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The recent acquisitions and collaborations made by Corning Life Sciences, combined with new technologies created in house, demonstrate that the company is committed to "growing our global business to serve drug discovery and biotechnology customers," says Richard Eglen, Ph.D., vp and general manager of this division of Corning. Corning has manufactured consumables for life science laboratories since the introduction of Pyrex® flasks in 1915.
In June, Corning Life Sciences introduced the Corning® Synthemax® II-SC substrate at the International Society for Stem Cell Research in Yokohama, Japan. This self-coating synthetic surface reportedly mimics the natural cell environment. It supports adhesion and expansion of stem cells in their undifferentiated state and directs differentiation into specialized cell types.
Synthemax II-SC is a xeno-free alternative to biological coatings and mouse feeder cell layers used to grow human embryonic stem and induced pluripotent stem cell cultures. Materials scientists at Corning created this flexible surface that can be coated onto any vessel.
"Our combined expertise in surface chemistry, injection molding, and plastics puts us in a position to develop surfaces to optimize growth of specific cell lines. Synthemax is just one example of how this expertise has allowed us to continually develop specialized surfaces to meet emerging needs," says Dr. Eglen.
Also in June, Corning Life Sciences entered into collaboration with TAP Biosystems to develop an automated system that handles up to four of Corning's Hyperstack®-120 cell culture vessels simultaneously. This provides better control and more consistent results for high-throughput bioprocessing at a lower cost, Dr. Elgen notes.
Corning's Hyperstack cell culture vessels "use our injection molding fabrication system to create a space to grow cells in high density within a small footprint," he explains.
Compared to other stacked-plate products, the multilayered, gas-permeable film technology delivers more cells per volume, he continues, adding that cells grow with less variability on the expanded surface area, saving labor and space costs.
Hyperstack cell culture vessels, which are also available as closed systems, can be used for cell-line development, seeding, and manufacturing in bioprocessing systems.
All types of cells need nutrients to grow, and Corning Life Sciences expanded its product offering to include the cellgro® brand of cell culture media and molecular biology reagents for tissue and cell culture applications when it acquired Mediatech at the end of last year.
"Corning has a strong footprint in cell culture vessels, so acquiring Mediatech was a natural step forward," says Dr. Eglen. The acquisition expands product offerings in off-the-shelf or fully customized beginning-to-end cell culture workflow solutions for upstream and downstream cell culture.
The product line, now sold as Corning cellgro, improves efficiencies and produces more reliable, consistent results, according to Dr. Eglen. Corning cellgro products include culture media, basal salt solutions, antibiotics, reagents, sera, and flexible packaging systems.
Combined with Corning's disposable vessels and specialized surfaces, the cell culture media products form a comprehensive portfolio for cell culture growth, scale-up, sample preparation, separation, and harvesting, maintains Dr. Eglen.
"The combination of Corning's Hyperstack vessels, closed system solutions, cellgro, and related single-use products play an important role in bioprocessing and scale-up operations," he notes.
The acquisition of France-based Plastiques Gosselin added a range of consumables for microbiology and quality control testing. Gosselin's products include Petri dishes, inoculating loops, dippers, containers, and disposable bags. These diversified consumables serve multiple industry segments, such as food, beverage, and environmental testing laboratories.
Currently undergoing regulatory approval is the agreement to acquire the Discovery Labware unit from Becton Dickinson. When complete, the acquisition will expand offerings in drug discovery tools, bioprocess solutions, and laboratory research instruments.
Corning Life Sciences will obtain four main product platforms from Discovery Labware—plastic consumables, including tubes, pipettes, Petri dishes, tissue culture dishes, and flasks; cell-based assays and cell cultureware; liquid-handling products; and ADME research.
"We expect the deal to close by the end of the year," says Dr. Eglen.
With a keen interest in emerging countries, Corning Life Sciences recently opened a manufacturing and distribution center in Wujiang, China.
"We see China as an important part of our growth strategy," points out Dr. Eglen, and the Wujiang facility "helps us capitalize on the growth of biotechnology and drug discovery there."
West coast clients have easier access to Corning technology and expertise at a recently opened demonstration laboratory located in the Corning West Technology Center in Palo Alto, CA. The lab allows clients to evaluate a range of Corning products, as well as collaborate directly with Corning scientists. Among other technologies, the lab houses a demonstration unit of the latest Corning Epic® label-free system.
This high-throughput screening platform is based on optical biosensor technology. It processes up to 40,000 wells in eight hours and integrates with existing automation.
The Epic System performs biochemical and cell-based drug discovery applications in 96-well, 384-well, and 1,536-well microplates and evaluates promising new drug leads. It also allows the observation of direct biological interactions that are not generally detected in high-throughput applications, explains Dr. Eglen.
Types of Epic assays include small-molecule binding, functional protease, kinase, protein-protein interactions, G-protein coupled receptors, viral detection, and ion channels. Corning field application scientists can provide hands-on training on the Epic System at the new demonstration lab. As Corning Life Sciences continues to grow, "we view drug discovery and biotechnology customers as strong components of our customer base," says Dr. Eglen. Other laboratories that offer Epic System demonstrations are located in Kennebunk, ME, and Fontainebleau, France.
Researchers can visit another applications laboratory at California-based Axygen, which Corning Life Sciences acquired in 2009. Axygen's product portfolio includes tips for manual and robotic applications, PCR consumables, and a range of magnetic bead-based kits and accessories to increase efficiencies in nextgen sequencing and genomics workflows.
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MDMA (commonly known as the empathogen "ecstasy") is classified as a Schedule 1 drug, which is reserved for compounds with no accepted medical use and a high abuse potential. Two researchers from Stanford, however, call for a rigorous scientific exploration of MDMA's effects to identify precisely how the drug works, the data from which could be used to develop therapeutic compounds.Do you agree that ecstasy should be studied for its potential therapeutic benefits?
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need a peacefull isolated hotel with easy eccess to other part of batam you will find GGI hotel is a place for you. Soon a new township and mall (Harbour Mall) will be opened in middle of next year.If you are looking forward to shope in one of the biggest mall in Batam just book this hotel in the middle of next year. Breakfast is average with varieties of western, local and eastern cuisine.Rooms are spacious and some of the rooms are just renovated and upgraded
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To download Audio Sermons, Right click on the name of the sermon you want, and select "Save Target As". Downloads typically last a few minutes. If the download pauses, cancel it, and repeat, however your computer will have kept in memory the portion it already downloaded. Audio Sermons provided by Landmark United Pentecostal Church.
Holiness Audio Sermons
Holy in the Word
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Holy Smoke - Part 1
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What an ... Apostolic Church looks like <---Be Wise
Christians Should be Holy - pt1 <---Be Wise
The Pos & Neg Aspect of Holiness - pt 2 <---Be Wise
The Mark of the Best - pt. 1
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- Neuroscientists' study sheds light on how words are represented in the brain 21 July 2016
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North Wales Sea Fishing Forum. Sunnyrhyl.com Sea Fishing Forum
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Message board for New Hampshire Bass Casters.


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Light Keepers: Ten Boys Who... 5-Volume Boxed Set
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Vendor: Christian Focus
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Ages: 5-11
Series: Light Keepers
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This giftbox collection of colorful stories makes a perfect present that will delight young adventurers. This edition includes Ten Boys who Changed the World, Ten Boys who Didn't Give In, Ten Boys who Made a Difference, Ten Boys who Made History, and Ten Boys who Used Their Talents.
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KarenAshburn, VAAge: 45-54Gender: female5 Stars Out Of 5Uplifting bedtime reading!January 9, 2014KarenAshburn, VAAge: 45-54Gender: femaleQuality: 5Value: 5Meets Expectations: 5My husband has been reading a chapter a night to my eight-year-old son at bedtime. They are relatively short and easy to read. They are very uplifting, encouraging and make for some wonderful bedtime discussion. My husband is talking to my son about praying for what God has planned for his life like the boys in this series. Brings tears to my eyes!
momma2ck5 Stars Out Of 5March 22, 2013momma2ckQuality: 5Value: 5Meets Expectations: 5Purchased the "Ten Girls Who" for my 8 year old daughter. Trying these for my son. My daughter plans to "steal" them from her brother- or at least listen in! : )
marjaydGrande Prairie, ABAge: 25-34Gender: female5 Stars Out Of 5Good reading material!May 7, 2012marjaydGrande Prairie, ABAge: 25-34Gender: femaleQuality: 4Value: 4Meets Expectations: 4Bought these for our 12 year old son for Easter, and he absolutely loved them! What I love about them is that they are true, educational, and inspiring to young minds. :)
Crystal SchmittAge: 25-34Gender: female3 Stars Out Of 5Not what I expectedAugust 6, 2011Crystal SchmittAge: 25-34Gender: femaleQuality: 4Value: 4Meets Expectations: 3These books give a 1 chapter summary of 10 boys (per book) who accomplished great things. I was hoping for more in-depth bios of fewer boys. (I was under the impression that it was 10 boys total, not 10 per book.) My son (8) said that he liked the books, and I suppose it would be good to spark interest and start further study on some of these men.
For what it is, it is well done.
