US20130158077A1 - Pharmaceutical compositions - Google Patents

Pharmaceutical compositions Download PDF

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Publication number
US20130158077A1
US20130158077A1 US13/654,632 US201213654632A US2013158077A1 US 20130158077 A1 US20130158077 A1 US 20130158077A1 US 201213654632 A US201213654632 A US 201213654632A US 2013158077 A1 US2013158077 A1 US 2013158077A1
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United States
Prior art keywords
ppar gamma
pioglitazone
nrf2
disease
fumarate
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Abandoned
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US13/654,632
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English (en)
Inventor
Bjoern C. Kahrs
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Ares Trading SA
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Ares Trading SA
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Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=48610741&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20130158077(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Ares Trading SA filed Critical Ares Trading SA
Priority to US13/654,632 priority Critical patent/US20130158077A1/en
Assigned to ARES TRADING S.A. reassignment ARES TRADING S.A. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KAHRS, BJOERN C.
Priority to TW101144629A priority patent/TW201334776A/zh
Priority to KR1020147019944A priority patent/KR102188487B1/ko
Priority to BR112014014809A priority patent/BR112014014809A2/pt
Priority to KR1020207033841A priority patent/KR20200140384A/ko
Priority to EP12801539.3A priority patent/EP2793876B1/en
Priority to US14/363,042 priority patent/US9504679B2/en
Priority to CA2859635A priority patent/CA2859635C/en
Priority to KR1020227033805A priority patent/KR20220139414A/ko
Priority to CN201280062704.0A priority patent/CN103998035B/zh
Priority to PCT/EP2012/074915 priority patent/WO2013092269A1/en
Priority to SG11201403241XA priority patent/SG11201403241XA/en
Priority to ES12801539T priority patent/ES2959111T3/es
Priority to EA201400729A priority patent/EA201400729A1/ru
Priority to AU2012358420A priority patent/AU2012358420B9/en
Priority to JP2014547838A priority patent/JP6132850B2/ja
Priority to MX2014007254A priority patent/MX2014007254A/es
Priority to ARP120104793A priority patent/AR089301A1/es
Priority to US13/756,687 priority patent/US20130172391A1/en
Publication of US20130158077A1 publication Critical patent/US20130158077A1/en
Priority to IL233134A priority patent/IL233134A0/en
Priority to HK15101190.9A priority patent/HK1200711A1/xx
Priority to US15/356,766 priority patent/US10426763B2/en
Priority to AU2017225019A priority patent/AU2017225019B2/en
Priority to AU2019204493A priority patent/AU2019204493B2/en
Priority to US16/553,219 priority patent/US11484530B2/en
Priority to AU2021201390A priority patent/AU2021201390B2/en
Priority to US18/049,652 priority patent/US12083107B2/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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Definitions

  • compositions comprising ppar agonists and Nrf2 activators (each an “agent” and together “agents”), and methods of using combinations of ppar agonists and Nrf2 activators for treating diseases such as psoriasis, asthma, multiple sclerosis, inflammatory bowel disease, and arthritis.
  • Perixome Proliferator Activated Receptors activate transcription by binding to elements of DNA sequences, known as peroxisome proliferator response elements (PPRE), in the form of a heterodimer with retinoid X receptors (known as RXRs).
  • PPRE peroxisome proliferator response elements
  • RXRs retinoid X receptors
  • glitazones including rosiglitazone, rosiglitazone maleate, pioglitazone, pioglitazone hydrochloride, troglitazone and ciglitazone and or its salt forms are potent and selective activators of PPAR-gamma (so-called PPAR gamma agonists) and bind directly to the PPAR-gamma receptor (J. M. Lehmann et al., J. Biol. Chem.
  • PPAR-gamma is a possible target for the therapeutic actions of the thiazolidinediones. Since this observation, activation of this nuclear hormone receptor has been shown to have pleiotropic metabolic and nonhypoglycemic effects.
  • Clinical use of the agents in the treatment of Type 2 diabetes mellitus (or non insulin dependent diabetes mellitus (NIDDM)) is associated with sensitization to the glucose lowering effects of insulin as well as potentiation of other biological actions of insulin in target tissues. When used as monotherapy, there are reports of fluid retention resulting in volume expansion and, in some patients, clinical edema.
  • Nuclear factor erythroid-2 related factor 2 or Nuclear Factor E2p45-Related Factor is a cap-and-collar basic leucine zipper transcription factor, regulates a transcriptional program that maintains cellular redox homeostasis and protects cells from oxidative insult (Rangasamy T, et al., J Clin Invest 114, 1248 (2004); Thimmulappa R K, et al. Cancer Res 62, 5196 (2002); So H S, et al. Cell Death Differ (2006)).
  • NRF2 activates transcription of its target genes through binding specifically to the antioxidant-response element (ARE) found in those gene promoters.
  • ARE antioxidant-response element
  • the NRF2-regulated transcriptional program includes a broad spectrum of genes, including antioxidants, such as ⁇ -glutamyl cysteine synthetase modifier subunit (GCLm), ⁇ -glutamyl cysteine synthetase catalytic subunit (GCLc), heme oxygenase-1, superoxide dismutase, glutathione reductase (GSR), glutathione peroxidase, thioredoxin, thioredoxin reductase, peroxiredoxins (PRDX), cysteine/glutamate transporter (SLC7A11) (7, 8)], phase II detoxification enzymes [NADP(H) quinone oxidoreductase 1 (NQO1), GST, UDP-glucuronosyltransferase (Rangasamy T, et al.
  • antioxidants such as ⁇ -glutamyl cysteine synthetase modifier subunit (GCLm),
  • KEAP1 Interlinked with Nrf2 is KEAP1, which is a cytoplasmic anchor of Nrf2 that also functions as a substrate adaptor protein for a Cul3-dependent E3 ubiquitin ligase complex to maintain steady-state levels of NRF2 and NRF2-dependent transcription
  • the Keap1 gene is located at human chromosomal locus 19p13.2.
  • the KEAP1 polypeptide has three major domains: (1) an N-terminal Broad complex, Tramtrack, and Bric-a-brac (BTB) domain; (2) a central intervening region (IVR); and (3) a series of six C-terminal Kelch repeats (Adams J, et al. Trends Cell Biol 10:17 (2000)).
  • the Kelch repeats of KEAP1 bind the Neh2 domain of Nrf2, whereas the IVR and BTB domains are required for the redox-sensitive regulation of Nrf2 through a series of reactive cysteines present throughout this region (Wakabayashi N, et al. Proc Natl Acad Sci USA 101: 2040 (2004)).
  • KEAP1 constitutively suppresses Nrf2 activity in the absence of stress. Oxidants, xenobiotics and electrophiles hamper KEAP1-mediated proteasomal degradation of Nrf2, which results in increased nuclear accumulation and, in turn, the transcriptional induction of target genes that ensure cell survival (Wakabayashi N, et al. Nat Genet. 35: 238 (2003)).
  • Prothymosin ⁇ a novel binding partner of KEAP1
  • Nrf2 activators according to the present invention are agents that after administration result in a stimulated and/or increased nuclear translocation of Nrf2 protein and causes the subsequent increases in gene products that detoxify and eliminate cytotoxic metabolites.
  • Nrf2 activators according to the present invention may act directly on Nrf2, KEAP1, the NRF2-KEAP1 complex and/or otherwise.
  • Nrf2 activators of the present invention may comprise a Michael addition acceptor, one or more fumaric acid esters, i.e.
  • fumaric acid mono- and/or diesters which are preferably selected from the group of monoalkyl hydrogen fumarate and dialkyl fumarate, such as monomethyl hydrogen fumarate, dimethyl fumarate, monoethyl hydrogen fumarate, and diethyl fumarate, furthermore ethacrynic acid, bardoxolone methyl (methyl 2-cyano-3,12-dioxooleana-1,9(11)dien-28-oate), isothiocyanate such as sulforaphane, 1,2-dithiole-3-thione such as oltipraz, 3,5-di-tert-butyl-4-hydroxytoluene, 3-hydroxycoumarin, or a pharmacologically active derivative or analog of the aforementioned agents.
  • monoalkyl hydrogen fumarate and dialkyl fumarate such as monomethyl hydrogen fumarate, dimethyl fumarate, monoethyl hydrogen fumarate, and diethyl fumarate, furthermore
  • Nrf2 activators for use in combination with PPAR gamma agonists according to the present invention are bardoxolone methyl and fumaric acid esters.
  • Fumaric acid esters are approved in Germany for the treatment of psoriasis, are being evaluated in the United States for the treatment of psoriasis and multiple sclerosis, and have been proposed for use in treating a wide range of immunological, autoimmune, and inflammatory diseases and conditions.
  • FAEs and other fumaric acid derivatives have been proposed for use in treating a wide-variety of diseases and conditions involving immunological, autoimmune, and/or inflammatory processes including psoriasis (Joshi and Strebel, WO 1999/49858; U.S. Pat. No.
  • Fumaderm® an enteric coated tablet containing a salt mixture of monoethyl fumarate and dimethylfumarate, which is rapidly hydrolyzed to monomethyl fumarate, was approved in Germany in 1994 for the treatment of psoriasis. Fumaderm® is dosed TID with 1-2 grams/day administered for the treatment of psoriasis.
  • Fumaric acid derivatives (Joshi and Strebel, WO 2002/055063, US 2006/0205659, and U.S. Pat. No. 7,157,423 (amide compounds and protein-fumarate conjugates); Joshi et al., WO 2002/055066 and Joshi and Strebel, U.S. Pat. No.
  • alkyl is specifically intended to include groups having any degree or level of saturation, i.e., groups having exclusively single carbon-carbon bonds, groups having one or more double carbon-carbon bonds, groups having one or more triple carbon-carbon bonds, and groups having combinations of single, double, and triple carbon-carbon bonds.
  • groups having any degree or level of saturation i.e., groups having exclusively single carbon-carbon bonds, groups having one or more double carbon-carbon bonds, groups having one or more triple carbon-carbon bonds, and groups having combinations of single, double, and triple carbon-carbon bonds.
  • alkanyl, alkenyl, and alkynyl are used.
  • an alkyl group can have from 1 to 20 carbon atoms (Ci-20) in certain embodiments, from 1 to 10 carbon atoms (Ci-I0), in certain embodiments from 1 to 8 carbon atoms (C]-8), in certain embodiments, from 1 to 6 carbon atoms (C1-6), in certain embodiments from 1 to 4 carbon atoms (C1-4), and in certain embodiments, from 1 to 3 carbon atoms (Ci-3).
  • alkoxy refers to a group O-alkyl, wherein alkyl has the meaning indicated above.
  • perfluoroalkyl refers to an alkyl group wherein all hydrogen atoms have been replaced by fluoro.
  • Treating” or “treatment” of any disease refers to reversing, alleviating, arresting, or ameliorating a disease or at least one of the clinical symptoms of a disease, reducing the risk of acquiring a disease or at least one of the clinical symptoms of a disease, inhibiting the progress of a disease or at least one of the clinical symptoms of the disease or reducing the risk of developing a disease or at least one of the clinical symptoms of a disease.
  • Treating” or “treatment” also refers to inhibiting the disease, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both, and to inhibiting at least one physical parameter that may or may not be discernible to the patient.
  • “treating” or “treatment” refers to delaying the onset of the disease or at least one or more symptoms thereof in a patient which may be exposed to or predisposed to a disease even though that patient does not yet experience or display symptoms of the disease.
  • “Therapeutically effective amount” refers to the amount of a compound that, when administered to a subject for treating a disease, or at least one of the clinical symptoms of a disease, is sufficient to affect such treatment of the disease or symptom thereof.
  • the “therapeutically effective amount” may vary depending, for example, on the compound, the disease and/or symptoms of the disease, severity of the disease and/or symptoms of the disease or disorder, the age, weight, and/or health of the patient to be treated, and the judgment of the prescribing physician. An appropriate amount in any given instance may be ascertained by those skilled in the art or capable of determination by routine experimentation.
  • “Therapeutically effective dose” refers to a dose that provides effective treatment of a disease or disorder in a patient.
  • a therapeutically effective dose may vary from compound to compound, and from patient to patient, and may depend upon factors such as the condition of the patient and the route of delivery.
  • a therapeutically effective dose may be determined in accordance with routine pharmacological procedures known to those skilled in the art.
  • strongly improved treatment results are obtained in the treatment of autoimmune and/or inflammatory diseases, when a ppar agonist and preferably a ppar gamma agonist and an Nrf2 activator are used in the treatment of the disease in combination as compared to the treatment with a ppar gamma agonist or an Nrf2 activator, alone.
  • Co-administration of a ppar gamma agonist and an Nrf2 activator or an administration of a fixed dose combination of a PPAR gamma agonists and an Nrf2 activator results in an improved therapeutic effect, which may be a more than additive effect, compared to the administration of a PPAR gamma agonist or Nrf2 activators, respectively, administered as mono-therapy.
  • a combination treatment comprising at least one PPAR gamma agonist, which may have no significant or only a minor modulating or activating effect on Nrf2, and at least one Nrf2, which may have no significant or only a minor modulating or activating effect on ppar gamma, result in improved and synergistic therapeutic effects, as compared to the administration of such PPAR gamma agonist or such Nrf2 activator, respectively, administered as mono-therapy.
  • the synergistic effect is often more pronounced with such combinations, where the agents employed are predominantly either PPAR gamma agonists or Nrf2 activators, which each have no significant activity on the respective other target.
  • the combination treatment according to the present invention can lead to improved treatment results over the mono-therapy.
  • a compound having dual effects on the targets PPAR gamma and Nrf2 is unlikely to show an ideally distributed effect on both targets for therapeutic use.
  • embodiments are preferred, wherein at least one agent is not both, PPAR gamma agonist and Nrf2 activator at the same time.
  • Combination treatments and fixed dose combinations according to the present invention are preferred, which comprise at least two different agents having either PPAR gamma agonistic or Nrf2 activating effects at the concentration used in the combination.
  • the present invention relates to combination treatments, compositions containing the inventive combination of agents and related fixed-dose combinations, wherein the ppar agonist, such as the ppar gamma agonist and the Nrf2 activator are different compounds which are preferably not belonging to the same chemical class.
  • the ppar agonist such as the ppar gamma agonist and the Nrf2 activator are different compounds which are preferably not belonging to the same chemical class.
  • Preferred PPAR agonists are compounds having a PPAR gamma agonistic effect without significantly activating Nrf2. These are preferably compounds having no ability to form covalent bonds with organic thiol groups under physiological conditions, such as with glutathione.
  • preferred PPAR gamma agonists are compounds that, contrary to e.g. 15-deoxy-delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), cannot bind covalently through e.g. Michael addition reaction to the PPA receptor.
  • Most preferred PPAR agonists are glitazones, glitazars and sartans.
  • Ppar agonists are ppar activators (e.g., ppar gamma agonist are ppar gamma activators).
  • the definition “ppar agonist” and “ppar gamma agonist” according to the present invention preferably includes such agonists, i.e., compounds, that directly bind to the ppa receptor and have an agonistic, i.e.
  • physiological ppar agonists and physiological ppar gamma agonists which do not necessarily bind to the ppar receptor, but result in an activation of ppar through other pathways, such as by increasing the concentration of endogenous ppar gamma agonist 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2).
  • PPAR agonists are known (e.g. see Michalik et al. (2006) Pharmacological Reviews 58:726-725; Gilde et al. (2003) Circulation Research 92(5):5 18-524; Peraza et al. (2005) Toxicological Sciences 90(2):269-295; and Desvergne & Wahli (1999) Endocrine Reviews 20(5):649-688). Some of these known agonists are specific for a single PPAR isotype, whilst others target multiple PPAR subtypes. PPAR agonists are preferred, if the ppar agonist stronger activate ppar gamma or ppar gamma and ppar alpha simultaneously, than other isoforms.
  • the ppar agonist may be selected from the group consisting of ppar gamma agonists, such as glitazones and dual ppar alpha/gamma agonists, such as glitazars.
  • the glitazone may be selected from the group consisting of troglitazone, pioglitazone, rosiglitazone, ciglitazone, englitazone, darglitazone, netoglitazone, isaglitazone, MC-555, balaglitazone, rivoglitazone, and the like.
  • the glitazar may be selected from the group consisting of muraglitazar, naveglitazar, tesaglitazar, ragaglitazar, reglitazar and farglitazar.
  • ppar agonists are selected from berberine, K-111, INT-131, MBX-102 (metaglidisen), MBX-2044, FK614, GSK-376501, GW 1929, S26948, psi-baptigenin and the like, such as those disclosed in U.S. Pat. No. 5,002,953, U.S. Pat. No. 4,687,777 and U.S. Pat. No. 5,965,584.
  • Pioglitazone and rosiglitazone are very preferred and most preferred are pioglitazone hydrochloride and rosiglitazone maleate.
  • ppar gamma agonists are selected from the class of statins or HMG-CoA reductase inhibitors, preferably selected from atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, mevastatin and pitavastatin.
