Papers by Yossi Gilgun-Sherki
BMC Neurology, Oct 8, 2015
Background: Studies suggest that patients with relapsing-remitting multiple sclerosis (RRMS) who ... more 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.
OBJECTIVE: Assess safety and tolerability of oral laquinimod doses administered daily in patients... more OBJECTIVE: Assess safety and tolerability of oral laquinimod doses administered daily in patients with relapsing remitting multiple sclerosis (RRMS) in phase 1 randomized dose-escalation study. BACKGROUND: Two phase 3 studies using laquinimod at a dose of .6mg showed modest reduction in relapse rate and significant reductions in disability progression and brain atrophy. A current phase 3 study is evaluating safety and efficacy of standard and higher doses (0.6mg and 1.2mg) of laquinimod compared to placebo for RRMS. Present report provides data on safety and tolerability of escalating doses of laquinimod ranging from 0.9mg to 2.7mg orally administered to patients with RRMS. DESIGN/METHODS: Patients (N=112) were randomly assigned to laquinimod or placebo in series of separate dose-escalating cohorts. In the first cohort, patients received 0.9mg (n=12), 1.2mg (n=12) or placebo (n=8) in 3:3:2 ratio. In each subsequent cohort, laquinimod was assigned in 0.3mg increments to patients in 3:1 ratio. Screening procedures for each subsequent cohort commenced when there was a Safety Committee (SC) decision to proceed to next dose level. For each cohort, study duration was 4 weeks of treatment with 2 weeks off-drug follow-up. RESULTS: All patients were recruited at seven sites in Germany: 28 received placebo and 84 received once daily doses of laquinimod ranging from 0.9mg - 2.7mg. No deaths occurred. One SAE was reported for a laquinimod-treated patient in the 0.9mg group (a case of perichondritis) which was unrelated to study drug. There were no increased incidence of total AEs with escalating doses, however, several AEs occurred more frequently in the higher doses without clear dose responsiveness. No clear dose response was detected for early terminations or laboratory findings. Laquinimod patients showed more abnormal lab levels in liver enzymes, P-amylase, CRP and fibrinogen but most shifts were clinically non-significant. CONCLUSIONS: Laquinimod doses up to 2.7mg were safely administered to patients with RRMS and no data suggestive of a dose-dependent safety signal was identified. Study Supported by: Teva Pharmaceuticals Disclosure: Dr. Tumani has received personal compensation for activities with Bayer Pharmaceuticals Corp., Biogen Idec, Merck Serono, Teva Neuroscience, Roche Diagnositcs Inc., and Genzyme Virotech. Dr. Tumani has received personal compensation for activities with Bayer Pharmaceuticals Corp., Biogen Idec, Merck Serono, Teva Neuroscience, Roche Diagnostics Corp., and Genzyme Virotech. Dr. Ziemssen has received personal compensation for activities with Almirall, Biogen Idec, Bayer, Genzyme Corporation, GlaxoSmithKline, Inc., MSD, Merck Serono, Novartis, Sanofi, Teva Neuroscience, and Synthon. Dr. Ziemssen has received research support from Bayer, Biogen Idec, Merck Serono, Novartis, Teva, and Sanofi. Dr. Paul has received personal compensation for activities with Teva Neuroscience, Sanofi-Aventis Pharmaceuticals Inc., Merck Serono, Biogen Idec, Bayer Pharmaceuticals Corp., Novartis, and the Guthy Jackson Charitable Foundation. Dr. Paul has received research support from Bayer Schering, Merck Serono, Teva Neuroscience and Novartis. Dr. Marziniak has received personal compensation for activities with Merck Serono, Biogen Idec, Bayer Pharmaceuticals Inc., Teva Neuroscience, Sanofi-Aventis Pharmaceuticals, Inc., and Novartis. Dr. Marziniak has received research support from Merck Serono, Bayer Pharmaceuticals Inc., and Beiersdorf. Dr. Richter has nothing to disclose. Dr. Heesen has received personal compensation for activities with Biogen Idec. Dr. Heesen has received research support from Novartis. Dr. Marglit has received personal compensation for activities with Teva Neuroscience. Dr. Sidi has received personal compensation for activities with Teva Neuroscience. Dr. Gorfine has received personal compensation for activities with Teva Neuroscience. Dr. Gilgun-Sherki has nothing to disclose.
