Patent number 8642566 is assigned to Pharnext (Issy les Moulineaux, FR).
The following quote was obtained by the news editors from the background information supplied by the inventors: "Neuroinflammation mainly involves the presence and activation, in neural tissue, of two types of immune cells: microglia (Stoll & Jander, 1999) and leukocytes (Man et al., 2007), causing local release of immune mediators. Microglial cells are resident cells of the central nervous system (CNS) (Kreutzberg, 1996), which participate in its immune surveillance and defence. They are activated under pathological conditions and acquire functions that finally lead to degeneration processes by damaging or killing neurons (Tilleux & Hermans, 2007). Leukocytes are located throughout the body, including the blood and lymphatic system. Under physiological condition, only small numbers of leukocytes such as T lymphocytes are present in CNS parenchyma. Their passage is limited by the blood-brain-barrier (BBB) (Wekerle et al., 1986; Hickey et al., 1991; Carvey et al., 2005), which is a hermetic barrier made of endothelial cells that controls the access of blood stream elements to the CNS (Rubin & Staddon, 1999; Prat et al., 2001). Under pathological condition, hematogenous leukocytes readily leave blood stream and reach the parenchyma to participate to a destructive inflammatory response (Man et al., 2007; Cardona et al., 2008), since it has been shown that BBB integrity is impaired during inflammation (Lossinsky & Shivers, 2004).
"Neuroinflammation has been proposed to be implicated in the progressive nature of neurodegenerative diseases (Block &
"Precise pathogenesis of AD remains unclear. However, it has been hypothesized that AD is manifested by BBB impairment and neuroinflammation. Indeed, an increased number of Ig (Ishii &
"PD is another neurodegenerative disorder of unknown aetiology. BBB impairment has been hypothesized as a causative mechanism in PD (Kortekaas et al., 2005). It has been suggested that under inflammatory state, VCAM-1 and
"Acute disseminated encephalomyelitis (ADEM) is an immune-mediated inflammatory disorder of the CNS. It is a monophasic disease that can arise spontaneously. However, 5 to 25% of patients experience relapse (Marchioni et al., 2005; Tenembaum et al., 2002) with recurrent or multiphasic forms. Most important symptoms include fever, headache, drowsiness, seizures and coma. The mortality rate can reach 5% (Menge et al., 2007). The exact aetiology of ADEM is at present unknown. It is characterized by a widespread of demyelination in the white matter of the brain and spinal cord. It can also involve the cortex and deep gray matter structures. From a histological point of view, ADEM is characterized by perivenular infiltrates of T cells and macrophages, associated with demyelination. Axonal damage has also been identified in the brains of some patients (
"Neuromyelitis optica (NMO) is an infrequent autoimmune, inflammatory and demyelinating disease of the CNS that affects myelin of the neurons placed at the optic nerves and spinal cord. The disease can be either monophasic or relapsing (Ghezzi et al., 2004). Extensive inflammation of the optic nerve (optic neuritis) and spinal cord (myelitis) usually leads to severe, permanent, relapse-related neurologic impairment (e.g., blindness, paraplegia) within 5 years (Wingerchuk & Weinshenker, 2003). Hallmarks of NMO are inflammatory lesions, cavitation, necrosis and axonal pathology. They have been observed in both grey and white matter of the spinal cord and optic nerves (Lucchinetti et al., 2002). At disease onset, the brain parenchyma is normal or may demonstrate few nonspecific subcortical white matter changes. It has been suggested that asymptomatic brain lesions are frequent in NMO at a later stage of the disease (Pittock et al., 2006). Until recently, NMO was considered to be a variant of multiple sclerosis. However, clinical, neuroimaging, laboratory and pathological characteristics differ. For example, NMO attacks are not mediated by T cells but rather by B cells in an autoimmune manner (Lucchinetti et al., 2002). There is at the moment no established optimal treatment for NMO since no randomized controlled trials have been performed. At present, parenteral corticosteroids are widely employed as first-line treatment of optic neuritis and myelitis attacks (Mandler et al., 1998), whereas therapeutic plasmapheresis that aims at removing autoantibodies, immune complexes and inflammatory mediators from the plasma, is applied in the case of corticosteroids failure (Keegan et al., 2002; Lehmann et al., 2006).
"Multiple sclerosis is considered as an inflammatory demyelinating disease of the CNS (Skaper, 2007; Lassmann et al., 2007). For 85% of patients, disease course begins with a phase of recurrent and reversible neurological troubles termed Relapsing-Remitting MS (RRMS). This condition appears by the third-fourth decade of life. It can last for years and decades, with alternate phases of attacks with relapses, during which the patients recuperate neurological function (Trapp & Nave, 2008). Attacks last from a few days to weeks, and remissions a few months to years. After 8 to 20 years, patients enter the Secondary Progressive MS (SPMS) that is characterized by a continuous and irreversible neurological decline. A rarer disease form named Primary Progressive MS (PPMS) affects 15% of MS patients. There are no relapses occurring in PPMS disease form and disease is progressive from the onset. It occurs later than RRMS form (39 vs 29 years). Fifty percent of MS patients are unable to perform household and employment responsibilities 10 years after disease onset, and 50% are nonambulatory 25 years after disease onset (Trapp & Nave, 2008). Morphological alterations in CNS anatomy lead to paralysis, sensory disturbances, lack of coordination, and visual impairment among the most common features. These alterations (detected by magnetic resonance imaging (MRI), histopathologic evaluations and disease course vary significantly among patients (Agrawal & Yong, 2007).