HomeschoolMamaCanadaAge: 25-34Gender: female5 Stars Out Of 5Wonderful, inspiring books for boys & girls alike!August 6, 2011HomeschoolMamaCanadaAge: 25-34Gender: femaleQuality: 5Value: 5Meets Expectations: 5I bought this set and the Ten Girls Who set for my 8-year-old daughter. The box is sturdy and colorful. There are no illustrations inside. The stories are interesting and engaging, and there are questions at the end to help the young reader go deeper, including some Scripture passages to consider. Each story starts when the character was a child, which makes it easier for children to relate to. If you want to encourage your young reader to follow Christ and do great things for God, as others who have gone before have done, I would definitely recommend these books!
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Ronald Wilson Fore
Learn about upgrading this memorial...
Dec. 7, 1937
Apr. 25, 2005
Source: Daily Ardmoreite, Ardmore, Oklahoma
Memorial service for Ronald Wilson Fore, 68, will be at 10 a.m. Wednesday, April 27, 2005, at First United Methodist Church.
Born Dec. 7 1937, in the Healdton, Okla. area to Wilson and Modell Clark Fore, he died April 25, 2005, in an Oklahoma City hospital. He was preceded in death by his parents; and brother, Clark "Butch" Fore.
Mr. Fore had been a resident of the Ardmore area all his life. He served his country in the U.S. Army. Ronald attended the University of Oklahoma. He was owner and operator of Fore Trucking Company, president of Robertson Drilling, and he owned Fore Lumber Company. He attended First Methodist Churches in Healdton and Ardmore. He and Mary Ann Sabo were married on July 30, 1986, in Love County. Survivors include his wife, of the home; a daughter, Lisa Walker and husband, Russ, Dallas; sons, Truett, Wesley and Chris Fore, all of Ardmore; stepsons, Bill Coe, Oklahoma City, and Bob Coe, Houston; stepdaughter, Kristi Pearson and husband, Jeff, Ardmore; grandchildren, Doak Walker, Dallas, Brittany Baxter, Ardmore, and Katie Coe, Oklahoma City.
Memorials can be made to the Oklahoma Medical Research Foundation (OMRF), American Cancer Society or Good Shepherd Clinic.
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Awesome to see this mappack still in development
Because there is nothing like murdering demons to that classic guitar riff.
Awesome to see this mappack still in development
Please dont forget about the HL1 stuff guys!
"Thanks for flooding my updates with yet another useless file."
Then why do you have a Moddb account? Get the whining somewhere else ********
Lookin great for being a WIP
Just remember: Quality>Quantity
Epic! How many missions there will be in the final release?
I want to know how to switch items with the new inventory, i can only use the shortcut keys for the lightamp and the hevsuit. For example your flares addon, i pick up a box of flares and i use one by pressing enter but i cant even use the old inventory.
From which game are the voices of the traitor marines?
Great work, but we're still going to have real OP4 entities?
LOL i had to use the gamma panel to see this. Great mapping!
Really lookin forward to this. Best wishes on finishing and releasing the mod.
Exactly, Das_M released a 15-map halfway version in 2015 but later the FB page dissapeared. And his YT channel is also inactive
I REALLY want to know what happened to the map pack Beyond hell and earth :(
Old school goodness.
Are you quitting on me? Well, are you? Then quit, you slimy ******* walrus-looking piece of ****! Get the **** off of my obstacle! Get the **** down off of my obstacle! NOW! MOVE IT! Or I'm going to rip your balls off, so you cannot contaminate the rest of the world! I will motivate you, Private Pyle, IF IT SHORT-DICKS EVERY CANNIBAL ON THE CONGO!
Keep the good mapping coming! Theres not enough quality content for OP4
Very Quake-ish
Standing Ovation
This mod is the cancer of Doom
High detailed maps with the oldschool alpha-HL style. YES
Very glad to see this still going strong, these outdoor zones are great!
Let's hope this won't have too many gimmicks as the original
Unless they have a museum at Black Mesa and the HECU took borrowed some stuff from there :P
Animal mother from Full Metal Jacket would be proud of this
Awesome, even if the music has nothing to do with Half Life it still fits OK. The WW2 german tanks at Mission 4 are placeholders?
Hey Sarge, this will cover Phobos, Deimos and Hell or its just a Episode 1 remake?
Carmack said via Twitter that he worked on SnapMap before leaving Id. This may be more than just a Timesplitters-ish editor, but i think a SDK would still be necessary.


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Golty: Soap
Maximum grip.
Advertising Agency: Euro RSCG Bogotá, Colombia
General Creative Director: Jimmy Vargas
Cretive Director: Bryan Moreno
Art Director: Gustavo Mantilla
Illustrator: Liberum
Executive Producer: Andrés Mejía
Published:March, 2010
10 comments
AdaddictedMar 28, 2010 - 2:12
there's not a wow factor, but this one is the best of the three.
Phil LestinoMar 28, 2010 - 5:04
So they take the gloves into the bath after the match..........
Ed RapportMar 28, 2010 - 14:25
nice ad. they could have at least used a different color other than black for the two toneness of a soccer ball. but good concept and the soccer ball ad is dope as well.
R U seriousMar 28, 2010 - 16:01
Sorry. This is bad. Not only the art is bad but showing the antithesis of the product benefit is stupid.
Say my name, say my name...


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Algeria EgyptLibyaSudan
AfghanistanChinaCentral AsiaIndia-PakistanIndonesiaKoreaMyanmarNepalPhilippinesMicronesiaSri LankaThailand
Potential HotspotsTerrorismTop Ten Conflicts
Pakistani terrorists continue to defy Pakistani police efforts to shut them down. Moreover, more of the Pakistani Islamic radicals are showing up in India, and taking part in suicide attacks there. All of this appears to be part of the radicals long held plan to increase hostility between India and Pakistan, and a eventually a nuclear war that would allow the radicals to take over in Pakistan.
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|Publication number
|Publication type
|Application number
|Publication date
|Feb 17, 2004
|Filing date
|Nov 13, 2001
|Priority date
|May 29, 2001
|Fee status
|Also published as
|Publication number
|Geeta Saxena, Christopher R. Tudan, Ahmed Merzouk, Hassan Salari
|Original Assignee
|Chemokine Therapeutics Corporation
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (8), Referenced by (18), Classifications (25), Legal Events (9)
|External Links: USPTO, USPTO Assignment, Espacenet
The invention relates to organic compounds acting as chemokine receptor ligands, including antagonists of CXC chemokine receptor-4 (CXCR-4) and therapeutic uses thereof, such as in the treatment of hematopoietic cells and in the treatment of chemokine or chemokine receptor mediated diseases.
Cytokines are soluble proteins secreted by a variety of cells including monocytes or lymphocytes that regulate immune responses. Chemokines are chemotactic cytokines that belongs to a large family of chemoattractant molecules involved in the directed migration of immune cells. They regulate a variety of biological responses and promote the recruitment of multiple lineages of leukocytes and lymphocytes to a specific body organ tissues. The functional role generally assigned to chemokines in the immune process is to elicit mobilization of immune cells against pathogenic organisms by direct recruitment and activation. Based on their structural similarity, chemokines may be subdivided into four subfamilies, CXC, CC, C and CX3C, depending on the position of their first two cysteine residues. SDF-1 belongs to the CXC chemokine family. It exerts its biological activities by binding to a specific cell surface receptor, CXC Chemokine receptor 4 (CXCR-4). In human, CXC chemokine genes are clustered on chromosome 4 (with the exception of SDF-1 gene, which has been localized to chromosome 10) and CC chemokine genes are clustered on chromosome 17.
The molecular targets for chemokines are cell surface receptors CXCR-4, one such receptor is a G protein coupled 7 transmembrane protein, and was previously called LESTR. Majority of chemokine receptors identified to date bind several distinct chemokines at high affinity, with the exception of CXCR-4, which binds only SDF-1. SDF-1 is thought to be the natural ligand for CXCR-4. CXCR-4 is widely expressed on cells of hematopoietic origin, and is a major co-receptor with CD4+ for human immunodeficiency virus 1 (HIV-1). CXCR-4 was found to be overexpressed in glioblastoma multiforme tumor tissue (GMTT), as compared to normal brain tissue (NBT). Expression analysis indicated that CXCR-4 is overexpressed in 57% of the primary glioblastoma tissues and in 8% of the glioblastoma cell lines. Gene-specific RT-PCR analysis indicated that the CXCR-4 gene is overexpressed in several malignant glioma tissues, breast tumor tissues and cell lines. Northern blot analysis indicated expression of CXCR-4 at high levels in certain leukemias, uterine cancer, and Burkitt's lymphoma cell lines. The occipital and temporal lobe showed high levels of CXCR-4 in normal human brain. In adult mouse, CXCR-4 is expressed only in brain, spinal cord, bone marrow, and pituitary gland. Antisense CXCR-4 overexpression in glioblastoma cells caused inhibition of cell proliferation and induction of cellular differentiation in vitro. These findings indicate that CXCR-4 expression may play an important role during embryonic development and also in the genesis of human gliomas; that CXCR-4 plays an important role in the tumorigenic properties of brain, breast, and other tumor types. Its unique expression during mouse development also indicates that CXCR-4 plays an important role in the normal function of brain, spinal cord, and bone marrow during development.
