back to OOC had a significant effect on patients' symptoms score in a prospective cohort. The MPOWERED OLE showed long-term maintenance of response and sustained safety with OOC.
    MeSH term(s) Humans ; Octreotide/adverse effects ; Acromegaly/drug therapy ; Prospective Studies ; Human Growth Hormone ; Treatment Outcome ; Peptides, Cyclic ; Insulin-Like Growth Factor I/metabolism
    Chemical Substances Octreotide (RWM8CCW8GP) ; Human Growth Hormone (12629-01-5) ; Peptides, Cyclic ; Insulin-Like Growth Factor I (67763-96-6)
    Language English
    Publishing date 2023-06-14
    Publishing country United States
    Document type Randomized Controlled Trial ; Journal Article
    ZDB-ID 3029-6
    ISSN 1945-7197 ; 0021-972X
    ISSN (online) 1945-7197
    ISSN 0021-972X
    DOI 10.1210/clinem/dgad365
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  3. Article ; Online: Pathological and clinical aspects of alpha/beta synuclein in Parkinson's disease and related disorders.

    Tolmasov, Michael / Djaldetti, Ruth / Lev, Nirit / Gilgun-Sherki, Yossi

    Expert review of neurotherapeutics

    2016  Volume 16, Issue 5, Page(s) 505–513

    Abstract: Parkinson's disease (PD) and related synucleinopathies are characterized by extensive neuronal cell loss, which is potentially triggered by α-synuclein misfolding and aggregation. Therefore it is reasonable to suggest that treatments targeting α- ... ...

    Abstract Parkinson's disease (PD) and related synucleinopathies are characterized by extensive neuronal cell loss, which is potentially triggered by α-synuclein misfolding and aggregation. Therefore it is reasonable to suggest that treatments targeting α-synuclein could reduce its levels and toxicity, rescue neuronal cells and halt the neurodegeneration process. Several approaches to decrease α-synuclein levels were employed thus far, mainly by using β-synuclein, another protein from the same family, or immunotherapies. These treatments demonstrated some positive results in preclinical studies, which may pave the road to the development of new promising disease-modifying therapies (DMTs). This approach should be further examined in preclinical and clinical settings, together with a clear process in order to advance candidates, enable the ability to define when there are target engagements and to detect what is a meaningful pharmacological response, and how it will be translated in clinical efficacy.
    MeSH term(s) Humans ; Parkinson Disease/metabolism ; Parkinson Disease/therapy ; alpha-Synuclein/metabolism ; beta-Synuclein/metabolism
    Chemical Substances alpha-Synuclein ; beta-Synuclein
    Language English
    Publishing date 2016-05
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 2112534-X
    ISSN 1744-8360 ; 1473-7175
    ISSN (online) 1744-8360
    ISSN 1473-7175
    DOI 10.1586/14737175.2016.1164600
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Disease and Treatment-Related Burden in Patients With Acromegaly Who Are Biochemically Controlled on Injectable Somatostatin Receptor Ligands.

    Fleseriu, Maria / Molitch, Mark / Dreval, Alexander / Biermasz, Nienke R / Gordon, Murray B / Crosby, Ross D / Ludlam, William H / Haviv, Asi / Gilgun-Sherki, Yossi / Mathias, Susan D

    Frontiers in endocrinology

    2021  Volume 12, Page(s) 627711

    Abstract: Medical treatment for acromegaly commonly involves receiving intramuscular or deep subcutaneous injections of somatostatin receptor ligands (SRLs) in most patients. In addition to side effects of treatment, acromegaly patients often still experience ... ...

    Abstract Medical treatment for acromegaly commonly involves receiving intramuscular or deep subcutaneous injections of somatostatin receptor ligands (SRLs) in most patients. In addition to side effects of treatment, acromegaly patients often still experience disease symptoms even when therapy is successful in controlling GH and IGF-1 levels. Symptoms and side effects can negatively impact patients' health-related quality of life. In this study, we examine the disease- and treatment-related burden associated with SRL injections as reported through the use of the Acromegaly Treatment Satisfaction Questionnaire (Acro-TSQ
    MeSH term(s) Acromegaly/drug therapy ; Cost of Illness ; Female ; Gastrointestinal Diseases/chemically induced ; Humans ; Injections ; Ligands ; Male ; Middle Aged ; Receptors, Somatostatin/metabolism
    Chemical Substances Ligands ; Receptors, Somatostatin
    Language English
    Publishing date 2021-03-15
    Publishing country Switzerland
    Document type Clinical Trial, Phase III ; Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
    ZDB-ID 2592084-4
    ISSN 1664-2392
    ISSN 1664-2392
    DOI 10.3389/fendo.2021.627711
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  5. Article ; Online: Glatiramer acetate: long-term safety and efficacy in relapsing-remitting multiple sclerosis.