  • Statins are a class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver. Increased cholesterol levels have been associated with cardiovascular diseases, and statins are therefore used in the prevention of these diseases.
  • Statins have also been suggested for the treatment of multiple sclerosis (e.g. US 2004/0013643).
  • statins are believed to activate ppar gamma only indirectly (Circ Res. 2007; 100:1442-1451), as physiological ppar gamma agonists they are included in the definition of ppar gamma agonists for the purposes of the present invention.
  • ppar gamma agonists are selected from the chemical classes of sartans, also known as angiotensin II receptor antagonists, angiotensin receptor blockers (ARBs) or AT1-receptor antagonists.
  • Sartans such as valsartan, losartan, azilsartan, irbesartan, olmesartan, telmisartan, candesartan and eprosartan are a group of pharmaceuticals which modulate the renin-angiotensin-aldosterone system.
  • Preferred sartans used in the present invention are selected from losartan, irbesartan, telmisartan and candesartan, which have shown to bind to and activate ppar gamma (Drug Development Research 67:579-581, 2006). Treatment with sartans has been suggested to improve multiple sclerosis.
  • the sartanes are predominantly used in the treatment of hypertension, diabetic nephropathy (kidney damage due to diabetes) and chronic kidney disease as well as congestive heart failure and are also preferably employed for these diseases and conditions when combined with Nrf2 activators according to the present invention.
  • ppar gamma agonists are selected from nonsteroidal anti-inflammatory drugs (NSAIDs) having ppar gamma activating properties, preferably indomethacin, flufenamic acid, fenoprofen and ibuprofen (The Journal of Biological Chemistry, vol. 272, no. 6, issue 7, pp. 3406-3410, 1997).
  • NSAIDs are included in the definition of PPAR gamma agonists for the purposes of the present invention as they may bind directly to the PPAR or act as a physiological PPAR gamma agonist. In one embodiment, NSAIDs other than aspirin are preferred.
  • the group of NSAIDs comprises the following compounds: Salicylates, such as aspirin (acetylsalicylic acid), diflunisal, salsalate, propionic acid derivatives such as ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, acetic acid derivatives such asindomethacin, sulindac, etodolac, ketorolac, diclofenac, nabumetone, enolic acid (oxicam) derivatives such as piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, isoxicam, fenamic acid derivatives (fenamates) such as mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, selective cox-2 inhibitors (
  • Nrf2-activating compounds can be classified based on their chemical structures: Diphenols, Michael reaction acceptors, isothiocyanates, thiocarbamates, trivalent arsenicals, 1,2-dithiole-3-thiones, hydroperoxides, vicinal dimercaptans, heavy metals, and polyenes. Moreover, Nrf2 activators (i) all are chemically reactive; (ii) nearly all are electrophiles; (iii) most are substrates for glutathione transferases; and (iv) all can modify sulfhydryl groups by alkylation, oxidation, or reduction (PNAS Feb. 17, 2004 vol. 101 no. 7 2040-2045, Mol. Cell. Biol. 2009, 29(2):493). The activity of the compounds can be identified by known methods.
  • Preferred Nrf2 activators are compounds without significant PPAR gamma agonistic effect. These are preferably compounds, which may or may not bind covalently to the PPA receptor, but are not able to change the conformation of the PPAR and preferably the PPA gamma receptor to an extent that this would result in an activation of the PPA receptor. According to the present invention these preferred Nrf2 activators are small and of low molecular weight. These compounds are preferably lacking the structural elements to bind to the PPA receptor non-covalently with the result of a change of conformation and activation of the PPA receptor. In a preferred embodiment, the Nrf2 activators may be able to bind covalently to the PPA receptor, e.g.
  • these preferred Nrf2 activators may not prevent PPAR agonists, and in particular PPAR gamma agonists, especially glitazones such as pioglitazone or rosiglitazone from binding non-covalently to the PPA receptor with the result of a conformation change.
  • the covalent binding of a Nrf2 activator such as monomethyl hydrogen fumarate or dimethyl fumarate and the non-covalent binding of a PPAR gamma agonist such as a glitazone, like pioglitazone or rosiglitazone leads to synergistic and strongly improved therapeutic results.
  • Nrf2 activators selected from organic compounds having not more than one or two 5- or 6-membered carbocyclic rings or 5- or 6-membered heterocyclic rings having 1, 2 or 3 N—, O or S-atoms as ring atoms which may be fused to each other or preferably no or only one carbocyclic or heterocyclic ring and/or less than 35, preferably less than 30, more preferably less than 25 and most preferably less than 20 or even less than 15 or less than 10 carbon atoms and/or have a molecular weight of less than 400, preferably less than 300 and most preferably less than 200 g/mol or less than 170 g/mol and are selected from the chemical classes of Michael reaction acceptors, phenols, diphenols, chalcones, isothiocyanates, thiocarbamates, quinones, naphtoquinones and 1,2 dithiole-3-thiones, wherein one or more, preferably up to seven H-atoms may be substituted by linear or
  • Nrf2 activator In cases where compounds of the chemical class of quinones are employed as Nrf2 activator, the respective hydroquinones can be used alternatively. However the respective oxidized form, i.e. the respective quinone, is preferred.
  • the Nrf2 activity can be determined according to e.g. JALA 2008; 13: 243-248. Bardoxolone methyl and derivatives are described in U.S. Pat. No. 8,129,429, U.S. Pat. No. 7,435,755 and US2009/0060873. Amorphous Bardoxolone methyl and suitable formulations are disclosed in WO2010/093944.
  • Nrf2 activators are capable of provoking or inducing a stimulated and/or increased nuclear translocation of Nrf2 protein and are:
  • c) have a molecular weight of less than 600 g/mol
  • d) contain no or not more than one or two fused or monocyclic 5- or 6-membered carbocyclic or heterocyclic rings, having 1, 2 or 3 ring atoms selected from N, O or S.
  • one or more, preferably up to seven H-atoms may be substituted preferably by linear or branched alkyl and perfluoroalkyl, such as methyl, ethyl, trifluoromethyl, halogen such as Br, Cl, F or I, hydroxy, alkoxy and perfluoroalkoxy, such as methoxy, ethoxy, trifluoromethoxy, cyano and nitro.
  • Nrf2 activators contain no ring system or only one or two rings, which may be carbocyclic and/or heterocyclic rings. Even more preferred Nrf2 activators contain less than 30, more preferably less than 25 and most preferably less than 20 or even less than 15 or less than 10 carbon atoms and/or have a molecular weight of less than 400 g/mol and more preferably less than 300 g/mol and most preferably less than 200 g/mol or less than 170 g/mol. Further preferred Nrf2 activators bind covalently to Keap1 protein, preferably via an S-atom of the proteins amino acids.
  • Preferred Michael reaction acceptors are ketones, aldehydes, carboxylic acid esters and carboxylic acid amides all of which being alpha, beta unsaturated.
  • Nrf2 activators are the compounds A to Z given below, including their tautomers and stereoisomers:
  • Hal is F, Cl, Br or I, preferably F or Cl.
  • A is preferably alkyl which denotes a straight or branched carbon chain having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms.
  • Alkyl preferably denotes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl.
  • A denotes cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms or branched or linear alkyl having 2 to 12 C-atoms, wherein one or more, preferably 1 to 7 H-atoms may be replaced by Hal, alkyl, alkoxy, cycloalkyl, phenyl, p-, m- o-hydroxyphenyl, p-, m- o-alkoxyphenyl, N(R 3 ) 2 , OH, CO 2 H, CF 3 and/or wherein one or more, preferably 1 to 7 non-adjacent CH 2 -groups may be replaced by —O—, —S—, —SO—, —NR 3 —, —CO—, —CO 2 —, —CH ⁇ CH—S— and/or —CH ⁇ CH—.
  • Cycloalkyl preferably denotes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or
  • Alkoxy is preferably a group O-alkyl, wherein alkyl is defined as above.
  • alkoxy denotes a group —O—(CH 2 ) n —CH 3 , wherein n is 0, 1, 2, 3 or 4, more preferably methoxy or ethoxy.
  • Perfluoroalkyl preferably denotes a straight or branched alkyl chain having 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, and wherein all hydrogen atoms are replaced by F atoms, preferably, for example, trifluoromethyl or pentafluoroethyl.
  • Perfluoroalkoxy is preferably a group O-perfluoroalkyl, wherein perfluoroalkyl is defined as above. Perfluoroalkoxy preferably denotes OCF 3 .
  • Amino denotes preferably the group —NR′R′′ where each R′, R′′ is independently hydrogen or alkyl.
  • the group —NR′R′′ can also form a cyclic group selected from piperidinyl, piperazinyl, pyrrolyl or morpholinyl, wherein one, two or three H atoms may be substituted by alkyl, such as methyl.
  • amino denotes dialkylamino, wherein alkyl has the meaning given above and is preferably dimethylamino.
  • Aryl preferably denotes a monocyclic or bicyclic, aromatic carbocyclic ring having 6 to 14 carbon atoms, which is unsubstituted or monosubstituted, disubstituted or trisubstituted by F, Cl, Br, CF 3 , OCF 3 , NO 2 , CN, alkyl, alkoxy, OH, amino, CO-amino, NHCO-alkyl, CO-alkyl, CO-alkoxy, SO 2 -alkyl, SO 2 -amino.
  • aryl denotes unsubstituted or monosubstituted phenyl.
  • Het preferably denotes, notwithstanding further substitutions, a 6 to 14 membered monocyclic or bicyclic saturated, unsaturated or aromatic heterocyclic ring system containing 1 or 2 heteroatoms selected from N, O and S, which is unsubstituted or monosubstituted, disubstituted or trisubstituted by F, Cl, Br, CF 3 , OCF 3 , NO 2 , CN, alkyl, alkoxy, OH, amino, CO-amino, NHCO-alkyl, CO-alkyl, CO-alkoxy, SO 2 -alkyl, SO 2 -amino.
  • Het is 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4-
  • heterocyclic radicals may also be partially or fully hydrogenated.
  • Het can thus also denote, for example, 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or -5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro
  • R 1 is preferably H, OH, F, methyl, methoxy, trifluoromethoxy.
  • R 2 is preferably H, OH, alkoxy, such as methoxy, OCH 2 CH 2 -phenyl.
  • R 3 is preferably H or alkyl, preferably H, methyl or tert-butyl.
  • R 4 is preferably H, OH, alkoxy, such as methoxy.
  • R 5 is preferably H or A.
  • R 6 is preferably H or Het.
  • R 7 is preferably (CH 2 ) m COR 2 , (CH 2 ) m COR 2 , O(CH 2 ) m COR 2 or O(CH 2 ) m COR 2 .
  • R 8 is preferably allyl or a group selected from (C(R 3 ) 2 ) q S-alkyl or (C(R 3 ) 2 ) q SO-alkyl, wherein q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
  • Nrf2 activators are selected from: Chalcone derivatives as disclosed in J. Med. Chem., 2011, 54 (12), pp 4147-4159, such as 2-trifluoromethyl-2′-methoxychalcone, auranofin, ebselen, 1,2-naphthoquinone, cynnamic aldehyde, caffeic acid and its esters, curcumin, reservatrol, artesunate, tert-butylhydroquinone, and -quinone, (tBHQ, tBQ), vitamins K1, K2 and K3, preferably menadione, fumaric acid esters, i.e.
  • fumaric acid mono- and/or diester which is preferably selected from the group of monoalkyl hydrogen fumarate and dialkyl fumarate, such as monomethyl hydrogen fumarate, dimethyl fumarate, monoethyl hydrogen fumarate, and diethyl fumarate, 2-cyclopentenones, ethacrynic acid and its alkyl esters, bardoxolone methyl (methyl 2-cyano-3,12-dioxooleana-1,9(11)dien-28-oate) (CDDO-Me, RTA 402), ethyl 2-cyano-3,12-dioxooleana-1,9(11)dien-28-oate, 2-cyano-3,12-dioxooleana-1,9(11)dien-28-oic acid (CDDO), 1[2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (
  • Nrf2 activators are selected from: carnosic acid, 2-naphthoquinone, cynnamic aldehyde, caffeic acid and its esters, curcumin, reservatrol, artesunate, tert-butylhydroquinone, vitamins K1, K2 and K3, fumaric acid esters, i.e.
  • fumaric acid mono- and/or diester which is preferably selected from the group of monoalkyl hydrogen fumarate and dialkyl fumarate, such as monomethyl hydrogen fumarate, dimethyl fumarate, monoethyl hydrogen fumarate, and diethyl fumarate, isothiocyanate such as sulforaphane, 1,2-dithiole-3-thione such as oltipraz, 3,5-di-tert-butyl-4-hydroxytoluene, 3-hydroxycoumarin, 4-hydroxynonenal, 4-oxononenal, malondialdehyde, (E)-2-hexenal, capsaicin, allicin, allylisothiocyanate, 6-methylthiohexyl isothiocyanate, 7-methylthioheptyl isothiocyanate, sulforaphane, 8-methylthiooctyl isothiocyanate, 8-iso prostaglandin A2, alkyl pyru
  • Nrf2 activators are Michael reaction acceptors such as dimethylfumarate, monomethyl hydrogen fumarate isothiocyanates and 1,2-dithiole-3-thiones.
  • very preferred Nrf2 activators are selected from monomethyl hydrogen fumarate, dimethyl fumarate, oltipraz, 1,2-naphthoquinone, tert-butylhydroquinone, methyl or ethyl pyruvate, 3,5-di-tert-butyl-4-hydroxytoluene, diethyl and dimethyl oxaloproprionate, hypoestoxide, parthenolide, eriodictyol, 4-Hydroxy-2-nonenal, 4-oxo-2nonenal, geranial, zerumbone, aurone, isoliquiritigenin, xanthohumol, [10]-Shogaol, eugenol, 1′-acetoxychavicol
  • the use of the PPAR gamma agonist and the Nrf2 activator according to the present invention may allow for the maximum dosage of each agent when used in mono-therapy, which result in maximal therapeutic effect. No or only very limited increase in adverse side effects known for the individual PPAR gamma agonist or the Nrf2 activator can be observed. It may also be advantageous to reduce the dose of one or both of the agents employed in the combination treatment of the present invention. Thus, side effects that may be observed in mono-therapy with the agents may be avoided or reduced.
  • the term “pharmacologically active derivatives” denotes preferably salts, amides and esters, such as alkylesters including methyl and ethyl esters, of pharmacologically active acids and alkanoic acid esters and ethers of pharmacologically active alcohols, such as acetic acid esters and methyl ethers as well as alkanoic acid amides of pharmacologically active amines, such as the respective acetic acid amide.
  • the combination treatment of the present invention can be further combined with treatments and medicaments that are generally used in the various indications as a standard treatment.
  • the combination treatment of the present invention can be further combined with interferon, such as interferon beta 1b or interferon beta 1a (Rebif, Avonex) or glatiramer acetate (Copaxone), a sphingosine 1-phosphate receptor modulator, such as Fingolimod (Gilenya) and/or methotrexate.
  • the combination treatment of the present invention can be further combined with RXR specific ligands, such as 9-cis-retinoic acid (RA) in order to obtain even further improved results, particularly in the treatment of psoriasis.
  • RA 9-cis-retinoic acid
  • the combination therapy according to the present invention may be administered as a simultaneous or sequential regimen, also referred to as co-administration.
  • the combination When administered sequentially, the combination may be administered in two or more administrations. It is also possible to combine any PPAR gamma agonist with an Nrf2 activator in a unitary dosage form for simultaneous or sequential administration to a patient.
  • compositions containing fumaric acid esters an administration twice daily (BID) or thrice daily (TID) is preferred.
  • BID twice daily
  • TID thrice daily
  • Co-administration of a PPAR gamma agonist with an Nrf2 activator generally and preferably refers to simultaneous or sequential administration of a PPAR gamma agonist and an Nrf2 activator, such that therapeutically effective amounts of the PPAR gamma agonist and the Nrf2 activator are both present at the same time in the body of the patient.
  • Co-administration includes simultaneous administration and administration of the an agent according to the invention before or after administration of the other agent, for example, administration of both agents according to the invention within seconds, minutes, or hours.
  • the first agent is administered, followed, after a period of hours, e.g., 0.25-12 hours, preferably 0.5 to 3 hours most preferably 1 to 2 hours), by administration of the second agent.
  • the combination therapy and co-administration according to the invention frequently provides “synergy” and “synergistic effect”, i.e. the therapeutic effect achieved when the PPAR gamma agonist and the Nrf2 activator are used together is more than additive, i.e. greater than the sum of the effects that result from using each agent alone.
  • An appropriate dose of a PPAR agonist and an Nrf2 activator or pharmaceutical composition comprising a PPAR agonist and an Nrf2 activator for use in the present invention may be determined according to any one of several well-established protocols. For example, animal studies such as studies using mice, rats, dogs, and/or monkeys may be used to determine an appropriate dose of a pharmaceutical compound. Results from animal studies may be extrapolated to determine doses for use in other species, such as for example, humans.