SDF-1 gene occurs in two alternative splicing variants, producing SDF-1 alpha and SDF-1 beta (together referred to herein as SDF-1). The native and genomic amino acid sequences of SDF-1 alpha and SDF-1 beta have been determined .
SDF-1 is functionally distinct from other chemokines in that it is reported to have a fundamental role in the trafficking, exporting and homing of bone marrow progenitor cells. It is also structurally distinct in that it has only about 22% amino acid sequence identity with other CXC chemokines. SDF-1 appears to be produced constitutively by several cell types, and particularly high levels are found in bone-marrow stromal cells. A basic physiological role for SDF-1 is implied by the high level of conservation of the SDF-1 sequence between species. In vitro, SDF-1 stimulates chemotaxis of a wide range of cells including monocytes and bone marrow derived progenitor cells. It also stimulates a high percentage of resting and activated T-lymphocytes.
Chemokines and their receptors determine the distribution of leukocytes within tissues both in healthy and disease states. CXCR-4 and its ligand SDF-1 are found to be involved in the perivascular accumulation of T cells in rheumatoid arthritis. Mast cells are generally considered to be less mobile, residing within tissue sites. However, mast cells increase during inflammation, and are recognized to be important in regulating local neutrophil infiltration. Stimulation of human mast cells with SDF-1 induces a significant increase in intracellular calcium levels. In vitro, SDF-1 mediates dose-dependent migration of human cord blood-derived mast cells and HMC-1 cells across HUVEC monolayer.
SDF-1 is a chemoattractant for CD34(+) progenitor cells, both in vitro and in vivo, and SDF-1 and CXCR-4 are involved in homing of progenitor cells to bone marrow. Experiments indicated that SDF-1 is involved in hematopoiesis, and promotion of the proliferation of human CD34(+) cells purified from normal adult peripheral blood (PB). When CXCR-4 was expressed on PB CD34(+) cells, the amount of CXCR-4 on PB CD34(+) cells was found to be 10 times higher when CD34(+) cells were purified following overnight incubation. CXCR-4 overexpression is correlated with a primitive PB CD34(+) cell subset defined by a CD34(high) CD38(low) CD71(low)c-Kit(low)Thy-1(+) antigenic profile. The functional significance of CXCR-4 expression was ascertained by the promoting effect of SDF-la on cell cycle, proliferation, and colony formation. SDF-1 alone increases the percentage of CD34(+) cells in the S+G(2)/M phases and sustains their survival. In synergy with cytokines, SDF-1 increases PB CD34(+) and CD34(high)CD38(low) cell expansion and colony formation.
A variety of diseases require treatment with agents, which are preferentially cytotoxic to dividing cells. Cancer cells, for example, may be targeted with cytotoxic doses of radiation or chemotherapeutic agents. A significant side-effect of cancer therapy is the pathological impact of such treatments on rapidly dividing normal cells. These normal cells may for example include hair follicles, mucosal cells and the hematopoietic cells, such as primitive bone marrow progenitor cells and stem cells.
Hematopoietic cells that are uncommitted to a final differentiated cell type are defined herein as "progenitor" cells. Hematopoietic progenitor cells possess the ability to differentiate into a variety of cell types directly or indirectly through a particular developmental lineage. Undifferentiated, pluripotent progenitor cells that are not committed to any lineage are referred to herein as "stem cells." All hematopoietic cells can in theory be derived from a single stem cell, which is also able to perpetuate the stem cell lineage as daughter cells become differentiated.
Indiscriminating destruction of hematopoietic cells, such as stem, progenitor or precursor cells, can lead to a reduction in normal mature blood cell counts, such as leukocytes and red blood cells. A major impact on mature cell numbers may be seen particularly with neutrophils (neutropaenia) and platelets (thrombocytopenia), cells which naturally have relatively short half-lives. A decrease in leukocyte count, with concomitant loss of immune system function, may increase a patient's risk of opportunistic infection. Neutropaenia resulting from chemotherapy may for example occur within two or three days of cytotoxic treatments, and may leave the patient vulnerable to infection for up to 2 weeks until the hematopoietic system has recovered sufficiently to regenerate neutrophil counts. A reduced leukocyte count (leukopenia) as a result of cancer therapy may become sufficiently serious that therapy must be interrupted to allow the white blood cell count to rebuild. Interruption of cancer therapy can in turn lead to survival of cancer cells, an increase in the incidence of drug resistance in cancer cells and ultimately in cancer relapse. There is accordingly a need for therapeutic agents and treatments, which facilitate the preservation or regeneration of hematopoietic cell populations in cases where the number of such cells has been reduced due to disease or to therapeutic treatments such as radiation and chemotherapy.
Bone marrow transplantation has been used in the treatment of a variety of hematological, autoimmune and malignant diseases. In conjunction with bone marrow transplantation, ex vivo hematopoietic (bone marrow) cell culture may be used to expand the population of hematopoietic cells, particularly progenitor or stem cells, prior to reintroduction of such cells into a patient. In ex vivo gene therapy, hematopoietic cells may be transformed in vitro prior to reintroduction of the transformed cells into the patient. In gene therapy, using conventional recombinant DNA techniques, a selected nucleic acid, such as a gene, may be isolated, placed into a vector, such as a viral vector, and the vector transfected into a hematopoietic cell, to transform the cell, and the cell may in turn express the product coded for by the gene.
The cell may then be introduced into a patient. Hematopoietic stem cells were initially identified as a prospective target for gene therapy. However, problems have been encountered in efficient hematopoietic stem cell transfection. There is accordingly a need for agents and methods, which may facilitate the proliferation of hematopoietic cells in ex vivo cell culture. There is also a need for agents that may be used to facilitate the establishment and proliferation of engrafted hematopoietic cells that have been transplanted into a patient.
A number of proteins have been identified as stimulators of hematopoietic cell proliferation (some of which are identified as hematopoietic growth factors). Cytokines involved in the induction of differentiation or proliferation of hematopoietic cells, particularly progenitor cells, include the following: G-CSF (granulocyte colony stimulating factor); LIF (leukemia inhibitory factor) and GM-CSF (granulocyte-macrophage colony stimulating factor).
The alpha Chemokine CXCR-4 and its ligand SDF-1 are postulated to be important in the development of the B-cell arm of the immune system. CXCR-4 is a critical coreceptor in support of viral entry by T-cell line tropic strains (X4) of the Human Immunodeficiency Virus Type 1 (HIV-1), viral variants, which predominate in some infected individuals in end stage disease. SDF-1 blocks X4-tropic HIV-1 infection of CD4+target cell in vitro, and allelic variants of the human gene encoding SDF-1 in vivo correlate with delayed disease progression. Thus, CXCR-4 may be an appropriate target for therapeutic intervention in acquired immunodeficiency syndrome (AIDS).
The localization of chronic lymphocytic leukemia (CLL) B-cells in bone marrow is not a adhesion phenomenon but a crucial step for their survival. SDF-1 produced by bone marrow stromal cells plays an important role in B-lymphocyte development and trafficking. It is found that Chemokine system SDF-1/CXCR-4 plays an important role in the accumulation of CLL B-cells.
Prostate neoplasm has a striking tendency to metastasize or "home" to bone. Metastases occur, when malignant cells escape from the primary tumor, penetrate and circulate through the bloodstream and subsequently arrest in the target tissues. It is found that metastatic prostate carcinoma utilizes the SDF-1/CXCR-4 pathway to localize to the bone marrow. Studies indicate that prostate cancers and perhaps other neoplasms (i.e. breast) may use the SDF-1/CXCR-4 pathway during their hematogenous spread to bone.
In various aspects, the invention provides methods for the use of chemokine-receptor-binding compounds (which may be chemokine receptor ligands such as chemokine receptor agonists or antagonist), and/or salts thereof, in treating chemokine mediated diseases or chemokine receptor mediated diseases, such as SDF-1 mediated diseases, or diseases mediated by chemokine receptors CXCR-4.
In some embodiments, the invention relates to methods of using a compound of formula (I), or a pharmaceutically acceptable salt thereof, to formulate a medicament for the treatment of a chemokine mediated disease state, or to treat such a disease:
In some embodiments, ring A may be aromatic and may be heterocyclic with one or more heteroatoms selected from the group consisting of oxygen and nitrogen. In Formula I, Ring B may be aromatic or non-aromatic, may be heterocyclic with one or more heteroatoms selected from the group consisting of oxygen and nitrogen , "x" may for example represent a substitution at any position in ring B (in accordance with the presence or absence of hetroatom) where the substituents may be from the group consisting of hydrogen, hydroxyl, methoxy, carboxyl, esters (alkyl, phenyl or benzyl) alkyl, alkenyls, alkynyls, amino, amido, thio, thiazolo, imidazolo or may be fatty acids.
In alternative embodiments, R1 and R2 at each occurance may independently be selected from substituents having 50 or fewer atoms, wherein the substituent may be selected from the group consisting of: hydrogen, cyano, nitro, amino, sulfonyls, methoxy and fluoro; and combinations thereof.
