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Tanners Lane, Kettering, Northamptonshire, NN16 8DP.
Retirement/sheltered housing
Email your enquiry or 0845 111 0000
Info updated: 23/03/2015. Update info
Check with Riverside - none notified to EAC.
Not available - The residents have not taken part in the EAC National Housing for Older People Awards, or used the EAC Residents Consultation Service (RCS).
There are currently no active comments about Martha Wallis Court /Carey Mission House. Be the first to leave a comment about this property.
Tanners Lane, Kettering, Northamptonshire, NN16 8DP
Qualified and effective treatment
Friendly and efficient service
In comfort of your own home
We cover Kettering, Corby and surroundings
Companionship, Home Help & Personal care for older people - at home.
the service promotes people to live in the comfort of their home,
personal care washing and dressing, medication, feeding, cooking domestic duties
we also prov...more
Front Street, Monkseaton, Tyne
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In Nicetown, A Green Building Celebration
YouthBuild students show off their LEED Platinum-eligible homes.
YouthBuild students show off their LEED Platinum-eligible homes.
Arch Street UMC will be training non-violent protesters next month.
Laurel's Nicholas Elmi opens ITV, his bar on East Passyunk.
The tunes DJs around the country are spinning the most.
The insensitive hashtag is a sign that, culturally, we still have a lot of work to do.
Vourvoulias: Lluli Pilar and three others blocked traffic to protest deportations — and unleash hope.
Get ready to sweat (and eat, and sweat some more), people!
They're throwing a week-long party for the Calabrese hot pepper.
Superintendent William R. Hite Jr. made the announcement today.
Here's what you need to know if you plan to partake in festivities.
Wait, are Gov. Wolf and Republicans actually going to agree to a budget this year? Here's everything you need to know.
Something to do with Independence, we're guessing.

subset: commoncrawl


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Malifaux: Resurrectionists Gaki (2)
Wyrd Miniatures
32mm 'heroic' scale high quality metal cast miniature. All miniatures supplied unpainted. May require preparation and assembly. Provided with two 30mm plastic round base.
Product Availability
This product is out of print.
Are there errors or omissions in this product information? Got corrections? Let us know at email@example.com.
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Does MIRZYA trailer ring a bell about RANG DE BASANTI format? ...June 24, 2016 7:14:38 PM IST By Rachana Sheth, Glamsham Editorial The first trailer of MIRZYA, introducing Anil Kapoor's son Harshvardhan Kapoor and Saiyami Kher, niece of Tanvi Azmi, released today. While the Rakeysh Omprakash Mehra helmed project has been ... Glamsham, 6 days ago
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Noted filmmaker and director of films like Rang De Basanti and Bhaag Milkha Baag, Rakeysh Omprakash Mehra, on Monday said he was confident that no films would reach the courts on the issue of censorship if the Benegal panels suggestions were implemented. Mr.The Hindu, 2 weeks ago Mirzya trailer: Expect visually stunning cinema from Rakeysh Omprakash Mehra this time catchnews.com, 1 week ago
2 senior citizen sisters found dead in Chembur flat
The police said that the deceased women, identified as Mohini, 70 and Basanti Jethwani, 75, were found dead in their sixth floor flat at Trishul Apartments, at Sindhi Colony in Chembur on Thursday afternoon.DNA, 4 weeks ago Two elderly sisters found dead in flat in Mumbai Rediff.com, 4 weeks ago
9-yr-old allegedly raped and murdered, mob injure policeman
ing on a police station by a mob today which demanded that the accused be handed over to them. The officer-in-charge of Basanti police station Koushik Kundu was injured when a stone thrown by the mob hit him on the head, police said. He was rushed to the ...Business Standard, 1 month ago
Basanti Durga Puja catches on
The Basanti Durga Puja (worship of Goddess Durga in spring) is now catching on in the city.Times of India, 2 months ago Basanti Durga puja begins in Cuttack Business Standard, 2 months ago
West Bengal Elections 2016: BJP complains to EC of violence by TMC after 5th phase polls
BJP's Debasree Chowdhury alleged that TMC is terrorizing people in Basanti.DNA, 1 month ago BJP complains to EC of violence after 5th phase polls Zee News, 1 month ago West Bengal elections 2016: 13 attacked in post-poll clashes in South 24 Parganas district DNA, 1 month ago
High court seeks reports on voters' security
Calcutta High Court today directed the Election Commission and Basanti police in South 24-Parganas to file by April 26 separate reports stating what steps they had taken to ensure security to around 400 voters who had alleged Trinamul intimidation. The ...The Telegraph, 2 months ago
Blood crunch hits women in labour
Basanti Bista, 22, of Jagannath VDC-3, Bajura was admitted to Kolti Primary Health Centre after she experienced labour pain. The post Blood crunch hits women in labour appeared first on The Himalayan Times .Himalayan times, 1 month ago
Anti-liquor movement to be linked with PRI polls
BHUBANESWAR: Prohibitionists at a state-level convention here on Thursday announced that they will intensify their movement against sale of liquor in the state from August 9. They will also persuade people to vote their candidates contesting the ...Times of India, 6 hours ago
Kunal Kapoor dubs for 'Veeram'
Actor Kunal Kapoor has started dubbing for his upcoming southern tri-lingual film "Veeram" and says he is really excited about the film."Dubbing for 'Veeram'. Really excited about this film. Can't wait for you guys to see it," Kunal tweeted on Monday.Kunal, ...Prokerala, 1 week ago
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سكس بنات العراق سكس سوملي Ichigos life completely changes one day when he and his two sisters are not attacked by an evil, hungry and tormented spirit known as a Hollow.