"Multiple sclerosis (MS) is the most frequent non traumatic neurological disease among young adults in
"Disease mechanisms pertinent to neuroinflammation have often been inferred from the Experimental Autoimmune Encephalomyelitis (EAE), an animal model of MS. This model is induced by sensitization of animals with brain tissue, myelin or protein antigens or by passive transfer of autoreactive T cells (Lassmann, 2008). Animals develop an inflammatory demyelinating disease that closely looks like MS (Lassmann, 2008). This model also supports the hypothesis according to which MS is an autoimmune disease. Indeed immunological data show autoreactive T cells and autoantibodies in circulation and in the cerebrospinal fluid. Since inflammation is a main hallmark of acute MS lesions, aggressive anti-inflammatory strategies have been assessed during RRMS, performing neuroprotective effects. Interferon .beta. (IFN.beta.) and glatiramer acetate (GA) are commonly used to treat RRMS. IFN.beta. inflammatory effects concern decrease of antigen presentation, apoptosis, and entry of immune cells into the CNS (Neuhaus et al., 2005). GA mimics myelin basic protein (MBP), a major component of CNS myelin. It reduces antigen presentation and stimulates T cell secretion of cytokines associated with anti-inflammatory or lymphocytes T helper 2 actions (Neuhaus et al., 2001). Natalizumab, a humanized monoclonal antibody specific for .alpha.4 integrins, has also been proposed for the treatment of RRMS (
"There exists a need for efficient therapies for treating neuroinflammation. There is also a strong need in the art for novel and effective therapies for the treatment of diseases having a neuroinflammatory component, such as multiple sclerosis, Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Acute disseminated encephalomyelitis and Neuromyelitis optica."
In addition to the background information obtained for this patent, NewsRx journalists also obtained the inventors' summary information for this patent: "The purpose of the present invention is to provide new therapeutic approaches for the treatment of neuroinflammatory condition, in particular specific for neurological diseases.
"The invention specifically provides novel compositions and methods for treating neuroinflammation by modulation (e.g., reduction or reversion) of such condition in a subject. In particular, the invention relates to combined therapies for treating neuroinflammation by affecting extravasation cascade.
"More specifically, the invention relates to a composition comprising a combination of at least two compounds selected from irbesartan, idraparinux, otamixaban, SR48692, cilostazol, mecamylamine, and clopidogrel, or salts, prodrugs, derivatives, or sustained release formulations thereof, for use in the treatment of neuroinflammation.
"The present invention also relates to compositions comprising compounds that modify leukocyte extravasation cascade by modulating endothelium permeability, extracellular matrix formation, cell adhesion and motility, shear stress on endothelium and platelets aggregation. Preferred compositions for treating neuroinflammation, comprise a combination of at least two compounds selected from the group consisting of a modulator of endothelium permeability, a modulator of extracellular matrix formation, a modulator of cell adhesion and motility, modulator of shear stress on endothelium and a modulator of platelets aggregation, or salts or prodrugs or derivatives or sustained release formulations thereof.
"The compositions according to the invention may be used for treating neuroinflammation in a subject having a neurodegenerative, autoimmune, infectious, toxic or traumatic disorder. Preferably, the compositions according to the invention are used for treating neuroinflammation in a subject having multiple sclerosis (MS).
"In this regard, a particular object of the invention relates to a composition for use in the treatment of multiple sclerosis, comprising a combination of at least two compounds selected from the group consisting of irbesartan, idraparinux, otamixaban, SR48692, mecamylamine, cilostazol, clopidogrel, or salts or prodrugs or derivatives or sustained release formulations thereof.
"Another particular object of the invention relates to a composition comprising a combination of at least mecamylamine and clopidogrel, or salts, prodrugs, derivatives or sustained release formulations thereof.
"Another particular object of the invention relates to a composition comprising a combination of at least mecamylamine and clopidogrel, or salts, prodrugs, derivatives or sustained release formulations thereof, for use in the treatment of multiple sclerosis.
"In an alternative embodiment, the composition according to the invention comprises a combination of at least two compounds chosen from the group consisting of irbesartan, idraparinux, otamixaban and SR48692, salts, prodrugs, derivatives or sustained release formulations thereof.
"In a further alternative embodiment, the composition according to the invention comprises a combination of at least irbesartan, idraparinux, otamixaban and SR48692, salts, prodrugs, derivatives or sustained release formulations thereof.
"A further object of the invention relates to a method for treating neuroinflammation in a human or animal subject, comprising administering to said subject, in need thereof, an effective amount of a composition of the invention.
"A further object of the invention relates to a method for treating multiple sclerosis in a subject, comprising administering to said subject, in need thereof, an effective amount of a composition of the invention.
"As will be further disclosed in the present application, the compounds of the compositions of the invention may be administered simultaneously, separately, sequentially and/or repeatedly in a same subject.
"A further object of the invention relates to a method for assessing neuroinflammation treatment efficacy in a subject, wherein cells derived from the subject are exposed in vitro to a composition of the invention."
URL and more information on this patent, see: Cohen, Daniel; Nabirochkin, Serguei; Chumakov,
Keywords for this news article include: Genetics, Peptides, Pharnext, Terpenes, Angiology, Cytokines, Microglia, Neuroglia, Neurology, Treatment, Blood Cells, Endothelium, Lymphocytes, Norbornanes, Spinal Cord, Hydrocarbons, Inflammation, Mecamylamine, Neurosurgery, Therapeutics, Autoantibodies, Blood Proteins, Erythropoietin, Optic Neuritis, Neuroimmunology.
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