US20100221340A1 - Method and compositions for treatment or prevention of inflammatory conditions - Google Patents

Method and compositions for treatment or prevention of inflammatory conditions Download PDF

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US20100221340A1
US20100221340A1 US12/678,352 US67835208A US2010221340A1 US 20100221340 A1 US20100221340 A1 US 20100221340A1 US 67835208 A US67835208 A US 67835208A US 2010221340 A1 US2010221340 A1 US 2010221340A1
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pharmaceutical composition
vinpocetine
vincamine
salts
composition according
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Chen Yan
Jian-Dong Li
Bradford Berk
Kye-im Jeon
Xiangbin Xu
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University of Rochester
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0046—Ear
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to the use of vincamine derivatives for treating or preventing an inflammatory condition, and pharmaceutical compositions useful for practicing these therapeutic or preventative treatments.
  • Inflammation is a hallmark of a variety of important human diseases, such as atherosclerosis (Libby et al., “Inflammation and Atherosclerosis,” Circulation 105:1135-43 (2002); Libby, “Inflammation in Atherosclerosis,” Nature 420:868-74 (2002)), lung inflammatory disease (Tetley, “Inflammatory Cells and Chronic Obstructive Pulmonary Disease,” Curr Drug Targets Inflamm Allergy 4:607-18 (2005)), and arthritis (Okamoto, “NF- ⁇ B and Rheumatic Diseases,” Endocr Metab Immune Disord Drug Targets 6:359-72 (2006)), etc.
  • steroids have been used as the main therapeutic anti-inflammatory agent.
  • steroids indeed exhibit a potent anti-inflammatory effect, the extensive usage of steroids also results in significant detrimental effects in patients.
  • NF- ⁇ B nuclear-factor ⁇ B
  • cytokines cytokines
  • chemokines chemokines
  • adhesion molecules a critical role in mediating inflammatory responses.
  • NF- ⁇ B is a dimeric transcription factor consisting of homo- or heterodimers of Rel-related proteins (Ghosh et al., “NF- ⁇ B and Rel Proteins: Evolutionarily conserveed Mediators of Immune Responses,” Annu Rev Immunol 16:225-60 (1998)).
  • NF- ⁇ B resides in the cytoplasm, forms a multi-protein complex with an inhibitory subunit, I ⁇ B ⁇ .
  • I ⁇ B ⁇ an inhibitory subunit
  • the inflammatory signals converge on a set of I ⁇ B kinases known as the IKK complex.
  • the LICK complex phosphorylates two conserved N-terminal serine residues of I ⁇ B ⁇ , leading to its ubiquitination and degradation by the proteasome.
  • NF- ⁇ B then enters the nucleus, interacts with ⁇ B elements in the promoter region of a variety of inflammatory response genes, and activates their transcription (Liu et al., “Nuclear Factor- ⁇ B Decoy: Infiltrating the Heart of the Matter in Inflammatory Heart Disease,” Circ Res 89:850-2 (2001)).
  • phosphorylation of I ⁇ B ⁇ appears to be the central point where diverse stimuli converge to regulate NF- ⁇ B.
  • IKKs IKK ⁇ (IKK1) and IKK ⁇ (IKK2)
  • IKK-1 and IKK-2 Cytokine-activated I ⁇ B Kinases Essential for NF- ⁇ B Activation,” Science 278:860-6 (1997)
  • Zandi et al. “The I ⁇ B Kinase Complex (IKK) Contains Two Kinase Subunits, IKK ⁇ and IKK ⁇ , Necessary for I ⁇ B Phosphorylation and NF- ⁇ B Activation,” Cell 91:243-52 (1997)).
  • IKK ⁇ and IKK ⁇ are Ser/Thr kinases, and each of them directly phosphorylates I ⁇ B proteins (Zandi et al., “Direct Phosphorylation of I ⁇ B by IKK ⁇ and IKK ⁇ : Discrimination Between Free and NF- ⁇ B-bound Substrate,” Science 281:1360-3 (1998); Lee et al., “MEKK1 Activates both I ⁇ B Kinase alpha and I ⁇ B Kinase beta,” Proc Natl Acad Sci USA 95:9319-24 (1998)).
  • ERIC signal-regulated kinase
  • MEKK1 NF- ⁇ B-inducing kinase
  • NM NF- ⁇ B essential modulator NEMO/IKKP1/IKK ⁇
  • IKK complex associated protein (Lee et al., “MEKK1 Activates both I ⁇ B Kinase alpha and I ⁇ B Kinase beta,” Proc Natl Acad Sci USA 95:9319-24 (1998); Yamaoka et al., “Complementation Cloning of NEMO, a Component of the I ⁇ B Kinase Complex Essential for NF- ⁇ B Activation,” Cell 93:1231-40 (1998); Rothwarf et al., “IKK-gamma is an Essential Regulatory Subunit of the I ⁇ B Kinase Complex,” Nature 395:297-300 (1998); Mercurio et al., “I ⁇ B
  • the present invention is directed to overcoming these and other deficiencies in the art.
  • a first aspect of the present invention relates to a method of treating or preventing an inflammatory condition that includes administering vincamine or a vincamine derivative to a patient under conditions effective to treat or prevent an inflammatory condition.
  • vinpocetine is either administered alone or in combination with another agent that is not a COX-2 inhibitor; and the inflammatory condition to be treated does not involve a gastrointestinal inflammatory condition.
  • a second aspect of the present invention relates to a pharmaceutical composition that includes vincamine or a vincamine derivative, and one or more of a steroid, angiotensin II receptor (type 1) antagonist, an angiotensin-converting enzyme (ACE) inhibitor, and a non-steroidal anti-inflammatory compound.
  • a pharmaceutical composition that includes vincamine or a vincamine derivative, and one or more of a steroid, angiotensin II receptor (type 1) antagonist, an angiotensin-converting enzyme (ACE) inhibitor, and a non-steroidal anti-inflammatory compound.
  • the data presented herein shows for the first time that the vincamine derivative vinpocetine acts in vitro and in vivo to inhibit NF- ⁇ B-dependent inflammatory response by targeting IKK.
  • Vinpocetine inhibits TNF ⁇ -induced NF- ⁇ B activation and the subsequent induction of pro-inflammatory mediators in a variety of cell types.
  • Vinpocetine also inhibits monocyte adhesion and chemotaxis.
  • vinpocetine potently inhibited TNF ⁇ - or LPS-induced inflammatory response in the lungs of mouse.
  • the IKK-targeted activity of vinpocetine was also shown to be independent of its well-known inhibitory effect on Phosphodiesterase 1 (PDE1) activity and Ca 2+ /Na + regulation.
  • PDE1 Phosphodiesterase 1
  • the present invention identifies vinpocetine and other vincamine derivatives as novel anti-inflammatory agents that act via disruption of the IKK pathway, which affords a novel therapeutic strategy for the treatment of various NF- ⁇ B-dependent inflammatory diseases or conditions. Based on these results, it is expected that vincamine and other vincamine derivatives that can induce IKK inhibition will similarly be useful.
  • FIGS. 1A-D show that vinpocetine inhibits TNF ⁇ -induced NF- ⁇ B-dependent promoter activity in a variety of cell types.
  • Rat aortic VSMCs FIG. 1A
  • Vascular ECs FIG. 1B
  • Lung epithelial cell A549 FIG. 1C
  • macrophage RAW264.7 FIG. 1D
  • NF- ⁇ B-Luc reporter plasmid were stimulated with or without TNF ⁇ (10 ng/ml) for 6 hours in the presence or absence of various doses of vinpocetine (Vinp) as indicated ( FIG. 1A ) or 50 ⁇ M vinpocetine ( FIGS. 1B-D ).
  • Cells were then lysed for luciferase assay. Data represent means ⁇ SD of at least three independent experiments and each experiment was performed in triplicate. *P ⁇ 0.05 vs. control and # P ⁇ 0.05 vs. TNF ⁇ alone.