  • a preferred PPAR gamma agonist is administered in combination with a preferred Nrf2 activator according to the invention, preferably orally, in daily dosages of 0.01 mg to 50 mg per kg body weight, dependent on the activity and safety of the respective PPAR gamma agonist. If not indicated otherwise, the dosages given above and below reflect the amount of free base of the PPAR gamma agonist, even if used in form of the maleate or another acid addition salt.
  • Preferred nrf 2 activators are bardoxolone methyl and dialkyl fumarate such as dimethyl fumarate and diethyl fumarate.
  • dialkyl fumarates to be used according to the invention are prepared by processes known in the art (see, for example, EP 0 312 697).
  • the active ingredients i.e. the agents
  • Preparations in the form of micro-tablets or pellets, optionally filled in capsules or sachets are preferred and are also a subject matter of the invention.
  • the size or the mean diameter, respectively, of the pellets or micro-tablets is in the range from 300 to 2,000 ⁇ m, especially in the range of 500 or 1,000 ⁇ m.
  • the oral preparations may be provided with an enteric coating.
  • Capsules may be soft or hard gelatine capsules.
  • dialkyl fumarates used according to the invention may be used alone or as a mixture of several compounds, optionally in combination with the customary carriers and excipients.
  • the amounts to be used are selected in such a manner that the preparations, such as tablets, obtained contain the active ingredient in an amount corresponding to 10 to 300 mg of fumaric acid per dosage unit.
  • Preferred preparations according to the invention contain a total amount of 10 to 300 mg of dimethyl fumarate and/or diethyl fumarate.
  • Fixed-dose combinations of a PPAR agonist and preferably a PPAR gamma agonist with an Nrf2 activator are preferred.
  • Fixed-dose combinations of rosiglitazone with dimethyl fumarate and rosiglitazone with bardoxolone methyl are particularly preferred.
  • Fixed-dose combinations of pioglitazone with dimethyl fumarate and rosiglitazone with bardoxolone methyl are particularly preferred.
  • rosiglitazone is preferably administered according to the invention in form of its maleate in daily dosages of 0.01 to 0.2 mg per kg body weight, more preferably in daily dosages of 0.02 to 0.16 mg per kg body weight and most preferably in daily dosages of 0.025 mg to 0.14 mg per kg body weight, such as in daily dosages of 0.03 mg, 0.06 mg or 0.12 mg per kg body weight.
  • Daily oral dosages of 2 mg, 4 mg and 8 mg rosiglitazone per patient are particularly preferred.
  • pioglitazone is preferably administered according to the invention in form of its hydrochloride in daily dosages of 0.05 to 1 mg per kg body weight, more preferably in daily dosages of 0.1 to 0.8 mg per kg body weight and most preferably in daily dosages of 0.15 mg to 0.7 mg per kg body weight, such as in daily dosages of about 0.2 mg, about 0.4 mg or about 0.6 mg per kg body weight.
  • Daily oral dosages of about 15 mg, about 30 mg and about 45 mg pioglitazone per patient are particularly preferred.
  • ciglitazone or troglitazone are preferably administered according to the invention in daily dosages of 1 to 20 mg per kg body weight, more preferably in daily dosages of 2 to 15 mg per kg body weight and most preferably in daily dosages of 3 mg to 10 mg per kg body weight. Oral dosages are particularly preferred.
  • a preferred Nrf2 activator is administered in combination with a preferred PPAR gamma agonist, preferably orally, in daily dosages of 0.1 mg to 20 mg per kg body weight, dependent on the activity and safety of the respective Nrf2 activator.
  • bardoxolone methyl is preferably administered according to the invention in daily dosages of 0.1 to 3 mg per kg body weight, more preferably in daily dosages of 0.2 to 2.5 mg per kg body weight and most preferably in daily dosages of 0.3 mg to 2.2 mg per kg body weight, such as in daily dosages of about 0.35 mg, about 1.1 mg or about 2 mg per kg body weight.
  • Daily oral dosages of about 25 mg, about 75 mg and about 150 mg bardoxolone methyl per patient are particularly preferred.
  • dimethyl fumarate is preferably administered according to the invention in daily dosages of 1 to 20 mg per kg body weight, more preferably in daily dosages of 2 to 15 mg per kg body weight and most preferably in daily dosages of 3 mg to 12 mg per kg body weight, such as in daily dosages of about 3.4 mg, about 7 mg or about 10 mg per kg body weight.
  • Daily oral dosages of about 240 mg, about 480 mg and about 720 mg dimethyl fumarate per patient are particularly preferred.
  • the ratio between the dosages of the PPAR gamma agonist and the Nrf2 activator used in the combinations according to the present invention depends on the activity of the particular PPAR gamma agonist and Nrf2 activator selected.
  • daily oral dosages of about 20 mg, about 25 mg, about 75 mg and about 150 mg bardoxolone methyl per patient are particularly preferred. In case bardoxolone methyl is employed in amorphous form, daily dosages of about 20 mg per patient are most preferred.
  • Daily oral dosages of about 120 mg, about 240 mg, about 360 mg, about 480 mg, about 600 mg and about 720 mg dimethyl fumarate per patient are particularly preferred.
  • Nrf2 activator is dimethyl fumarate, once or twice daily dosing is preferred.
  • Preferred dosage forms and in particular oral dosage forms such as tablets or capsules may contain:
  • dosage forms such as tablets or capsules may contain preferably about 2 mg rosiglitazone and about 25 mg bardoxolone methyl or about 2 mg rosiglitazone and about 75 mg bardoxolone methyl or about 2 mg rosiglitazone and about 150 mg bardoxolone methyl or about 4 mg rosiglitazone and about 25 mg bardoxolone methyl or about 4 mg rosiglitazone and about 75 mg bardoxolone methyl or about 4 mg rosiglitazone and about 150 mg bardoxolone methyl or about 8 mg rosiglitazone and about 25 mg bardoxolone methyl or about 8 mg rosiglitazone and about 75 mg bardoxolone methyl or about 8 mg rosiglitazone and about 150 mg bardoxolone methyl.
  • a dosage form may contain about 8 mg rosiglitazone and about 150 mg bardoxolone methyl.
  • preferred dosage forms such as tablets or capsules may contain about 0.7 mg, preferably about 0.67 mg, rosiglitazone and 240 mg dimethyl fumarate or about 1.3 mg, preferably about 1.33 mg, rosiglitazone and about 240 mg dimethyl fumarate or about 2.7 mg preferably about 2.67 mg, rosiglitazone and about 240 mg dimethyl fumarate or about 0.7 mg, preferably about 0.67 mg, rosiglitazone and 120 mg dimethyl fumarate or about 1.3 mg, preferably about 1.33 mg, rosiglitazone and about 120 mg dimethyl fumarate or about 2.7 mg preferably about 2.67 mg, rosiglitazone and about 120 mg dimethyl fumarate.
  • a dosage form may contain about 2.7 mg preferably about 2.67 mg, rosiglitazone and about 240 mg dimethyl fumarate.
  • preferred dosage forms such as tablets or capsules may contain about 1 mg rosiglitazone and about 240 mg dimethyl fumarate or about 2 mg rosiglitazone and about 240 mg dimethyl fumarate or about 4 mg rosiglitazone and about 240 mg dimethyl fumarate.
  • dosage forms such as tablets or capsules may contain preferably about 15 mg pioglitazone and about 25 mg bardoxolone methyl or about 15 mg pioglitazone and about 75 mg bardoxolone methyl or about 15 mg pioglitazone and about 150 mg bardoxolone methyl or about 30 mg pioglitazone and about 25 mg bardoxolone methyl or about 30 mg pioglitazone and about 75 mg bardoxolone methyl or about 30 mg pioglitazone and about 150 mg bardoxolone methyl or about 45 mg pioglitazone and about 25 mg bardoxolone methyl or about 45 mg pioglitazone and about 75 mg bardoxolone methyl or about 45 mg pioglitazone and about 150 mg bardoxolone methyl.
  • a dosage form may contain about 45 mg pioglitazone and about 150 mg bardoxolone methyl.
  • preferred dosage forms such as tablets or capsules may contain about 5 mg pioglitazone and 240 mg dimethyl fumarate or about 10 mg pioglitazone and about 240 mg dimethyl fumarate or about 15 mg pioglitazone and about 240 mg dimethyl fumarate or about 5 mg pioglitazone and 120 mg dimethyl fumarate or about 10 mg pioglitazone and about 120 mg dimethyl fumarate or about 15 mg pioglitazone and about 120 mg dimethyl fumarate, Most preferably, a dosage form may contain about 15 mg pioglitazone and about 240 mg dimethyl fumarate.
  • preferred dosage forms such as tablets or capsules may contain about 7.5 mg pioglitazone and about 240 mg dimethyl fumarate or about 15 mg pioglitazone and about 240 mg dimethyl fumarate or about 22.5 mg pioglitazone and about 240 mg dimethyl fumarate.
  • atorvastatin is preferably administered according to the invention in form of its calcium salt in daily oral dosages of about 10, about 20, about 40 or about 80 mg per patient.
  • atorvastatin is combined in the above dosages with dimethylfumarate in dosages of about 120, about 240 or about 360, about 480 or about 720 mg per day.
  • Most preferred are combinations containing about 20 mg or about 40 mg of atorvastatin in form of its calcium salt, and about 240 mg dimethyl fumarate.
  • atorvastatin is combined in the above dosages with bardoxolone methyl in its amorphous form in dosages of about 20 mg per day. Most preferred are combinations containing about 40 mg or about 80 mg of atorvastatin in form of its calcium salt, and about 20 mg bardoxolone methyl in its amorphous form.
  • losartan is preferably administered according to the invention in daily oral dosages of about 25, about 50, about 75 or about 100 mg per patient.
  • losartan is combined in the above dosages with dimethylfumarate in dosages of about 120, about 240 or about 360, about 480 or about 720 mg per day.
  • Most preferred are combinations containing about 25 mg or about 50 mg of losartan, and about 240 mg dimethyl fumarate. The combination is preferably administered twice daily.
  • the combination treatments of sartanes and preferably losartan, irbesartan, telmisartan and candesartan with Nrf2 activators such as dimethyl fumarate and bardoxolone methyl are particularly effective for the treatment of diabetic nephropathy (kidney damage due to diabetes) and chronic kidney disease, but also for the treatment of multiple sclerosis.
  • losartan is combined in the above dosages with bardoxolone methyl in its amorphous form in dosages of about 20 mg per day.
  • Most preferred are combinations containing about 25 mg or about 50 mg of losartan, and about 20 mg bardoxolone methyl in its amorphous form.
  • the combination is preferably administered once daily.
  • ibuprofen is preferably administered according to the invention in daily dosages that are applicable to the monotherapy with ibuprofen, such as about 600 mg, about 800 mg or about 1200 mg or about 2400 mg per patient. Most preferred are combinations containing about 600 mg of ibuprofen and about 240 mg dimethyl fumarate. The combination is preferably administered twice daily.
  • ibuprofen is combined in the above dosages with bardoxolone methyl in its amorphous form in dosages of about 20 mg per day.
  • Most preferred are combinations containing about 800 mg of ibuprofen, and about 20 mg bardoxolone methyl in its amorphous form.
  • the combination is preferably administered once daily.
  • Preferred ratios between rosiglitazone and dimethyl fumarate are selected from 1/20 to 1/400 (w/w, rosiglitazone/dimethyl fumarate), preferably from 1/25 to 380, more preferably from 1/28 to 1/360. Most preferably the ratios are about 1/30, about 1/45, such as about 1/44.4, about 1/60, about 1/90, such as about 1/88.9 or about 1/92.3, about 1/120, about 1/180, such as 1/171.4 or 1/184.6, about 1/240, about 1/340, such as about 1/342.9.
  • Preferred ratios between pioglitazone and dimethyl fumarate are selected from 1/3 to 1/60 (w/w, pioglitazone/dimethyl fumarate), preferably from 1/4 to 1/55, more preferably from 1/5 to 1/52. Most preferably the ratios are about 1/5.3, about 1/8, about 1/10, such as 1/10.7, about 1/12, about 1/16, about 1/24, about 1/32, about 1 to 48.
  • ratios between rosiglitazone and bardoxolone methyl are selected from 1/1 to 1/100 (w/w, rosiglitazone/bardoxolone methyl), preferably from 1/1.5 to 1/80, more preferably from 1/2 to 1/75. Most preferably the ratios are about 1/2.5, such as about 1/3.1 or about 1/5, such as 1/6.3, about 1/10, such as about 1/9.4 or about 1/12.5, about 1/20, such as 1/18.8, about 1/40, such as about 1/37.5, about 1/70, such as about 1/75.
  • ratios between pioglitazone and bardoxolone methyl are selected from 1/0.1 to 1/20 (w/w, pioglitazone/bardoxolone methyl), preferably from 1/0.3 to 1/15, more preferably from 1/0.4 to 1/12. Most preferably the ratios are about 1/0.5, such as about 1/0.4 or about 1/0.6 or about 1/0.7, or about 1/0.8, about 1/2, such as about 1/1.7 or about 1/2.5, about 1/3, such as about 1/3.3, about 1/5 or about 1/10.
  • amorphic bardoxolone methyl is employed more preferably in a pharmaceutical formulation comprising amorphous bardoxolone methyl, preferably obtained as spray-dried dispersion with a glass-forming excipient, such as methacrylic acid copolymer Type C, USP, e.g. in a 4/6 weight ratio of bardoxolone methyl to methacrylic acid copolymer Type C, USP (Eurdagit), more preferably admixed with particles comprised of at least one hydrophilic binder, such as hydroxypropylmethylcellulose, according to US2012/022156.
  • a glass-forming excipient such as methacrylic acid copolymer Type C, USP, e.g. in a 4/6 weight ratio of bardoxolone methyl to methacrylic acid copolymer Type C, USP (Eurdagit)
  • particles comprised of at least one hydrophilic binder such as hydroxypropylmethylcellulose
  • compositions of bardoxolone methyl according to the present invention also contain a surface active ingredient, such as sodium lauryl sulfate, preferably in amounts of about 1 to 5 weight %, preferably about 3%, such as 2.73%, of the total composition.
  • a surface active ingredient such as sodium lauryl sulfate
  • amorphous bardoxolone methyl is administered according to the invention in daily dosages of 0.05 to 1 mg per kg body weight, more preferably in dosages of 0.1 to 0.8 mg per kg body weight and most preferably in dosages of 0.2 mg to 0.6 mg per kg body weight, such as in daily dosages of about 0.15 mg, about 0.25 mg or about 0.35 mg per kg body weight.
  • Daily oral dosages of about 10 mg, about 20 mg, and about 30 mg bardoxolone methyl per patient are particularly preferred.
  • amorphous bardoxolone methyl For daily administration of amorphous bardoxolone methyl, the following dosages are employed per patient: About 2 mg rosiglitazone and about 10 mg bardoxolone methyl or about 2 mg rosiglitazone and about 20 mg bardoxolone methyl or about 2 mg rosiglitazone and about 30 mg bardoxolone methyl or about 4 mg rosiglitazone and about 10 mg bardoxolone methyl or about 4 mg rosiglitazone and about 20 mg bardoxolone methyl or about 4 mg rosiglitazone and about 30 mg bardoxolone methyl or about 8 mg rosiglitazone and about 10 mg bardoxolone methyl or about 8 mg rosiglitazone and about 20 mg bardoxolone methyl or about 8 mg rosiglitazone and about 30 mg bardoxolone methyl. Most preferably, about 8 mg rosiglitazone and about 20 mg bardox
  • the following dosages are employed per patient: About 15 mg pioglitazone and about 10 mg bardoxolone methyl or about 15 mg pioglitazone and about 20 mg bardoxolone methyl or about 15 mg pioglitazone and about 30 mg bardoxolone methyl or about 30 mg pioglitazone and about 10 mg bardoxolone methyl or about 30 mg pioglitazone and about 20 mg bardoxolone methyl or about 30 mg pioglitazone and about 30 mg bardoxolone methyl or about 45 mg pioglitazone and about 10 mg bardoxolone methyl or about 45 mg pioglitazone and about 20 mg bardoxolone methyl or about 45 mg pioglitazone and about 30 mg bardoxolone methyl.
  • preferred ratios between rosiglitazone and bardoxolone methyl are from 1/1 to 1/20 (“/” indicates “to” throughout this application, when a ratio is concerned, w/w, rosiglitazone/bardoxolone methyl), preferably from 1/1.1 to 1/17, more preferably from 1/1.2 to 1/16. Most preferably the ratios are about 1/1.3, such as about 1/1.25, about 1/2.5, about 1/3.5, such as 1/3.75, about 1/5, about 7.5, about 1/10.
  • preferred ratios between pioglitazone and bardoxolone methyl are from 1/0.1 to 1/3 (w/w, pioglitazone/bardoxolone methyl), preferably from 1/0.15 to 1/2.5, more preferably from 1/0.2 to 1/2.2. Most preferably the ratios are about 1/0.2, such as about 1/0.22, about 1/0.3, such as about 1/0.33, about 1/0.4, such as about 1/0.44, about 1/0.7, such as about 1/0.67, about 1/1 or about 1/2.