In alternative embodiments, R3, R4, R5, R6, R7 and R8 at each occurance may independently be selected from substituents having 30 or fewer atoms, wherein the substituent may be selected from the group consisting of: H; substituted or unsubstitued alkyls, such as C1-5 alkyls; substituted or unsubstitued cycloalkyls, such as C3-5 cycloalkyls; substituted or unsubstitued alkenyls, such as C2-5 alkenyls; substituted or unsubstitued alkynyls, such as C2-6 alkynyls; substituted or unsubstitued aryls; such as benzyl and benzyl esters; substituted or unsubstitued heterocycles; hydroxyls; aminos; nitros; thiols; primary, secondary or tertiary amines; imines; amides; imidos, imidazoles; thiazoles; phosphonates; phosphines; carbonyls; carboxyls; silyls; ethers; thioethers; sulfonyls; sulfonates; selenoethers; ketones; aldehydes; esters; —CF3; —CN; amino acids, long chain amino acids, fatty acids and combinations thereof.
In formula I, "X" represents substitution in ring 'B' at any position, where 'n' may be 0 or an integer from 1 to 4. "Y" may be a variable group, representing 'O' (oxygen) or 'N' (nitrogen). "Z" may be an sp2 carbon that may be part of a functional group as follows:
For compounds of formula I, VI and VII, "n" may be 0 or an integer from 1 to 4 and "n′" may be 0 or an integer from 1 to 4.
In some embodiments, the chemokine may be selected from the group consisting of: SDF-1, and chemokines that bind to CXCR-4.
In various embodiments, the invention provides for the use of compounds of the invention in the treatment of diseases selected from the group consisting of inflammation, chronic and acute inflammation, arthritis, rheumatoid arthritis, osteoarthritis, ARDS, psoriasis, allograft rejection, chronic transplant rejection, asthma, atherosclerosis, mononuclear-phagocyte dependent lung injury, idiopathic pulmonary fibrosis, atopic dermatitis, chronic obstructive pulmonary disease, sickle cell disease, ulcerative colitis, septic shock, endotoxic shock, urosepsis, glomerulonephritis, lupus nephritis, thrombosis, graft vs. host disease, angiogenesis, NSCLC, human ovarian cancer, human pancreatic cancer, breast carcinoma, colon carcinoma, rectum carcinoma, lung carcinoma, oropharynx carcinoma, hypopharynx carcinoma, esophagus carcinoma, stomach carcinoma, pancreas carcinoma, liver carcinoma, gallbladder carcinoma, bile duct carcinoma, small intestine carcinoma, uterine carcinoma, kidney carcinoma, bladder carcinoma, urothelium carcinoma, female genital tract carcinoma, cervix carcinoma, uterus carcinoma, ovarian carcinoma, choriocarcinoma, gestational trophoblastic disease, male genital tract carcinoma, prostate carcinoma, seminal vesicles carcinoma, testes carcinoma, germ cell tumors, endocrine gland carcinoma, thyroid carcinoma, adrenal carcinoma, pituitary gland carcinoma, skin carcinoma, hemangiomas, melanomas, sarcomas, bone and soft tissue sarcoma, Kaposi's sarcoma, tumors of the brain, tumors of the nerves, tumors of the eyes, tumors of the meninges, astrocytomas, gliomas, malignant gliomas, glioblastomas, retinoblastomas, neuromas, neuroblastomas, Schwannomas, meningiomas, solid tumors arising from hematopoietic malignancies (such as leukomias, chloromas, plasmacytomas, and the plaques and tumors of mycosis fungoides and cutaneous T-cell lymphoma/leukemia), solid tumors arising from lymphomas, non Hodgkin's lymphoma (NHL), diseases relating to abnormal proliferation of hematopoietic cells, hematopoietic stemcytopenia after bone marrow transplantation, leukocytopenia, neutropenia, thromocytopenia, leukopenia, lymphopenia after chemotherapy, ex vivo gene therapy in bone marrow transplant and/or blood transufion, in the treatment of hematopoietic progenitor and stem cell proliferation and migration disorders, antiviral infections, HIV, AIDS, and neurodegenerative diseases such as Alzheimer, Parkinson's, multiple sclerosis, disorder of bone metabolism such as osteoporesis.
In accordance with various aspects of the invention, CXCR4 antagonists may be used to treat hematopoietic cells, for example to increase the rate of hematopoietic stem or progenitor cellular multiplication, self-renewal, expansion, proliferation, or peripheralization. In various aspects, the invention relates to methods of promoting the rate of hematopoietic cell multiplication, which encompases processes that increase and/or maintain cellular multiplication, self-renewal, expansion, proliferation or peripheralization. This may for example be useful in some embodiments for in vitro hematopoietic cell cultures used in bone marrow transplantation, peripheral blood mobilization, or ex vivo expansion. CXCR4 antagonists may also be used therapeutically to stimulate hematopoietic cell multiplication, self-renewal, expansion, proliferation or peripheralization in vivo, for example in some embodiments involving human diseases such as a cancer or an autoimmune disease. The hematopoietic cells targeted by the methods of the invention may include hematopoietic progenitor or stem cells.
In alternative embodiments, CXCR4 antagonists may be used to treat a variety of hematopoietic cells, and such cells may be isolated or may form only part of a treated cell population in vivo or in vitro. Cells amenable to treatment with CXCR4 antagonists may for example include cells in the hematopoietic lineage, beginning with pluripotent stem cells, such as bone marrow stem or progenitor cells, lymphoid stem or progenitor cells, myeloid stem cells, CFU-GEMM cells (colony-forming-unit granulocyte, erythroid, macrophage, megakaryocye), B stem cells, T stem cells, DC stem cells, pre-B cells, prothymocytes, BFU-E cells (burst-forming unit—erythroid), BFU-MK cells (burst-forming unit—megakaryocytes), CFU-GM cells (colony-formng unit—granulocyte-macrophage), CFU-bas cells (colony-forming unit—basophil), CFU-Mast cells (colony forming unit—mast cell), CFU-G cells (colony forming unit granulocyte), CFU-M/DC cells (colony forming unit monocyte/dendritic cell), CFU-Eo cells (colony forming unit eosinophil), CFU-E cells (colony forming unit erythroid), CFU-MK cells (colony forming unit megakaryocyte), myeloblasts, monoblasts, B-lymphoblasts, T-lymphoblasts, proerythroblasts, neutrophillic myelocytes, promonocytes, or other hematopoietic cells that differentiate to give rise to mature cells such as macrophages, myeloid related dendritic cells, mast cells, plasma cells, erythrocytes, platelets, neutrophils, monocytes, eosinophils, basophils, B-cells, T-cells or lymphoid related dendritic cells.
In some embodiments, the invention provides methods of increasing the circulation of hematopoietic cells by mobilizing them from the marrow to the peripheral blood comprising administering an effective amount of a CXCR4 antagonist to hematopoietic cells of a patient undergoing autologous mobilization where hematopoietic stem/progenitor cells may be mobilized into the peripheral blood (1) during the rebound phase of the leukocytes and/or platelets after transient granulocytopenia and thrombocytopenia induced by myelosuppressive chemotherapy, (2) by hematopoietic growth factors, or (3) by a combination of both. Such treatment may for example be carried out so as to be effective to mobilize the hematopoietic cells from a marrow locus (i.e. a location in the bone marrow) to a peripheral blood locus (i.e. a location in the peripheral blood). Such treatments may for example be undertaken in the context of or for the clinical procedure of leukapheresis or apheresis. In alternative embodiments, CXCR4 antagonists may be used in ex vivo stem cell expansion to supplement stem cell grafts with more mature precursors to shorten or potentially prevent hematopoietic cell depletion, including conditions such as pancytopenia, granulocytopenia, thrombocytopenia, anemia or a combination thereof; to increase the number of primitive progenitors to help ensure hematopoietic support for multiple cycles of high-dose therapy; to obtain sufficient number of stem cells from a single marrow aspirate or apheresis procedure, thus reducing the need for large-scale harvesting of marrow of multiple leukopheresis; to generate sufficient cells from a single cord-blood unit to allow reconstitution in an adult after high-dose chemotherapy; to purge stem cell products of contaminating tumour cells; to generate large volumes of immunologically active cells with antitumour activity to be used in immunotherapeutic regimens or to increase the pool of stem cells that could be targets for the delivery of gene therapy.
In alternative embodiments, the invention provides methods to enrich CD34+progenitor cells which are utilized in bone marrow (BM) and peripheral blood (PB) stem cell transplantation, wherein the hematopoietic stem cell transplantation (HSCT) protocols may for example be utilized for the purpose of treating the following diseases (from Ball, E. D., Lister, J., and Law, P. Hematopoietic Stem Cell Therapy, Chruchill Livingston (of Harcourt Inc.), New York (2000)): Aplastic Anemia; Acute Lymphoblastic Anemia.; Acute Myelogenous Leukemia; Myelodysplasia; Multiple Myeloma; Chronic Lymphocytic Leukemia; Congenital Immunodeficiencies (such as Autoimmune Lymphoproliferative disease, Wiscott-Aldrich Syndrome, X-linked Lymphoproliferative disease, Chronic Granulamatous disease, Kostmann Neutropenia, Leukocyte Adhesion Deficiency); Metabolic Diseases (for instance those which have been HSCT indicated such as Hurler Syndrome (MPS I/II), Sly Syndrome (MPS VII), Chilhood onset cerebral X-adrenoleukodystrophy, Globard_cell Leukodystrophy).