  • FIG. 2 shows that vinpocetine inhibits TNFa-induced NF- ⁇ B-dependent promoter activity in Hela cells.
  • the Hela cells were transfected with the NF-kB-Luc reporter plasmid and stimulated with or without TNF ⁇ as described for FIGS. 1A-D , using various doses of vinpocetine injection solution (Vinp), an injectable commercial vinpocetine pharmaceutical composition. Cells were then lysed for luciferase assay. Data represent means ⁇ SD of at least three independent experiments and each experiment was performed in triplicate. *P ⁇ 0.05 vs. control and # P ⁇ 0.05 vs. TNF ⁇ alone.
  • FIGS. 3A-D show that vinpocetine inhibits TNF ⁇ -induced expression of pro-inflammatory mediators in a variety of cell types.
  • Rat aortic VSMCs FIG. 3A
  • Vascular ECs FIG. 3B
  • Lung Epithelial A549 cells FIG. 3C
  • Macrophage RAW264.7 FIG. 3D
  • TNF ⁇ 10 ng/ml
  • Expression of TNF ⁇ , IL-1 ⁇ , IL-8, MCP-1 and VCAM-1, ICAM-1, MIP-1 at mRNA levels were measured by Real-time quantitative RT-PCR (Q-PCR). Data represent means ⁇ SD of at least three independent experiments and each experiment was performed in triplicate. *p ⁇ 0.05 vs. control and # p ⁇ 0.05 vs. TNF ⁇ alone.
  • FIG. 4 shows that vinpocetine inhibits TNF ⁇ -induced expression of pro-inflammatory mediators dose-dependently in A549 cells.
  • the A549 cells were treated with or without TNF ⁇ (10 ng/ml) for 6 hours in the presence or absence of various doses of vinpocetine (Vinp) injection solution (commercial vinpocetine pharmaceutical composition) as indicated.
  • Vinp vinpocetine
  • Expression of TNF ⁇ , IL-1 ⁇ , and IL-8 at mRNA levels were measured by Q-PCR. Data represent means ⁇ SD of at least three independent experiments and each experiment was performed in triplicate. *p ⁇ 0.05 vs. control and # p ⁇ 0.05 vs. TNF ⁇ alone.
  • FIGS. 5A-C show that vinpocetine inhibits monocyte adhesion of EC and chemotactic activity of VSMC.
  • FIG. 5A illustrates microscopic images showing U937 monocytes adhering to HUVECs as assessed by in vitro adhesion assay. HUVECs were pretreatment with vehicle (DMSO), or 50 ⁇ M vinpocetine for 30 min exposed to TNF ⁇ (10 ng/ml) or vehicle for 6 hours. U937 monocyte adhesion on TNF ⁇ - or vehicle-stimulated HUVECs was analyzed.
  • FIG. 5B shows quantitative monocyte adhesion to HUVECs.
  • FIG. 5C shows monocyte chemotaxis to VSMCs measured by transwell migration.
  • Rat aortic VSMCs were treated with or without TNF ⁇ (10 ng/ml) for 9 hours in the presence or absence of various doses of vinpocetine.
  • VSMC-conditional medium was collected and used for monocyte chemotaxis assays in Boyden Chambers. Data represent means ⁇ SD of at least three independent experiments and each experiment was performed in triplicate. p ⁇ 0.05 vs. control and # p ⁇ 0.05 vs. TNF ⁇ alone.
  • FIGS. 6A-B shows that vinpocetine inhibits lung inflammatory response in vivo.
  • FIG. 6A shows that intraperitoneal (i.p.) administration of vinpocetine (2.5, 5, and 10 mg/kg body weight) significantly inhibited induction of TNF ⁇ , IL-1 ⁇ and MIP-2 mRNA in the lungs of mice by intratracheal (i.t.) administration of LPS (2 ⁇ g/mouse).
  • FIG. 6B shows that vinpocetine (10 mg/kg body weight) inhibited polymorphonuclear neutrophil (PMN) infiltration in broncho-alveolar lavage (BAL) fluids from the lungs of mice treated with LPS.
  • PMN polymorphonuclear neutrophil
  • BAL broncho-alveolar lavage
  • FIG. 7A-C illustrate that vinpocetine inhibits lung inflammatory response in vivo using injectable Vinpocetine solution.
  • FIG. 7A shows that intraperitoneal (i.p.) administration of vinpocetine injection solution (10 mg/kg body weight) significantly inhibited induction of TNF ⁇ , IL-1b and MIP-2 mRNA in the lungs of mice by intratracheal (i.t.) administration of LPS (2 ⁇ g/mouse).
  • FIG. 7B-C show that vinpocetine inhibited polymorphonuclear neutrophil (PMN) infiltration in broncho-alveolar lavage (BAL) fluids from the lungs of mice treated with LPS. Data represent means ⁇ SD of at least three independent experiments. *P ⁇ 0.05 vs. untreated group. # P ⁇ 0.05 vs. LPS alone.
  • PMN polymorphonuclear neutrophil
  • FIGS. 8A-H shows that vinpocetine inhibits TNF ⁇ -induced NF- ⁇ B activation by targeting IKK.
  • FIG. 8A shows the effects of vinpocetine on TNF ⁇ -induced I ⁇ B ⁇ phosphorylation and degradation.
  • Rat aortic VSMCs were treated with TNF ⁇ (10 ng/ml) for different time periods (0-30 minutes) as indicated in the presence or absence of vinpocetine (50 ⁇ M). Western Blotting analysis was carried out to evaluate the levels of phosphorylated I ⁇ B ⁇ , total I ⁇ B ⁇ - and ⁇ -actin.
  • FIG. 8B shows TNF ⁇ (10 ng/ml) induces IKK kinase activity in rat aortic VSMCs.
  • FIG. 8C shows that vinpocetine inhibits TNF ⁇ -induced IKK kinase activity.
  • VSMCs were treated with TNF ⁇ for 10 min in the presence of various doses of vinpocetine as indicated.
  • FIG. 8C shows that vinpocetine inhibits TNF ⁇ -induced IKK kinase activity.
  • VSMCs were treated with TNF ⁇ for 10 min in the presence of various doses of vinpocetine as indicated.
  • FIG. 8D illustrates the relative IKK activity as indicated. Intensities of the GST-I ⁇ B ⁇ bands in the autoradiogram were measured by densitometric scanning. Results were normalized to
  • 8E-II illustrate the effects of vinpocetine on NF- ⁇ B activation induced by expressing constitutive active form of either MEKK1 (CA-MEKK1) ( FIG. 8E ), IKK ⁇ (CA-IKK ⁇ ) ( FIG. 8F ), IKK ⁇ (CA-IKK ⁇ ) ( FIG. 8G ), or WT p65 ( FIG. 8H ) in VSMCs.
  • Data represent means ⁇ SD of at least three independent experiments. *p ⁇ 0.05 vs. vector control group. # p ⁇ 0.05 vs. either CA-MEKK1, CA-IKK ⁇ , CA-IKK ⁇ , or WT p65 alone.
  • FIGS. 9A-B shows the effects of vinpocetine on inhibition of IKK activity.
  • IKK kinase activity was analyzed by in an immune complex kinase assay.
  • IKK immune complex was obtained by immunoprecipitation from VSMCs treated with TNF ⁇ for 10 minutes.
  • Kinase assays were conducted with GST-I ⁇ B ⁇ and [ ⁇ - 32 P]ATP in the presence of cell lysates prepared from VSMCs preincubated with vinpocetine at various concentrations as indicated.
  • FIG. 9A is a representative autoradiogram showing IKK kinase activity (top) and Western blot analysis showing IKK ⁇ levels (bottom).
  • FIG. 9B shows the relative IKK activity as indicated.