    Boster, Aaron L / Ford, Corey C / Neudorfer, Orit / Gilgun-Sherki, Yossi

    Expert review of neurotherapeutics

    2015  Volume 15, Issue 6, Page(s) 575–586

    Abstract: Glatiramer acetate (GA) is approved for relapsing-remitting multiple sclerosis in 57 countries worldwide, with more than 2 million patient-years of exposure and over 20 years of continuous clinical use without new safety concerns. GA has an overall ... ...

    Abstract Glatiramer acetate (GA) is approved for relapsing-remitting multiple sclerosis in 57 countries worldwide, with more than 2 million patient-years of exposure and over 20 years of continuous clinical use without new safety concerns. GA has an overall favorable risk-benefit profile: 30% reduced annual relapse rate and decreased brain lesion activity. In clinically definite MS or clinically isolated syndrome, GA slows brain atrophy, which may be related to its unique anti-inflammatory and neuroprotective mechanisms of action. Early treatment with GA delays the onset of clinically definite MS more effectively than late treatment in clinically isolated syndrome. GA is not associated with immunosuppression, autoimmune disease, infections or development of neutralizing antibodies. A new three-times-weekly formulation of GA is available to potentially reduce the incidence of injection-related side effects. Other safety advantages of GA include its pregnancy rating (Category B) and limited uncontrolled data suggesting that tolerability is similar in children with MS.
    MeSH term(s) Antirheumatic Agents/therapeutic use ; Female ; Glatiramer Acetate/therapeutic use ; Humans ; Longitudinal Studies ; Male ; Multiple Sclerosis, Relapsing-Remitting/drug therapy ; Pregnancy
    Chemical Substances Antirheumatic Agents ; Glatiramer Acetate (5M691HL4BO)
    Language English
    Publishing date 2015-06
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2112534-X
    ISSN 1744-8360 ; 1473-7175
    ISSN (online) 1744-8360
    ISSN 1473-7175
    DOI 10.1586/14737175.2015.1040768
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Central nervous system effects of the histamine-3 receptor antagonist CEP-26401, in comparison with modafinil and donepezil, after a single dose in a cross-over study in healthy volunteers.

    Baakman, Anne C / Zuiker, Rob / van Gerven, Joop M A / Gross, Nicholas / Yang, Ronghua / Fetell, Michael / Gershon, Ari / Gilgun-Sherki, Yossi / Hellriegel, Edward / Spiegelstein, Ofer

    British journal of clinical pharmacology

    2019  Volume 85, Issue 5, Page(s) 970–985

    Abstract: Aims: In previous studies, the histamine-3 receptor antagonist CEP-26401 had a subtle effect on spatial working memory, with the best effect seen at the lowest dose tested (20 μg), and a dose-dependent disruption of sleep. In the current study, 3 low- ... ...