Journal of Hepatology, Jul 1, 2022
British Journal of Clinical Pharmacology, Mar 14, 2019
In previous studies, the histamine-3 receptor antagonist CEP-26401 had a subtle effect on spatial... more 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 lowdose 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.
Stroke is a leading cause of morbidity in the western world, resulting in chronic disability in m... more Stroke is a leading cause of morbidity in the western world, resulting in chronic disability in many cases. Although huge efforts have been made in the search for effective treatment, so far results have been quite disappointing. Recently, cell replacement therapy has emerged as an experimental approach aiming to restore brain function, which is impaired in several neurodegenerative diseases, as well as in stroke. Porcine fetal cells, neuronal progenitor cells (NPCs), embryonic stem cells (ESCs), immortalized cell lines, bone marrow stromal cells (BMSCs), and umbilical cord blood cells (UCBCs) have been introduced as potential sources for neuronal cells in experimental and clinical stroke trials. However, limited knowledge about their biology (including long-term safety) and insufficient data regarding several issues such as the preferred stroke type and its severity, specific location of the injection, and the preferred cell type restrict their potential clinical use. Therefore, further research on the molecular mechanisms of stroke, the candidate cell lines for transplantation, and bioengineering strategies, is needed before this technique can be implemented safely and effectively in stroke victims.
Journal of Neurology, Feb 18, 2014
The phase III placebo-controlled BRAVO study assessed laquinimod effects in patients with relapsi... more The phase III placebo-controlled BRAVO study assessed laquinimod effects in patients with relapsing-remitting MS (RRMS), and descriptively compared laquinimod with interferon beta (IFNβ)-1a (Avonex(®) reference arm). RRMS patients age 18-55 years with Expanded Disability Status Scale (EDSS) scores of 0-5.5 and documented pre-study relapse (≥ 1 in previous year, 2 in previous 2 years, or 1 in previous 1-2 years and ≥ 1 GdE lesion in the previous year) were randomized (1:1:1) to laquinimod 0.6 mg once-daily, matching oral placebo, or IFNβ-1a IM 30 μg once-weekly (rater-blinded design), for 24 months. The primary endpoint was annualized relapse rate (ARR); secondary endpoints included percent brain volume change (PBVC) and 3-month confirmed disability worsening. In all, 1,331 patients were randomized: laquinimod (n = 434), placebo (n = 450), and IFNβ-1a (n = 447). ARR was not significantly reduced with laquinimod [-18 %, risk ratio (RR) = 0.82, 95 % CI 0.66-1.02; p = 0.075] vs. placebo. Laquinimod significantly reduced PBVC (28 %, p < 0.001). Confirmed disability worsening was infrequent (10 % laquinimod, 13 % placebo). The change in confirmed disability worsening with laquinimod measured using EDSS was -31 % [hazard ratio (HR) 0.69, p = 0.063], and using Multiple Sclerosis Functional Composite (MSFC) z-score was -77 % (p = 0.150), vs. placebo. IFNβ-1a reduced ARR 26 % (RR = 0.74, 95 % CI 0.60-0.92, p = 0.007), showed no effect on PBVC loss (+11 %, p = 0.14), and changes in disability worsening were -26 and -66 % as measured using the EDSS (HR 0.742, p = 0.13) and MSFC (p = 0.208), respectively. Adverse events occurred in 75, 82, and 70 % of laquinimod, IFNβ-1a, and placebo patients, respectively. Once-daily oral laquinimod 0.6 mg resulted in statistically nonsignificant reductions in ARR and disability progression, but significant reductions in brain atrophy vs. placebo. Laquinimod was well-tolerated.