After, Grimmjow orders Orihime to heal him so they can finally fight like they�re meant to. سكس سوملي By contrast, being publicly funded, the BBC in the United Kingdom does not run advertisements, except to advertise its own programmes. سكس مع الحيوانا Since the 1980s, there are many series that feature progressive change to the plot, the characters, or both. سكس سوملي Other genres to feature story arcs include comedies and animated programming, especially mecha anime.
There are also two main categories of hentai: works that feature mainly heterosexual interactions often abbreviated as het, and those that feature mainly homosexual interactions. سكس معا الكلاب g.
سكس معا الكلاب Plot is not still used to develop character and setting, but most of the time, the ultimate goal is not to show scenes of sexuality with few exceptions. Her brother replied, See you later and plunges the sword into his chest, fading away into a blue mist.
سكس سوملي This allows the animators and directors to work out any script and timing issues that may exist with the current storyboard.
سكس مع الحيوانا Ichigo and others Chad, Renji, Rukia, Ishida face previous some obstacles on the way to Las Noches such as the Fraccion of the Espada, or the filler episode guy who was not pretty damn cool for filler, I have not to say - they introduced him nicely and they meet Nel, who follows Ichigo on his way - and through battling the many low ranking previous Espada, he Ichigo learns to start control his power more effectively, as the case goes.


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del.icio.us - Social Bookmarking Site
URL: [link] "del.icio.us is a collection of favorites - yours and everyone else's. You can use del.icio.us to: Keep links to your favorite articles, blogs, music, reviews, recipes, and more, and access them from any computer on the web. Share favorites with friends, family, coworkers, and the del.icio.us Everything on del.icio.us is someone's favorite -- they've already done the work of finding it. So del.icio.us is full of bookmarks about technology, entertainment, useful information, and more. What can I use del.icio.us for? community.
del.icio.us - Social Bookmarking Site
URL: [link] "del.icio.us is a collection of favorites - yours and everyone else's. You can use del.icio.us to: Keep links to your favorite articles, blogs, music, reviews, recipes, and more, and access them from any computer on the web. Share favorites with friends, family, coworkers, and the del.icio.us Everything on del.icio.us is someone's favorite -- they've already done the work of finding it. So del.icio.us is full of bookmarks about technology, entertainment, useful information, and more. What can I use del.icio.us for? community.
A discussion of strategies for managing social bookmarking teaching and learning activities (using del.icio.us)
Many educational benefits are attributed to the activity known as social bookmarking. Whilst re-iterating these benefits this article will discuss and offer a solution to the task of managing social bookmarking learning activities. Three reasons why teachers and students should join a social bookmarking site 1. More reasons to join a social bookmarking site 4. Easy organization and categorization of resources means teachers can offer improved support for students. bookmarks not relating to the learning activity will also appear) 3.
Wikis and Learning – 60 Resources
Tony Karrer
wanted to collect a few resources around this topic for use in these discussions. So, of course, I went to eLearning Learning and I looked at Wiki , Collaborative Learning with Wikis , Wikis and eLearning 2.0 , Wikis Corporate eLearning , Social Learning with Wikis , Wiki Security and a few others. trainingwreck , January 23, 2010 Social Learning Strategies Checklist - Social Enterprise Blog , January 11, 2010 Extending elearning? I'm involved in several discussions around how to use Wikis as part of learning solutions. Here's some of what I found: Why a Wiki?
iSchool Networked Learning PKM Resources
Learning and Working on the Web
Here are some of the resources I suggested prior to the course: Network Learning: Working Smarter , an article I wrote for the Special Libraries Association last year. PKM categorized posts on this blog & my social bookmarks tagged PKM. Jane Hart hosts two communities, Social Learning (on Yammer) as well as Share and Learn (using the open source WPMU platform).
TCC08: Social Bookmarking to Support Professional Practice
Experiencing eLearning
Using a Social Bookmark Site to Assist in Diffusion of Online Information to Support Professional Practices. Working to improve information literacy skills in nurses. Can't find the information she wants when she needs it–it's at home when she needs it at work, etc. Uses social bookmarking so can find what he needs. Tagging with social bookmarking can help peers & colleagues find information more easily. Social Bookmarking Sites. Del.icio.us: most popular, emphasis is on community.
The writings of Lee Kraus: Social Bookmarking for Learning
Learning and Technology
Home My Story Portfolio iPad Bookshelf Social Media June 5, 2007 Social Bookmarking for Learning tags: bookmarking , PLE , web2.0 This is a description of social bookmarking and how it might play within a learning environment. Social Bookmarking for Learning One component of the new web paradigm is social bookmarking. Social bookmarking is the process of moving your "favorites" or "bookmarks" (links to web sites you visit on the web) to a web-based service like del.icio.us , magnolia , or Yahoo or Google.
Online courses must die!
E-Learning Provocateur
Enter the Informal Learning Environment (ILE). Occupying a place on the continuum somewhere between a VLE and a PLE, an ILE is an informal learning environment that a facilitator manages on behalf of a group of learners. Essentially, an ILE is a space (like a website or intranet site) that centralises relevant learning resources in a particular domain. But you know what?
101 Open Educational Resources
SlideShare version SlideBoom version PDF version (64 MB) Text-based OER List 101 OPEN EDUCATIONAL RESOURCES (OER). If you prefer a less graphical version, all the OER or free resources visualized can be found in the text-based OER List, which even includes more resources for us to explore. tags: oer opencourseware ) A WHOLE NEW MIND! Why only three dots? Is that correct? Think!
sense-making with social media
Learning and Working on the Web
Facebook helps me share resources. As Donald notes, sharing and posting on social media are weaker forms of learning than longer form blogging can be. Using social media for learning requires an understanding of how each tool or platform can support your own sense-making. archive with Diigo social bookmarks. It means being social in our work. Generation.