    Abstract Aims: In previous studies, the histamine-3 receptor antagonist CEP-26401 had a subtle effect on spatial working memory, with the best effect seen at the lowest dose tested (20 μg), and a dose-dependent disruption of sleep. In the current study, 3 low-dose levels of CEP-26401 were compared with modafinil and donepezil.
    Methods: In this double-blind, placebo- and positive-controlled, randomized, partial 6-way cross-over study, 40 healthy subjects received single doses of placebo, CEP-26401 (5, 25 or 125 μg) or modafinil 200 mg or donepezil 10 mg. Pharmacokinetic and pharmacodynamic measurements were performed predose and at designated time points postdose.
    Results: The main endpoint between-errors of the spatial working memory-10-boxes task only improved for the 125 μg dose of CEP-26401 with a difference of 2.92 (confidence interval [CI] -1.21 to 7.05), 3.24 (CI -1.57 to 8.04) and 7.45 (CI 2.72 to 12.19) for respectively the 5, 25 and 125 μg dose of CEP-26401, -1.65 (CI -0.572 to 1.96) for modafinil and - 3.55 (CI -7.13 to 0.03) for donepezil. CEP-26401 induced an improvement of adaptive tracking, saccadic peak velocity and reaction time during N-back, but a dose-related inhibition of sleep and slight worsening of several cognitive parameters at the highest dose. CEP-26401 significantly changed several subjective visual analogue scales, which was strongest at 25 μg, causing the same energizing and happy feeling as modafinil, but with a more relaxed undertone.
    Discussion: Of the doses tested, the 25 μg dose of CEP-26401 had the most optimal balance between favourable subjective effects and sleep inhibition. Whether CEP-26401 can have beneficial effects in clinical practice remains to be studied.
    MeSH term(s) Adolescent ; Adult ; Brain/drug effects ; Brain/physiology ; Cognition/drug effects ; Cognition/physiology ; Cognitive Dysfunction/drug therapy ; Cohort Studies ; Cross-Over Studies ; Donepezil/administration & dosage ; Donepezil/pharmacokinetics ; Dose-Response Relationship, Drug ; Double-Blind Method ; Female ; Healthy Volunteers ; Histamine Antagonists/administration & dosage ; Histamine Antagonists/pharmacokinetics ; Humans ; Male ; Memory/drug effects ; Memory/physiology ; Middle Aged ; Modafinil/administration & dosage ; Modafinil/pharmacokinetics ; Pyridazines/administration & dosage ; Pyridazines/pharmacokinetics ; Pyrrolidines/administration & dosage ; Pyrrolidines/pharmacokinetics ; Reaction Time/drug effects ; Reaction Time/physiology ; Receptors, Histamine H3/metabolism ; Sleep/drug effects ; Sleep/physiology ; Young Adult
    Chemical Substances Histamine Antagonists ; Pyridazines ; Pyrrolidines ; Receptors, Histamine H3 ; Donepezil (8SSC91326P) ; Modafinil (R3UK8X3U3D) ; 6-(4-(3-(2-methylpyrrolidin-1-yl)propoxy)phenyl)-2H-pyridazin-3-one (WH7ISP34KA)
    Language English
    Publishing date 2019-03-14
    Publishing country England
    Document type Clinical Trial, Phase I ; Comparative Study ; Journal Article ; Randomized Controlled Trial
    ZDB-ID 188974-6
    ISSN 1365-2125 ; 0306-5251 ; 0264-3774
    ISSN (online) 1365-2125
    ISSN 0306-5251 ; 0264-3774
    DOI 10.1111/bcp.13885
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  7. Article ; Online: Maintenance of response to oral octreotide compared with injectable somatostatin receptor ligands in patients with acromegaly: a phase 3, multicentre, randomised controlled trial.

    Fleseriu, Maria / Dreval, Alexander / Bondar, Irina / Vagapova, Gulnar / Macut, Djuro / Pokramovich, Yulia G / Molitch, Mark E / Leonova, Nina / Raverot, Gerald / Grineva, Elena / Poteshkin, Yury E / Gilgun-Sherki, Yossi / Ludlam, William H / Patou, Gary / Haviv, Asi / Gordon, Murray B / Biermasz, Nienke R / Melmed, Shlomo / Strasburger, Christian J

    The lancet. Diabetes & endocrinology

    2021  Volume 10, Issue 2, Page(s) 102–111

    Abstract: Background: Despite biochemically responding to injectable somatostatin receptor ligands (iSRLs), many patients with acromegaly experience treatment burdens. We aimed to assess maintenance of biochemical response and symptomatic control with oral ... ...