  • Dosage forms and in particular oral dosage forms such as tablets or capsules containing both a PPAR gamma agonist and a Nrf2 activator in a fixed dose combination comprising the above compositions in the given ratios and especially those containing amorphic bardoxolone methyl, are preferred.
  • compositions provided by the present disclosure may comprise a therapeutically effective amount of a PPAR gamma agonist and an Nrf2 activator together with a suitable amount of one or more pharmaceutically acceptable vehicles so as to provide a composition for proper administration to a patient.
  • suitable pharmaceutical vehicles are described in the art.
  • a PPAR gamma agonist and an Nrf2 activator may together be incorporated into pharmaceutical compositions to be administered orally. Oral administration of such pharmaceutical compositions may result in uptake of the PPAR gamma agonist and the Nrf2 activator throughout the intestine and entry into the systemic circulation.
  • Such oral compositions may be prepared in a manner known in the pharmaceutical art and comprise a PPAR gamma agonist and an Nrf2 activator and at least one pharmaceutically acceptable vehicle.
  • Oral pharmaceutical compositions may include a therapeutically effective amount of a PPAR gamma agonist and an Nrf2 activator and a suitable amount of a pharmaceutically acceptable vehicle, so as to provide an appropriate form for administration to a patient.
  • a PPAR gamma agonist and an Nrf2 activator may together be incorporated into pharmaceutical compositions to be administered by any other appropriate route of administration including intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intracerebral, intravaginal, transdermal, rectal, inhalation, or topical.
  • a topical formulation containing a ppar agonist, such as a glitazone like pioglitazone or rosiglitazone and an Nrft2 activator, preferably Nrf2 activator that does not or only rarely cause an allergic skin reaction, such as bardoxolone methyl, CDDO, CDDO-IM, CDDO-MA, TP-225, menadione, vitamin K1, BHA, BHT, tBHQ, tBQ, curcumin, reservatrol, cynnamic aldehyde or oltipraz.
  • a ppar agonist such as a glitazone like pioglitazone or rosiglitazone and an Nrft2 activator, preferably Nrf2 activator that does not or only rarely cause an allergic skin reaction, such as bardoxolone methyl, CDDO, CDDO-IM, CDDO-MA, TP-225, menadione, vitamin K1, BHA, BHT,
  • the topical formulation is preferably used in the treatment of psoriasis, acne, rosacea and skin rash such as skin rash caused by EGFR inhibitors like cetuximab, zalutumumab, nimotuzumab, and matuzumab, gefitinib, erlotinib, and lapatinib.
  • the formulations are prepared with customary ingredients and processes known in the art and/or disclosed herein.
  • compositions comprising a PPAR gamma agonist and an Nrf2 activator may be manufactured by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes.
  • Pharmaceutical compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers, diluents, excipients, or auxiliaries, which facilitate processing of the PPAR gamma agonist and the Nrf2 activator or crystalline forms thereof and one or more pharmaceutically acceptable vehicles into formulations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • compositions provided by the present disclosure may take the form of solutions, suspensions, emulsion, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for administration to a patient.
  • Pharmaceutical compositions provided by the present disclosure may be formulated in a unit dosage form.
  • a unit dosage form refers to a physically discrete unit suitable as a unitary dose for patients undergoing treatment, with each unit containing a predetermined quantity of a PPAR gamma agonist and an Nrf2 activator calculated to produce an intended therapeutic effect.
  • a unit dosage form may be for a single daily dose, for administration 2 times per day, or one of multiple daily doses, e.g., 3 or more times per day. When multiple daily doses are used, a unit dosage form may be the same or different for each dose.
  • One or more dosage forms may comprise a dose, which may be administered to a patient at a single point in time or during a time interval.
  • compositions comprising a PPAR gamma agonist and an Nrf2 activator may be formulated for immediate release or controlled or sustained or delayed release.
  • an oral dosage form provided by the present disclosure may be a controlled release dosage form.
  • Controlled delivery technologies can improve the absorption of a drug in a particular region or regions of the gastrointestinal tract.
  • Controlled drug delivery systems may be designed to deliver a drug in such a way that the drug level is maintained within a therapeutically effective window and effective and safe blood levels are maintained for a period as long as the system continues to deliver the drug with a particular release profile in the gastrointestinal tract.
  • Controlled drug delivery may produce substantially constant blood levels of the PPAR gamma agonist and the Nrf2 activator over a period of time as compared to fluctuations observed with immediate release dosage forms.
  • PPAR gamma agonists and Nrf2 activators maintaining a constant blood and tissue concentration throughout the course of therapy is the most desirable mode of treatment. Immediate release of the PPAR gamma agonist and the Nrf2 activator may cause blood levels to peak above the level required to elicit a desired response, which may waste the agents and may cause or exacerbate toxic side effects. Controlled drug delivery can result in optimum therapy, and not only can reduce the frequency of dosing, but may also reduce the severity of side effects. Examples of controlled release dosage forms include dissolution controlled systems, diffusion controlled systems, ion exchange resins, osmotically controlled systems, erodable matrix systems, pH independent formulations, gastric retention systems, and the like.
  • An appropriate oral dosage form for a particular pharmaceutical composition provided by the present disclosure may depend, at least in part, on the gastrointestinal absorption properties of the PPAR gamma agonist and the Nrf2 activator and the stability of these agents in the gastrointestinal tract, the pharmacokinetics thereof and the intended therapeutic profile.
  • An appropriate controlled release oral dosage form may be selected for a particular a PPAR gamma agonist and Nrf2 activator.
  • gastric retention oral dosage forms may be appropriate for agents absorbed primarily from the upper gastrointestinal tract
  • sustained release oral dosage forms may be appropriate for agents absorbed primarily from the lower gastrointestinal tract.
  • compositions provided by the present disclosure may be practiced with dosage forms adapted to provide sustained release of a PPAR gamma agonist and an Nrf2 activator upon oral administration.
  • Sustained release oral dosage forms may be used to release the PPAR gamma agonist and/or the Nrf2 activator over a prolonged time period and are useful when it is desired that an agent be delivered to the lower gastrointestinal tract.
  • Sustained release oral dosage forms include any oral dosage form that maintains therapeutic concentrations of the agents in a biological fluid such as the plasma, blood, cerebrospinal fluid, or in a tissue or organ for a prolonged time period.
  • Sustained release oral dosage forms include diffusion-controlled systems such as reservoir devices and matrix devices, dissolution-controlled systems, osmotic systems, and erosion-controlled systems. Sustained release oral dosage forms and methods of preparing the same are well known in the art.
  • the PPAR gamma agonist may be formulated together in admixture or preferably separately from the Nrf2 activator.
  • Each of the PPAR gamma agonist and Nrf2 activator may preferably be contained in separate form within the dosage form, such as an oral dosage form, which is preferably a tablet or capsule.
  • each agent may be formulated with different excipients.
  • the PPAR gamma agonist and the Nrf2 activator may also be each contained in formulations with different release profiles, i.e. with immediate, controlled or delayed release.
  • the formulations and in particular the solid oral dosage forms containing a PPAR gamma agonist and/or an Nrf2 activator may contain a conventional additive in the field of pharmaceutical preparation and can be also produced according to a known method.
  • a conventional additive for example, excipient, disintegrant, binder, lubricant, coloring agent, pH regulator, surfactant, release-sustaining agent, stabilizer, sour agent, flavor, glidant and the like can be mentioned.
  • these additives are used in an amount conventionally employed in the field of pharmaceutical preparation.
  • starches such as corn starch, potato starch, wheat starch, rice starch, partly pregelatinized starch, pregelatinized starch, porous starch and the like; sugars and sugar alcohols such as lactose, fructose, glucose, D-mannitol, sorbitol and the like; anhydrous calcium phosphate, crystalline cellulose, precipitated calcium carbonate, calcium silicate and the like can be mentioned.
  • the disintegrant for example, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropyl starch and the like are used.
  • the amount of the disintegrant to be used is preferably 0.5-25 parts by weight, more preferably 1-15 parts by weight, per 100 parts by weight of the solid preparation.
  • binder for example, crystalline cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, gum arabic powder and the like can be mentioned.
  • the amount of the binder to be used is preferably 0.1-50 parts by weight, more preferably 0.5-40 parts by weight, per 100 parts by weight of the solid preparation.
  • the lubricant include magnesium stearate, calcium stearate, talc, sucrose esters of fatty acids, sodium stearyl fumarate and the like.
  • the coloring agent for example, food colors such as Food Yellow No. 5, Food Red No. 2, Food Blue No. 2 and the like, food lake colors, ferric oxide and the like can be mentioned.
  • the pH regulator citrate, phosphate, carbonate, tartrate, fumarate, acetate, amino acid salt and the like can be mentioned.
  • the surfactant sodium lauryl sulfate, polysorbate 80, polyoxyethylene (160) polyoxypropylene (30) glycol and the like can be mentioned.
  • cellulose polymers such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose (preferably hydroxypropylmethyl cellulose 2910, hydroxypropylmethyl cellulose 2208 and the like), cellulose acetate (preferably cellulose acetate having an acetyl content of 39.3-40%), cellulose diacetate, cellulose triacetate, cellulose acetate propionate, ethyl cellulose, sodium carboxymethyl cellulose, crystalline cellulose sodium carboxymethyl cellulose and the like; sodium alginate, carboxyvinyl polymer; acrylic acid polymers such as aminoalkylmethacrylate copolymer RS [Eudragit RS (trademark), Rohm Pharma], ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit NE (trademark), Rohm Pharma] and the like; and the like can be mentioned.
  • cellulose polymers such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose (preferably hydroxypropylmethyl cellulose 29
  • the release-sustaining agent may contain, for example, flux enhancers (e.g., sodium chloride, potassium chloride, sucrose, sorbitol, D-mannitol, polyethylene glycol (preferably polyethylene glycol 400 and the like), propylene glycol, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate, polyvinyl alcohol, methacrylic acid polymer), plasticizers (e.g., triacetin, acetylated monoglyceride, grape seed oil, olive oil, sesame oil, acetyltributyl citrate, acetyltriethyl citrate, glycerin sorbitol, diethyl oxalate, diethyl maleate, diethyl fumarate, dibutyl succinate, diethyl malonate, dioctyl phthalate, dibutyl sebacate, triethy
  • the release-sustaining agent include (1) a semipermeable membrane coating containing cellulose acetate (preferably cellulose acetate having an acetyl content of 39.3-40%), polyethylene glycol (preferably polyethylene glycol 400 and the like) and triacetin; (2) a release-sustaining composition containing sodium carboxymethyl cellulose, hydroxypropylmethyl cellulose 2910, hydroxypropylmethyl cellulose 2208 and microcrystalline cellulose; and the like.
  • tocopherol for example, tocopherol, tetrasodium edetate, nicotinamide, cyclodextrins and the like
  • sour agent for example, ascorbic acid, citric acid, tartaric acid, malic acid and the like can be mentioned.
  • flavor for example, menthol, peppermint oil, lemon oil, vanillin and the like can be mentioned.
  • glidant for example, light anhydrous silicic acid, hydrated silicon dioxide and the like can be mentioned.
  • the above-mentioned additives may be used in a mixture of two or more kinds thereof in an appropriate ratio.
  • each a PPAR gamma agonist and Nrf2 activator may be determined based on several factors, including, for example, the body weight and/or condition of the patient being treated, the severity of the disease being treated, the incidence and/or severity of side effects, the manner of administration, and the judgment of the prescribing physician. Appropriate dose ranges may be determined by methods known to those skilled in the art.
  • the invention provides a combination of an Nrf2 activator and a PPAR gamma agonist for use in the treatment of inflammatory and autoimmune diseases.
  • the invention provides a PPAR gamma agonist for use in combination with a fumaric acid mono- and/or diester, characterized in that the PPAR gamma agonist is selective and has no substantial activity on PPAR alpha or delta.
  • a therapeutically effective amount of a combination of a PPAR gamma agonist and an Nrf2 activator may be administered as a treatment or preventative measure to a patient having a predisposition for and/or history of immunological, autoimmune, and/or inflammatory diseases including psoriasis, asthma and chronic obstructive pulmonary diseases, cardiac insufficiency including left ventricular insufficiency, myocardial infarction and angina pectoris, mitochondrial and neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, retinopathia pigmentosa and mitochondrial encephalomyopathy, transplantation rejection, autoimmune diseases including multiple sclerosis, ischemia and reperfusion injury, advanced glycation endproducts (AGE)-induced genome and protein damage, inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, thyroid eye disease-related inflammation, fibrosis, such as lung fibrosis, chronic lymphocytic leukemia,
  • the present invention can also be used in the prevention of cardiovascular disease, for plaque stabilization, reduction of inflammation, reversal of endothelial dysfunction, and decreased thrombogenicity and wound healing in diabetes.
  • the combination treatment of the present invention can be used in the treatment and prevention of atopic dermatitis, dementia, gastritis, fibrosis, insulin resistance, type I and type II diabetes and Syndrome X.
  • the combination treatment is preferably used in the prophylaxis or treatment of polycystic ovary syndrome (PCOS).
  • PCOS polycystic ovary syndrome
  • compounds being both, PPAR gamma agonists and Nrf2 activators show suitable effects as a monotherapeutic agent.
  • Preferred compounds which can be used in the prophylaxis and treatment of PCOS as a single active ingredient in a dosage form such as a tablet are bardoxolone methyl, CDDO, CDDO-IM, CDDO-MA or TP-225.
  • another object of the present invention is the use of bardoxolone methyl, CDDO, CDDO-IM, CDDO-MA or TP-225 in the prophylaxis and treatment of PCOS and a method of treating PCOS by administration of a pharmacologically effective amount of bardoxolone methyl, CDDO, CDDO-IM, CDDO-MA or TP-225 to a patient in need thereof.
  • the mono-therapy with the aforementioned Nrf2 activators can be further improved with co-administration of a PPAR agonist, such as a glitazone like pioglitazone or rosiglitazone.
  • NF- ⁇ B mediated and/or other diseases are described in the following.
  • the administration or co-administration of a combination of a PPAR gamma agonist and an Nrf2 activator is effective for treating a member of the group of diseases consisting of a neurological disorder, an ophthalmological disorder, in a mammal, including, without limitation, a human.
  • the neurological disorder, an ophthalmological disorder, or a combination thereof results from at least one member of the group consisting of trauma, ischemia, and hypoxia.
  • the neurological disorder, ophthalmological disorder, or combination thereof is selected from the group consisting of painful neuropathy, neuropathic pain, diabetic neuropathy, drug dependence, drug addition, drug withdrawal, nicotine withdrawal, opiate tolerance, opiate withdrawal, depression, anxiety, a movement disorder, tardive dyskinesia, a cerebral infection that disrupts the blood-brain barrier, meningitis, meningoencephalitis, stroke, hypoglycemia, cardiac arrest, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, glaucoma, retinal ischemia, ischemic optic neuropathy, macular degeneration, multiple sclerosis, sequalae of hyperhomocystinemia, convulsion, pain, schizophrenia, muscle spasm, migraine headache, urinary incontinence, emesis, brain edema, tardive dyskinesia, AIDS-induced dementia, ocular damage, retinopathy, a cognitive disorder, and a neuron
  • the neurological disorder, ophthalmological disorder, or combination thereof is selected from the group consisting of epilepsy, Alzheimer's disease, vascular (multi-infarct) dementia, Huntington's disease, Parkinsonism, multiple sclerosis, amyotrophic lateral sclerosis, and minimal cognitive impairment (MCI).
  • epilepsy Alzheimer's disease
  • vascular (multi-infarct) dementia Huntington's disease
  • Parkinsonism multiple sclerosis
  • amyotrophic lateral sclerosis amyotrophic lateral sclerosis
  • MCI minimal cognitive impairment
  • Psoriasis is characterized by hyperkeratosis and thickening of the epidermis as well as by increased vascularity and infiltration of inflammatory cells in the dermis.
  • Psoriasis vulgaris manifests as silvery, scaly, erythematous plaques on typically the scalp, elbows, knees, and buttocks.
  • Guttate psoriasis occurs as tear-drop size lesions.
  • Fumaric acid esters are recognized for the treatment of psoriasis and dimethyl fumarate is approved for the systemic treatment of psoriasis in Germany (Mrowietz and Asadullah, Trends MoI Med 2005, 11(1), 43-48; and Mrowietz et al, Br J Dermatology 1999, 141, 424-429). Efficacy for treating psoriasis can be determined using animal models and in clinical trials. Contrary to fumaric acid esters, it has been found that PPAR gamma agonists are not advantageous in the treatment of psoriasis (Placebo response in two long-term randomized psoriasis studies that are negative for rosiglitazone. Am J Clin Dermatol. 2007; 8(2):93-102). Contrary to this result, it can be found that PPAR gamma agonist provide therapeutic benefit in a combined treatment of psoriasis according to the present invention.
  • Inflammatory arthritis includes diseases such as rheumatoid arthritis, juvenile rheumatoid arthritis (juvenile idiopathic arthritis), psoriatic arthritis, and ankylosing spondylitis produce joint inflammation.