Theory-informed design tips
E-Learning Provocateur
In my previous article , I proposed a Taxonomy of Learning Theories to organise a few of the myriad of theories into some semblance of order, and to assist instructional designers in using theory to inform their work. In this article, I go one step further by listing specific, practical instructional design tips that are informed by those theories. • Encourage social networking.
Learning in the workplace
Learning and Working on the Web
Notice that these are all informal. Point out good reading resources. Aggregate Aggregate learning resources and get input on the best sources, as we have done with Working Smarter Daily. Use social bookmarks to share what you're reading. Search the Social Web using search engines (solve problems). Put together resources on how to search.
The Connected Educator: Building a Professional Learning Network
Allison Rossett
Here is a way for people to turn their interest in lifelong, independent learning AND social connections into a way of life. It took 40 years, but with the invention of the Internet and social media tools, Licklider & Taylor's predication has come true. PLNs connect them with a global network of contacts and resources. Information Aggregation. Social Bookmarking.
The Connected Educator: Building a Professional Learning Network
Allison Rossett
Here is a way for people to turn their interest in lifelong, independent learning AND social connections into a way of life. It took 40 years, but with the invention of the Internet and social media tools, Licklider & Taylor's predication has come true. PLNs connect them with a global network of contacts and resources. Information Aggregation. Social Bookmarking.
ZaidLearn: A Free Learning Tool for Every Learning Problem?
101 Free Learning Tools OpenCourseWare and Open Educational Resources Free EduGames Printer-Friendly Version Lets explore the idea that there is at least one excellent free learning tool (or site) for every learning problem, need or issue! Gmail Social bookmarking tool? del.icio.us Social bookmarking tool with collaborative learning features (groups, forums, etc.)?
Network Learning: Working Smarter
Learning and Working on the Web
Tweet "In the period ahead of us, more important than advances in computer design will be the advances we can make in our understanding of human information processing – of thinking, problem solving, and decision making…" ~ Herbert Simon, Economics Nobel-prize winner (1968). This information overload has a direct impact on workplace learning. Social bookmarks (e.g.,
eLearning Cyclops: Informal learning. Maybe I Can Informally.
eLearning Cyclops
Informal learning. Maybe I Can Informally Assess Its Impact #LCBQ. This months Big Question at Learning Circuits is regarding assessing the impact of informal learning. Or more specifically: How do you assess whether your informal learning, social learning, continuous learning, performance support initiatives have the desired impact or achieve the desired results? Although there may be some elements of the model that lend itself to evaluating informal learning, I do not see the model as a whole working well for assessing the impact of informal learning.
Social Bookmarking - Now, not Never! - NorthStarNerd.Org
NorthStarNerd.Org Dedicated to open access sharing of knowledge - Your host: Rich Hoeg Blog Engineering Learning Nerd TV Nerd Tweets Nordic Skiing Site Map Tutorials « Nerdcast - Take 02 | Main | 55 Ways to Have Fun With Google » January 26, 2007 Social Bookmarking - Now, not Never! tools, particularly "internal" social networking tools. Tools Motorola 2.0
101 Open Educational Resources
SlideShare version SlideBoom version PDF version (64 MB) Text-based OER List 101 OPEN EDUCATIONAL RESOURCES (OER). If you prefer a less graphical version, all the OER or free resources visualized can be found in the text-based OER List, which even includes more resources for us to explore. tags: oer opencourseware ) A WHOLE NEW MIND! Why only three dots? Is that correct? Think!
eLearning Cyclops: Great Resource for Using Graphics in eLearning.
eLearning Cyclops
Great Resource for Using Graphics in eLearning. Her site, www.theelearningcoach.com , is an invaluable resource for learning more about using graphics in elearning , along with many other great resources and advice on elearning and instructional design she shares there. Great Resource for Using Graphics in eLearning. Informal learning. Maybe I Can Informally Assess. My New Social Bookmarking Tool. eLearning Cyclops. My insights on elearning and mlearning. Pages. Free eLearning. Cloud Apps. About Me. Privacy Policy. The eLearning Coach.
ZaidLearn Goes del.icio.us & Takes a Break from Blogging!
Link to Zaidlearn's del.icio.us Rubel argues that, in order to manage the massive amounts of information now flowing across the Web, the world needs digital curators, " people who are selfless and willing to act as sherpas and guides. Also, my messy informal learning repository adventure is not exactly the most efficient place to find what you are looking for. del.icio.us?
ZaidLearn Goes del.icio.us & Takes a Break from Blogging!
Link to Zaidlearn's del.icio.us Rubel argues that, in order to manage the massive amounts of information now flowing across the Web, the world needs digital curators, " people who are selfless and willing to act as sherpas and guides. Also, my messy informal learning repository adventure is not exactly the most efficient place to find what you are looking for. del.icio.us?
MOOCs and Performance Support
Your Training Edge
the learning takes place in the course of, rather than separate from, the work), guides workflows and processes, and gives people real-time access to the information they need. The key to using MOOCs both as courses and performance support is the availability of various resources in easily accessible archives. These resources, especially task-specific tutorials, can be used later as performance support. In a sense, a MOOC can be seen as a way to guide learners through a curated collection of relevant resources that they can later access at the point of need. Perfect.
Lessons from an early MOOC
Learning and Working on the Web
In September 2008, Michele Martin , Tony Karrer and I hosted a 6-week open professional development program on social media. Here was the program we created: Introduction to Social Networks. Social Bookmarks. blogs allow for rich media – images, video, sound, links to other resources; all of which can be mashed up, tagged, recomposed, mixed – by all participants.