    Abstract Background: Despite biochemically responding to injectable somatostatin receptor ligands (iSRLs), many patients with acromegaly experience treatment burdens. We aimed to assess maintenance of biochemical response and symptomatic control with oral octreotide capsules versus iSRLs in patients with acromegaly who previously tolerated and responded to both.
    Methods: This global, open-label, randomised controlled phase 3 trial was done in 29 clinical sites in Austria, France, Germany, Hungary, Italy, Lithuania, Russia, Serbia, Spain, and the USA. Eligible patients were adults aged 18-75 years with acromegaly who were receiving iSRLs (long-acting octreotide or lanreotide autogel) for at least 6 months before baseline with a stable dose for at least 4 months, and were deemed to be biochemically responding (insulin-like growth factor I [IGF-I] <1·3 × upper limit of normal [ULN] and mean integrated growth hormone <2·5 ng/mL). In the 26-week run-in phase, all patients received oral octreotide (40 mg a day, optional titration to 60 or 80 mg a day). Eligibility for the randomised treatment phase was completion of the run-in phase as a biochemical responder (IGF-I <1·3 × ULN and mean integrated growth hormone <2·5 ng/mL at week 24) and investigator assessment of acromegaly being adequately controlled. Patients were randomly assigned (3:2) to oral octreotide capsules or iSRL at the same dose and interval as before enrolment. Randomisation and drug dispensing were conducted through a qualified randomisation service provider (eg, interactive web or voice response system). The primary endpoint was a non-inferiority assessment (margin -20 percentage points) of proportion of participants maintaining biochemical response throughout the randomised treatment phase (IGF-I <1·3 × ULN using time-weighted average; assessed by comparing the lower bound of the 2-sided 95% CI for the difference in biochemical response between groups). IGF-I was assessed once a month during the run-in and randomised treatment phases (single sample). Efficacy and safety assessments were performed on the randomised population. This trial is registered with ClinicalTrials.gov, NCT02685709.
    Findings: Between Feb 11, 2016, and Aug 20, 2020, 218 patients were assessed for eligibility. 72 patients were excluded, and 146 participants were enrolled into the run-in phase. 116 patients completed the run-in phase and 30 participants discontinued treatment. 92 participants were randomly assigned to oral octreotide (n=55) or iSRL (n=37). 50 (91%) of 55 participants who received oral octreotide (95% CI 44-53) and 37 (100%) of 37 participants who received iSRLs (34-37) maintained biochemical response. The lower bound of the 2-sided 95% CI for the adjusted difference in proportions between the two treatment groups achieved the prespecified non-inferiority criterion of -20% (95% CI -19·9 to 0·5). 19 (35%) of 55 participants in the oral octreotide group and 15 (41%) of 37 participants in the iSRL group had treatment-related adverse events; the most common of which in both groups were gastrointestinal.
    Interpretation: Oral octreotide was non-inferior to iSRL treatment, and might be a favourable alternative to iSRLs for many patients with acromegaly.
    Funding: Chiasma.
    Translation: For the Russian translation of the abstract see Supplementary Materials section.
    MeSH term(s) Acromegaly/drug therapy ; Adult ; Capsules/therapeutic use ; Growth Hormone ; Human Growth Hormone/therapeutic use ; Humans ; Insulin-Like Growth Factor I/metabolism ; Insulin-Like Growth Factor I/therapeutic use ; Ligands ; Octreotide/adverse effects ; Octreotide/therapeutic use ; Receptors, Somatostatin/therapeutic use ; Treatment Outcome
    Chemical Substances Capsules ; Ligands ; Receptors, Somatostatin ; Human Growth Hormone (12629-01-5) ; Insulin-Like Growth Factor I (67763-96-6) ; Growth Hormone (9002-72-6) ; Octreotide (RWM8CCW8GP)
    Language English
    Publishing date 2021-12-22
    Publishing country England
    Document type Clinical Trial, Phase III ; Journal Article ; Multicenter Study ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
    ISSN 2213-8595
    ISSN (online) 2213-8595
    DOI 10.1016/S2213-8587(21)00296-5
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  8. Article ; Online: Anti-inflammatory drugs in the treatment of neurodegenerative diseases: current state.

    Gilgun-Sherki, Yossi / Melamed, Eldad / Offen, Daniel

    Current pharmaceutical design

    2006  Volume 12, Issue 27, Page(s) 3509–3519

    Abstract: Increasing evidence indicates that inflammation is involved in the pathogenesis of many neurological, particularly neurodegenerative diseases. Even if inflammation is not a primary causative process, its presence may contribute to the continued loss of ... ...