  • the pathogenesis of immune-mediated inflammatory diseases including inflammatory arthritis is believed to involve TNF and NK- ⁇ B signaling pathways (Tracey et al., Pharmacology & Therapeutics 2008, 117, 244-279).
  • Dimethyl fumarate has been shown to inhibit TNF and inflammatory diseases including inflammatory arthritis are believed to involve TNF and NK- ⁇ B signaling and therefore may be useful in treating inflammatory arthritis (Lowewe et al., J Immunology 2002, 168, 4781-4787).
  • the inventive method of treatment and combinations can be used in the prophylaxis and treatment of neurodegenerative diseases, such as multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, dementia, mitochondrial encephalomyopathy and amyotrophic lateral sclerosis (ALS).
  • neurodegenerative diseases such as multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, dementia, mitochondrial encephalomyopathy and amyotrophic lateral sclerosis (ALS).
  • MS Multiple sclerosis
  • MS is typified pathologically by multiple inflammatory foci, plaques of demyelination, gliosis, and axonal pathology within the brain and spinal cord, all of which contribute to the clinical manifestations of neurological disability (see e.g., Wingerchuk, Lab Invest 2001, 81, 263-281; and Virley, NeuroRx 2005, 2(4), 638-649).
  • axonal pathology within the brain and spinal cord
  • evidence implicates an autoimmune etiology together with environmental factors, as well as specific genetic predispositions.
  • Functional impairment, disability, and handicap are expressed as paralysis, sensory and octintive disturbances spasticity, tremor, a lack of coordination, and visual impairment, which impact on the quality of life of the individual.
  • the clinical course of MS can vary from individual to individual, but invariably the disease can be categorized in three forms: relapsing-remitting, secondary progressive, and primary progressive.
  • Inflammatory Bowel Disease is a group of inflammatory conditions of the large intestine and in some cases, the small intestine that includes Crohn's disease and ulcerative colitis.
  • Crohn's disease which is characterized by areas of inflammation with areas of normal lining in between, can affect any part of the gastrointestinal tract from the mouth to the anus. The main gastrointestinal symptoms are abdominal pain, diarrhea, constipation, vomiting, weight loss, and/or weight gain. Crohn's disease can also cause skin rashes, arthritis, and inflammation of the eye. Ulcerative colitis is characterized by ulcers or open sores in the large intestine or colon.
  • ulcerative colitis The main symptom of ulcerative colitis is typically constant diarrhea with mixed blood of gradual onset.
  • Other types of intestinal bowel disease include collagenous colitis, lymphocytic colitis, ischaemic colitis, diversion colitis, Behcet's colitis, and indeterminate colitis.
  • Asthma is reversible airway obstruction in which the airway occasionally constricts, becomes inflamed, and is lined with an excessive amount of mucus. Symptoms of asthma include dyspnea, wheezing, chest tightness, and cough. Asthma episodes may be induced by airborne allergens, food allergies, medications, inhaled irritants, physical exercise, respiratory infection, psychological stress, hormonal changes, cold weather, or other factors.
  • fumaric acid esters may be useful in treating pulmonary diseases such as asthma and chronic obstructive pulmonary disorder.
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive airway disease
  • the airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lungs to noxious particles and gases.
  • COPD is characterized by a shortness of breath the last for months or years, possibly accompanied by wheezing, and a persistent cough with sputum production. COPD is most often caused by tobacco smoking, although it can also be caused by other airborne irritants such as coal dust, asbestos, urban pollution, or solvents. COPD encompasses chronic obstructive bronchiolitis with fibrosis and obstruction of small airways, and emphysema with enlargement of airspaces and destruction of lung parenchyma, loss of lung elasticity, and closure of small airways.
  • Neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease and amyoptrophic lateral sclerosis are characterized by progressive dysfunction and neuronal death.
  • Parkinson's disease is a slowly progressive degenerative disorder of the nervous system characterized by tremor when muscles are at rest (resting tremor), slowness of voluntary movements, and increased muscle tone (rigidity).
  • nerve cells in the basal ganglia e.g., substantia nigra, degenerate, and thereby reduce the production of dopamine and the number of connections between nerve cells in the basal ganglia.
  • the basal ganglia are unable to smooth muscle movements and coordinate changes in posture as normal, leading to tremor, incoordination, and slowed, reduced movement (bradykinesia) (Blandini, et ah, MoI. Neurobiol. 1996, 12, 73-94).
  • Alzheimer's disease is a progressive loss of mental function characterized by degeneration of brain tissue, including loss of nerve cells and the development of senile plaques and neurofibrillary tangles.
  • parts of the brain degenerate, destroying nerve cells and reducing the responsiveness of the maintaining neurons to neurotransmitters.
  • Abnormalities in brain tissue consist of senile or neuritic plaques, e.g., clumps of dead nerve cells containing an abnormal, insoluble protein called amyloid, and neurofibrillary tangles, twisted strands of insoluble proteins in the nerve cell.
  • Huntington's disease is an autosomal dominant neurodegenerative disorder in which specific cell death occurs in the neostriatum and cortex (Martin, N Engl J Med 1999, 340, 1970-80). Onset usually occurs during the fourth or fifth decade of life, with a mean survival at age of onset of 14 to 20 years. Huntington's disease is universally fatal, and there is no effective treatment. Symptoms include a characteristic movement disorder (Huntington's chorea), cognitive dysfunction, and psychiatric symptoms. The disease is caused by a mutation encoding an abnormal expansion of CAG-encoded polyglutamine repeats in the protein, huntingtin.
  • ALS Amyotrophic lateral sclerosis
  • ALS is a progressive neurodegenerative disorder characterized by the progressive and specific loss of motor neurons in the brain, brain stem, and spinal cord (Rowland and Schneider, N Engl J Med 2001, 344, 1688-1700).
  • ALS begins with weakness, often in the hands and less frequently in the feet that generally progresses up an arm or leg. Over time, weakness increases and spasticity develops characterized by muscle twitching and tightening, followed by muscle spasms and possibly tremors.
  • the average age of onset is 55 years, and the average life expectancy after the clinical onset is 4 years.
  • the only recognized treatment for ALS is riluzole, which can extend survival by only about three months.
  • MG Myasthenia gravis
  • AChR acetylcholine receptor
  • CFA complete Freund's adjuvant
  • Alopecia greata is a common disease, but for ethical reasons it seems difficult to perform large-scale studies to elucidate the pathogenesis and to develop new therapeutic approaches in man. It is therefore helpful to develop appropriate animal models.
  • the Dundee experimental bald rat (DEBR) and the C3H/HeJ mouse are well-established animal models for alopecia greata and can be used for the study of genetic aspects, pathogenesis and therapy of the disease (J Dtsch Dermatol Ges. 2004 April; 2(4):260-73).
  • a mouse model for diabetic nephropathy can be utilized according to Kidney International 77, 749-750 (May 2010), in order to prove the effect of the combination according to the present invention.
  • diseases and conditions for which treatment with the combination of a PPAR gamma agonist and an Nrf2 activator can be useful include rheumatica, granuloma annulare, lupus, autoimmune carditis, eczema, sarcoidosis, and autoimmune diseases including acute disseminated encephalomyelitis, Addison's disease, alopecia greata, ankylosing spondylitis, antiphospholipid antibody syndrome, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, bullous pemphigoid, Behcet's disease, celiac disease, Chagas disease, chronic obstructive pulmonary disease, Crohn's disease, dermatomyositis, diabetes mellitus type I, endometriosis, Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome, Hashimoto's disease, hidradenitis suppurativea,
  • Nrf2 activator and a PPAR gamma agonist and pharmaceutical compositions thereof may be administered orally or by any other appropriate route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal, and intestinal mucosa, etc.).
  • Other suitable routes of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intracerebral, intravaginal, transdermal, rectal, inhalation, or topical.
  • Administration may be systemic or local.
  • Various delivery systems are known, e.g., encapsulation in liposomes, microparticles, microcapsules, capsules, etc.) that may be used to administer a compound and/or pharmaceutical composition.
  • a therapeutically effective dose may be estimated initially from in vitro assays.
  • a dose may be formulated in animal models to achieve a beneficial circulating composition concentration range.
  • Initial doses may also be estimated from in vivo data, e.g., animal models, using techniques that are known in the art. Such information may be used to more accurately determine useful doses in humans.
  • One having ordinary skill in the art may optimize administration to humans based on animal data.
  • PPAR gamma agonist for use in combination with a fumaric acid mono- and/or diester in the treatment of an autoimmune and/or inflammatory disease relates to a method of use of at least one PPAR gamma agonist in combination with a fumaric acid mono- and/or diester in the treatment of an autoimmune and/or inflammatory disease.
  • PPAR gamma agonist for use in combination with a fumaric acid mono- and/or diester in the treatment of an autoimmune and/or inflammatory disease.
  • PPAR gamma agonist such as rosiglitazone, for use in combination with a fumaric acid mono- and/or diester according to embodiment 1, characterized in that the autoimmune and/or inflammatory disease is psoriasis.
  • PPAR gamma agonist for use in combination with a fumaric acid mono- and/or diester according to embodiment 1, characterized in that the autoimmune and/or inflammatory disease is selected from the group of psoriatic arthritis, multiple sclerosis, inflammatory bowel disease (IBS), colitis ulcerosa, Crohn's disease, hepatitis, effluvium, allopecia greata, cicatricial alopecia, diabetic nephrophathy, CKD and myasthenia gravis.
  • IBS inflammatory bowel disease
  • colitis ulcerosa Crohn's disease
  • hepatitis hepatitis
  • effluvium effluvium
  • allopecia greata cicatricial alopecia
  • diabetic nephrophathy CKD
  • myasthenia gravis myasthenia gravis
  • PPAR gamma agonist for use in combination with a fumaric acid mono- and/or diester, according to the aforementioned embodiments, characterized in that the PPAR gamma agonist is selected from the group of rosiglitazone, pioglitazone, troglitazone and ciglitazone.
  • PPAR gamma agonist for use in combination with a fumaric acid mono- and/or diester, according to the aforementioned embodiments, characterized in that the fumaric acid mono- and/or diester is selected from the group of monomethyl hydrogen fumarate, dimethyl fumarate, monoethyl hydrogen fumarate and diethyl fumarate.
  • a pharmaceutical composition comprising a PPAR gamma agonist and a fumaric acid mono- and/or diester and optionally one or more excipients.
  • a pharmaceutical composition comprising rosiglitazone, pioglitazone, troglitazone or ciglitazone and a fumaric acid mono- and/or diester and optionally one or more excipients.
  • a solid oral dosage form comprising a PPAR gamma agonist and a fumaric acid mono- and/or diester.
  • a solid oral dosage form comprising rosiglitazone, pioglitazone, troglitazone or ciglitazone as a PPAR gamma agonist and a fumaric acid mono- and/or diester.
  • Kit of parts comprising a) a PPAR gamma agonist and b) a fumaric acid mono- and/or diester and optionally c) instructions for a dosing regime.
  • Kit of parts comprising a) rosiglitazone, pioglitazone, troglitazone or ciglitazone b) a fumaric acid mono- and/or diester and optionally c) instructions for a dosing regime.
  • PPAR gamma agonist for use in combination with an Nrf2 activator selected from the group of monoalkyl hydrogen fumarate, dialkyl fumarate and bardoxolone alkyl in the treatment of multiple sclerosis.
  • PPAR gamma agonist for use in combination with an Nrf2 activator according to the foregoing embodiment, characterized in that multiple sclerosis includes relapsing-remitting (RR), secondary progressive (SP), primary progressive (PP) and progressive relapsing (PR) multiple sclerosis and the first demyelinating event suggestive of MS or clinically isolated syndrome (CIS).
  • RR relapsing-remitting
  • SP secondary progressive
  • PP primary progressive
  • PR progressive relapsing
  • PPAR gamma agonist for use in combination with an Nrf2 activator according to the foregoing embodiments, characterized in that the PPAR gamma agonist is a glitazone.
  • PPAR gamma agonist for use in combination with an Nrf2 activator according to the foregoing embodiments, characterized in that the PPAR gamma agonist is a glitazone selected from the group of pioglitazone and rosiglitazone.
  • Nrf2 activator selected from the group of monomethyl hydrogen fumarate, dimethyl fumarate and bardoxolone methyl.
  • PPAR gamma agonist for use in combination with an Nrf2 activator according to the foregoing embodiments, characterized in that ratios between rosiglitazone and dimethyl fumarate are selected from 1/20 to 1/400 (w/w, rosiglitazone/dimethyl fumarate).
  • PPAR gamma agonist for use in combination with an Nrf2 activator according to the foregoing embodiments, characterized in that ratios between pioglitazone and dimethyl fumarate are selected from 1/3 to 1/60 (w/w, pioglitazone/dimethyl fumarate).
  • PPAR gamma agonist for use in combination with an Nrf2 activator characterized in that ratios between rosiglitazone and bardoxolone methyl are selected from 1/1 to 1/100 (w/w, rosiglitazone/bardoxolone methyl).
  • PPAR gamma agonist for use in combination with an Nrf2 activator according to the foregoing embodiments, characterized in that bardoxolone methyl is employed in amorphic form and ratios between rosiglitazone and bardoxolone methyl are from 1/1 to 1/20 (w/w, rosiglitazone/bardoxolone methyl).
  • PPAR gamma agonist for use in combination with an Nrf2 activator according to the foregoing embodiments, characterized in that ratios between pioglitazone and bardoxolone methyl are selected from 1/0.1 to 1/20 (w/w, pioglitazone/bardoxolone methyl).
  • PPAR gamma agonist for use in combination with an Nrf2 activator according to the foregoing embodiments, characterized in that bardoxolone methyl is employed in amorphic form and ratios between pioglitazone and bardoxolone methyl are from 1/0.1 to 1/3 (w/w, pioglitazone/bardoxolone methyl).
  • a pharmaceutical composition comprising a PPAR gamma agonist and an Nrf2 activator selected from the group of monoalkyl hydrogen fumarate, dialkyl fumarate and bardoxolone alkyl and optionally one or more excipients.
  • Nrf2 activator selected from the group of monomethyl hydrogen fumarate, dimethyl fumarate and bardoxolone methyl.
  • a pharmaceutical composition according to embodiments 28 to 30, characterized in bardoxolone methyl is employed in amorphic form and ratios between pioglitazone and bardoxolone methyl are from 1/0.1 to 1/3 (w/w, pioglitazone/bardoxolone methyl).
  • a solid oral dosage form comprising the pharmaceutical composition according to embodiments 27 to 36.
  • a solid oral dosage form comprising a PPAR gamma agonist and an Nrf2 activator selected from the group of monoalkyl hydrogen fumarate, dialkyl fumarate and bardoxolone alkyl and optionally one or more excipients, wherein the PPAR gamma agonist and the Nrf2 activator are each contained in a separate pharmaceutical formulation.
  • Nrf2 activator is bardoxolone methyl contained in an amorphous dispersion formulation obtained by spray drying or freeze drying.
  • Nrf2 activator is bardoxolone methyl contained in an amorphous dispersion formulation with methacrylic acid copolymer Type C, USP.
  • Nrf2 activator is bardoxolone methyl contained in an amorphous dispersion formulation with methacrylic acid copolymer Type C, USP in a weight ratio of 4/6.
  • a surface active agent such as sodium lauryl sulfate
  • Kit of parts comprising a) a PPAR gamma agonist and b) an Nrf2 activator selected from the group of monoalkyl hydrogen fumarate, dialkyl fumarate and bardoxolone alkyl and optionally c) instructions for a dosing regime.
  • Kit of parts comprising a) a PPAR agonist and b) an Nrf2 activator selected from the group of monoalkyl hydrogen fumarate, dialkyl fumarate and bardoxolone alkyl and optionally c) instructions for a dosing regime.
  • Nrf2 activator is dimethyl fumarate or bardoxolone methyl.
  • PPAR gamma agonist for use in combination with an Nrf2 activator for the treatment of multiple sclerosis according to the foregoing embodiments, wherein said PPAR agonist is administered to a patient simultaneously with or up to 2 days before or after an Nrf2 activator, such as those selected from the group of monoalkyl hydrogen fumarate, dialkyl fumarate and bardoxolone alkyl, is administered to said patient.
  • an Nrf2 activator such as those selected from the group of monoalkyl hydrogen fumarate, dialkyl fumarate and bardoxolone alkyl
  • PPAR gamma agonist for use in combination with an Nrf2 activator for the treatment of multiple sclerosis according to the foregoing embodiments, wherein said PPAR agonist is administered once or twice daily.
  • PPAR gamma agonist for use in combination with an Nrf2 activator for the treatment of multiple sclerosis according to the foregoing embodiments, wherein said Nrf2 activator is administered once or twice daily.
  • PPAR gamma agonist for use in combination with an Nrf2 activator in the treatment of autoimmune and/or inflammatory diseases other than psoriasis.