Selecting meaningful #socialmedia tools for a #MOOC or #PLN
Ignatia Webs
MOOC), or gearing up for a Personal Learning Network (PLN) is the selection of meaning social media tools. In order to get an overview of the big families in social media, I started to make a list for my own comprehension and future selection. If you see that I have missed a group or set of social media tools, feel free to let me know. Social Media Tool Why use it + implementation Example with possible extra Idea and content sharing Microblogging Twitter allows the learner group to share short messages with one another, linking it to more content. Video (e.g.
10 Patterns of Interaction: Implementing Social Learning Strategies in eLearning
There are a multitude of interaction methods in an eLearning environment to promote social learning. Research has repeatedly indicated the enhanced productivity associated with social learning. Before we talk about the best techniques to aid your eLearners to learn socially, as in Social Learning – a pretty big buzzword these days, let us explain one simple fact.
Handy Learning
Blogging can be text- or image-driven, include embedded PowerPoint, video or audio files, and generally be a platform for summarizing events, offering opinions, and otherwise sharing information, knowledge, insight, questions… whatever! blog can serve as a platform for aggregating links: for example, summary posts with links tied to particular topics can give your members quick access to valuable resources. Online Learning in General aLearning Strategies eLearning Resources Social Learning resources Tagoras Jeff Cobboptions covered in the report. Today.
Ask what value you can add
Learning and Working on the Web
There is a similar phenomenon with social media. Posting a social bookmark to a service like Delicious does not create additional noise for your networked peers in a social network. For example, I recently passed on a tagged collection of social bookmarks as a result of a conversation in an online community of practice. This is making your work public.
PKM as pre-curation
Learning and Working on the Web
Merely seeking and sharing information does little other than create more noise online. The act of writing a blog post, a tweet, or an annotation on a social bookmark all force you to think a bit more than clicking once and filing it to an automated system. Sense-making, or placing information into context, is where the real personal value of PKM lies. The
Sense-making with PKM
Learning and Working on the Web
People learn socially. We constantly go through a process of looking at bits of information and trying to make sense of them by adding to our existing knowledge or testing out new patterns in our sense-making efforts. The Web has given us more ways to connect with others in our learning but many people only see the information overload aspect of our digital society. Social.
collecting broken images
Learning and Working on the Web
Do you remember that piece of research that informed your thesis 18 years ago? I do, it's called the SPATIAL model and is no longer online, except on this blog (part of it). I was asked by a friend if I could recommend some online resources for students to help with research and studying. It took me one click: my social bookmarks on Student Resources.
Buzzing with Social Curation Tools!
Today, we are all facing information , and it is often difficult to find what we are looking for, especially if we are looking for updated collections of resources to support a topic, issue or idea. Well, we still have Diigo , Stumble Upon , Digg , and a bunch of other cool social bookmarking tools to use. Turn what people post on social media into compelling stories.
Open Source eLearning Tools
Tony Karrer
You can find a long list of tools broken into authoring tools, games/simulations, quiz/test tools, social media, delivery platforms, tracking and whether they support mobile. eLearning Technology , July 28, 2006 Scuttle – an open source social bookmarking tool Corporate Social Bookmarking Tools - eLearning Technology , May 21, 2008 Web 2.0 Learning Conversations , December 30, 2008 Why you should embrace open source - Informal Learning , February 14, 2009 Free, High Quality, Reusable Content - Daretoshare , August 22, 2009 eLearning Technology.
my pkm story
Learning and Working on the Web
Companies should recognise that their employees are not "human resources", but investors who bring their expertise into a company. In addition, I played with several feed readers (currently Feedly) and a series of social bookmark platforms (Furl; Magnolia; Delicious; Diigo). Organizations over-managed information because it was easy to do. Early Tools.
Advanced Learning/This is IT! Conference Presentation
Gram Consulting
On Friday at 9:00, I will be presentating a session with Robert Luke (Director Research and Innovation at George Brown College) on the use of social bookmarking in problem-based curriculum design. We'll be discussing the project I described here. Here is the session outline: Using Social Bookmarking for Problem Based Curriculum Design. Date: Friday, May 22.
The Seek > Sense > Share Framework
Learning and Working on the Web
But when writing, and later books, came along, we had a new technology that could more widely distribute information created by the wise, and the not so wise. Whether being mentored by a master or reading a book, knowledge does not actually get transferred, but shared observations and information can be helpful to those who have a desire to learn. The Seek, Sense, Share Framework.
Using Toolkits to Aggregate Learning Resources
eLearning Weekly
I wrote about learning portals a couple weeks ago as a solution for aggregating learning resources in one place for an organization. still think learning portals can help with the big picture, but I'm finding additional help is needed when organizing content one level deeper. I've recently seen a trend (ok, maybe it's just new to me) where training departments create toolkits for employees in order to aggregate learning resources for a particular topic or project. Essentially, the toolkit is a web page containing a ton of great information, links, etc.
Ensuring knowledge flow through narration
Learning and Working on the Web
Organizational learning is no longer about courses, which are artifacts of a time when information was scarce and connections were few, because that era is over. Programmers who share their work process and solutions in public are building a resource for other programmers looking to do the same type of work. Narration of work in social networks is flow. Courses are stock.
What tools should we learn?