  • FIG. 10 shows the effects of Ca 2+ and PDE inhibitor on TNF ⁇ -induced IKK kinase activity, I ⁇ B phosphorylation, and I ⁇ B degradation.
  • Rat aortic VSMCs were treated with TNF ⁇ (10 ng/ml) for 10 minutes in the presence of either 50 ⁇ M vinpocetine, 30 ⁇ M nifedipine (Ca 2+ channel blocker), 15 ⁇ M IC86340 (PDE1 inhibitor), 2 mM EGTA (extracellular Ca 2+ chelator), or 30 ⁇ M BAPTA/AM (intracellular Ca 2+ chelator).
  • Representative autoradiogram shows IKK kinase activity analyzed by an IKK immune complex kinase assay as described. Western Blotting analysis was carried out to evaluate the levels of phosphorylated I ⁇ B ⁇ total I ⁇ B ⁇ and ⁇ -actin. Data represent at least three independent experiments.
  • FIG. 11 shows that vinpocetine reduces the dosage of dexamethasone in inhibiting lung inflammatory response in vivo.
  • FIG. 12 is a schematic diagram depicting how vinpocetine inhibits NF- ⁇ B-dependent inflammatory response in vitro and in vivo. As indicated, vinpocetine inhibits NF- ⁇ B-dependent inflammatory response by targeting IKK, independently of its well-known action on PDE1 and Ca 2+ regulation.
  • the present invention relates to methods of treating or preventing an inflammatory condition that include the administering of vincamine or a vincamine derivative to a patient under conditions effective to treat or prevent the inflammatory condition.
  • Pharmaceutical compositions that can be used in the method of the present invention are also disclosed herein.
  • the patient can be any mammal, but preferably the mammal is a human, a non-human primate, a rodent, a cow, a horse, a sheep, or a pig. Other mammals can also be treated in accordance with the present invention.
  • the vincamine derivative can be any known or hereafter developed derivative of vincamine that can induce IKK inhibition.
  • the induced IKK inhibition can be caused either directly or indirectly by the vincamine derivative.
  • directly it is intended that' administered derivative acts on IKK itself, whereas by indirectly it is intended that either a metabolite of the derivative antagonizes IKK, or a native cellular component acted upon by the derivative (or its metabolite) antagonizes IKK.
  • vincamine or vincamine derivatives can be used to treat inflammatory conditions that are mediated via NF- ⁇ B.
  • Vincamine has the structure
  • vincamine derivatives have been synthesized and are well tolerated for therapeutic administration.
  • a number of known vincamine derivatives are identified in PubChem Substance database of the National Center for Biotechnology Information. These include, without limitation, derivatives of the ester sidechain, derivatives of the A ring to include one or more halo, hydroxyl, or alkyl substituents, derivatives of the C ring to include a keto or hydroxyl substituent, derivatives of the D ring to include one or more hydroxyl or alkyl substituents with or without unsaturation of the D ring, and unsaturation of the E ring.
  • Preferred vincamine derivatives are those that share an ability to directly or indirectly induce inhibition of (i.e., antagonize) IKK.
  • Antagonists of IKK can be measured in vitro via IKK kinase assay as described in the accompanying examples and elsewhere (see Shishodia et al., “Ursolic Acid Inhibits Nuclear Factor- ⁇ B Activation Induced by Carcinogenic Agents through Suppression of I ⁇ B ⁇ kinase and p65 Phosphorylation: Correlation with Down-regulation of Cyclooxygenase 2, Matrix Metalloproteinase 9, and Cyclin D1 ,” Cancer Res. 63(15):4375-83 (2003), which is hereby incorporated by reference in its entirety.
  • the ability of vincamine derivatives to indirectly antagonize LICK can be assessed by recovering cell lysates (following uptake of the vincamine derivative) and assessing the ability of the cell lysates to antagonize IKK; the cell lysates contain a metabolite of the vincamine derivative or a native cellular component acted upon by vincamine derivative or its metabolite, which native cellular component—when acted upon—inhibits IKK.
  • Exemplary vincamine derivatives include, without limitation:
  • R 1 is a halogen
  • R 2 can be a hydroxy group whereas R 3 can be hydrogen, or R 2 and R 3 together form an additional bond between the carbon atoms which carry them, or salts thereof (as described in U.S. Pat. No. 4,285,949 to Hannart, which is hereby incorporated by reference in its entirety);
  • Y is hydrogen, in which case Z 1 and Z 2 together represent simultaneously an oxygen atom or Z 1 is a methoxycarbonyl radical and Z 2 is a hydroxy radical, or (ii) where Y and Z 2 together form a carbon-carbon bond and Z 1 is a methoxycarbonyl radical, or salts thereof (as described in U.S. Pat. No. 4,033,969 to Sevenét et al., which is hereby incorporated by reference in its entirety);
  • R 4 is hydrogen or a hydroxyl group
  • R 5 is an alkyl group, or salts thereof (as described in U.S. Pat. No. 4,364,947 to Toyomaki et al., which is hereby incorporated by reference in its entirety);
  • R 6 is hydrogen or methoxy
  • X and Y are hydrogen or are together are a double bond between the ring carbon atoms to which they are bonded, or salts thereof (as described in U.S. Pat. No. 4,145,552 to Heymès, which is hereby incorporated by reference in its entirety); and (xviii) combinations of any two or more of the above compounds or salts thereof.
  • the vincamine derivatives can also be in the form of a salt, preferably a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salt refers to those salts that retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable.
  • the salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxylic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine and the like.
  • Other salts are known to those of skill in the art and can readily be adapted for use in accordance with the present invention.
  • vincamine derivative is also intended to encompass prodrugs of vincamine or its derivative compounds.
  • a “prodrug” refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug, or may demonstrate increased palatability or be easier to formulate.
  • prodrug a compound of the present invention which is administered as an ester (the “prodrug”) to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the active entity, such as a carboxylic acid derivative, once inside the cell where water-solubility is beneficial.
  • active entity such as a carboxylic acid derivative
  • vincamine derivative is also intended to encompass any active metabolites of these compounds. For instance, as demonstrated in the accompanying examples, vinpocetine itself does not block IKK activity; whereas cell lysates from cells treated with vinpocetine do block IKK activity. The cell lysates are believed to contain a vinpocetine metabolite that possesses the requisite activity.
  • peripherally active vincamine derivatives such as RGH-0537 and RGH-2981, both identified above.
  • those vincamine derivatives capable of crossing the blood-brain barrier can be used, such as vinpocetine.
  • the vincamine derivative is vinpocetine, but the vinpocetine is not used in combination with any other therapeutic agents (described infra).
  • Vinpocetine is produced by slightly altering the vincamine molecule, an alkaloid extracted from the Periwinkle plant, Vince minor. Vinpocetine was originally discovered and marketed in 1978 under the trade name Vavinton (Hungary).
  • vinpocetine has been widely used in many countries for preventative treatment of cerebrovascular disorder and cognitive impairment including stroke, senile dementia, and memory disturbances due to the beneficial cerebrovascular effect and neuroprotective profile (Bönöczk et al., “Role of Sodium Channel Inhibition in Neuroprotection: Effect of Vinpocetine,” Brain Res Bull 53:245-54 (2000), each of which is hereby incorporated by reference in its entirety).
  • different types of vinpocetine-containing memory enhancer named Intelectol® in Europe, and Memolead® in Japan
  • Intelectol® Intelectol® in Europe
  • Memolead® in Japan
  • Vinpocetine is a cerebral vasodilator that improves brain blood flow (Bönöczk et al., “Role of Sodium Channel Inhibition in Neuroprotection: Effect of Vinpocetine,” Brain Res Bull 53:245-54 (2000), each of which is hereby incorporated by reference in its entirety). Vinpocetine has also been shown to act as a cerebral metabolic enhancer by enhancing oxygen and glucose uptake from blood and increasing neuronal ATP bio-energy production (Bönöczk et al., “Role of Sodium Channel Inhibition in Neuroprotection: Effect of Vinpocetine,” Brain Res Bull 53:245-54 (2000), each of which is hereby incorporated by reference in its entirety).