    Abstract Increasing evidence indicates that inflammation is involved in the pathogenesis of many neurological, particularly neurodegenerative diseases. Even if inflammation is not a primary causative process, its presence may contribute to the continued loss of CNS neurons. Therefore, it seems reasonable to propose that use of anti-inflammatory drugs might diminish the cumulative effects of inflammation in the brain. Indeed, some epidemiological studies performed to date, especially in Alzheimer's disease, suggests that sustained use of anti-inflammatory drugs (AIDs) may prevent or slow down the progression of neurodegenerative diseases. However, small number of clinical trials carried out so far using AIDs, were minimal and equivocal in their outcome. Potential reasons for these mixed results include timing of AIDs administration, nonselective inhibition of cyclooxygenase (COX), inappropriate use of particular anti-inflammatory drugs for a given disease or disease progression/ severity, sub-optimal dose in target site, or limited penetration to the brain through the blood-brain barrier (BBB). Therefore, design of AIDs for the treatment of neurodegenerative diseases based upon better BBB penetration, and with minimal adverse events, would be appropriate. In addition, relevant genetic differences among patients should be considered planning new AIDs, for improved efficacy. Furthermore, due to the possible co-involvement of oxidative stress and excitotoxicity in the pathogenesis of these diseases, combination therapy with antioxidants or glutamate antagonists or a multi-potent drug might be much more effective in successfully treating neurodegenerative diseases.
    MeSH term(s) Animals ; Anti-Inflammatory Agents/pharmacology ; Anti-Inflammatory Agents/therapeutic use ; Central Nervous System/drug effects ; Central Nervous System/pathology ; Humans ; Inflammation/drug therapy ; Inflammation/pathology ; Neurodegenerative Diseases/drug therapy ; Neurodegenerative Diseases/pathology ; Neurons/drug effects ; Neurons/pathology
    Chemical Substances Anti-Inflammatory Agents
    Language English
    Publishing date 2006-01-23
    Publishing country United Arab Emirates
    Document type Journal Article ; Review
    ZDB-ID 1304236-1
    ISSN 1873-4286 ; 1381-6128
    ISSN (online) 1873-4286
    ISSN 1381-6128
    DOI 10.2174/138161206778343091
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  9. Article: The role of oxidative stress in the pathogenesis of multiple sclerosis: the need for effective antioxidant therapy.

    Gilgun-Sherki, Yossi / Melamed, Eldad / Offen, Daniel

    Journal of neurology

    2004  Volume 251, Issue 3, Page(s) 261–268

    Abstract: Accumulating data indicate that oxidative stress (OS) plays a major role in the pathogenesis of multiple sclerosis (MS). Reactive oxygen species (ROS), leading to OS, generated in excess primarily by macrophages, have been implicated as mediators of ... ...

    Abstract Accumulating data indicate that oxidative stress (OS) plays a major role in the pathogenesis of multiple sclerosis (MS). Reactive oxygen species (ROS), leading to OS, generated in excess primarily by macrophages, have been implicated as mediators of demyelination and axonal damage in both MS and experimental autoimmune encephalomyelitis (EAE), its animal model. ROS cause damage to cardinal cellular components such as lipids, proteins and nucleic acids (e. g., RNA, DNA), resulting in cell death by necrosis or apoptosis. In addition, weakened cellular antioxidant defense systems in the central nervous system (CNS) in MS, and its vulnerability to ROS effects may increase damage. Thus, treatment with antioxidants might theoretically prevent propagation of tissue damage and improve both survival and neurological outcome. Indeed, several experimental studies have been performed to see whether dietary intake of several antioxidants prevents or reduces the progression of EAE. Although a few antioxidants showed some efficacy in these studies, little information is available on the effect of treatments with such compounds in patients with MS. Well-designed clinical studies using antioxidant intake, as well as investigations based on larger cohorts studied over a longer periods of time, are needed in order to assess whether antioxidant intake together with other conventional treatments, might be beneficial in treating MS.
    MeSH term(s) Animals ; Antioxidants/pharmacology ; Antioxidants/therapeutic use ; Clinical Trials as Topic/methods ; Free Radicals/metabolism ; Humans ; Multiple Sclerosis/drug therapy ; Multiple Sclerosis/metabolism ; Oxidative Stress/drug effects ; Oxidative Stress/physiology
    Chemical Substances Antioxidants ; Free Radicals
    Language English
    Publishing date 2004-03
    Publishing country Germany
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 187050-6
    ISSN 1432-1459 ; 0340-5354 ; 0012-1037 ; 0939-1517 ; 1619-800X
    ISSN (online) 1432-1459
    ISSN 0340-5354 ; 0012-1037 ; 0939-1517 ; 1619-800X
    DOI 10.1007/s00415-004-0348-9
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  10. Article ; Online: Placebo-controlled evaluation of a bioengineered, cocaine-metabolizing fusion protein, TV-1380 (AlbuBChE), in the treatment of cocaine dependence.