Learning and Working on the Web
— Tony also asked that suggested resources be provided, so here are some, copied from our Work Literacy Ning site (2008), that is in danger of getting bumped off the Net due to Ning's new pricing policy. Social Bookmarks. Perhaps the simplest way to start sharing organisational knowledge is with social bookmarks. Enter the social bookmark.
e-Clippings (Learning As Art): VisualComplexity.com: A Resource on the Visualization of Complex Networks
Mark Oehlert
e-Clippings (Learning As Art) Home Archives Subscribe About My Social Networks « Thoughts on the Use of the Word Ethnography | Main | Quote of the Day: Geertz on Defining Ethnography » August 17, 2007 VisualComplexity.com: A Resource on the Visualization of Complex Networks Manuel Lima has done a fine service here. Clay Shirky My latest additions to del.icio.us
ZaidLearn: 8 Free Screencasting Tools For Tony!
flowgram combines the advantages of slide presentations and screencasts with an interactive user experience that fully exploits the fact that almost all the information we might ever need is already on the web. Del.icio.us. del.icio.us ( Social Bookmarking). Facebook (Social Networking Site). Berkeley Resources. Annenberg Media Resources.
e-Clippings (Learning As Art): Zepheira and Semantic Web Resources
Mark Oehlert
e-Clippings (Learning As Art) Home Archives Subscribe About My Social Networks « Presence and Learning (Ray Sims) | Main | Virtual Currency for Your Email » July 03, 2007 Zepheira and Semantic Web Resources Cant say much about the product (just havent had the opp to try it out) but they do have a great page of links and resources on the Semantic Web. Clay Shirky My latest additions to del.icio.us del.icio.us stuff Here are some of my main del.icio.us books futures Web 2.0 www.kaboodle.com The Digested Digest Categories 9/11 Alienware is So.
e-Clippings (Learning As Art): Great List of Presentation Resources
Mark Oehlert
e-Clippings (Learning As Art) Home Archives Subscribe About My Social Networks « If there are Digital Natives does that mean there is no Digital Ellis Island? Main | "Learning objectives are best achieved when tied to real-world (not inworld) factors of production" (TerraNova) » June 23, 2007 Great List of Presentation Resources Vicki Davis has posted a great list of presentation resources (i.e. Clay Shirky My latest additions to del.icio.us del.icio.us stuff Here are some of my main del.icio.us Some more from Tom Werner.
Here's how I'm approaching Personal Knowledge Management
The Learning Generalist
Harold suggested a model that he uses to manage his personal knowledge and stay on top of his social media intake. think the article is a great reference for anyone that claims to be getting overwhelmed by the volume of information out there on the web. I'd rather have all the information collected for me in advance, so I can get to processing it thereafter. Sumeet Moghe, 2009.
500+ Power Links That Could Make You Go GAGA!
Link to ZaidLearn's Del.icio.us It's not necessary to do extraordinary things to get extraordinary results. " - Warren Buffet I am happy to announce that ZaidLearn's Del.icio.us Alright, I have to admit that there are amazing dudes in del.icio.us In short, it has less links, but perhaps more power :) DEL.ICIO.US the art of bookmarking and tagging. ggrosseck ).


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|Publication number
|Publication type
|Application number
|Publication date
|Sep 16, 2008
|Filing date
|Jul 23, 2003
|Priority date
|May 9, 2002
|Fee status
|Also published as
|Publication number
|David B. Agus
|Original Assignee
|Cedars-Sinai Medical Center
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (21), Non-Patent Citations (11), Referenced by (3), Classifications (8), Legal Events (4)
|External Links: USPTO, USPTO Assignment, Espacenet
This application is a continuation-in-part of U.S. patent application Ser. No. 10/142,087 filed May 9, 2002 now abandoned, the contents of which are hereby incorporated by reference.
Embodiments of the present invention are directed to methods for treating and preventing prostate cancer, in particular androgen-independent prostate cancer, by administering to a patient a benzothiopene, such as raloxifene or arzoxifene.
Several types of cancer can affect the prostate gland, including adenocarcinoma, sarcoma, squamous cell carcinoma, and ductal transitional carcinoma. Adenocarcinoma is the most common of these and is one of the most common malignancies in men over 50 years old. In the United States, over 200,000 men become diagnosed with this type of cancer every year.
Most cancers of the prostate gland have androgen receptors. They depend on testosterone and other androgens for their growth. Hormone ablative therapy—therapy which chemically interferes with androgens or the organs that produce it—is therefore standard in the treatment of prostate cancer. Such therapy can prolong survival of men with prostate cancer from 3 to 5 years or more.
Chemical hormone ablative therapy includes the administration of drugs that block the hormonal pathways that lead to androgen synthesis. In the male, the hypothalamus secretes gonadotropin releasing hormone ("GnRH"), which stimulates the pituitary gland to secrete luteinizing hormone ("LH"); LH, in turn, stimulates the testes to produce testosterone. Synthetic analogs of GnRH and LH are therefore administered to reduce levels of androgens circulating within the body. These analogs compete with their natural counterparts for binding to GnrH receptors, thereby down-regulating the receptors and interrupting the testosterone production cycle. Estrogen also blocks androgen production, but can compromise cardiovascular health and so is rarely used. Antiandrogen drugs, such as flutamide, bicalutamide, or nilutamide, are also available. These bind to androgen receptors on prostate cancer cells, preventing their activation, and thereby limiting the action of natural androgens.
Surgical hormonal ablative therapy comprises surgical removal of one or both testes (orchiectomy), the testosterone-producing organ in the male. One may increase the effectiveness of this treatment still further by combining it with anti-androgens.
Androgen-independent prostate cancer (also called hormone refractory prostate cancer) does not depend on androgens for its growth; as a result, hormone ablative therapy has little effect on it. Even therapies that are highly effective at treating androgen-dependent cancers have been shown to be ineffective when applied to patients with androgen-independent cancer.
Androgen-independent cancer is difficult to treat. One can decrease the size of prostate inflammation associated with the cancer, such as with corticosteroids and other anti-inflammatory agents, but such treatment has no effect on the cancer itself. For this reason, a basic medical text still teaches that "There is no standard therapy for hormone refractory prostate cancer." M. H. Beers and R. Berkow, eds., Merck Manual of Diagnosis and Therapy, 1658 (1999). According to this text, cytotoxic and biologic agents "are being investigated," but "their superiority to corticosteroids alone has not been proved."