  • Vinpocetine appears to have multiple cellular targets such as Ca 2+ /Calmodulin-stimulated phosphodiesterases (PDE1), voltage-dependent Na + -channels and Ca 2+ -channels (Bönöczk et al., “Role of Sodium Channel Inhibition in Neuroprotection: Effect of vinpocetine,” Brain Res Bull 53:245-54 (2000), each of which is hereby incorporated by reference in its entirety).
  • PDE1 Ca 2+ /Calmodulin-stimulated phosphodiesterases
  • the vincamine derivative is vinpocetine, which is used in combination with an effective amount another agent that can be used to treat the inflammation, where such agent is not a COX-2 inhibitor.
  • exemplary agents are identified hereinafter.
  • the vincamine derivative is a vincamine derivative other than vinpocetine.
  • Many of the other vincamine derivatives identified above have also been identified as vasodilators (Vas et al., “Eburnamine Derivatives and the Brain,” Med Res Rev. 25(6):737-57 (2005), which is hereby incorporated by reference in its entirety).
  • the use of vincamine derivatives other than vinpocetine in combination with an effective amount of another agent that can be used to treat the inflammation is also contemplated. Exemplary agents are identified hereinafter.
  • the present invention encompasses administration of vincamine or the vincamine derivatives prior to the onset of inflammation as a preventative (e.g., prior to surgical trauma) or after onset of an inflammatory condition as a therapeutic.
  • a preventative e.g., prior to surgical trauma
  • Chronic inflammatory conditions may be treated repeatedly. It is therefore contemplated that the administration of the vincamine or vincamine derivative can be used to reduce inflammation at an anatomical site, and thereby control symptoms associated with inflammation such as pain.
  • treating or preventing inflammation it is intended that the degree (i.e., severity) of inflammation can be reduced (as compared to the absence of treatment) or that the longevity of the inflammatory response can be shortened.
  • Exemplary modes of administration include, without limitation, orally, by inhalation, by intranasal or airway instillation, optically, intranasally, by middle ear injection, by ear drops, topically, transdermally, parenterally, subcutaneously, intravenous injection, intra-arterial injection, injection to a site of inflammation, intradermal injection, intramuscular injection, intrapleural instillation, intraperitoneally injection, intraventricularly, intralesionally, by application to mucous membranes, or implantation of a sustained release vehicle.
  • the inflammatory condition can be any inflammatory condition that is mediated via NF- ⁇ B.
  • exemplary inflammatory conditions include, without limitation, atherosclerosis, acute and chronic lung inflammation (e.g., chronic bronchitis, asthma, lung infection including bacterial and viral infections such as SARS and influenza, cystic fibrosis, etc.), inflammation of virus-infected tissues (e.g., viral lung infections, viral myocarditis, viral meningitis, etc.), ulcerative colitis, endotoxic shock, arthritis (e.g, rheumatoid arthritis, juvenile arthritis, osteoarthritis, psoriatic arthritis, reactive arthritis, viral or post-viral arthritis, ankylosing spondylarthritis, etc.), psoriasis, Crohn's disease, inflammatory bowel disease, insulin dependent diabetes mellitus, injury independent type II diabetes, ischemia induced inflammation, otitis media (middle ear infection), gout, multiple sclerosis, cachexia, and Ataxi
  • the inflammatory condition to be treated preferably is not a gastrointestinal inflammatory condition, such as ulcerative colitis, Crohn's disease, inflammatory bowel disease.
  • vincamine or vincamine derivatives can also be administered in combination with one or more other therapeutic agents, including steroids, preferably corticosteroids, angiotensin II receptor (type 1) antagonists, angiotensin-converting enzyme (ACE) inhibitors, and non-steroidal anti-inflammatory drugs (NSAIDs).
  • steroids preferably corticosteroids, angiotensin II receptor (type 1) antagonists, angiotensin-converting enzyme (ACE) inhibitors, and non-steroidal anti-inflammatory drugs (NSAIDs).
  • NSAIDs non-steroidal anti-inflammatory drugs
  • ACE inhibitors The mechanism of action for ACE inhibitors is via an inhibition of angiotensin-converting enzyme (ACE) that prevents conversion of angiotensin Ito angiotensin II, a potent vasoconstrictor, resulting in lower levels of angiotensin II, which causes a consequent increase in plasma renin activity and a reduction in aldosterone secretion.
  • ACE angiotensin-converting enzyme
  • Angiotensin Receptor Blockers ARBs
  • ARBs work as their name implies by directly blocking angiotensin II receptors and thus preventing the action of angiotensin II.
  • ACE inhibitor is intended to embrace any agent or compound, or a combination of two or more agents or compounds, having the ability to block, partially or completely, the rapid enzymatic conversion of the physiologically inactive decapeptide form of angiotensin (“Angiotensin I”) to the vasoconstrictive octapeptide form of angiotensin (“Angiotensin II”).
  • ACE inhibitors include, without limitation, the following compounds: AB-103, ancovenin, benazeprilat, BRL-36378, BW-A575C, CGS-13928C, CL242817, CV-5975, Equaten, EU4865, EU-4867, EU-5476, foroxymithine, FPL 66564, FR-900456, Hoe-065, 15B2, indolapril, ketomethylureas, KR1-1177, KR1-1230, L681176, libenzapril, MCD, MDL-27088, MDL-27467A, moveltipril, MS41, nicotianamine, pentopril, phenacein, pivopril, rentiapril, RG-5975, RG-6134, RG-6207, RGH0399, ROO-911, RS-10085-197, RS-2039, RS 5139, RS 86127, RU-44403, S-83
  • ACE inhibitor also embraces so-called NEP/ACE inhibitors (also referred to as selective or dual acting neutral endopeptidase inhibitors) which possess neutral endopeptidase (NEP) inhibitory activity and angiotensin converting enzyme (ACE) inhibitory activity.
  • NEP/ACE inhibitors particularly preferred and suitable for use herein are those disclosed in U.S. Pat. Nos.
  • angiotensin II receptor (type 1) antagonist is intended to embrace any agent or compound, or a combination of two or more agents or compounds, having the ability to block, partially or completely the binding of angiotensin II at angiotensin receptors, specifically at the AT 1 receptor. These agents are also known as Angiotension Receptor Blockers (ARBs).
  • ARBs Angiotension Receptor Blockers
  • angiotensin II antagonists include, without limitation, the following compounds: saralasin acetate, candesartan cilexetil, CGP-63170, EMD-66397, KT3-671, LR-B/081, valsartan, A-81282, MR-363, BIBS-222, BMS-184698, candesartan, CV-11194, EXP-3174, KW-3433, L-161177, L-162154, LR-B/057, LY-235656, PD-150304, U-96849, U-97018, UP-275-22, WAY-126227, WK-1492.2K, YM-31472, losartan potassium, E-4177, EMD-73495, eprosartan, HN-65021, irbesartan, L-159282, ME-3221, SL-91.0102, Tasosartan, Telmisartan, UP-269-6, YM-358
  • corticosteroids include, without limitation, triamcinolone, fluocinolone, cortisone, hydrocortisone, ciclesonide, fluticasone, flunisolide, mometasone, betamethasone, depomedrol, dexamethasone, budesonide, beclomethasone, prednisone, methylprednisolone, prednisolone, and combinations thereof.