In alternative embodiments, the invention relates to the use as CXCR4 antagonists of compounds of Formula I, with the exception of one or more of the compounds of formulae II or III or IV or V or VI or VII.
FIG. 1 shows the inhibitory effect of 3-Hydroxy-2-naphthoic acid (designated herein as CTCM226) on the binding of SDF-1 to CXCR-4 receptor.
FIG. 2 shows Inhibition effect of CTCM226 on SDF-1 induced [Ca++2] mobilization.
In some embodiments, the compounds of the invention may have a specific chemokine receptor binding affinity (IC50) below 1 mM, below 500 uM, below 200 uM, below 100 uM, below 50 uM, below 10 uM, below 1000 nM, below 100 nM, below 50 nM, below 10 nM or below 1 nM; and may have a selective affinity for a selected chemokine receptor, such as a 10-fold selective affinity, a 50-fold selective affinity or a 100-fold selective affinity, for a selected chemokine receptor relative to an alternative chemokine receptor. For example, in some embodiments, the compounds may have a binding affinity for CXCR-4 of below 1 mM, below 500 uM, below 200 uM, below 100 uM, below 50 uM, below 10 uM, below 1000 nM, below 100 nM, below 50 nM, below 10 nM or below 1 nM. Receptor binding affinities may by assayed by any of a number of standard methods, such as competitive displacement of radioactively labeled ligands.
In various aspects, the invention relates to compounds having alternative substitutions and substituent groups, designated in formulae herein as "R", typically with a numeric superscript to identify the substituent group. A substituent group is generally a group that replaces one or more hydrogen atoms attached to a parent structure. The organic substituent groups are for example identified in the Handbook of Chemistry and Physics, 79th Edition, CRC Press (all of which are hereby incorporated by reference). Substituent groups of the invention may for example be selected from groups having from 1 to 100 atoms, such as groups having 100 or fewer, 50 or fewer, 25 or fewer, 20 or fewer, 15 or fewer, 10 or fewer, 5 or fewer, 4, 3, 2, or 1 atom(s). Atoms in such substituents may for example be selected from the group consisting of carbon, hydrogen, oxygen, nitrogen, halogen, sulfur, silicon, arsenic, boron, selenium and phosphorus.
Substituent groups may for example be substituted or unsubstitued alkyls, such as, C1-10 alkyls, C1-6 alkyls; substituted or unsubstitued cycloalkyls, such as C1-10 cycloalkyls, C3-6 cycloalkyls; substituted or unsubstitued alkenyls, such as C1-10 alkenyls, C2-6 alkenyls; substituted or unsubstitued alkynyls, such as C1-10 alkynyls, C2-6 alkynyls; substituted or unsubstitued aryls; substituted or unsubstitued heterocycles; hydroxyls; aminos; nitros; thiols; primary, secondary or tertiary amines; imines; amides; imides, amino acids; amino esters; phosphonates; phosphines; carbonyls; carboxyls; silyls; ethers; thioethers; sulfonyls; sulfonates; selenoethers; ketones; aldehydes; esters; —CF3; —CN; imidazoles; thiazoles; pyrazoles; and combinations thereof. Substituent groups which are themselves substituted may be substituted with similar substituents.
In some embodiments, a substituent group may comprise a cyclic, heterocyclic or polycyclic group. The term "cyclic group", as used herein, includes cyclic saturated or unsaturated (optionally aromatic) group having from 3 to 10, 4 to 8, or 5 to 7 carbon atoms. Exemplary cyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Cyclic groups may be unsubstituted or substituted at one or more ring positions. A cyclic group may for example be substituted with halogens, alkyls, cycloalkyls, alkenyls, alkynyls, aryls, heterocycles, hydroxyls, aminos, nitros, thiols, pyroles; imidazoles, thiazoles, pyrazoles; amines, imines, amides, amino acids, amino esters; phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, sulfonates, selenoethers, ketones, aldehydes, esters, —CF3, —CN.
The term "heterocyclic group" includes cyclic saturated, unsaturated and aromatic groups having from 3 to 10, 4 to 8, or 5 to 7 carbon atoms, wherein the ring structure includes about one or more heteroatoms. Heterocyclic groups may include pyrane, pyrone, pyrrolidine, oxolane, thiolane, imidazole, oxazole, pyrazole, thiazole, piperidine, piperazine, morpholine. The heterocyclic ring may be substituted at one or more positions with such substituents as, for example, halogens, alkyls, cycloalkyls, alkenyls, alkynyls, aryls, other heterocycles, hydroxyl, amino, nitro, thiol, amines, imines, amides, amino acids, amino esters, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, —CF3, —CN. Heterocycles may also be bridged or fused to other cyclic groups as described below.
The term "polycyclic group" as used herein is intended to refer to two or more saturated, unsaturated or aromatic cyclic rings in which two or more carbons are common to two adjoining rings, so that the rings are "fused rings". Rings that are joined through non-adjacent atoms may be termed "bridged" rings. Each of the rings of the polycyclic group may be substituted with such substituents as described above, as for example, halogens, alkyls, cycloalkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol, amines, imines, amides, esters, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, —CF3, or —CN.
The term "alkyl" refers to the radical of saturated aliphatic groups, including straight chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In some embodiments, a straight chain or branched chain alkyl has 20 or fewer carbon atoms in its backbone (C1-C20 for straight chain, C3-C20 for branched chain), or 10 or fewer carbon atoms. In some embodiments, cycloalkyls may have from 4-10 carbon atoms in their ring structure, such as 5, 6 or 7 carbon rings. Unless the number of carbons is otherwise specified, "lower alkyl" as used herein means an alkyl group, as defined above, having from one to ten carbon atoms in its backbone structure. Likewise, "lower alkenyl" and "lower alkynyl" have chain lengths often or less carbons.
The term "alkyl" (or "lower alkyl") as used throughout the specification and claims is intended to include both "unsubstituted alkyls" and "substituted alkyls", the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, halogen, hydroxyl, carbonyl (such as carboxyl, ketones (including alkylcarbonyl and arylcarbonyl groups), and esters (including alkyloxycarbonyl and aryloxycarbonyl groups)), thiocarbonyl, acyloxy, alkoxyl, phosphoryl, phosphonate, phosphinate, amino, acylamino, amido, amidine, imino, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety. The moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For instance, the substituents of a substituted alkyl may include substituted and unsubstituted forms of aminos, azidos, iminos, amidos, phosphoryls (including phosphonates and phosphinates), sulfonyls (including sulfates, sulfonamidos, sulfamoyls and sulfonates), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), —CF3, —CN and the like. Exemplary substituted alkyls are described below. Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls, —CF3, —CN, and the like.
The terms "alkenyl" and "alkynyl" refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
The term "aralkyl", as used herein, refers to an alkyl or alkylenyl group substituted with at least one aryl group. Exemplary aralkyls include benzyl (i.e., phenylmethyl), 2-naphthylethyl, 2-(2-pyridyl)propyl, 5-dibenzosuberyl, and the like.
The term "alkylcarbonyl", as used herein, refers to —C(O)-alkyl. Similarly, the term "arylcarbonyl" refers to —C(O)-aryl. The term "alkyloxycarbonyl", as used herein, refers to the group —C(O)—O-alkyl, and the term "aryloxycarbonyl" refers to —C(O)—O-aryl. The term "acyloxy" refers to —O—C(O)-R7, in which R7 is alkyl, alkenyl, alkynyl, aryl, aralkyl or heterocyclyl.
The term "amino", as used herein, refers to —N(R)(R), in which R and R are each independently hydrogen, alkyl, alkyenyl, alkynyl, aralkyl, aryl, or in which R and R together with the nitrogen atom to which they are attached form a ring having 4-8 atoms. Thus, the term "amino", as used herein, includes unsubstituted, monosubstituted (e.g., monoalkylamino or monoarylamino), and disubstituted (e.g., dialkylamino or alkylarylamino) amino groups. The term "amido" refers to —C(O)—N(R8)(R9), in which R8 and R9 are as defined above. The term "acylamino" refers to —N(R′8)C(O)-R7, in which R7 is as defined above and R′8 is alkyl.
The term "amino acids", as used herein, refers to —CH(N+H3)COO−, in which a substitution could be at either or both 'C' and 'N' positions.
The term "amino acid esters", as used herein, refers to —CH(NHCOOR10)COO—; where R10 is defined as above.
As used herein, the term "nitro" means —NO2; the term "halogen" designates —F, —Cl, —Br or —I; the term "sulthydryl" means —SH; and the term "hydroxyl" means —OH.
The term "aryl" as used herein includes 5-, 6- and 7-membered aromatic groups that may include from zero to four heteroatoms in the ring, for example, phenyl, pyrrolyl, furyl, thiophenyl, imidazolyl, oxazole, thiazolyl, triazolyl, pyrazolyl, pyridyl, pyrazinyl, pyridazinyl and pyrimidinyl, and the like. Those aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles" or "heteroaromatics". The aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, —CF3, —CN, or the like. Aryl groups can also be part of a polycyclic group. For example, aryl groups include fused aromatic moieties such as naphthyl, anthracenyl, quinolyl, indolyl, and the like.