    Gilgun-Sherki, Yossi / Eliaz, Rom E / McCann, David J / Loupe, Pippa S / Eyal, Eli / Blatt, Kathleen / Cohen-Barak, Orit / Hallak, Hussein / Chiang, Nora / Gyaw, Shwe

    Drug and alcohol dependence

    2016  Volume 166, Page(s) 13–20

    Abstract: Background: TV-1380 (AlbuChE) is a novel recombinant fusion protein of mutated butyrylcholinesterase (BChE) that has increased catalytic efficiency for cocaine metabolism compared to wild-type BChE.: Methods: Intra-muscular injections of TV-1380 ( ... ...

    Abstract Background: TV-1380 (AlbuChE) is a novel recombinant fusion protein of mutated butyrylcholinesterase (BChE) that has increased catalytic efficiency for cocaine metabolism compared to wild-type BChE.
    Methods: Intra-muscular injections of TV-1380 (150mg or 300mg) or placebo were administered once weekly to participants (n=66-69 per group) in a randomized, double-blind study to evaluate the ability of TV-1380 to facilitate abstinence in treatment-seeking, cocaine-dependent individuals. The primary endpoint was the proportion of participants achieving abstinence from cocaine during the last three weeks of the 12 week treatment phase, based on daily self-report of "no use" confirmed by urine testing.
    Results: Although there were no significant differences between the TV-1380 treatment groups and placebo for the primary endpoint, 6% of participants in the 150mg and 300mg TV-1380 groups and no participants in the placebo group achieved abstinence. For the only declared secondary endpoint, there was a dose-dependent increase in the group mean percentage of urine samples testing negative for cocaine metabolites during weeks 5-12 (8.1% and 14.6% for the 150mg and 300mg TV-1380 groups, respectively, compared to 4.7% for the placebo group; p=0.0056 for 300mg vs. placebo). No meaningful differences in adverse events were seen between treatment groups.
    Conclusions: While the apparent reduction in cocaine use may be of insufficient magnitude to justify further trials of TV-1380 in cocaine dependence, the results argue for development of improved enzymes with greater catalytic activity.
    MeSH term(s) Adolescent ; Adult ; Albumins/administration & dosage ; Bioengineering/methods ; Butyrylcholinesterase/administration & dosage ; Cocaine/metabolism ; Cocaine-Related Disorders/diagnosis ; Cocaine-Related Disorders/drug therapy ; Cocaine-Related Disorders/metabolism ; Double-Blind Method ; Female ; Follow-Up Studies ; Humans ; Inactivation, Metabolic/drug effects ; Inactivation, Metabolic/physiology ; Injections, Intramuscular ; Male ; Middle Aged ; Recombinant Fusion Proteins/administration & dosage ; Recombinant Proteins/administration & dosage ; Treatment Outcome ; Young Adult
    Chemical Substances Albumins ; Recombinant Fusion Proteins ; Recombinant Proteins ; TV-1380 (EC 3.1.1.-) ; Butyrylcholinesterase (EC 3.1.1.8) ; Cocaine (I5Y540LHVR)
    Language English
    Publishing date 2016-05-28
    Publishing country Ireland
    Document type Clinical Trial, Phase II ; Controlled Clinical Trial ; Journal Article ; Multicenter Study ; Randomized Controlled Trial
    ZDB-ID 519918-9
    ISSN 1879-0046 ; 0376-8716
    ISSN (online) 1879-0046
    ISSN 0376-8716
    DOI 10.1016/j.drugalcdep.2016.05.019
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