  • PPAR gamma agonist for use in combination with an Nrf2 activator belonging to a different chemical class, in the treatment of autoimmune and/or inflammatory diseases, such as multiple sclerosis, psoriasis or chronic kidney disease.
  • PPAR gamma agonist preferably other than pioglitazone, for use according to the aforementioned embodiment, wherein the Nrf2 activator having no significant PPAR gamma agonistic effect.
  • PPAR gamma agonist preferably other than pioglitazone, having no significant activating effect on Nrf2, for use in combination with an Nrf2 activator having no significant PPAR gamma agonistic effect, in the treatment of autoimmune and/or inflammatory diseases, such as multiple sclerosis, psoriasis or chronic kidney disease.
  • PPAR gamma agonist for use in combination with an Nrf2 activator belonging to different chemical class, wherein the Nrf2 activator is other than bardoxolone methyl and its derivatives, in the treatment of autoimmune and/or inflammatory diseases, such as multiple sclerosis, psoriasis or chronic kidney disease.
  • Composition comprising a PPAR gamma agonist and an Nrf2 activator belonging to a different chemical class, for use in the treatment of autoimmune and/or inflammatory diseases, such as multiple sclerosis, psoriasis or chronic kidney disease.
  • composition according to the aforementioned embodiment comprising a PPAR gamma agonist having no significant activating effect on Nrf2, and an Nrf2 activator having no significant PPAR gamma agonistic effect, for use in the treatment of autoimmune and/or inflammatory diseases, such as multiple sclerosis, psoriasis or chronic kidney disease.
  • Composition comprising a PPAR gamma agonist, such as pioglitazone and an Nrf2 activator.
  • Composition comprising a PPAR gamma agonist, such as pioglitazone and an Nrf2 activator having no significant PPAR gamma agonistic effect.
  • composition comprising pioglitazone and an Nrf2 activator having no significant
  • PPAR gamma agonistic effect for use in the treatment of psoriasis and other autoimmune and/or inflammatory diseases, such as multiple sclerosis, psoriasis or chronic kidney disease.
  • PPAR gamma agonist for use in combination with an Nrf2 activator having no significant PPAR gamma agonistic effect, in the treatment of multiple sclerosis.
  • PPAR gamma agonist for use in combination with an Nrf2 activator other than bardoxolone methyl, in the treatment of CKD or multiple sclerosis.
  • PPAR gamma agonist for use in combination with an Nrf2 activator according to the foregoing embodiment, characterized in that multiple sclerosis includes relapsing-remitting (RR), secondary progressive (SP), primary progressive (PP) and progressive relapsing (PR) multiple sclerosis and the first demyelinating event suggestive of MS or clinically isolated syndrome (CIS).
  • RR relapsing-remitting
  • SP secondary progressive
  • PP primary progressive
  • PR progressive relapsing
  • PPAR gamma agonist for use in combination with an Nrf2 activator according to the foregoing embodiments, characterized in that the PPAR gamma agonist is a glitazone.
  • PPAR gamma agonist for use in combination with an Nrf2 activator according to any of the foregoing embodiments, characterized in that the PPAR gamma agonist is a glitazone selected from the group of pioglitazone and rosiglitazone.
  • Nrf2 activator is selected chemical compounds belonging to the group of Michael reaction acceptors, phenols, diphenols, chalcones, isothiocyanates, thiocarbamates, quinones, naphtoquinones and 1,2 dithiole-3-thiones, wherein one or more, preferably 1, 2, 3, 4, 5, 6 or 7 H-atoms may be substituted by linear or branched alkyl and perfluoroalkyl, such as methyl, ethyl, trifluoromethyl, halogen such as Br, Cl F or I, hydroxy, alkoxy and perfluoroalkoxy, such as methoxy, ethoxy, trifluoromethoxy, cyano and nitro, which chemical compounds have not more than one or two 5- or 6-membered carbocyclic rings or 5- or 6-membered heterocyclic rings having 1, 2
  • Nrf2 activators for use in combination according to the invention and particularly according to embodiment 71 above are chemical compounds, containing less than 35, preferably less than 30, more preferably less than 25 and most preferably less than 20 or even less than 15 or less than 10 carbon atoms and/or having a molecular weight of less than 400, preferably less than 300 and most preferably less than 200 g/mol or less than 170 g/mol and/or having no significant PPAR gamma agonistic activity.
  • Compositions containing these Nrf2 activators are preferred.
  • PPAR gamma agonist for use in combination with an Nrf2 activator and compositions according to any of the foregoing embodiments, characterized in that the nrf2 activator is selected from 2-naphthoquinone, cynnamic aldehyde, caffeic acid and its esters, curcumin, reservatrol, artesunate, tert-butylhydroquinone, vitamins K1, K2 and K3 and the respective quinone or hydroquinone forms of the aforementioned quinone and hydroquinone derivatives, fumaric acid esters, i.e.
  • fumaric acid mono- and/or diester which is preferably selected from the group of monoalkyl hydrogen fumarate and dialkyl fumarate, such as monomethyl hydrogen fumarate, dimethyl fumarate, monoethyl hydrogen fumarate, and diethyl fumarate, isothiocyanate such as sulforaphane, 1,2-dithiole-3-thione such as oltipraz, 3,5-di-tert-butyl-4-hydroxytoluene, 3-hydroxycoumarin, 4-hydroxynonenal, 4-oxononenal, malondialdehyde, (E)-2-hexenal, capsaicin, allicin, allylisothiocyanate, 6-methylthiohexyl isothiocyanate, 7-methylthioheptyl isothiocyanate, sulforaphane, 8-methylthiooctyl isothiocyanate, 8-iso prostaglandin A2, alkyl pyru
  • PPAR gamma agonist for use in combination with an Nrf2 activator and compositions according to any the foregoing embodiments, characterized in that the nrf2 activator is selected from monomethyl hydrogen fumarate, dimethyl fumarate, oltipraz, 1,2-naphthoquinone, tert-butylhydroquinone, methyl or ethyl pyruvate, 3,5-di-tert-butyl-4-hydroxytoluene, diethyl and dimethyl oxaloproprionate.
  • Kit of parts comprising a) a PPAR gamma agonist other than pioglitazone and b) an Nrf2 activator selected from the group of monoalkyl hydrogen fumarate, dialkyl fumarate and bardoxolone alkyl and optionally c) instructions for a dosing regime.
  • Kit of parts comprising a) a PPAR gamma agonist having no significant activating effect on Nrf2, b) an Nrf2 activator selected from the group of monoalkyl hydrogen fumarate, dialkyl fumarate and bardoxolone and optionally c) instructions for a dosing regime.
  • Kit of parts comprising a) a PPAR gamma agonist having no significant activating effect on Nrf2, b) an Nrf2 activator having no significant PPAR gamma agonistic effect and optionally c) instructions for a dosing regime.
  • Kit of parts comprising a) a PPAR gamma agonist having no significant activating effect on Nrf2, b) an Nrf2 activator selected chemical compounds belonging to the group of Michael reaction acceptors, phenols, diphenols, chalcones, isothiocyanates, thiocarbamates, quinones, naphtoquinones and 1,2 dithiole-3-thiones, wherein one or more, preferably 1, 2, 3, 4, 5, 6 or 7 H-atoms may be substituted by linear or branched alkyl and perfluoroalkyl, such as methyl, ethyl, trifluoromethyl, halogen such as Br, Cl F or I, hydroxy, alkoxy and perfluoroalkoxy, such as methoxy, ethoxy, trifluoromethoxy, cyano and nitro, which chemical compounds have not more than one or two 5- or 6-membered carbocyclic rings or 5- or 6-membered heterocyclic rings having 1, 2 or 3 N—
  • Composition comprising a) a PPAR gamma agonist, preferably other than pioglitazone and b) an Nrf2 activator selected from the group of monoalkyl hydrogen fumarate, dialkyl fumarate and bardoxolone alkyl.
  • Composition comprising a) a PPAR gamma agonist having no significant activating effect on Nrf2, b) an Nrf2 activator selected from the group of monoalkyl hydrogen fumarate, dialkyl fumarate and bardoxolone.
  • Composition comprising a) a PPAR gamma agonist having no significant activating effect on Nrf2, b) an Nrf2 activator having no significant PPAR gamma agonistic effect.
  • composition comprising a) a PPAR gamma agonist having no significant activating effect on Nrf2, b) an Nrf2 activator selected chemical compounds belonging to the group of Michael reaction acceptors, phenols, diphenols, chalcones, isothiocyanates, thiocarbamates, quinones, naphtoquinones and 1,2 dithiole-3-thiones, wherein one or more, preferably 1, 2, 3, 4, 5, 6 or 7 H-atoms may be substituted by linear or branched alkyl and perfluoroalkyl, such as methyl, ethyl, trifluoromethyl, halogen such as Br, Cl F or I, hydroxy, alkoxy and perfluoroalkoxy, such as methoxy, ethoxy, trifluoromethoxy, cyano and nitro, which chemical compounds have not more than one or two 5- or 6-membered carbocyclic rings or 5- or 6-membered heterocyclic rings having 1, 2 or 3 N—,
  • Method of treating or preventing cancer preferably heamatological cancer such as leukemia such as acute myeloid leukaemia (AML), comprising administration of a ppar gamma agonist and an Nrf2 activator to a patient in need thereof, wherein said Nrf2 activator is capable of provoking or inducing a stimulated and/or increased nuclear translocation of Nrf2 protein and is
  • c) has a molecular weight of less than 600 g/mol
  • d) contains no or not more than one or two fused or monocyclic 5- or 6-membered carbocyclic or heterocyclic rings, having 1, 2 or 3 ring atoms selected from N, O or S.
  • the Nrf2 activator is preferably other than arsenic trioxide.
  • the Nrf2 activator is dimethyl fumarate, monomethyl hydrogen fumarate or bardoloxolone methyl.
  • Method of treating or preventing diabetes such as type II diabetes and its complications, such as arthritis, chronic kidney disease and syndrome x, comprising administration of a ppar gamma agonist and an Nrf2 activator to a patient in need thereof, wherein said Nrf2 activator is capable of provoking or inducing a stimulated and/or increased nuclear translocation of Nrf2 protein and is
  • c) has a molecular weight of less than 600 g/mol
  • d) contains no or not more than one or two fused or monocyclic 5- or 6-membered carbocyclic or heterocyclic rings, having 1, 2 or 3 ring atoms selected from N, O or S.
  • the Nrf2 activator is preferably other than bardoxolone methyl and/or a corticosteroide.
  • the Nrf2 activator is dimethyl fumarate or monomethyl hydrogen fumarate.
  • Method of treating or preventing cardiovascular diseases comprising administration of a ppar gamma agonist and an Nrf2 activator to a patient in need thereof, wherein said Nrf2 activator is capable of provoking or inducing a stimulated and/or increased nuclear translocation of Nrf2 protein and is
  • c) has a molecular weight of less than 600 g/mol
  • d) contains no or not more than one or two fused or monocyclic 5- or 6-membered carbocyclic or heterocyclic rings, having 1, 2 or 3 ring atoms selected from N, O or S.
  • Method of treating or preventing respiratory diseases comprising administration of a ppar gamma agonist and an Nrf2 activator to a patient in need thereof, wherein said Nrf2 activator is capable of provoking or inducing a stimulated and/or increased nuclear translocation of Nrf2 protein and is
  • c) has a molecular weight of less than 600 g/mol
  • d) contains no or not more than one or two fused or monocyclic 5- or 6-membered carbocyclic or heterocyclic rings, having 1, 2 or 3 ring atoms selected from N, O or S.
  • the Nrf2 activator is preferably other than a corticosteroide.
  • the Nrf2 activator is dimethyl fumarate, monomethyl hydrogen fumarate or bardoloxolone methyl.
  • Method of treating or preventing graft rejection and/or necrosis comprising administration of a ppar gamma agonist and an Nrf2 activator to a patient in need thereof, wherein said Nrf2 activator is capable of provoking or inducing a stimulated and/or increased nuclear translocation of Nrf2 protein and is
  • c) has a molecular weight of less than 600 g/mol
  • d) contains no or not more than one or two fused or monocyclic 5- or 6-membered carbocyclic or heterocyclic rings, having 1, 2 or 3 ring atoms selected from N, O or S.
  • Method of treating or preventing psoriasis comprising administration of a ppar agonist and an Nrf2 activator to a patient in need thereof, wherein said Nrf2 activator is capable of provoking or inducing a stimulated and/or increased nuclear translocation of Nrf2 protein and is
  • c) has a molecular weight of less than 600 g/mol
  • d) contains no or not more than one or two fused or monocyclic 5- or 6-membered carbocyclic or heterocyclic rings, having 1, 2 or 3 ring atoms selected from N, O or S.
  • no therapeutic amounts of hydroxurea are co-administrated to the patient.
  • no therapeutic amounts of monomethyl hydrogen fumarate are co-administrated to the patient.
  • no therapeutic amounts of dimethyl fumarate are co-administrated to the patient.
  • the Nrf2 activator is bardoloxolone methyl.
  • the ppar agonist is other than pioglitazone, such as rosiglitazone.
  • Method of treating or preventing autoimmune and/or inflammatory diseases other than psoriasis comprising administration of a ppar agonist and dialkyl fumarate and/or monoalkyl hydrogen fumarate to a patient in need thereof.
  • Method of treating or preventing autoimmune and/or inflammatory diseases other than chronic kidney disease comprising administration of a ppar agonist and bardoxolone methyl to a patient in need thereof.
  • Method of treating or preventing cardiovascular diseases, respiratory disorders, graft rejection, cancer and diabetes and its complications comprising administration of a ppar agonist and dimethyl fumarate and/or monomethyl hydrogen fumarate to a patient in need thereof.
  • Method of treating or preventing autoimmune/inflammatory and cardiovascular diseases, respiratory disorders, graft rejection, cancer and diabetes and its complications comprising administration of a ppar agonist other than pioglitazone, and dimethyl fumarate and/or monomethyl hydrogen fumarate to a patient in need thereof.
  • PPAR gamma agonist for use in combination with an Nrf2 activator in the treatment of an autoimmune and/or inflammatory disease.
  • PPAR gamma agonist for use in combination with an Nrf2 activator according to embodiment 92, characterized in that the Nrf2 activator is dimethyl fumarate.
  • PPAR gamma agonist for use in combination with an Nrf2 activator according to claim 92 , characterized in that the Nrf2 activator is bardoxolone methyl.
  • PPAR gamma agonist for use in combination with an Nrf2 activator according to one of the foregoing embodiments, characterized in that the PPAR gamma agonist is pioglitazone.
  • PPAR gamma agonist for use in combination with an Nrf2 activator according to one of the foregoing embodiments, characterized in that the PPAR gamma agonist is selected from the group of rosiglitazone, troglitazone and ciglitazone.
  • PPAR gamma agonist for use in combination with an Nrf2 activator according to one of the foregoing embodiments, characterized in that the autoimmune and/or inflammatory disease is psoriasis.
  • PPAR gamma agonist for use in combination with an Nrf2 activator according to one of the foregoing embodiments, characterized in that the autoimmune and/or inflammatory disease is multiple sclerosis.
  • PPAR gamma agonist for use in combination with an Nrf2 activator according to one of the foregoing embodiments, characterized in that the autoimmune and/or inflammatory disease is colitis ulcerosa.
  • PPAR gamma agonist for use in combination with an Nrf2 activator according to one of the foregoing embodiments, characterized in that the autoimmune and/or inflammatory disease is Crohn's disease.
  • PPAR gamma agonist for use in combination with an Nrf2 activator according to one of the foregoing embodiments, characterized in that the autoimmune and/or inflammatory disease is allopecia greata or cicatricial alopecia.
  • PPAR gamma agonist for use in combination with an Nrf2 activator according to one of the foregoing embodiments, characterized in that the autoimmune and/or inflammatory disease is diabetic nephrophathy.
  • PPAR gamma agonist for use in combination with an Nrf2 activator according to one of the foregoing embodiments, characterized in that the autoimmune and/or inflammatory disease is myasthenia gravis.
  • a pharmaceutical composition comprising pioglitazone, dimethyl fumarate and optionally one or more excipients.
  • a pharmaceutical composition comprising dimethyl fumarate and a PPAR gamma agonist selected from rosiglitazone, troglitazone and ciglitazone, and optionally one or more excipients.
  • a pharmaceutical composition comprising bardoxolone methyl and a PPAR gamma agonist selected from pioglitazone, rosiglitazone, troglitazone and ciglitazone, and optionally one or more excipients.
  • Method of treating or preventing neurodegenerative diseases comprising administration of a PPAR gamma agonist selected from the group of glitazones and a fumaric acid monoalkyl and/or dialkyl ester to a patient in need thereof.
  • a pharmaceutical composition comprising a ppar gamma agonist selected from the group of glitazones and a fumaric acid monoalkyl and/or dialkyl ester and optionally one or more excipients.
  • Method of treating or preventing neurodegenerative diseases comprising administration of a pharmaceutical composition according to embodiments 111, 112 or 113 to a patient in need thereof.
  • Method according to embodiment 114, wherein the neurodegenerative disease is multiple sclerosis.