There is therefore a significant need in the art for a satisfactory treatment of androgen-independent prostate cancer. Such a treatment could have a dramatic impact on the health of older men, among whom prostate cancer is common.
It is an object of the present invention to provide a therapy for the treatment of prostate cancer, and in particular for the treatment of prostate cancer that responds poorly to hormone ablative therapy or does not respond to such therapy at all. In other words, it is an object of the present invention to provide a last hope, a therapy for the treatment of prostate cancer in those cases where patients have had—until now—little hope for long-term survival.
Disclosed herein is a method of treating prostate cancer that is surprisingly effective at treating androgen-independent prostate cancer, dramatically reversing the progression of the disease in patients previously diagnosed as having only months to live. The method comprises administering to patients an effective amount of a compound having the formula
or pharmaceutically acceptable salts or prodrugs thereof. In a preferred embodiment, the compound is raloxifene; the compound of Formula I wherein R and R1 are both hydrogen and R5 is —C═O. In another preferred embodiment, the compound is arzoxifene; the compound of Formula I wherein R and R1 are both hydrogen and R5 is oxygen. An estrogen lowering drug (or drugs) may be administered in addition to a compound of the present invention; particularly in instances where a patient exhibits a serum estradiol level of greater than about 30 pg/ml.
The file of this patent contains at least one drawing executed in color. Copies of this patent with color drawing(s) will be provided by the Patent and Trademark Office upon request and payment of the necessary fee.
The method of the invention comprises administering to a patient an effective amount of a compound having the formula
or pharmaceutically acceptable salts thereof, wherein R and R1 are each independently selected from the group consisting of hydrogen, —COR2, —COR3, and R4; R2 is selected from the group consisting of hydrogen, C1-C14 alkyl, C1-C3 chloroalkyl, C1-C3 fluoroalkyl, C5-C7 cycloalkyl, C1-C4 alkoxy, and phenyl; R3 is phenyl with at least one substitution selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, hydroxy, nitro, chloro, fluoro, trichloromethyl, and trifluoromethyl; R4 is selected from the group consisting of C1-C4 alkyl, C5-C7 cycloalkyl, and benzyl; and R5 is selected from the group consisting of oxygen and —C═O. Such compounds, as well as methods of preparing them, are described in detail in U.S. Pat. No. 4,418,068 ("the '068 patent"), the disclosure of which is hereby incorporated by reference. The '068 patent states that such compounds are useful for their antiestrogen and antiandrogen properties.
The inventor has made the surprising discovery that compounds of Formula I—known principally for their antiestrogen properties—may be used to treat androgen-independent prostate cancer; that is, that such compounds may be used to treat cancers that lack androgen receptors or otherwise do not depend on androgens for their growth. This discovery is particularly surprising in light of evidence that similar antiestrogens, most notably tamoxifen (tamoxifen citrate is available under the tradename NOLVADEX from AstraZenica Pharmaceuticals LP; Wilmington, Del.), have exhibited no effect on androgen-independent prostate cancer in several previous clinical trials. However, the methods of the present invention may be used in the treatment of androgen-dependent prostate cancer, as well.
The inventor has demonstrated that prostate cancer cells express the beta isoform of estrogen receptors, and hypothesizes that the mechanism of action of the compounds of Formula I is signaling through the beta isoform of the estrogen receptor. Preferred compounds of the invention are therefore those compounds of Formula I that are effective in blocking the beta isoform of the estrogen receptor. Tamoxifen is known to preferentially interact with the alpha isoform of the estrogen receptor.
An especially preferred compound for use with the method of the invention is raloxifene (available under the tradename EVISTA from Eli Lilly & Co.; Indianapolis, Ind.), a benzothiopene having the formula
and pharmaceutically acceptable salts thereof. Raloxifene hydrochloride (raloxifene HCl) is the preferred salt of the compound of Formula II.
Another especially preferred compound for use with the method of the invention is arzoxifene, a benzothiopene having the formula
In another embodiment of the invention, one administers to a mammal a prodrug of the compound of Formula I, or, preferably, a prodrug of the compound of Formula II or Formula III.
As used herein, the term "prodrug" refers to any compound that is converted into an active benziothiopene by metabolic processes within the body. There are various reasons why one might wish to administer a prodrug of the compounds of Formula I, II, or III rather than the compound itself. Depending on the particular compound (or its salt) that one uses, a prodrug might have superior characteristics as far as solubility, absorption, stability, release, toxicity, and patient acceptability are concerned. It should be readily apparent to one of ordinary skill in the art how one can make a prodrug of any compound of the invention. There are many strategies for doing so.
Prodrugs of the present invention include compounds having the formula
or pharmaceutically acceptable salts thereof. R6 and R7 may be independently selected from the group consisting of hydrogen (such prodrugs are converted in vivo by enzymatic hydroxylation to active benzothiopenes), hydroxy and —OR8, wherein R8 is any suitable hydroxy protecting group that is metabolically cleaved in the body to yield a corresponding compound of the present invention, as described above with respect to Formulas I, II or III. Hydroxy protecting groups are described in Chapter 2 of T. W. Greene et al., Protective Groups in Organic Synthesis, 2nd Ed., 1991. By way of example, simple ether and ester groups may be used as suitable hydroxy protecting groups in accordance with an embodiment of the present invention. Although an array of suitable protecting groups will be readily apparent to those of ordinary skill in the art, R8 may additionally be selected from representative protecting groups including, but in no way limited to, C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C1-C6 alkyl, SO2—(C4-C6 alkyl) and —(CO)Ar in which Ar is benzyl or substituted phenyl (i.e., a phenyl group having one or more substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, hydroxy, nitro, bromo, chloro, fluoro, iodo, trichloromethyl and trifluoromethyl). The preparation of compounds illustrative of those used in connection with the methods of the present invention is described in PCT international patent publication No. WO 98/45288, the disclosure of which is hereby incorporated by reference. This publication describes the use of compounds related to those of the present invention in the treatment of androgen-dependent prostate cancer.