Current Pharmaceutical Design, Sep 1, 2006
European Journal of Neuroscience, Feb 25, 2005
It is believed that oxidative stress (OS) plays an important role in the loss of dopaminergic nig... more It is believed that oxidative stress (OS) plays an important role in the loss of dopaminergic nigrostriatal neurons in Parkinson's disease (PD) and that treatment with antioxidants might be neuroprotective. However, most currently available antioxidants cannot readily penetrate the blood brain barrier after systemic administration. We now report that AD4, the novel low molecular weight thiol antioxidant and the N‐acytel cysteine (NAC) related compound, is capable of penetrating the brain and protects neurons in general and especially dopaminergic cells against various OS‐generating neurotoxins in tissue cultures. Moreover, we found that treatment with AD4 markedly decreased the damage of dopaminergic neurons in three experimental models of PD. AD4 suppressed amphetamine‐induced rotational behaviour in rats with unilateral 6‐OHDA‐induced nigral lesion. It attenuated the reduction in striatal dopamine levels in mice treated with 1‐methyl‐4‐phenyl‐1,2,3,6,‐tetrahydropyridine (MPTP). It also reduced the dopaminergic neuronal loss following chronic intrajugular administration of rotenone in rats. Our findings suggest that AD4 is a novel potential new neuroprotective drug that might be effective at slowing down nigral neuronal degeneration and illness progression in patients with PD.
Neuroscience Research, Oct 1, 2003
Glatiramer acetate (GA) is efficacious in reducing demyelinating-associated exacerbations in pati... more Glatiramer acetate (GA) is efficacious in reducing demyelinating-associated exacerbations in patients with relapsing-remitting multiple sclerosis (RRMS) and in several experimental autoimmune encephalomyelitis (EAE) models. Here we report that GA reduced the clinical and pathological signs of mice in chronic EAE induced by myelin oligodendrocyte glycoprotein (MOG). GA-treated mice demonstrated only mild focal inflammation, and less demyelination, compared with controls. Moreover, we also found minimal axonal disruption, as assessed by silver staining, antibodies against amyloid precursor protein (APP) and non-phosphorylated neurofilaments (SMI-32), in the GA-treated group. In conclusion, our study demonstrated for the first time that axonal damage is reduced following GA treatment in C57/bl mice with chronic MOG-induced EAE.
Frontiers in Endocrinology, Mar 15, 2021
acromegaly symptoms that interfere with daily life, leisure, and work. GI side effects and ISRs w... more acromegaly symptoms that interfere with daily life, leisure, and work. GI side effects and ISRs were also common. This study highlights the significant disease burden that still persists for patients with acromegaly that have achieved biochemical control with the use of injectable SRLs.
Clinical Neuropharmacology, Nov 1, 2005
Background: Tardive dyskinesia (TD), characterized by abnormal movements, is the major late-onset... more Background: Tardive dyskinesia (TD), characterized by abnormal movements, is the major late-onset chronic side effect of antipsychotic treatment found in about 30% of those patients. The association of oxidative stress and the release of free radicals is one of the hallmarks of dopaminergic malfunctions and is one of the leading theories suggested for the pathophysiology of TD. To this day, no brain-targeted antioxidant has been tested as a potential treatment of TD. In light of this assumption, the authors chose a novel, lowmolecular weight thiol antioxidant, N-acetyl cysteine amide (AD4), that crosses the blood-brain barrier as a possible treatment of TD. Objective: To examine the protective effects of the novel brainpenetrating antioxidant AD4 on TD experimental models. Methods: The typical vacuous chewing movement occurs in rats following chronic haloperidol injections (1.5 mg/kg/day intraperitoneally for 21 days). This purposeless mouth opening in the vertical plane is similar to TD symptoms in humans. The authors tested rats treated with haloperidol without or with AD4 in the drinking water (1 g/kg orally). Thiobarbituric acid reactive substances and anticarbonyl antibodies were used to measure oxidation of membranes and proteins. Results: Haloperidol increased the vacuous chewing movements to 66.5 6 7.6 movements/5 minutes compared with 16.4 6 2.4 movements/5 minutes in untreated rats (P , 0.01). Coadministration of haloperidol and AD4 decreased the vacuous chewing movements level to 42.1 6 6.7 movements/5 minutes (P , 0.05). Haloperidol also increased the level of lipid peroxidation and protein oxidation in the rat brain, whereas coadministration with AD4 preserved their normal levels. Conclusion: Haloperidol causes behavioral abnormalities associated with oxidative stress in rats, similar to TD. AD4, the brain-targeted potent antioxidant, reduces the cellular oxidation markers and improves the typical clinical behavior. Hence, AD4 is a potential new treatment of antipsychotic-induced TD.