With reference to FIG. 3 in one aspect, the compounds of the invention may comprise two hydrophobic aromatic rings, A and B, in which one ring or both the rings can be substituted at different positions as shown in ring A in FIG. 3. In some embodiments, substitutions may be made to the hydrophobic aromatic rings that preserve the hydrophobic and aromatic characteristic of the rings, such as the substitution of heteroatoms within the ring or exocyclic substituents. Similarly, substitutions may be made at different positions such as hydroxyl at C3 and carboxylic at C2 in ring A.
In one aspect, the present invention relates to uses of a naphthoic acid derivative designated herein as 3-Hydroxy-2-naphthoic acid;
3-Hydroxy-2-naphthoic acid (Compound 1); [CAS 92-70-6]
Molecular Formula: C11H8O3
Molecular Weight: 188.18
The following examples are illustrative of various aspects of the invention.
The 3-Hydroxy-2-naphthoic acid (Compound 1, CAS number 92-70-6) is commercially available and may also be prepared in a variety of ways known to those skilled in the art. For example, naphthalene, commonly known as tar camphor, containing ring A and B, is a natural chemical that can be isolated from dry coal tar. This may be used as a starting analog to synthesize 3-hydroxy-2-naphthoic acid via oxidation and then treating beta-naphthol with CO2 under pressure to yield compound 1.
Alternative compounds of the invention may be synthesized using known methods, such as methods disclosed in International Patent Publication WO 00/02871 published Jan. 20, 2000 and U.S. Pat. No. 5,866,545 issued to Hagmann et al. on Feb. 2, 1999, for the synthesis of 2-(2-(3-hydroxy)naphthyl)-4-(3-thiophenyl)-5-acetamidooxazole).
Receptor Binding
This example discloses the ability of compounds of the invention, such as naphthoic acid derivatives, such as CTCM226 (1), to inhibit binding of SDF-1 to CXCR-4 receptor. The binding studies were conducted using I125 labeled SDF-1 as competitor ligand. FIG. 1 shows the inhibitory effect of compound (1) on the binding of SDF-1 to CXCR-4 receptor. The IC50 was evaluated at 150 uM.
Calcium Release
A rapid, transient rise in the free cytosolic Ca2+ concentration ([Ca2+]i) is one of the events associated with the Chemokine mediated induction of the associated receptors and is assumed to be involved in many of the subsequent cellular reactions. Both Ca2+ release from intracellular stores and Ca2+ influx from the extracellular space contribute to the rise in [Ca2+]i. FIG. 2 shows the inhibition of SDF-1 induced intracellular [Ca2+]i mobilization by CTCM226 in THP-1 cells. Fura-2,AM loaded THP-1 cells were incubated with CTCM226 for 60 min prior to induction of [Ca2+]i mobilization by 10 nM SDF-1. Results illustrate the effect of CTCM226 (1) on SDF-1 induced Ca2+ mobilization.
Compound 1 showed an inhibition of SDF-1 induced [Ca2+]i mobilization in THP-1 cells to concentration to 3 uM where the IC50 was evaluated to be 600 nM. In accordance with this aspect of the invention, the naphthoic acid derivative, such as compound 1 or corresponding salts may be used for the treatment of a wide range of inflammatory diseases such as gout, arthritis, osteoarthritis, rheumatoid arthritis, and ARDS.
Therapeutic Formulations
In one aspect, the invention provides a variety of therapeutic uses for naphthoic acid derivative, such as compound (1). In various embodiments, the compounds of the invention may be used therapeutically in formulations or medicaments for the treatment of CXCR-4 mediated diseases. The invention provides corresponding methods of medical treatment, in which a therapeutic dose of a compound of the invention is administered in a pharmacologically acceptable formulation. Accordingly, the invention also provides therapeutic compositions comprising compounds of the invention and a pharmacologically acceptable excipient or carrier. The therapeutic composition may be soluble in an aqueous solution at a physiologically acceptable pH.
The invention provides pharmaceutical compositions (medicaments) containing (comprising) compound of the invention. In one embodiment, such compositions include compound of the invention in an effective amount, meaning a therapeutically or prophylactically effective amount, sufficient to modulate CXCR-4 activity, and a pharmaceutically acceptable carrier. In other embodiments, the compositions of the invention may include compound of the invention in a therapeutically or prophylactically effective amount sufficient to modulate the activity SDF-1, and a pharmaceutically acceptable carrier. Compounds of the invention may also be used in combination with other compositions and procedures for the treatment of diseases.
A "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result, such as modulation of CXCR-4 or SDF-1 activity. A therapeutically effective amount of a compound of the invention may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of compounds of the invention to elicit a desired response in the individual. Dosage regimens may be adjusted to provide the optimum therapeutic response. A therapeutically effective amount is also one in which any toxic or detrimental effects of compounds of the invention are outweighed by the therapeutically beneficial effects.
A "prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result, such as modulation of CXCR-4, SDF-1 activity. A prophylactically effective amount can be determined as described above for the therapeutically effective amount. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.
In particular embodiments, a preferred range for therapeutically or prophylactically effective amounts of compounds of the invention may be 0.1 nM -0.1 M, 0.1 nM -0.05M, 0.05 nM -10 1M or 0.01 nM -100 1M. Alternatively, total daily dose may range from about 0.001 to about 100 mg/kg, or up to 10 mg/kg or up to 1 mg/kg of patients body mass. Dosage values may vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgement of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the methods of the invention.
The amount of a compound of the invention in a therapeutic composition may vary according to factors such as the disease state, age, sex, and weight of the individual. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals.
As used herein "pharmaceutically acceptable carrier" or "excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. In one embodiment, the carrier is suitable for parenteral administration. Alternatively, the carrier can be suitable for intravenous, intraperitoneal, intramuscular, sublingual or oral administration. Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the pharmaceutical compositions of the invention is contemplated. Supplementary active compounds can also be incorporated into the compositions.
Therapeutic compositions typically must be sterile and stable under the conditions of manufacture and storage. The composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, monostearate salts and gelatin. Moreover, compounds of the invention can be administered in a time release formulation, for example in a composition which includes a slow release polymer. The active compounds can be prepared with carriers that will protect the compound against rapid release, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid and polylactic, polyglycolic copolymers (PLG). Many methods for the preparation of such formulations are patented or generally known to those skilled in the art.
Sterile injectable solutions can be prepared by incorporating compounds of the invention in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle, which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. In accordance with an alternative aspect of the invention, compounds of the invention may be formulated with one or more additional compounds that enhance the solubility of compounds of the invention.
Pharmaceutically acceptable salts include salts that are well known to those skilled in the art such as basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, alicylic acid, phenylacetic acid and mandelic acid. In alternative embodiments, pharmaceutically acceptable cation salts may include alkaline, alkaline earth, ammonium and quaternary ammonium cations.
In accordance with another aspect of the invention, therapeutic compositions of the present invention, comprising compound of the invention, may be provided in containers having labels that provide instructions for use of compounds of the invention to treat chemokine or chemokine receptor mediated diseases, inflammation, chronic and acute inflammation, arthritis, rheumatoid arthritis, osteoarthritis, ARDS, psoriasis, allograft rejection, chronic transplant rejection, asthma, atherosclerosis, mononuclear-phagocyte dependent lung injury, idiopathic pulmonary fibrosis, sarcoidosis, focal ischemia, atopic dermatitis, chronic obstructive pulmonary disease, sickle cell disease, ulcerative colitis, septic shock, endotoxic shock, urosepsis, glomerulonephritis, thrombosis, graft vs. host disease, angiogenesis, NSCLC, human ovarian cancer, human pancreatic adenocarcinoma, breast carcinoma, colon carcinoma, rectum carcinoma, lung carcinoma, oropharynx carcinoma, hypopharynx carcinoma, esophagus carcinoma, stomach carcinoma, pancreas carcinoma, liver carcinoma, gallbladder carcinoma, bile duct carcinoma, small intestine carcinoma, uterine carcinoma, kidney carcinoma, bladder carcinoma, urothelium carcinoma, female genital tract carcinoma, cervix carcinoma, uterus carcinoma, ovarian carcinoma, choriocarcinoma, gestational trophoblastic disease, male genital tract carcinoma, prostate carcinoma, seminal vesicles carcinoma, testes carcinoma, germ cell tumors, endocrine gland carcinoma, thyroid carcinoma, adrenal carcinoma, pituitary gland carcinoma, skin carcinoma, hemangiomas, melanomas, sarcomas, bone and soft tissue sarcoma, Kaposi's sarcoma.