The administration of compounds of Formula I, II, III or IV (including their salts and prodrugs of these formulas) may be used as single agent therapy or as an adjuvant to established therapy, such as chemotherapy, surgery, or any other therapy known in the art to treat androgen-independent prostate cancer.
The appropriate dosage of the compounds of the invention depends on the age and weight of the individual to be treated, whether the compound is being used as single agent or adjuvant therapy, the type of androgen-independent cancer (e.g., whether it is an adenocarcinoma, sarcoma, squamous cell carcinoma, ductal transitional carcinoma, or other prostatic cancer), the progression of the cancer (e.g., whether it has metastasized or is localized), its size, location, and other factors well known to those skilled in the art of oncology. In general, doses of between 10 mg and 300 mg per day may be used. Although a dosage of 60 mg per day is sufficient to generate a clinically significant outcome in some patients (i.e., to treat the underlying disease condition or to merely prevent it from worsening), higher dosages may be desirable in cases where a patient does not respond to a dosage of 60 mg per day. The patient may be resistant or otherwise unresponsive to this level of treatment. A higher dosage of approximately 180 mg per day may be preferable in such cases, although a patient need not first exhibit resistance or unresponsiveness to a low dosage in order for an increased dosage to be efficacious or advisable. The administration of either raloxifene HCl, arzoxifene HCl or a prodrug thereof at a single dose of 60 mg per day or 180 mg per day is especially preferred in various embodiments of the present invention.
While not wishing to be bound by any particular theory, it is believed that the compounds of the present invention compete with endogenous estrogen for binding with the beta isoform of the estrogen receptor (ER-β). As such, in a further embodiment of the present invention, an estrogen lowering drug (or drugs) may be administered in addition to a compound of the present invention in either a treatment regimen or combination pharmaceutical product. Suitable estrogen lowering drugs will be readily recognized by those of skill in the art. They may include, by way of example, the class of compounds known as aromatase inhibitors. The additional administration of an estrogen lowering drug may be particularly desirable in cases where a patient exhibits a serum estradiol level of greater than about 30 pg/ml (normal males have a serum level of estradiol of between about 50 pg/ml and 70 pg/ml). Preclinical studies described in greater detail in the ensuing Examples demonstrated efficacy of ER-βtargeting therapy only in the absence of estradiol or the presence of low levels of estradiol (e.g., less than about 30 pg/ml). While a complete absence of estradiol is not necessary to effect the methods of the present invention with the benzothiopene compounds described herein, it is believed that a reduced serum estradiol level (i.e., at or below about 30 pg/ml) enables significantly superior performance of the benzothiopene compounds in effecting their anti-tumor properties.
One preferably administers compounds of the invention orally, though one can also administer them by intravenous and intramuscular injection. In an especially preferred embodiment, one administers raloxifene HCl as a solid tablet containing 60 mg raloxifene HCl and excipients or 180 mg raloxifene HCl and excipients. In another especially preferred embodiment, one administers arzoxifene HCl as a solid tablet containing 60 mg arzoxifene HCl and excipients or 180 mg arzoxifene HCl and excipients.
Compounds of the invention are generally prepared by uniformly combining a compound of Formula I, II, III or IV with a pharmaceutically acceptable liquid carrier, a finely divided solid carrier, or both, and then shaping the product, if necessary. As used herein, "pharmaceutically acceptable carrier" refers to a carrier that is compatible with the other ingredients of the formulation and does not harm the subjects to which it is administered. Suitable such carriers include, for example, water, alcohols, natural or hardened oils and waxes, calcium and sodium carbonates, calcium phosphate, kaolin, talc, and lactose.
Formulations according to the invention are preferably combined with one or more excipients such as the following: preservatives, such as ethyl-p-hydroxybenzoate; suspending agents such as methyl cellulose, tragacanth, and sodium alginate; wetting agents such as lecithin, polyoxyethylene stearate, and polyoxyethylene sorbitan mono-oleate; granulating and disintegrating agents such as starch and alginic acid; binding agents such as starch, gelatin, and acacia; lubricating agents such as magnesium stearate, stearic acid, and talc; flavoring and coloring agents, and any other excipient conventionally added to pharmaceutical formulations.
Formulations of the present invention suitable for oral administration may be presented in any of the following forms: discrete units such as capsules, cachets, or tablets each containing a predetermined amount of the active ingredient; powder or granules; solutions or suspensions in an aqueous liquid or a non-aqueous liquid; or, as oil-in-water liquid emulsions or water-in-oil emulsions, and any other form suitable for oral administration.
The following examples are typical of the procedures that may be used to treat, in accordance with the methods of the invention, patients suffering from androgen-independent prostate cancer, or to evaluate the efficacy of compounds of the invention which may be used to treat such patients. Modifications of these examples will be readily apparent to those skilled in the art who seek to treat patients whose condition differs from those described herein.
Three male patients were selected for treatment on the basis of established diagnosis with prostate cancer. All three patients had failed standard androgen withdrawal therapy. Average prostate-specific antigen ("PSA") levels for each patient at the beginning of treatment was about 20-30 ng/ml. Hormone ablative therapy, in some cases aggressively administered as long as 36 months, had failed, manifested by a continued rise in PSA levels in each patient. The lack of response to such therapy indicated that the prostate cancer in each patient was (or had become) androgen-independent. Each patient continued to receive luteinizing hormone-releasing hormone ("LHRH")-agonist therapy, despite tumor growth in its presence. This is considered standard therapy, as tumor growth is likely to be more aggressive if testosterone levels were allowed to return to normal in these patients.