  • NSAIDs include, without limitation, ibuprofen (2-(isobutylphenyl)-propionic acid); methotrexate (N-[4-(2,4 diamino 6-pteridinyl-methyl]methylamino]benzoyl)-L-glutamic acid); aspirin (acetylsalicylic acid); salicylic acid; diphenhydramine (2-(diphenylmethoxy)-N,N-dimethylethylamine hydrochloride); naproxen (2-naphthaleneacetic acid, 6-methoxy-9-methyl-, sodium salt, ( ⁇ )); ketorolac (1H-Pyrrolizine-1-carboxylic acid, 2,3-dihydro-5-benzoyl-, (+ ⁇ )); phenylbutazone (4-butyl-1,2-diphenyl-3,5-pyrazolidinedione); sulindac-(2)-5-fluoro-2-methyl-1-[[p-
  • Additional therapeutic agents can be co-administered either in a single formulation or separately as multiple doses. Administration is preferably carried out directly to a site or adjacent to a site of inflammation, although systemic administration routes are also contemplated. Suitable modes of administration include those identified above.
  • active agents are preferably administered in the form of pharmaceutical formulations that include one or more vincamine derivatives (or vincamine itself), alone or in combination with one or more additional active agents, together with a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier refers to any suitable adjuvants, carriers, excipients, or stabilizers, and can be in solid or liquid form such as, tablets, capsules, powders, solutions, suspensions, or emulsions.
  • the composition will contain from about 0.01 to 99 percent, preferably from about 20 to 75 percent of active compound(s), together with the adjuvants, carriers and/or excipients.
  • application to mucous membranes can be achieved with an aerosol spray containing small particles of the active agent(s) in a spray or dry powder form.
  • the solid unit dosage forms can be of the conventional type.
  • the solid form can be a capsule and the like, such as an ordinary gelatin type containing the compounds of the present invention and a carrier, for example, lubricants and inert fillers such as, lactose, sucrose, or cornstarch.
  • these compounds are tableted with conventional tablet bases such as lactose, sucrose, or cornstarch in combination with binders like acacia, cornstarch, or gelatin, disintegrating agents, such as cornstarch, potato starch, or alginic acid, and a lubricant, like stearic acid or magnesium stearate.
  • the tablets, capsules, and the like can also contain a binder such as gum tragacanth, acacia, corn starch, or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose, or saccharin.
  • a binder such as gum tragacanth, acacia, corn starch, or gelatin
  • excipients such as dicalcium phosphate
  • a disintegrating agent such as corn starch, potato starch, alginic acid
  • a lubricant such as magnesium stearate
  • a sweetening agent such as sucrose, lactose, or saccharin.
  • a liquid carrier such as a fatty oil.
  • tablets can be coated with shellac, sugar, or both.
  • a syrup can contain, in addition to active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye, and flavoring such as cherry or orange flavor.
  • the active agent(s) may also be administered in injectable dosages by solution or suspension of these materials in a physiologically acceptable diluent with a pharmaceutical adjuvant, carrier or excipient.
  • adjuvants, carriers and/or excipients include, but are not limited to, sterile liquids, such as water and oils, with or without the addition of a surfactant and other pharmaceutically and physiologically acceptable components.
  • Illustrative oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, or mineral oil.
  • water, saline, aqueous dextrose and related sugar solution, and glycols, such as propylene glycol or polyethylene glycol, are preferred liquid carriers, particularly for injectable solutions.
  • active compounds may also be administered parenterally.
  • Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils.
  • Illustrative oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, or mineral oil.
  • water, saline, aqueous dextrose and related sugar solution, and glycols such as, propylene glycol or polyethylene glycol, are preferred liquid carriers, particularly for injectable solutions. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the compounds of the present invention in solution or suspension may be packaged in a pressurized aerosol container together with suitable propellants, for example, hydrocarbon propellants like propane, butane, or isobutane with conventional adjuvants.
  • suitable propellants for example, hydrocarbon propellants like propane, butane, or isobutane with conventional adjuvants.
  • the materials of the present invention also may be administered in a non-pressurized form such as in a nebulizer or atomizer.
  • Preferred pharmaceutical compositions include, without limitation, (1) a vincamine derivative in combination with a corticosteroid, in a pharmaceutically acceptable vehicle; (2) a vincamine derivative in combination with an angiotensin II receptor antagonist, in a pharmaceutically acceptable vehicle; (3) a vincamine derivative in combination with an ACE inhibitor, in a pharmaceutically acceptable vehicle; (4) a vincamine derivative other than vinpocetine in combination with an NSAID, in a pharmaceutically acceptable vehicle; (5) a vincamine derivative in combination with a corticosteroid and an NSAID, in a pharmaceutically acceptable vehicle; and (6) a vincamine derivative in combination with a corticosteroid and one or both of an angiotensin II receptor antagonist and an ACE inhibitor, in a pharmaceutically acceptable vehicle.
  • the pharmaceutical composition for use in treating or preventing inflammation of the lungs, is in the form of a lung surfactant formulation or an inhalable formulation (either powder or nebulized fluid).
  • suitable surfactant formulations that can be modified to include vincamine or the vincamine derivative include, without limitation, exogenous lung surfactant formulations (e.g., Infasurf® (Forest Laboratories), Survanta® (Ross Products), and Curosurf® (DEY, California, USA)) and synthetic lung surfactant formulations (e.g., Exosurf® (GlaxoWellcome Inc.) and ALEC). These surfactant formulations are typically administered via airway instillation (i.e., after intubation) or intratracheally.
  • exogenous lung surfactant formulations e.g., Infasurf® (Forest Laboratories), Survanta® (Ross Products), and Curosurf® (DEY, California, USA
  • synthetic lung surfactant formulations e.g., Exosurf® (GlaxoWellcome Inc.) and ALEC.
  • the pharmaceutical composition is in the form of an injectable formulation, a transdermal formulation, or topical formulation.
  • Transdermal formulations include, without limitation, a transdermal delivery system, typically in the form of a patch that contains a depot of the active drug(s) in a pharmaceutically acceptable transdermal carrier, or simply a solution phase carrier that is deposited onto the skin, where it is absorbed.
  • transdermal delivery systems are known in the art, such as U.S. Pat. No. 6,149,935 to Chiang et al., PCT Application Publ. No. WO2006091297 to Mitragotri et al., EP Patent Application EP1674068 to Reed et al., PCT Application Publ. No. WO2006044206 to Kanios et al., PCT Application Publ. No. WO2006015299 to Santini et al., each of which is hereby incorporated by reference in its entirety.
  • Topical formulations include, without limitation, gels, pastes, creams, lotions, ointments, sprays, powders, oils, and solutions.
  • the composition may optionally be delivered via a liposome, nanosome, or mycel.
  • the topical delivery vehicle may also include one or more other topically acceptable additives known in the art.
  • a cream is a formulation that contains water and oil and is stabilized with an emulsifier.
  • Lipophilic creams are called water-in-oil emulsions, and hydrophilic creams oil-in-water emulsions.
  • the cream base for water-in-oil emulsions are normally absorption bases such as vaseline, ceresin or lanolin.
  • the bases for oil-in-water emulsions are generally mono-, di- and triglycerides of fatty acids or fatty alcohols with soaps, alkyl sulfates or alkyl polyglycol ethers as emulsifiers.
  • a lotion is an opaque, thin, non-greasy emulsion liquid dosage form for external application to the skin, which generally contains a water-based vehicle with greater than 50% of volatiles and sufficiently low viscosity that it may be delivered by pouring. Lotions are usually hydrophilic, and contain greater than 50% of volatiles as measured by LOD (loss on drying). A lotion tends to evaporate rapidly with a cooling sensation when rubbed onto the skin.
  • a paste is an opaque or translucent, viscous, greasy emulsion or suspension semisolid dosage form for external application to the skin, which generally contains greater than 50% of hydrocarbon-based or a polyethylene glycol-based vehicle and less than 20% of volatiles.
  • a paste usually contains a large proportion (20-50%) of dispersed solids in a fatty or aqueous vehicle. An ointment tends not to evaporate or be absorbed when rubbed onto the skin.