  • a solid oral dosage form comprising a ppar gamma agonist selected from the group of glitazones and a fumaric acid monoalkyl and/or dialkyl ester and optionally one or more excipients.
  • Method of treating or preventing neurodegenerative diseases comprising oral administration of a solid oral dosage form according to embodiments 116, 117 or 118 to a patient in need thereof.
  • Method according to embodiment 119 wherein the neurodegenerative disease is multiple sclerosis.
  • Kit of parts comprising a) a ppar gamma agonist selected from the group of glitazones and b) a fumaric acid monoalkyl and/or dialkyl ester and optionally c) instructions for a dosage regime.
  • the PPAR agonist and the Nrf2 activator used in the present invention do not belong to the same chemical class of compounds, i.e. the Nrf2 activator preferably belongs to a different class of compounds as the PPAR agonist.
  • Solid oral dosage forms comprising the inventive combinations for use in treatment of inflammatory and/or autoimmune diseases are preferred.
  • Preferred is also a composition comprising dimethyl fumarate, monomethyl fumarate, optionally in form of its zinc, magnesium and/or calcium salts and a PPAR agonist.
  • This composition in the treatment of psoriasis is particularly preferred.
  • Pioglitazone and rosiglitazone tablets are commercially available and can be used as such for the combination therapy according to the invention.
  • preferred tablets are film-coated tablets containing rosiglitazone maleate equivalent to rosiglitazone, 2 mg, 4 mg, or 8 mg, for oral administration, with the following inactive ingredients: Hypromellose 2910, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol 3000, sodium starch glycolate, titanium dioxide, triacetin, and 1 or more of the following: Synthetic red and yellow iron oxides and talc.
  • preferred tablet for oral administration contain 15 mg, 30 mg, or 45 mg of pioglitazone (as the base) formulated with the following excipients: lactose monohydrate NF, hydroxypropylcellulose NF, carboxymethylcellulose calcium NF, and magnesium stearate NF.
  • no significant PPAR gamma agonistic activity or “no significant PPAR gamma agonistic effect” means that at the therapeutically useful concentration of the Nrf2 activator, no therapeutically useful PPAR gamma activation can be obtained or measured.
  • no significant effect on Nrf2 or “no significantly activating effect on Nrf2” or “no significant effect on Nrf2 activity” means that at the therapeutically useful concentration of the PPAR gamma agonist, no therapeutically useful Nrf2 activation can be obtained or measured.
  • monoalkyl fumarate and monoalkyl hydrogen fumarate are used synonymously, such as monomethyl fumarate and monomethyl hydrogen fumarate.
  • Dimethyl fumarate is added to the entire powder mixture, mixed, homogenized by means of a sieve 200, processed in the usual manner with a 2% aqueous solution of polyvidon pyrrolidone (Kollidon® K25) to obtain a binder granulate and then mixed in the dry state with the outer phase.
  • Said outer phase consists of 0.50 kg of Mg stearate and 1.50 kg of talcum.
  • the powder mixture is compressed in the usual manner into 10 mg-micro tablet cores.
  • HPMCP hydroxy propyl methyl cellulose phthalate
  • a suspension of the following composition is applied as a film coat in the same apparatus: 0.340 kg of talcum, 0.400 kg of titanium(VI) oxide Cronus RN 56, 0.324 kg of coloured lacquer L-Rot-lack 86837, 4.800 kg of Eudragit E 12.5% and 0.120 kg of polyethylene glycol 6000, pH 11 XI in a solvent mixture of the following composition: 8.170 kg of 2-propanol, 0.200 kg of demineralised water and 0.600 kg of glycerine triacetate (Triacetin). This procedure resulted in enteric-coated micro-tablets.
  • Triacetin glycerine triacetate
  • enteric-coated micro-tablets are filled into hard gelatine capsules and are sealed for use according to the invention.
  • Micro pellets can be obtained similarly according to U.S. Pat. No. 7,320,999.
  • the resulting granulated powder is then granulated by spraying a suspension obtained by dispersing lactose (36 g) in 148.6 g of an aqueous solution of hydroxypropylcellulose (7.59 g) thereon in a fluid bed granulator (manufactured by Powrex Corp., Model: LAB-1) to obtain pioglitazone hydrochloride-containing granulated powder coated with lactose.
  • croscarmellose sodium (0.728 g) and magnesium stearate (0.096 g) are added and mixed to obtain pioglitazone hydrochloride-containing mixed powder.
  • the pioglitazone hydrochloride-containing mixed powder is compressed in the form of laminate with a powder obtained according to example 1, containing dimethyl fumarate, a starch derivative (STA-RX® 1500), microcrystalline cellulose (Avicel® PH 101), PVP (Kollidon® 120), Primogel®, and colloidal silicic acid (Aerosil®).
  • a powder obtained according to example 1 containing dimethyl fumarate, a starch derivative (STA-RX® 1500), microcrystalline cellulose (Avicel® PH 101), PVP (Kollidon® 120), Primogel®, and colloidal silicic acid (Aerosil®).
  • hydroxypropyl cellulose (26.4 g, Grade SSL, Nippon Soda Co., Ltd.) (viscosity of 5% aqueous solution at 20° C.: 8 mPa ⁇ s), polyethylene glycol 6000 (1.32 g), titanium oxide (2.64 g) and pioglitazone hydrochloride (16.5 g) are dispersed in water (297 g) to give a coating solution.
  • the enteric coated micro-tablets obtained in example 1 are fed in a film coating equipment (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated with the aforementioned coating solution to give a coated preparation. Subsequently, these enteric-coated micro-tablets, which are coated with pioglitazone hydrochloride, are filled into hard gelatine capsules and are sealed for use according to the present invention.
  • an enteric-coated tablet containing the desired amount of dimethyl fumarate can be obtained, followed by a coating with a pioglitazone formulation as described above.
  • the tablets can be used as such for the combination treatment according to the invention.
  • the resulting granulated powder is then granulated by spraying a suspension obtained by dispersing lactose (36 g) in 148.6 g of an aqueous solution of hydroxypropylcellulose (7.59 g) thereon in a fluid bed granulator (manufactured by Powrex Corp., Model: LAB-1) to obtain pioglitazone hydrochloride-containing granulated powder coated with lactose.
  • a desired amount of the granulated powder thus obtained, is filled in a capsules containing dimethyl fumarate enteric-coated micro tablets obtained according to example 1, which are thereafter sealed.
  • a capsule is filled a dispersion of 20 mg of amorphous bardoxolone methyl in methacrylic acid copolymer Type C, USP in a 4/6 weight ratio of bardoxolone methyl to methacrylic acid copolymer Type C, USP having the following composition is prepared according to US2012/022156:
  • SMCC (90LM, silicified microcrystalline cellusose, as listed in the FDA Inactive Ingredients Guide): 36.36%
  • colloidal silicon dioxide 0.91%
  • the capsule is filled with an equivalent of 45 mg of pioglitazone in form of its hydrochloride as a granulated powder coated with lactose obtained according to the first part of example 4.
  • the capsule is thereafter sealed for use.
  • the bardoxolone methyl containing mixture and the pioglitazone containing mixture can be compressed into a tablet, preferably a layered tablet, wherein the formulations are arranged in a laminar manner.
  • an enteric coat is applied to the tablet.
  • Treatment in the following animal models consists of, or animals are treated with, dimethyl fumarate and pioglitazone which are dissolved or dispersed in 0.5% methocellulose/0.1% Tween80 in distilled water and administered by oral gavage twice daily.
  • Treatment groups are generally as follows: vehicle alone, dimethyl fumarate alone, pioglitazone alone or the combination of dimethyl fumarate and pioglitazone.
  • the combination according to the invention results in an improved response to treatment over the vehicle and the respective agents alone.
  • mice Female C57BL/6 mice, 8-10 weeks old (Harlan Laboratories, Livermore, Calif.), are immunized subcutaneously in the flanks and mid-scapular region with 200 ⁇ g of myelin oligodendrocyte glycoprotein peptide (MOG3S-Ss) (synthesized by Invitrogen) emulsified (1:1 volume ratio) with complete Freund's adjuvant (CFA) (containing 4 mg/nL Mycobacterium tuberculosis ).
  • CFA complete Freund's adjuvant
  • Emulsion is prepared by the syringe-extrusion method with two glass Luer-Lock syringes connected by a 3-way stopcock.
  • mice are also given an intraperitoneal injection of 200 ng pertussis toxin (List Biological Laboratories, Inc, Campbell, Calif.) on the day of immunization and on day two post immunization. Mice are weighed and examined daily for clinical signs of experimental autoimmune encephalomyelitis (EAE). Food and water is provided ad libitum and once animals start to show disease, food is provided on the cage bottom.
  • EAE experimental autoimmune encephalomyelitis
  • mice are scored daily beginning on day 7 post immunization.
  • SCID severe, combined immunodeficient
  • SCID mice are used as tissue recipients.
  • One biopsy for each normal or psoriatic volunteer is transplanted onto the dorsal surface of a recipient mouse.
  • Treatment is initiated 1 to 2 weeks after transplantation. Animals with the human skin transplants are divided into treatment groups. Animals are treated twice daily for 14 days. At the end of treatment, animals are photographed and then euthanized.
  • the transplanted human tissue along with the surrounding mouse skin is surgically removed and fixed in 10% formalin and samples obtained for microscopy. Epidermal thickness is measured. Tissue sections are stained with an antibody to the proliferation-associated antigen Ki-67 and with an anti-human CD3+ monoclonal antibody to detect human T lymphocytes in the transplanted tissue.
  • Sections are also probed with antibodies to c-myc and ⁇ -catenin.
  • a positive response to treatment is reflected by a reduction in the average epiderma thickness of the psoriatic skin transplants.
  • a positive response is also associated with reduced expression of Ki-67 in keratinocytes.
  • mice aged 4-6 weeks belong to the C57BL/6 strain weighing 17-20 g.
  • Experimental autoimmune encephalomyelitis EAE is actively induced using >95% pure synthetic myelin oligodendrocyte glycoprotein peptide 35-55 (MOG35-55, MEVGWYRSPFSRVVHLYRNGK, SEQ ID NO: 1).
  • MOG35-55 MEVGWYRSPFSRVVHLYRNGK, SEQ ID NO: 1
  • Each mouse is anesthetized and receives 200 ⁇ g of MOG peptide and 15 ⁇ g of Saponin extract from Quilija bark emulsified in 100 ⁇ L of phosphate-buffered saline.
  • a 25 ⁇ L volume is injected subcutaneously over four flank areas.
  • Mice are also intraperitoneally injected with 200 ng of pertussis toxin in 200 ⁇ L of PBS.
  • a second, identical injection of pertussis toxin is given after 48
  • Clinical scores are obtained daily from day 0 post-immunization until day 60.
  • Clinical signs are scored using the following protocol: 0, no detectable signs; 0.5, distal tail limpness, hunched appearance and quiet demeanor; 1, completely limp tail; 1.5, limp tail and hindlimb weakness (unsteady gait and poor grip with hindlimbs); 2, unilateral partial hindlimb paralysis; 2.5, bilateral hindlimb paralysis; 3, complete bilateral hindlimb paralysis; 3.5, complete hindlimb paralysis and unilateral forelimb paralysis; 4, total paralysis of hindlimbs and forelimbs (Eugster et al., Eur J Immunol 2001, 31, 2302-2312).
  • Inflammation and demyelination are assessed by histology on sections from the CNS of EAE mice. Mice are sacrificed after 30 or 60 days and whole spinal cords are removed and placed in 0.32 M sucrose solution at 40 C overnight. Tissues are prepared and sectioned. Luxol fast blue stain is used to observe areas of demyelination. Haematoxylin and eosin staining is used to highlight areas of inflammation by darkly staining the nuclei of mononuclear cells. Immune cells stained with H&E are counted in a blinded manner under a light microscope. Sections are separated into gray and white matter and each sector is counted manually before being combined to give a total for the section.
  • T cells are immunolabeled with anti-CD3+ monoclonal antibody. After washing, sections are incubated with goat anti-rat HRP secondary antibody. Sections are then washed and counterstained with methyl green. Splenocytes isolated from mice at 30 and 60 days post-immunization are treated with lysis buffer to remove red blood cells. Cells are then resuspended in PBS and counted. Cells at a density of about 3 ⁇ 106 cells/mL are incubated overnight with 20 ⁇ g/mL of MOG peptide. Supernatants from stimulated cells are assayed for IFN- ⁇ protein levels using an appropriate mouse IFN- ⁇ immunoassay system.
  • mice Female ICR mice are used. Mice are divided into treatment groups. Groups are given either water (control), 5% DSS in tap water is given at the beginning of the experiment to induce colitis, or treatment is given. After administering the treatment for 1 week, 5% DSS in tap water is also administered to the groups receiving treatment for 1 week. At the end of the experiment, all mice are killed and the large intestine is removed. Colonic mucosa samples are obtained and homogenized. Proinflammatory mediators (e.g., IL-1 ⁇ , IL-1 ⁇ , TNF- ⁇ , PGE2, and PGF2 ⁇ ) and protein concentrations are quantified. Each excised large intestine is histologically examined and the damage to the colon scored.
  • IL-1 ⁇ , IL-1 ⁇ , TNF- ⁇ , PGE2, and PGF2 ⁇ Proinflammatory mediators
  • protein concentrations are quantified. Each excised large intestine is histologically examined and the damage to the colon scored.
  • mice chronically exposed to cigarette smoke can be used for assessing efficacy in treating emphysema (see, e.g., Martorana et al., Am J Respir Crit Care Med 2005, 172, 848-835; and Cavarra et al., Am J Respir Crit Care Med 2001, 164, 886-890).
  • Six-week old C57B1/6J male mice are used. In the acute study, the mice are exposed either to room air or to the smoke of five cigarettes for 20 minutes. In the chronic study, the mice are exposed to either room air or to the smoke of three cigarettes/day for 5 days/week for 7 months.
  • mice are divided into three groups. These groups are then divided into four subgroups of 10 mice each as follows: (1) no treatment/air-exposed; (2) no treatment/smoke-exposed; (3) the combination of dimethyl fumarate and pioglitazone plus smoke-exposed; and (4) pioglitazone plus smoke-exposed; and (5) dimethyl fumarate plus smoke-exposed.
  • trolox equivalent antioxidant capacity is assessed at the end of the exposure in bronchoalveolar lavage fluid.
  • cytokines and chemokines are determined in bronchoalveolar lavage fluid using a commercial cytokine panel at 4 hours; and in the third group bronchoalveolar lavage fluid cell count is assessed at 24 hours.
  • MPTP or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine is a neurotoxin that produces a Parkinsonian syndrome in both man and experimental animals.
  • MPP+ major metabolite
  • Inhibitors of monoamine oxidase block the neurotoxicity of MPTP in both mice and primates.
  • the specificity of the neurotoxic effects of MPP+ for dopaminergic neurons appears to be due to the uptake of MPP+ by the synaptic dopamine transporter. Blockers of this transporter prevent MPP+ neurotoxicity.
  • MPP+ has been shown to be a relatively specific inhibitor of mitochondrial complex I activity, binding to complex I at the retenone binding site and impairing oxidative phosphorylation.
  • MPTP can deplete striatal ATP concentrations in mice. It has been demonstrated that MPP+ administered intrastriatally to rats produces significant depletion of ATP as well as increased lactate concentration confined to the striatum at the site of the injections. Compounds that enhance ATP production can protect against MPTP toxicity in mice.
  • mice or rats are treated either with vehicle alone, dimethyl fumarate alone pioglitazone alone or the combination of dimethyl fumarate and pioglitazone for three weeks before treatment with MPTP.
  • MPTP is administered at an appropriate dose, dosing interval, and mode of administration for 1 week before sacrifice.
  • Control groups receive either normal saline or MPTP hydrochloride alone. Following sacrifice the two striate are rapidly dissected and placed in chilled 0.1 M perchloric acid. Tissue is subsequently sonicated and aliquots analyzed for protein content using a fluorometer assay. Dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) are also quantified. Concentrations of dopamine and metabolites are expressed as nmol/mg protein.
  • DOPAC 3,4-dihydroxyphenylacetic acid
  • HVA homovanillic acid
  • mice used in the experiments are housed in a controlled environment and allowed to acclimatize before experimental use. One and one-half (1.5) hours before testing, mice are administered 0.2 mg/kg haloperidol, a dose that reduces baseline locomotor activity by at least 50%. Treatment is administered a suitably long prior to testing. The animals are then placed individually into clean, clear polycarbonate cages with a flat perforated lid.
  • Horizontal locomotor activity is determined by placing the cages within a frame containing a 3 ⁇ 6 array of photocells interfaced to a computer to tabulate beam interrupts. Mice are left undisturbed to explore for 1 h, and the number of beam interruptions made during this period serves as an indicator of locomotor activity, which is compared with data for control animals for statistically significant differences.
  • the neurochemical deficits seen in Parkinson's disease can be reproduced by local injection of the dopaminergic neurotoxin, 6-hydroxydopamine (6-OHDA) into brain regions containing either the cell bodies or axonal fibers of the nigrostriatal neurons.