An alternative aspect of the invention, chemokine or chemokine receptor mediated diseases may include cancers susceptible to anti-angiogenic treatment, including both primary and metastatic solid tumors, including carcinomas of breast, colon, rectum, lung, orpharynx, hypopharynx, esophagus, stomach, pancreas, liver, gallbladder and bile ducts, small intestine, urinary tract (including kidney, bladder and urothelium), female genital tract, (including cervix, uterus, and ovaries as well as choriocarcinoma and gestational trophoblastic disease), male genital tract (including prostate, seminal vesicles, testes and germ cell tumors), endocrine glands (including the thyroid, adrenal and pituitary glands), and skin, as well as hemangiomas, melanomas, sarcomas (including those arising from bone and soft tissues as well as Kaposi's sarcoma) and tumors of the brain, nerves, eyes, and meninges (including astrocytomas, gliomas, glioblastomas, retinoblastomas, neuromas, neuroblastomas, Schwannomas, and meningiomas). In some aspects of the invention, compounds of the invention may also be useful in treating solid tumors arising from hematopoietic malignancies such as leukemias (i.e. chloromas, plasmacytomas and the plaques and tumors of mycosis fungoides and cutaneous T-cell lymphoma/leukemia) as well as in the treatment of lymphomas (both Hodgkin's and non-Hodgkin's lymphomas), diseases relating to abnormal proliferation and/or migration of hematopoietic cells, hematopoietic stemcytopenia after bone marrow transplantation, leukocytopenia, neutropenia, thromocytopenia, leukopenia, lymphopenia after chemotherapy, ex vivo gene therapy in bone marrow transplant and/or blood transfusion, antiviral infections, HIV, AIDS, and neurodegenerative diseases such as Alzheimer, Parkinson's, multiple sclerosis, disorder of bone metabolism such as osteoporesis.
In addition, compounds of the invention may be useful in the prevention of metastases from the tumors described above either when used alone or in combination with radiotherapy and/or other chemotherapeutic agents.
Although various embodiments of the invention are disclosed herein, many adaptations and modifications may be made within the scope of the invention in accordance with the common general knowledge of those skilled in this art. Such modifications include the substitution of known equivalents for any aspect of the invention in order to achieve the same result in substantially the same way. Numeric ranges are inclusive of the numbers defining the range. In the specification, the word "comprising" is used as an open-ended term, substantially equivalent to the phrase "including, but not limited to", and the word "comprises" has a corresponding meaning. Citation of references herein shall not be construed as an admission that such references are prior art to the present invention. All publications, including but not limited to patents and patent applications, cited in this specification are incorporated herein by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein and as though fully set forth herein.
|Cited Patent
|Filing date
|Publication date
|Aug 17, 1993
|Feb 14, 1995
|Lilly Industries Limited
|Naphthalene carboxamides
|Aug 8, 1994
|Feb 2, 1999
|Merck & Co., Inc.
|Substituted ketone derivatives as inhibitors of interleukin-1β converting enzyme
|Nov 4, 1996
|Aug 3, 1999
|Signal Pharmaceuticals, Inc.
|Anti-viral agents and methods relating to the use thereof
|Feb 5, 1998
|Jun 11, 2002
|Pfizer Inc.
|Heteroaryl-hexanoic acid amide derivatives, their preparation and their use as selective inhibitors of MIP-1-α binding to its CCR 1 receptor
|Aug 8, 1994
|Feb 23, 1995
|Merck & Co., Inc.
|SUBSTITUTED KETONE DERIVATIVES AS INHIBITORS OF INTERLEUKIN-1β CONVERTING ENZYME
|Jul 6, 1999
|Jan 20, 2000
|Merck & Co., Inc.
|Novel angiogenesis inhibitors
|Mar 2, 2000
|Jan 4, 2001
|Idun Pharmaceuticals, Inc.
|C-terminal modified (n-substituted)-2-indolylcarbonyldipeptides as inhibitors of the ice/ced-3 family of cysteine proteases
|Jul 13, 2000
|Jan 25, 2001
|Takeda Chemical Industries, Ltd.
|Sustained release compositions, process for producing the same and use thereof
|Citing Patent
|Filing date
|Publication date
|Sep 13, 2002
|Aug 15, 2006
|Chemokine Therapeutics Corporation
|Chemokine analogs for the treatment of human disease
|Feb 16, 2005
|Apr 8, 2008
|The University Of British Columbia
|Methods of treating autoimmune diseases comprising administering CXCR4 antagonists
|Mar 24, 2006
|May 6, 2008
|Chemokine Therapeutics Corp.
|Cyclic peptides for modulating growth of neo-vessels and their use in therapeutic angiogenesis
|Feb 26, 2002
|May 27, 2008
|The University Of British Columbia
|CXC chemokine receptor 4 agonist peptides
|May 23, 2005
|Sep 9, 2008
|The University Of British Columbia
|Therapeutic chemokine receptor antagonists
|Sep 20, 2004
|Oct 14, 2008
|Chemokine Therapeutics Corp.
|CXCR4 antagonist treatment of hematopoietic cells
|Aug 9, 2011
|British Canadian Biosciences Corp
|Chemokine mimetics synthesis and their use
|Feb 26, 2002
|Aug 7, 2003
|Tudan Christopher R.
|CXCR4 agonist treatment of hematopoietic cells
|Sep 13, 2002
|Oct 7, 2004
|Ahmed Merzouk
|Design of chemokine analogs for the treatment of human disease
|Aug 16, 2002
|Mar 17, 2005
|Ahmed Merzouk
|Novel chemokine mimetics synthesis and their use
|Feb 16, 2005
|Jul 28, 2005
|The University Of British Columbia Of Industry Liaison Office
|Therapeutic chemokine receptor antagonists
|Sep 20, 2004
|Jan 19, 2006
|Chemokine Therapeutics Corporation
|CXCR4 antagonist treatment of hematopoietic cells
|Aug 31, 2004
|Oct 19, 2006
|Ahmed Merzouk
|Mimetics of interleukin-8 and methods of using them in the prevention, treatment, diagnosis, and ameliorization of symptoms of a disease
|Mar 29, 2006
|Nov 9, 2006
|Chemokine Therapeutics Corp.
|Novel chemokine mimetics synthesis and their use
|Jul 26, 2006
|Mar 22, 2007
|Chemokine Therapeutics Corp.
|Chemokine analogs for the treatment of human diseases
|Oct 30, 2006
|May 24, 2007
|Chemokine Therapeutics Corporation
|Interferon-inducible protein-10 (IP-10 or CXCL10) chemokine analogs for the treatment of human diseases
|Mar 24, 2006
|Sep 27, 2007
|Ahmed Merzouk
|Cyclic peptides for modulating growth of neo-vessels and their use in therapeutic angiogenesis
|Mar 29, 2006
|Nov 29, 2007
|Chemokine Therapeutics Corp.
|Novel chemokine mimetics synthesis and their use
|U.S. Classification
|International Classification
|Cooperative Classification
|European Classification
|Jun 11, 2002
Owner name: CHEMOKINE THERAPEUTICS CORPORATION, BRITISH COLUMB
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:SAXENA, GEETA;MERZOUK, AHMED;SALARI, HASSAN;REEL/FRAME:012968/0175;SIGNING DATES FROM 20020116 TO 20020212
|Sep 10, 2002
Owner name: CHEMOKINE THERAPEUTICS, BRITISH COLUMBIA
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:SAXENA, GEETA;TUDAN, CHRISTOPHER;MERZOUK, AHMED;AND OTHERS;REEL/FRAME:013278/0493;SIGNING DATES FROM 20020116 TO 20020830
|Sep 14, 2004
|Certificate of correction
|Aug 27, 2007
|Maintenance fee reminder mailed
|Oct 29, 2007
|Surcharge for late payment
|Oct 29, 2007
|Fee payment
Year of fee payment: 4
|Oct 3, 2011
|Maintenance fee reminder mailed
|Feb 17, 2012
|Lapse for failure to pay maintenance fees
|Apr 10, 2012
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Effective date: 20120217


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Earth Island Institute
Home › Get Involved › IslandWire: News & Action Alerts
IslandWire: News & Action Alerts
The latest campaign updates from Earth Island's global network of environmental projects.
Get Involved
Something Wild
Join Earth Island for its "Something Wild" dinner on Saturday, June 11 to celebrate more than three decades of innovative achievements and learn more about the Institute's plans to continue growing environmental leadership. The festive evening event at the David Brower Center in Berkeley, California will draw on the concept of the "wildness within," which EII founder David Brower so often wrote and spoke of. Guests will enjoy delicious food and enjoy a brief talk by guest of honor, Joanna Macy, a treasured and distinguished elder in the environmental community. More details and tickets.
Thursday June 9, 2016
Refill Revolution at Bonnaroo
The 2015 Bonnaroo Music and Arts Festival in Tennessee produced more than 679 tons of waste over four days. That's 15 pounds of waste per festival-goer — nearly twice the average amount a US consumer produces daily. The biggest component of that waste was single-use disposable plastic like water bottles, beer cups, and food wrappers. The good news is that musicians and festivals are committing to reduce their plastic and carbon footprints, both on stage and behind the scenes. Join EII's Plastic Pollution Coalition and Bonnaroo at this year's festival in June for the Refill Revolution, a program that helps festival-goers reduce plastic waste and pollution! Read more about this campaign in Rolling Stone.
Thursday May 26, 2016
Something Wild
Join Earth Island for its "Something Wild" dinner on Saturday, June 11 to celebrate more than three decades of innovative achievements and learn more about the Institute's plans to continue growing environmental leadership. The festive evening event at the David Brower Center in Berkeley, California will draw on the concept of the "wildness within," which EII founder David Brower so often wrote and spoke of. Guests will enjoy delicious food and a talk by guest of honor, Joanna Macy, a treasured and distinguished elder in the environmental community. More details and tickets.