  • An ointment is an opaque or translucent, viscous, greasy emulsion or suspension semisolid dosage form for external application to the skin, which generally contains greater than 50% of hydrocarbon-based or a polyethylene glycol-based vehicle and less than 20% of volatiles.
  • An ointment is usually lipophilic, and contains >50% of hydrocarbons or polyethylene glycols as the vehicle and ⁇ 20% of volatiles as measured by LOD. An ointment tends not to evaporate or be absorbed when rubbed onto the skin.
  • a gel is usually a translucent, non-greasy emulsion or suspension, semi-solid dosage form for external application to the skin, which contains a gelling agent in quantities sufficient to impart a three-dimensional, cross-linked matrix.
  • a gel is usually hydrophilic, and contains sufficient quantities of a gelling agent such as starch, cellulose derivatives, carbomers, magnesium-aluminum silicates, xanthan gum, colloidal silica, and aluminum or zinc soaps.
  • the composition may further include one or more drying agents, anti-foaming agents; buffers, neutralizing agents, agents to adjust pH; coloring agents; emollients; emulsifying agents, emulsion stabilizers and viscosity builders; humectants; odorants; preservatives, antioxidants, and chemical stabilizers; solvents; and thickening, stiffening, and suspending agents, and a balance of water or solvent.
  • the pharmaceutical formulation may be in the form of a polymeric matrix in which the agents (vincamine or vincamine derivative) to be administered are captured. Release of the vincamine or vincamine derivative can be controlled via selection of materials and the amount of drug loaded into the vehicle.
  • Implantable drug delivery systems include, without limitation, microspheres, hydrogels, polymeric reservoirs, cholesterol matrices, polymeric systems, and non-polymeric systems. A number of suitable implantable delivery systems are known in the art, such as U.S. Pat. No. 6,464,687 to Ishikawa et al., U.S. Pat. No. 6,074,673 to Guillen, each of which is hereby incorporated by reference in its entirety.
  • Preferred dosages of vincamine or the vincamine derivative are between about 0.01 to about 2 mg/kg, preferably 0.05 to about 1 mg/kg, most preferably about 0.05 to about 0.5 mg/kg.
  • vinpocetine is commercially available in 10 mg doses.
  • Dosages for corticosteroids, ACE inhibitors, angiotensin II receptor antagonists, and NSAIDs are well known in the art. However, it is expected that the dosages of these other active agent(s) can, under certain circumstances, be reduced when co-administered with vincamine or the vincamine derivative.
  • Vinpocetine as a compound was purchased from BIOMOL (PA, USA); CavintonTM (injectable vinpocetine composition, 50 ⁇ M) was obtained from Gedeon Richter Co. (Hungary).
  • Recombinant mouse TNF ⁇ was purchased from Roche (Mannheim, Germany).
  • IC86340 PDE1 inhibitor
  • Polyclonal antibody against I ⁇ B ⁇ (sc-371) and actin (sc-1616) were purchased from Santa Cruz (CA, USA).
  • Polyclonal antibody against phospho-Ser32 I ⁇ B ⁇ (#9241) was purchased from Cell Signaling (MA, USA).
  • IKK ⁇ and IKK ⁇ antibodies were purchased from Santa Cruz (CA, USA) and Cell Signaling (MA, USA), respectively.
  • Rat aortic vascular smooth muscle cells were isolated from 250-300 g male Sprague-Dawley rats using enzymatic dissociation method and maintained in DMEM medium with 10% fetal bovine serum (FBS) (Life Technologies, Rockville, Md.) as described previously (Aizawa et al., “Role of Phosphodiesterase 3 in NO/cGMP-mediated Anti-inflammatory Effects in Vascular Smooth Muscle Cells,” Circ Res 93:406-13 (2003), which is hereby incorporated by reference in its entirety). Cells at passages 5-10 were used for experiment.
  • FBS fetal bovine serum
  • Human umbilical vein endothelial cells were isolated from human umbilical veins and grown in Medium 200 with low serum growth supplement (Cascade Biologics, Inc., Portland, Oreg.) as described previously (Che et al., “Insulin-like Growth Factor-1 Enhances Inflammatory Responses in Endothelial Cells: Role of Gab1 and MEKK3 in TNF- ⁇ -induced c-Jun and NF- ⁇ B Activation and Adhesion Molecule Expression,” Circ Res 90: 1222-30 (2002), which is hereby incorporated by reference in its entirety). Cells at passages 4 were used for experiments.
  • Human lung epithelial cell line A549 were maintained in F-12K medium supplemented with 10% FBS as described previously (19).
  • Macrophage-like cell line (U937) and monocyte cell line (THP1) were grown in RPMI 1640 medium supplemented with 10% FBS.
  • Mouse macrophage cell line RAW 264.7 (American Type Culture Collection, Manassas, Va.) was cultured in DMEM supplemented with 10% FBS. All cells were cultured at under standard conditions (5% CO 2 in air in a humidified environment at 37° C.).
  • Hela cells were maintained in minimal essential medium supplemented with 10% FBS as described previously (Shuto et al., “Activation of NF- ⁇ B by Nontypeable Hemophilus influenzae is Mediated by Toll-like Receptor 2-TAK1-dependent NIK-IKK ⁇ / ⁇ -I ⁇ B ⁇ and MKK3/6-p38 MAP Kinase Signaling Pathways in Epithelial cells,” Proc Natl Acad Sci USA 98:8774-8779 (2001), which is hereby incorporated by reference in its entirety).
  • RNA isolation and real-time RT-PCR Total RNA was isolated with TRIzol reagent (Invitrogen) by following the manufacturer's instructions.
  • TRIzol reagent Invitrogen
  • TaqMan reverse transcription reagents Applied Biosystems
  • the reverse transcription reaction was performed for 60 min at 37° C., followed by 60 min at 42° C. by using oligo (dT) and random hexamers.
  • PCR amplifications were performed by using SYBR Green Universal Master Mix.
  • reactions were performed in duplicate containing 2 ⁇ Universal Master Mix, 1 ⁇ l of template cDNA and 100 nM primers in a final volume of 12.5 ⁇ l, and they were analyzed in a 96-well optical reaction plate (Applied Biosystems).
  • the relative quantities of mRNAs were obtained by using the comparative Ct method and were normalized with predeveloped Taqman assay reagent rat or mouse glyceraldehydes-3-phosphate dehydrogenase or human cyclophilin as an endogenous control (Applied Biosystems)
  • the primer sequences are shown in Table 1 below.
  • Dual Luciferase Reporter Assay To determine the NF- ⁇ B promoter activity in response to TNF ⁇ , cells were seeded in 6-well plates (1.5 ⁇ 10 5 cells/well) overnight and transiently transfected with NF- ⁇ B promoter-luciferase constructs or a control luciferase construct pRL-TK (Promega, Calif., USA) using either FuGENE6 Transfection Reagent (Roche, Mannheim, Germany) or TransIT-LT1 transfection reagent (Minis Bio) as described previously (Aizawa et al., “Role of Phosphodiesterase 3 in NO/cGMP-mediated Anti-inflammatory Effects in Vascular Smooth Muscle Cells,” Circ Res 93:406-13 (2003), which is hereby incorporated by reference in its entirety).
  • pFC-MEKK1 were from Stratagene. Transfected cells were serum-starved for 48 h followed by exposure to TNF ⁇ for 6 h. Firefly and Renilla luciferase activities in cell extracts were measured using Dual-Luciferase Reporter Assay System (Promega, Calif., USA). The relative luciferase activity was then calculated by normalizing NF- ⁇ B promoter-driven firefly luciferase activity to control Renilla luciferase activity. Data from all experiments are presented as the relative luciferase activity (mean ⁇ S.D.) from at least three independent sets of experiments, each with triplicate measurements.