Journal of Molecular Neuroscience, 2003
Accumulating data from experimental and human studies indicate that oxidative stress (OS) plays a... more Accumulating data from experimental and human studies indicate that oxidative stress (OS) plays a major role in the pathogenesis of Alzheimer's disease (AD). The production of reactive oxygen species (ROS), which leads to OS, can occur very early, even before the appearance of symptoms and molecular events (beta-amyloid plaques and neurofibrillary tangles), leading to tissue damage via several different cellular molecular pathways. ROS can cause damage to cardinal cellular components such as lipids, proteins, and nucleic acids (e.g., RNA, DNA), causing cell death by modes of necrosis or apoptosis. The damage can become more widespread because of the weakened cellular antioxidant defense systems. Therefore, treatment with antioxidants might theoretically act to prevent propagation of tissue damage and improve both survival and neurological outcome. Indeed, several studies preformed to date examined whether dietary intake of several antioxidants, mainly vitamins, might prevent or reduce the progression of AD. Although a few of the antioxidants showed some efficacy in these trials, no answer is yet available as to whether antioxidants are truly protective against AD. Reasons for these results might include, in part, blood-brain barrier (BBB) permeability, inappropriate timing of administration, or suboptimal drug levels at the target site in the central nervous system. Thus, antioxidant cocktails or antioxidants combined with other drugs may have more successful synergistic effects. Further, well-designed intervention, as well as observational investigations based on large cohorts studied over a long period of time with several methods for assessing antioxidant exposure, including relation to BBB penetration, are needed to test this hypothesis.
Pharmacological Reviews, Jun 1, 2002
Free radicals are highly reactive molecules generated predominantly during cellular respiration a... more Free radicals are highly reactive molecules generated predominantly during cellular respiration and normal metabolism. Imbalance between cellular production of free radicals and the ability of cells to defend against them is referred to as oxidative stress (OS). OS has been implicated as a potential contributor to the pathogenesis of acute central nervous system (CNS) injury. After brain injury by ischemic or hemorrhagic stroke or trauma, the production of reactive oxygen species (ROS) may increase, sometimes drastically, leading to tissue damage via several different cellular molecular pathways. Radicals can cause damage to cardinal cellular components such as lipids, proteins, and nucleic acids (e.g., DNA), leading to subsequent cell death by modes of necrosis or apoptosis. The damage can become more widespread due to weakened cellular antioxidant defense systems. Moreover, acute brain injury increases the levels of excitotoxic amino acids (such as glutamate), which also produce ROS, thereby promoting parenchymatous destruction. Therefore, treatment with antioxidants may theoretically act to prevent propagation of tissue damage and improve both the survival and neurological outcome. Several such agents of widely varying chemical structures have been investigated as therapeutic agents for acute CNS injury. Although a few of the antioxidants showed some efficacy in animal models or in small clinical studies, these findings have not been supported in comprehensive, controlled trials in patients. Reasons for these equivocal results may include, in part, inappropriate timing of administration or suboptimal drug levels at the target site in CNS. Better understanding of the pathological mechanisms of acute CNS injury would characterize the exact primary targets for drug intervention. Improved antioxidant design should take into consideration the relevant and specific harmful free radical, blood brain barrier (BBB) permeability, dose, and time administration. Novel combinations of drugs providing protection against various types injuries will probably exploit the potential synergistic effects of antioxidants in stroke.