  • 6-OHDA dopaminergic neurotoxin
  • a behavioral asymmetry in movement inhibition is observed.
  • unilaterally-lesioned animals are still mobile and capable of self maintenance, the remaining dopamine-sensitive neurons on the lesioned side become supersensitive to stimulation. This is demonstrated by the observation that following systemic administration of dopamine agonists, such as apomorphine, animals show a pronounced rotation in a direction contralateral to the side of lesioning.
  • dopamine agonists such as apomorphine
  • mice Male Sprague-Dawley rats are housed in a controlled environment and allowed to acclimatize before experimental use. Fifteen minutes prior to surgery, animals are given an intraperitoneal injection of the noradrenergic uptake inhibitor desipramine (25 mg/kg) to prevent damage to nondopamine neurons. Animals are then placed in an anesthetic chamber and anesthetized using a mixture of oxygen and isoflurane. Once unconscious, the animals are transferred to a stereotaxic frame, where anesthesia is maintained through a mask. The top of the head is shaved and sterilized using an iodine solution. Once dry, a 2 cm long incision is made along the midline of the scalp and the skin retracted and clipped back to expose the skull.
  • desipramine 25 mg/kg
  • a small hole is then drilled through the skull above the injection site.
  • the injection cannula is slowly lowered to position above the right medial forebrain bundle at ⁇ 3.2 mm anterior posterior, ⁇ 1.5 mm medial lateral from the bregma, and to a depth of 7.2 mm below the duramater.
  • 6-OHDA is infused at a rate of 0.5 ⁇ L/min over 4 min, to provide a final dose of 8 ⁇ g.
  • the cannula is left in place for an additional 5 min to facilitate diffusion before being slowly withdrawn.
  • the skin is then sutured shut, the animal removed from the sterereotaxic frame, and returned to its housing.
  • the rats are allowed to recover from surgery for two weeks before behavioral testing.
  • Rotational behavior is measured using a rotameter system having stainless steel bowls (45 cm dia ⁇ 15 cm high) enclosed in a transparent Plexiglas cover around the edge of the bowl and extending to a height of 29 cm.
  • rats are placed in a cloth jacket attached to a spring tether connected to an optical rotameter positioned above the bowl, which assesses movement to the left or right either as partial (45°) or full (360°) rotations.
  • Treatment is given for a suitable period prior to testing. Animals are given a subcutaneous injection of a subthreshold dose of apomorphine, and are then placed in the harness. The number of rotations are recorded for one hour. The total number of full contralateral rotations during the hour test period serves as an index of antiparkinsonian drug efficacy.
  • Heterozygous transgenic mice expressing the Swedish AD mutant gene, hAPPK670N, M671L are used as an animal model of Alzheimer's disease. Animals are housed under standard conditions with a 12:12 light/dark cycle and food and water available ad libitum. Beginning at 9 months of age, mice are divided into two groups. The groups of animals receive treatment over six weeks.
  • Behavioral testing is performed at each drug dose using the same sequence over two weeks in all experimental groups: (1) spatial reversal learning, (2) locomotion, (3) fear conditioning, and (4) shock sensitivity.
  • mice Acquisition of the spatial learning paradigm and reversal learning are tested during the first five days of test compound administration using a water T-maze as described in Bardgett et al., Brain Res Bull 2003, 60, 131-142. Mice are habituated to the water T-maze during days 1-3, and task acquisition begins on day 4. On day 4, mice are trained to find the escape platform in one choice arm of the maze until 6 to 8 correct choices are made on consecutive trails. The reversal learning phase is then conducted on day 5. During the reversal learning phase, mice are trained to find the escape platform in the choice arm opposite from the location of the escape platform on day 4. The same performance criteria and inter-trial interval are used as during task acquisition.
  • the capacity of an animal for contextual and cued memory is tested using a fear conditioning paradigm beginning on day 9. Testing takes place in a chamber that contains a piece of absorbent cotton soaked in an odor-emitting solution such as mint extract placed below the grid floor. A 5-min, 3 trial 80 db, 2800 Hz tone-foot shock sequence is administered to train the animals on day 9. On day 10, memory for context is tested by returning each mouse to the chamber without exposure to the tone and foot shock, and recording the presence or absence of freezing behavior every 10 seconds for 8 minutes. Freezing is defined as no movement, such as ambulation, sniffing or stereotypy, other than respiration.
  • the animals are tested to assess their sensitivity to the conditioning stimulus, i.e., foot shock.
  • the conditioning stimulus i.e., foot shock.
  • animals are anesthetized and the brains removed, post-fixed overnight, and sections cut through the hippocampus. The sections are stained to image ⁇ -amyloid plaques.
  • mice of the N171-82Q strain and non-transgenic littermates are treated from 10 weeks of age.
  • the mice are placed on a rotating rod (“rotarod”).
  • the length of time at which a mouse falls from the rotarod is recorded as a measure of motor coordination.
  • the total distance traveled by a mouse is also recorded as a measure of overall locomotion.
  • Mice showing improved response to treatment with the combination of dimethyl fumarate and pioglitazone remain on the rotarod for a longer period of time and travel farther than mice administered vehicle or either agent alone.
  • a series of reversible and irreversible inhibitors of enzymes involved in energy generating pathways has been used to generate animal models for neurodegenerative diseases such as Parkinson's and Huntington's diseases.
  • inhibitors of succinate dehydrogenase an enzyme that impacts cellular energy homeostasis, has been used to generate a model for Huntington's disease.
  • Brains are sectioned at 2 mm intervals in a brain mold. Slices are then placed posterior side down in 2% 2,3,5-tiphenyltetrazolium chloride. Slices are stained in the dark at room temperature for 30 min and then removed and placed in 4% paraformaldehyde pH 7.3. Lesions, noted by pale staining, are evaluated on the posterior surface of each section. The measurements are validated by comparison with measurements obtained on adjacent Nissl stain sections.
  • SOD1 superoxide dismutase
  • SOD1 mice exhibit a dominant gain of the adverse property of SOD, and develop motor neuron degeneration and dysfunction similar to that of human ALS.
  • the SOD1 transgenic mice show signs of posterior limb weakness at about 3 months of age and die at 4 months.
  • Features common to human ALS include astrocytosis, microgliosis, oxidative stress, increased levels of cyclooxygenase/prostaglandin, and, as the disease progresses, profound motor neuron loss.
  • mice overexpressing human Cu/Zn-SOD G93A mutations (B6S JL-TgN(SOD1-G93A) 1 Gur) and non-transgenic B6/SJL mice and their wild litter mates.
  • Mice are housed on a 12-hr day/light cycle and (beginning at 45 d of age) allowed ad libitum access to either test compound-supplemented chow, or, as a control, regular formula cold press chow processed into identical pellets.
  • Genotyping can be conducted at 21 days of age as described in Gurney et ah, Science 1994, 264(5166), 1772-1775.
  • the SOD1 mice are separated into groups and treatment is administered for a suitable period.
  • mice are observed daily and weighed weekly. To assess health status mice are weighed weekly and examined for changes in lacrimation/salivation, palpebral closure, ear twitch and pupillary responses, whisker orienting, postural and righting reflexes and overall body condition score. A general pathological examination is conducted at the time of sacrifice.
  • Motor coordination performance of the animals can be assessed by one or more methods known to those skilled in the art.
  • motor coordination can be assessed using a neurological scoring method.
  • neurological scoring the neurological score of each limb is monitored and recorded according to a defined 4-point scale: 0—normal reflex on the hind limbs (animal will splay its hind limbs when lifted by its tail); 1—abnormal reflex of hind limbs (lack of splaying of hind limbs weight animal is lifted by the tail); 2—abnormal reflex of limbs and evidence of paralysis; 3—lack of reflex and complete paralysis; and 4—inability to right when placed on the side in 30 seconds or found dead.
  • the primary end point is survival with secondary end points of neurological score and body weight.
  • the rotarod test evaluates the ability of an animal to stay on a rotating dowel allowing evaluation of motor coordination and proprioceptive sensitivity.
  • the apparatus is a 3 cm diameter automated rod turning at, for example, 12 rounds per min.
  • the rotarod test measures how long the mouse can maintain itself on the rod without falling. The test can be stopped after an arbitrary limit of 120 sec. Should the animal fall down before 120 sec, the performance is recorded and two additional trials are performed. The mean time of 3 trials is calculated. A motor deficit is indicated by a decrease of walking time.
  • mice are placed on a grid (length: 37 cm, width: 10.5 cm, mesh size: 1 ⁇ 1 cm2) situated above a plane support. The number of times the mice put their paws through the grid is counted and serves as a measure for motor coordination.
  • the hanging test evaluates the ability of an animal to hang on a wire.
  • the apparatus is a wire stretched horizontally 40 cm above a table. The animal is attached to the wire by its forepaws. The time needed by the animal to catch the string with its hind paws is recorded (60 sec max) during three consecutive trials.
  • Electrophysiological measurements can also be used to assess motor activity condition. Electromyographic recordings are performed using an electromyography apparatus. During EMG monitoring mice are anesthetized. The measured parameters are the amplitude and the latency of the compound muscle action potential (CMAP). CMAP is measured in gastrocnemius muscle after stimulation of the sciatic nerve. A reference electrode is inserted near the Achilles tendon and an active needle placed at the base of the tail. A ground needle is inserted on the lower back of the mice. The sciatic nerve is stimulated with a single 0.2 msec pulse at supramaximal intensity (12.9 mA). The amplitude (mV) and the latency of the response (ms) are measured.
  • CMAP compound muscle action potential
  • the amplitude is indicative of the number of active motor units, while distal latency reflects motor nerve conduction velocity.
  • the effect of the combinations according to the present invention can also be evaluated using biomarker analysis.
  • biomarker analysis To assess the regulation of protein biomarkers in SOD1 mice during the onset of motor impairment, samples of lumbar spinal cord (protein extracts) are applied to ProteinChip Arrays with varying surface chemical/biochemical properties and analyzed, for example, by surface enhanced laser desorption ionization time of flight mass spectrometry. Then, using integrated protein mass profile analysis methods, data is used to compare protein expression profiles of the various treatment groups. Analysis can be performed using appropriate statistical methods.
  • mice are immunized s.c. along the shoulders and back with 20 ⁇ g AChR with CFA in a total volume of 100 ⁇ l, and boosted twice at monthly intervals with 20 ⁇ g of AChR in CFA s.c. at four sites on the shoulders and thighs.
  • the mice are observed every other day in a blinded fashion for signs of muscle weakness characteristic of EAMG.
  • the clinical symptoms are graded between 0 and 3 (4): 0, no definite muscle weakness; 1, normal strength at rest but weak with chin on the floor and inability to raise the head after exercise consisting of 20 consecutive paw grips; 2, as grade 1 and weakness at rest; and 3, moribund, dehydrated and paralyzed.
  • Clinical EAMG is confirmed by injection of neostigmine bromide and atropine sulfate. The mice are grouped and treatment is administered for a suitable period before testing.
  • the Dundee experimental bald rat (DEBR) and the C3H/HeJ mouse are well-established animal models for alopecia greata and can be used for the study of genetic aspects, pathogenesis and therapy of the disease.
  • C3H/HeJ mice alopecia greata can be experimentally induced by grafting lesional skin from an affected mouse to a histocompatible recipient which offers the possibility to study the influence of various factors on the development of the disease.
  • the mice are grouped and treatment is administered for a suitable period before testing.
  • Treatment in the following animal models consists of, dimethyl fumarate dissolved or dispersed in 0.5% Hydroxypropyl methylcellulose (HPMC) K4 M/0.25% Tween 20 and pioglitazone dissolved or dispersed in kleptose in distilled water. Treatments were administered by oral gavage once or twice daily. Treatment groups were generally as follows: appropriate vehicles, dimethyl fumarate, pioglitazone or the combination of dimethyl fumarate and pioglitazone. The combination according to the invention results in an improved response to treatment over the vehicle and the respective agents alone.
  • HPMC Hydroxypropyl methylcellulose
  • mice Female C57BL/6 mice are ordered (Janvier France or Charles River) between 7-8 weeks old and used between 9-11 weeks after an acclimatization period.
  • Experimental autoimmune encephalomyelitis (EAE) is actively induced using >95% pure synthetic myelin oligodendrocyte glycoprotein peptide 35-55 (MOG35-55), Met-Glu-Val-Gly-Trp-Tyr-Arg-Ser-Pro-Phe-Ser-Arg-Val-Val-His-Leu-Tyr-Arg-Asn-Gly-Lys (SEQ ID NO: 1), Ref SC1272, NeoMPS).
  • Each mouse is anesthetized and receives a subcutaneous injection of 100 ⁇ l of a Complete Freunds Adjuvant (Ref 263810, Difco) emulsion containing 200 ⁇ g of MOG35-55 and 250 ⁇ g of dried and killed M. Tuberculosis H37 Ra, Ref 231141 Difco) into the lower back.
  • the emulsion is prepared by the syringe method with two syringes connected through a Luer-lock tube.
  • Mice also receive an intra-peritoneal injection of 300 ng of Pertussis Toxin (Ref BML-G100, Enzo Lifescience) diluted in 200 ⁇ l PBS. Pertussis Toxin injection is repeated 48 hours later. Mice are weighed and examined daily for clinical signs of EAE. Food and water are provided ad libitum.
  • mice were assessed for neurological deficits (clinical score) and weighed daily.
  • FIG. 2 depicts a Kaplan Meier analysis showing that control group mice start developing EAE from day 9 with complete susceptibility by day 14 post-immunisation.
  • the combination treatment with dimethyl fumarate+pioglitazone shifted the EAE onset curve. Not all animals treated with the drug combination developed signs of disease until the termination of the experiment i.e. day 22 post-immunisation.
  • the effect of the combination treatment was statistically different not only in comparison with the control group, but also in comparison with each of the drugs dosed alone.
  • FIG. 2B is a different representation of the same data.
  • Gastrointestinal changes including haemorrhage are known side-effects of dimethyl fumarate treatment.
  • Combination treatment and dimethyl fumarate alone treatment resulted in similar hyperplasia of the macrovilosity of the stomach. There was no worsening of symptoms with combination treatment.
  • Representative images of the stomach of mice chronically treated for 22 days with dimethyl fumarate, pioglitazone or their vehicles are shown in FIG. 3 to demonstrate some of these observations.
  • the synergistic efficacy discussed in the previous paragraphs was not associated with increased gastrointestinal adverse events.
  • FIGS. 1A-1B Combination treatment with dimethyl fumarate+pioglitazone is significantly more efficacious than each individual drug as stand-alone treatments or treatment with vehicle on mean clinical scores and also on body weight changes associated with disease.
  • Kruskal-Wallis non-parametric ANOVA with Dunn's multiple test correction was applied in A and Student's t-test in B.
  • Horizontal bars represent P ⁇ 0.05 where ⁇ compares combination treatment versus vehicle; ⁇ combination treatment versus dimethyl fumarate and ⁇ combination treatment versus pioglitazone.
  • FIGS. 2A-2B Combination treatment with dimethyl fumarate+pioglitazone causes a delay on the onset of disease in comparison with each individual drug as stand-alone treatments or treatment with vehicle.
  • the onset of disease was defined as the day mice first exhibit a clinical score ⁇ 1.
  • Gehan-Breslow-Wilcoxon test was applied in A and Kruskal-Wallis followed by Dunn's multiple test correction in B.
  • Horizontal bars represent P ⁇ 0.05 where ⁇ compares combination treatment versus vehicle; ⁇ combination treatment versus dimethyl fumarate and ⁇ combination treatment versus pioglitazone.
  • FIGS. 3A-3E Alteration in the macroscopical appearance of the stomach of mice chronically treated with dimethyl fumarate, but not with pioglitazone or vehicle.
  • mice or dimethyl fumarate 60 mg/kg b.i.d plus pioglitazone 10 mg/kg q.d. (D).
  • An additional group of five mice were sham-immunized (emulsion without MOG35-55) and treated with HPMC0.5%/Tween20 0.25% b.i.d. plus Kleptose 20% q.d. (E). Throughout the length of the experiment three mice were either sacrificed due to humane end-points or succumbed to disease. The forty-two remaining animals were euthanized under pentobarbital terminal anesthesia, the right atrium of the heart was incised and mice were perfused with 4% paraformaldehyde through the left ventricle.
  • the stomach of each mouse was dissected by a transection of the proximal segment of the oesophagus and the duodenum then cut open via a longitudinal incision through the longest possible axis linking the remaining stretch of duodenum and the Fundus .
  • Each piece was washed with phosphate buffered saline and open-mounted.
  • the images shown are from one representative mouse from each group. Note the normal appearance of stomachs of all groups of mice that were not exposed to dimethyl fumarate (A, C, E) and the seemingly pathological increase in macrovilosity of the stomachs of groups B and D that were treated with dimethyl fumarate as stand-alone or combination treatment with pioglitazone, respectively, giving them a thickened and rugous appearance.

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