  • Immunoprecipitation and in vitro IKK kinase assay Cell lysates were prepared as described above. 1 mg of cell lysates were incubated with 1-2 ⁇ g of anti-IKK ⁇ (Santa Cruz, Calif., USA) for 1-2 h, followed by 50 ⁇ l of 50% of slurry protein A/G plus-Agarose for another 1 h or overnight at 4° C. Immunoprecipitants were then washed two times with lysis buffer and once with kinase buffer without ATP.
  • In vitro kinase assay were performed in kinase buffer containing 20 mM HEPES (pH 7.7), 2 mM MgCl 2 , 2 mM MnCl 2 , 10 ⁇ M ATP, 5 ⁇ Ci of [ ⁇ - 32 P]ATP (Amersham Biosciences, NJ, USA), 10 mM glycerophosphate, 10 mM NaF, 100 ⁇ M Na 3 VO 4 , 1 mM benzamidine, 2 ⁇ M PMSF, 1 mM DTT and protease inhibitor cocktail (Sigma, Mo., USA) at 30° C.
  • Monocyte adhesion and chemotaxis assay For monocyte adhesion assay, HUVECs were plated on 2% gelatin-coated 6-well plates and cultured to confluence. The cells were incubated in 50 ⁇ M vinpocetine for 30 min and then were treated with 10 ng/ml TNF ⁇ for 6 hours. Human U937 cells were washed 3 times with serum-free RPMI 1640 medium. Approximately 1 ml of the cells (20,000 cells/ml) were put into the wells and incubated for 20 minutes. Then un-adhered cells in the wells were washed out 3 times with serum-free RPMI 1640 medium.
  • rat aortic VSMCs were grown in normal culture medium in 12-well dish until reaching 70-80% confluence, followed by grown in serum-free medium for at least 16 hours. VSMCs were then pretreated with various doses of vinpocetine or vehicle for 30 minutes, and stimulated with TNF ⁇ (10 ng/ml) for 9 hours. The conditional medium from each well was collected for further chemotaxis assays. Monocyte chemotaxis was performed by transwell migration using a 24-well Boyden chamber (Corning Life Science, NY, USA) containing a polycarbonate filter with 5- ⁇ m pore size. 600 ⁇ l of each VSMC-conditional medium was added into duplicate wells in the lower chambers.
  • THP-1 monocytes
  • mice C57BL/6 mice were purchased from NCI, and 7 to 8 weeks-old mice were used in this study as previously described (Ishinaga et al., “TGF- ⁇ Induces p65 Acetylation to Enhance Bacteria-induced NF- ⁇ B Activation,” EMBO J 26:1150-62 (2007), which is hereby incorporated by reference in its entirety). Under the anesthesia, mice were intratracheally inoculated with lipopolysaccharide (LPS, Escherichia coli serotype 055:B5, 2 ⁇ g per mouse, Sigma) in 50 ⁇ l of PBS vehicle or TNF ⁇ (500 ng per mouse), or same volume of saline as control for 6 hours.
  • lipopolysaccharide LPS, Escherichia coli serotype 055:B5, 2 ⁇ g per mouse, Sigma
  • Vinpocetine (10 mg/kg body weight) or equal volume of vehicle control was administered via an intraperitoneal route 2 hours prior to the intratracheal inoculation of LPS or TNF ⁇ .
  • Lung tissues were collected and then stored at ⁇ 80° C. for mRNA expression analysis.
  • PMN polymorphonuclear neutrophil
  • BAL broncho-alveolar lavage
  • NF- ⁇ B plays a critical role in regulating inflammatory response
  • vinpocetine acts as an anti-inflammatory agent by inhibiting NF- ⁇ B
  • the effect of vinpocetine on NF- ⁇ B-dependent promoter activity was first evaluated by using luciferase reporter plasmids in a variety of cell types. As shown in FIG. 1A , vinpocetine potently inhibited TNF ⁇ -induced NF- ⁇ B-dependent promoter activity in vascular smooth muscle cells (VSMCs) in a dose-dependent manner. Similar results were also observed in human umbilical vein endothelial cells (HUVECs, FIG. 1B ), human lung epithelial A549 cells ( FIG.
  • FIG. 1C macrophage cell line
  • FIG. 1D macrophage cell line
  • IL-1- and LPS-induced NF- ⁇ B-dependent promoter activity was also inhibited by vinpocetine. It should be noted that no significant cytotoxic effects on cell morphology and viability were observed at the tested doses.
  • vinpocetine also inhibits TNF ⁇ -induced up-regulation of NF- ⁇ B-dependent pro-inflammatory mediators including cytokines, chemokines and adhesion molecules at the mRNA level. As shown in FIG. 3A , vinpocetine potently inhibited TNF ⁇ -induced expression of TNF ⁇ , IL-1 ⁇ , IL-8, monocot chemotactic protein 1 (MCP-1) and vascular cell adhesion molecule 1 (VCAM-1) in VSMCs, as assessed by real-time RT-PCR analysis.
  • MCP-1 monocot chemotactic protein 1
  • VCAM-1 vascular cell adhesion molecule 1
  • vinpocetine was also found to inhibit TNF ⁇ -induced expression of TNF ⁇ , IL-1 ⁇ , IL-8, MCP-1, VCAM-1, and intercellular adhesion molecule 1 (ICAM-1) in HUVECs ( FIG. 3B ), expression of TNF ⁇ , IL-1 ⁇ , and IL-8 in A549 cells ( FIG. 3C ), and expression of TNF ⁇ , IL-1 ⁇ , and macrophage-inflammatory protein 2 (MIP-2) in RAW264.7 ( FIG. 3D ).
  • IAM-1 intercellular adhesion molecule 1
  • monocyte adhesion and chemotactic activities in ECs and VSMCs were measured, respectively. These cells types are known to be dependent on adhesion molecules (such as ICAM-1 and VCAM-1) and chemokines (such as MCP-1) (Kunsch et al., “Oxidative Stress as a Regulator of Gene Expression in the Vasculature,” Circ Res 85:753-66 (1999), which is hereby incorporated by reference in its entirety).
  • adhesion molecules such as ICAM-1 and VCAM-1
  • chemokines such as MCP-1
  • monocyte adhesion to HUVECs was markedly inhibited by vinpocetine, as assessed by adhesion assay.
  • vinpocetine also inhibited monocyte chemotaxis to VSMCs induced by TNF ⁇ in a dose-dependent manner ( FIG. 5C ), as measured by transwell migration with Boyden chamber.
  • TNF ⁇ induced phosphorylation and degradation of I ⁇ B ⁇ in a time-dependent manner and pretreatment with vinpocetine markedly inhibited TNF ⁇ -induced I ⁇ B ⁇ phosphorylation and degradation. Similar results were also observed in other cell types, including ECs and macrophage. These results thus suggest that vinpocetine inhibits TNF ⁇ -induced NF- ⁇ B activation through inhibition of I ⁇ B ⁇ phosphorylation and degradation.
  • IKK is known as the major upstream kinase for I ⁇ B ⁇ phosphorylation and degradation
  • whether vinpocetine inhibits I ⁇ B phosphorylation and degradation via inhibition of IKK was determined.
  • TNF ⁇ -induced activation of IKK was confirmed by performing IKK kinase assay in TNF ⁇ -stimulated VSMCs.
  • the crude cell lysates from treated VSMCs were first immunoprecipitated with an anti-IKK ⁇ antibody and IKK kinase activity was then measured in vitro with IKK immune complexes incubated with the substrate GST-I ⁇ B ⁇ in the presence of [ ⁇ - 32 P]-ATP. As shown in FIG.
  • TNF ⁇ activity was undetectable in non-stimulated cells, became evident at 5 min upon TNF ⁇ treatment, peaked at 10 min, and declined thereafter.