Neuropharmacology, Jun 1, 2001
Oxidative stress (OS) has been implicated in the pathophysiology of many neurological, particular... more Oxidative stress (OS) has been implicated in the pathophysiology of many neurological, particularly neurodegenerative diseases. OS can cause cellular damage and subsequent cell death because the reactive oxygen species (ROS) oxidize vital cellular components such as lipids, proteins, and DNA. Moreover, the brain is exposed throughout life to excitatory amino acids (such as glutamate), whose metabolism produces ROS, thereby promoting excitotoxicity. Antioxidant defense mechanisms include removal of O 2 , scavenging of reactive oxygen/nitrogen species or their precursors, inhibition of ROS formation, binding of metal ions needed for the catalysis of ROS generation and up-regulation of endogenous antioxidant defenses. However, since our endogenous antioxidant defenses are not always completely effective, and since exposure to damaging environmental factors is increasing, it seems reasonable to propose that exogenous antioxidants could be very effective in diminishing the cumulative effects of oxidative damage. Antioxidants of widely varying chemical structures have been investigated as potential therapeutic agents. However, the therapeutic use of most of these compounds is limited since they do not cross the blood brain barrier (BBB). Although a few of them have shown limited efficiency in animal models or in small clinical studies, none of the currently available antioxidants have proven efficacious in a large-scale controlled study. Therefore, any novel antioxidant molecules designed as potential neuroprotective treatment in acute or chronic neurological disorders should have the mandatory prerequisite that they can cross the BBB after systemic administration.
Endocrine Practice, Jun 1, 2021
Brain Research, Nov 1, 2003
Recent studies suggest that glutamate neurotoxicity is involved in the pathogenesis of multiple s... more Recent studies suggest that glutamate neurotoxicity is involved in the pathogenesis of multiple sclerosis (MS), and that treatment with glutamate receptor (AMPA / kainate) antagonists inhibits experimental autoimmune encephalomyelitis (EAE), the conventional model of MS. Therefore, we examined whether riluzole, an inhibitor of glutamate transmission, affects the pathogenesis and clinical features of MS-like disease in myelin oligodendrocyte glycoprotein (MOG)-induced EAE in mice. Here we report that riluzole (10 mg / kg32 / day, i.p.), administered before and even after the appearance of clinical symptoms, dramatically reduced the clinical severity of MOG-induced EAE, while all the MOG-immunized control mice developed significant clinical manifestations. Moreover, the riluzole-treated mice demonstrated only mild focal inflammation, and less demyelination, compared to MOG-treated mice, using histological methods. Furthermore, riluzole markedly reduced axonal disruption, as assessed by Bielshowesky's silver staining and by antibodies against non-phosphorylated neurofilaments (SMI-32). No difference was detected in the immune system potency, as T-cell proliferative responses to MOG were similar in both groups. In conclusion, our study demonstrates, for the first time, that riluzole can reduce inflammation, demyelination and axonal damage in the CNS and attenuate the clinical severity of MOG-induced EAE. These results suggest that riluzole, a drug used in amyotrophic lateral sclerosis (ALS), might be beneficial for the treatment of MS.
The Journal of Clinical Endocrinology and Metabolism, Jun 16, 2023
Context: The MPOWERED core trial (NCT02685709) and open-label extension (OLE) phase investigated ... more 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.
Journal of the Endocrine Society, Nov 1, 2022
/week to 7.8 mm 3 /week (p=0.12) and decreased cumulative mortality (83% in untreated animals ver... more /week to 7.8 mm 3 /week (p=0.12) and decreased cumulative mortality (83% in untreated animals versus 33% in treated animals, p=0.08).
Endocrine Abstracts, May 7, 2022
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Papers by Yossi Gilgun-Sherki