Thursday May 26, 2016
KIDS for the BAY Field Trips
Investigating rocky shorelines, discovering green sea anemones, and spotting birds are just a few of the fun, hands-on science activities students enjoy on KIDS for the BAY field trips. This spring, the Earth Island project helped 1,630 East Bay elementary school students connect with nature in creek, bay, delta, and ocean habitats. Learn more about KIDS for the BAY's exciting new community-building field trips for schools this fall, or sign your kids up for the last few nature-based summer camp spaces. And don't forget to check out KIDS for the BAY's Spring E-Newsletter.
Thursday May 26, 2016
Standing Up for Endangered Science
Last week EII's Project Coyote joined forces with the Union of Concerned Scientists to submit a petition to Interior Secretary Sally Jewell and Commerce Secretary Penny Pritzker asking the federal government to live up the standards of the Endangered Species Act and base wildlife management decisions on the best available science. The petition follows several alarming decisions by the Department of the Interior, including a 2014 declaration that gray wolves were recovered nationwide, that not only omitted independent scientific review, but also rejected the recommendations of agency biologists. Nearly 1,000 US scientists and scholars signed the petition. Read more.
Thursday May 26, 2016
Hemp History Week
Celebrate the upcoming seventh annual Hemp History Week this June with EII's Hempstead Project HEART! Learn about the myriad uses and benefits of industrial hemp at the "Makers and Tasters" event at the Oakland Museum of California on Friday, June 3 at 6 p.m. Hempstead Project HEART's Linda Delair and Annalisa Rush of HempX.net will speak about hemp, sustainability, and California's "Green Rush," accompanied by raw fiber and textile displays. Hemp foods and apparel will also be available. The event is free and open to the public. More details.
Thursday May 26, 2016
Book Launch with Barbara Boxer
Join Earth Island's International Marine Mammal Project and Senator Barbara Boxer for a book launch event at the David Brower Center in downtown Berkeley on Saturday, June 18 at 7 p.m. IMMP is partnering with Hachette Books and the Brower Center for this event, which will celebrate Senator Boxer's new book, The Art of Tough, and honor her environmental achievements. Learn more and reserve your tickets before they run out! This is a FREE event, but guests are encouraged to donate $30 or more to IMMP to receive a signed copy of Senator Boxer's book. Email Mary Jo Rice for details.
Thursday May 26, 2016
Swim With Mermaids
It's almost time to get your mermaid on! Join Earth Island's All One Ocean on June 12 for the Mermaid Festival at the Mill Valley Community Center in Marin County, California. The festival, which will begin at 1 p.m., will include an art show, face painting, and swimming with live mermaids. If you're interested in volunteering at the event, email Tracy. See you there!
Thursday May 26, 2016
The Best of Earth Island Journal
Get the latest environmental news from Earth Island Journal. Here are our favorite web-only stories from the last two weeks:
Most Popular: Flame Retardant Exposure Poses a Significant Health Risk to Women. Reporter Elizabeth Grossman examines new research linking exposure to toxic flame retardant chemicals to thyroid problems in women.
Editors' Pick: The Real Threat to Europe's Last Primeval Forest: Bark Beetles or Undemocratic Politicians? Journal contributor Eunice Blavascunas delves into a controversial proposal to log Poland's ancient Białowieża forest that has pit environmentalists and the scientific community against logging interests and the country's right-wing government.
Thursday May 26, 2016
Food Shift Is Hiring
Food Shift is looking to hire two people to join its Oakland team! The Fundraising and Grants Coordinator will play a critical role in raising funds to launch and sustain the Alameda Kitchen, among other Food Shift programs. The Communications and Outreach Coordinator will play a critical role in promoting the Alameda Kitchen, engaging the community, and communicating with the public about Food Shift's work. Both positions are based in Oakland, California, and are VISTA volunteer positions with small stipends. The deadline to apply is June 1, 2016. Learn more about the positions.
Thursday May 26, 2016
Something Wild
Earth Island's "Something Wild" dinner on Saturday, June 11 will celebrate three decades of innovative achievements and share the Institute's plans to continue growing environmental leadership. The evening event at the David Brower Center in Berkeley will draw on the inspiration of EII founder David Brower, who so often drew upon his "wildness within." Guests will enjoy delicious food, hear from members of the Earth Island team, and gain insight from a brief talk by guest of honor, Joanna Macy, a treasured veteran of the environmental community. Details and tickets.
Thursday May 12, 2016
Apply for the Brower Youth Awards
The Brower Youth Awards 2016 deadline is Monday May 16th! Don't miss this chance for your environmental project and leadership to be recognized. The annual awards are given to six young people based in North America, ages 13 to 22, who show outstanding environmental leadership. Now in its 17th year, the BYA prize includes a $3,000 cash award, a professionally produced short film about the winner, and a weeklong leadership trip in the San Francisco Bay Area that culminates in a public award ceremony. Learn more and apply. And mark your calendars for October 18 to join us for the award ceremony!
Thursday May 12, 2016
Tell The EPA To Stop Poisoning Wildlife
The US EPA is re-registering several dangerous second-generation rodenticides – the very worst of the worst – this year. In 2014, the EPA pulled these same products from consumer shelves due to the "unacceptable risk" they pose to non-target wildlife. A public comment period on the re-registration ends on June 10. Please join EII's Raptors Are the Solution in taking a stand against these dangerous products. Take a few minutes to tell the EPA you want to see these "one feeding kills" type poisons banned completely because they continue to poison wildlife, pets, and children. Comment on four different rodenticides – brodifacoum, bromadiolone, difenacoum, and difethialone. (You have to comment separately for each rodenticide.)
Thursday May 12, 2016
Supperclub with Keba Konte
Join EII's Real Food Real Stories on May 26 for an unforgettable supperclub with Keba Konte, founder of Red Bay Coffee, at his brand new warehouse in Oakland's Fruitvale district. Meet fellow coffee enthusiasts and learn more about how Konte became one of the first black coffee roasters in the country and is now committed to creating a more diverse and inclusive coffee culture. Jazz records will be deejayed by chef and author Bryant Terry, winner of the 2015 James Beard Foundation Leadership Award. An East Bay chef will curate a story-inspired meal. More information and tickets here.
Thursday May 12, 2016
The Best of Earth Island Journal
Get the latest environmental news from Earth Island Journal. Here are our favorite web-only stories from the last two weeks:
Most Popular: One in Five of World's Plant Species at Risk of Extinction. Journalist Damian Carrington reports on how risks to global flora are putting food and medicine supplies at risk.
Editors' Pick: The Fall and Resurrection of the Vosso Salmon. Author Kevin Bailey weaves a compelling narrative about the collapse of Norway's Vosso salmon fishery and examines how biologists are racing to revive the "king of fish."
Thursday May 12, 2016


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Amasya Hotel Tips by maykal
Amasya Hotels: 5 reviews and 12 photos
Most RecentBest Rated
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A mosque in old Amasya
I stayed at the Yuvam Pansiyon, located on the main road...it doesn't look much from the outside (you enter via a pharmacy), but the view from the roof is what made this place worth staying in. The rooms weren't bad, and had a functioning private bathroom...for me, this is a luxury! The only complaint was the fact that the only rooms are located on the 5th and 6th floor...not funny when there is no lift and the temperature is in the mid-30's.
I've got a funny feeling we paid 15 million lira per night for a twin room, although I don't know where that figure came from...sounds about right though, as that would be around $10 I think.
Unique Qualities: The owner doubled as a pharmacist, and when she was busy, reception was manned by her over-keen son. I think the small amount of power had gone to his head, as he used to make a fuss about leaving the key at reception every time we went out, which meant that we had to disturb his mother in the pharmacy every time we wanted to go back...she soon put a stop to that, but he did get a bit surly when he saw we hadn't left our keys at reception!
Price Comparison: least expensive
Theme: Pension/Guesthouse
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- 1
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Please vent your HATE out on me. I can take it.
Poster Handle
Post Content
Sorry for this OP it's been building for a while so here goes.....
I fucking hate you with every fiber of my being. I was there for you for 4 and a half years. I did nothing but give you unconditional love. You told me you loved me, you told me you would never leave me, you told me you wanted to get married, you told me you wanted children. So I in turn told you I loved you. I aked you to marry me and you said yes. I wanted nothing more than just you. And everything was fine. Sure there are ups and downs like any other relationship. But you wanted to live a fucking fantasy like some fucking twilight book. And what did you do for everything I did for you? You fucking left when things got serious. You just fucking ran. You just left me here to deal with everything on my own. And when I asked you why? I got nothing. Nothing but a BS immature line of "It's me not you" And to top it all off You left when I lost my job. I was depressed for months and fucking suicidal. But did you give a fuck? Fuck no. You just fucking left. And you wanna know the worst part? I still love you. You haunt my dreams. I still would do anything for you. And you will always be in my heart. Because when I said I love you I meant it. When I asked you to marry me I meant it. And when you get older I hope you realize that you walked out on the one person who will love you forever. ..... WHEEEEWWW. Thanks OP I really needed that LOL
Anonymous Coward 1445981
I wish to stand up and applaud YOU right now. That was exactly what I meant for this thread...
Thanks gooes to you and please feel free to use this place any time and I promise I will read them all.
That really seemed like it would have lightened you a little at least...If it builds up again come back.
Please verify you're human:
Reason for copyright violation:
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Northern Germany consists of Bremen, Hamburg, Lower Saxony and Schleswig-Holstein.
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