  • vinpocetine inhibited TNF ⁇ -induced IKK activity in a dose-dependent manner ( FIGS. 8C and 8D ), thereby suggesting that vinpocetine inhibits TNF ⁇ -induced NF- ⁇ B activation at the level of or upstream of IKK but not at the level of I ⁇ B ⁇ .
  • IC86340 a PDE1 selective inhibitor that inhibited VSMC growth (Nagel et al., “Role of Nuclear Ca 2+ /Calmodulin-stimulated Phosphodiesterase 1A in Vascular Smooth Muscle Cell Growth and Survival,” Circ Res 98:777-84 (2006), which is hereby incorporated by reference in its entirety), did not exhibit any inhibitory effects on TNF ⁇ -induced I ⁇ B phosphorylation.
  • nifedipine a Ca 2+ -channel blocker, EGTA an extracellular Ca 2+ chelator, or BAPTA/AM, an intracellular Ca 2+ chelator
  • TNF ⁇ -induced IKK kinase activity I ⁇ B phosphorylation
  • ha degradation were examined in VSMCs.
  • none of them exhibited any significant inhibitory effects on TNF ⁇ -induced IKK kinase activity, I ⁇ B phosphorylation and I ⁇ B degradation.
  • vinpocetine inhibits TNF ⁇ -induced IKK-dependent NF- ⁇ B activation independently of its known actions on PDE1 and Ca 2+ regulation, thereby revealing a novel action of vinpocetine on IKK-NF- ⁇ B signaling.
  • FIG. 11 shows that vinpocetine reduces the dosage of dexamethasone in inhibiting lung inflammatory response in vivo.
  • Mice were administered LPS (2 ⁇ g/mouse) intratracheally (i.t.), which induces an inflammatory response indicated by induction of TNF ⁇ , IL-1 ⁇ and MIP-2 mRNA (see LPS+/Dex ⁇ /Vinp ⁇ bars in each graph).
  • Inflammation is a hallmark of a variety of important human diseases including, among others, atherosclerosis (Libby et al., “Inflammation and Atherosclerosis,” Circulation 105:1135-43 (2002); Libby, “Inflammation in Atherosclerosis,” Nature 420:868-74 (2002), each of which is hereby incorporated by reference in its entirety), lung inflammatory disease (Tetley, “Inflammatory Cells and Chronic Obstructive Pulmonary Disease,” Curr Drug Targets Inflamm Allergy 4:607-18 (2005), which is hereby incorporated by reference in its entirety), and arthritis (Okamoto, “NF- ⁇ B and Rheumatic Diseases,” Endocr Metab Immune Disord Drug Targets 6:359-72 (2006), which is hereby incorporated by reference in its entirety).
  • vinpocetine dilates blood vessels, enhances circulation in the brain, enhances oxygen utilization and glucose uptake from blood and thus activates cerebral metabolism and neuronal ATP bio-energy production.
  • vinpocetine also elicits neuronal protection effects which increase resistance of the brain to hypoxia and ischemic injury. Vinpocetine was shown to easily cross the blood-brain barrier, which makes vinpocetine one of the rather few drugs that exert a potent, favorable effect on the cerebral circulation.
  • vinpocetine was identified as a potent anti-inflammatory agent in vitro and in vivo.
  • vinpocetine is purified from natural products and has been already used in the clinic for decades, makes vinpocetine a highly promising candidate anti-inflammatory agent for the treatment of inflammatory diseases such as atherosclerosis, lung inflammatory disease, and arthritis (among others).
  • PDEs Ca 2+ /calmodulin-stimulated phosphodiesterases
  • PDEs constitute a large superfamily of enzymes grouped into eleven broad families based on their distinct kinetic properties, regulatory mechanisms, and sensitivity to selective inhibitors (Yan et al., “Functional Interplay Between Angiotensin II and Nitric Oxide: Cyclic GMP as a Key Mediator,” Arterioscler Thromb Vasc Biol 23:26-36 (2003), which is hereby incorporated by reference in its entirety).
  • Four major families of PDEs have been identified in VSMCs, including Ca 2+ /calmodulin-stimulated PDE1, cGMP-inhibited PDE3, cAMP-specific PDE4, and cGMP-specific PDE5.
  • vinpocetine is also capable of interacting with glutamate receptor as well as inhibiting voltage-gated Ca 2+ -channels in neurons at a relative high concentration, and thus regulating Ca 2+ signaling (Bönöczk et al., “Role of Sodium Channel Inhibition in Neuroprotection: Effect of Vinpocetine,” Brain Res Bull 53:245-54 (2000), which is hereby incorporated by reference in its entirety).
  • vinpocetine inhibits neuronal voltage-dependent Na + -channels and protects neurons against a Na + influx (Bönöczk et al., “Role of Sodium Channel Inhibition in Neuroprotection: Effect of Vinpocetine,” Brain Res Bull 53:245-54 (2000), which is hereby incorporated by reference in its entirety). These effects at least partially contribute to the neuroprotective effect of vinpocetine.
  • the presented data further indicate that a commercially available, injectable vinpocetine formulation, which has been widely used in patients, also has potent anti-inflammatory effect.
  • This commercial formulation was suitable to significantly inhibit TNF ⁇ -induced NF- ⁇ B activation ( FIG. 2 ) and the subsequent induction of pro-inflammatory mediators (TNF ⁇ , IL-1 ⁇ , and IL-8) ( FIG. 4 ) in a dose dependent manner in vitro.
  • Vinpocetine injection also potently inhibited LPS-induced up-regulation of pro-inflammatory mediators including TNF ⁇ , IL-1 ⁇ , and MIP-2 ( FIG. 7A ) as well as interstitial infiltration of polymorphonuclear leukocyte (PMN) in the lungs ( FIGS.
  • vinpocetine acts as a novel anti-inflammatory agent in vitro and in vivo.
  • Vinpocetine inhibits NF- ⁇ B-dependent inflammatory response by targeting IKK, independently of its well-known action on PDE1 and Ca 2+ regulation, and independent of its known role on Ca 2+ and Na + channels.
  • IKK NF- ⁇ B-dependent inflammatory response
  • the present investigation should lead to development of novel therapeutic strategies for the treatment of various mammalian inflammatory diseases.
  • vinpocetine Based on the successful use of vinpocetine, it is believed that other vincamine derivatives that share similar structure and function are promising for the treatment or prevention of inflammatory diseases in mammalian patients.
  • therapeutic agents other than selective COX-2 inhibitors such as corticosteroids, angiotensin II receptor (type 1) antagonists, angiotensin-converting enzyme (ACE) inhibitors
  • corticosteroids such as corticosteroids, angiotensin II receptor (type 1) antagonists, angiotensin-converting enzyme (ACE) inhibitors
  • ACE angiotensin-converting enzyme
  • the use of vincamine derivatives other than vinpocetine, alone or in combination with other therapeutic agents such as corticosteroids, angiotensin II receptor (type 1) antagonists, ACE inhibitors, and NSAIDs is also preferred.

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CN103265541A (zh) * 2013-06-17 2013-08-28 长沙理工大学 一种长春西汀中间体的合成方法
CN103554102A (zh) * 2013-11-22 2014-02-05 长沙理工大学 一种长春西汀的简便合成方法
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CN102911171A (zh) * 2012-10-15 2013-02-06 绍兴民生医药有限公司 一种长春西汀的半合成方法
CN102911171B (zh) * 2012-10-15 2015-03-04 绍兴民生医药有限公司 一种长春西汀的半合成方法
CN103265541A (zh) * 2013-06-17 2013-08-28 长沙理工大学 一种长春西汀中间体的合成方法
CN103554102A (zh) * 2013-11-22 2014-02-05 长沙理工大学 一种长春西汀的简便合成方法
WO2017062988A1 (en) * 2015-10-09 2017-04-13 Case Western Reserve University Compositions and methods for treating pulmonary diseases
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