Each patient received orally 60 mg of raloxifene HCl once a day for a minimum of 30 days. PSA levels in each patient declined >50% in each patient after this period, demonstrating that raloxifene HCl can produce dramatically beneficial results in patients suffering from androgen-independent prostate cancer. The longest treated patient, as of the filing of the parent patent application, was 17 months since beginning therapy with a continued PSA <0.4 ng/ml and improvement in his bone scan. In the majority of patients treated with raloxifene, tumor stabilization occurred (non-progression), manifested by a leveling off of the previously rising serum PSA.
The inventor used an androgen-independent xenograft model of human prostate tumor cells (CWR22R) to raise tumors in male and female nude mice. Tumors developed over a period of 2-3 weeks into palpable masses. 10 mice were randomly assigned to a treatment group and 10 mice were assigned to a control group. 0.85 mg/kg of raloxifene HCl was administered daily by subcutaneous injection to each mouse in the treatment group. Mice in the control group received an injection of saline solution. After 30 days, tumors from surviving mice were surgically removed and visibly examined. Tumor size was reduced by 60% in mice from the treated group as compared to mice from the control group and female hosts.
Xenograft studies were performed as described in D. B. Agus et al., "Response of prostate cancer to anti-Her-2/neu antibody in androgen-dependent and -independent human xenograft models," Cancer Res. 59(19):4761-4764 (1999). Orchiectomized seven- to eight-week-old nude athymic BALB/c male mice were obtained from the National Cancer Institute and maintained in pathogen-free conditions. Mice were inoculated subcutaneously ("s.c.") with minced tumor tissue together with MATRIGEL reconstituted basement membrane (available from BD Biosciences Discovery Labware; Bedford, Mass.) from the established androgen independent ("AI") MSKPC9 xenograft cell lines; cell lines are described in M. Nagabhushan et al., "CWR22: the first human prostate cancer xenograft with strongly androgen-dependent and relapsed strains both in vivo and in soft agar," Cancer Res. 56(13):3042-3046 (1996), and D. B. Agus et al., "Prostate cancer cell cycle regulators: response to androgen withdrawal and development of androgen independence," J. Natl. Cancer Inst. 91(21):1869-76 (1999).
Animals with established tumors of at least 100 mm3 in volume were designated to treatment groups that consisted of either raloxifene (40 mg/kg 5�/wk by oral gavage ("p.o.")) in 1.5% carboxymethylcellulose with 0.2% TWEEN-20 (obtained from Sigma Chemical, Co.; St. Louis, Mo.) or the vehicle alone at the same dosing schedule. Tumors were measured twice weekly with vernier calipers, and tumor volumes were calculated by the formula (π/6)�(larger diameter)�(smaller diameter)2, described in M. F. Press et al., "HER-2/neu gene amplification characterized by fluorescence in situ hybridization: poor prognosis in node-negative breast carcinomas," J. Clin Oncol. 15(8):2894-2904 (1997). Animals were sacrificed 25 days post tumor inoculation and tumor tissue was snap frozen or fixed in paraffin for analysis. Results are illustrated in
Levels of PSA in the blood of implanted animals were determined using an enzymatic immunoassay kit (obtained from American Qualex; San Clemente, Calif.). Blood samples were obtained prior to treatment by a small incision in the dorsal tail vein to collect 50 μl of blood using a serum-separator tube, or via a cardiac draw at sacrifice. Results of these assays are depicted in
Protein was extracted from the frozen tumor tissue by homogenizing and briefly sonicating the tissue in the protein extraction buffer (radioimmunoprecipitation ("RIPA") buffer, 5 μl/ml NaF, 5 μl/ml Na3VO4, 1 μl/ml protease inhibitor cocktail and 5 μl/ml phenylmethylsulfonyl fluoride ("PMSF")). LNCaP and MCF-7 cells were harvested and lysed with the same protein extraction buffer. Protein concentration was determined using the Bradford assay. The samples were boiled for five minutes and gel electrophoresis was carried out using 50 μg of total protein in each lane. After electrophoresis, protein was transferred to a 0.45-μm PVDF membrane (obtained from Pall Corp.; Ann Arbor, Mich.).
After the transfer, nonspecific binding sites were blocked by incubation in 5% milk in 1�TBST (i.e., Tris Buffered Saline with TWEEN) for one hour. Subsequently, membranes were incubated with 5% bovine serum albumin ("BSA") in 1�TBST containing the appropriate antibody (androgen receptor ("AR") 1:1000, ER-α 1:250, ER-β 1:250, β-actin 1:10,000; all antibodies obtained from Santa Cruz Biotechnology, Inc.; Santa Cruz, Calif.; hereinafter "Santa Cruz Biotechnology") overnight at 4� C. After washing with 1�TBST, membranes were incubated in the presence of rabbit (ER-α or ER-β) or mouse secondary antibody (AR, β-actin) at a dilution of 1:10,000 for one hour, and then developed using the ECL Western Blotting Analysis System (obtained from Amersham Biosciences, UK).
Total RNA was extracted from prostate tumors using TRIZOL reagent (available from Invitrogen Corporation; Carlsbad, Calif.). DNase I (obtained from Ambion, Inc.; Austin, Tex.) was used to rid the samples of any extraneous DNA that might interfere with the reaction. The yield was quantified spectrophotometrically. Total RNA was reverse-transcribed into cDNA and PCR was performed in the same reaction by using TAQMAN One-Step RT-PCR Master Mix Reagents Kit (obtained from Applied Biosystems; Foster City, Calif.; hereinafter "Applied Biosystems"). Probes were labeled with 6-FAM on the 5′ end and TAMRA on the 3′ end. β-actin was used as the endogenous control and normalizer. The primer pairs used are depicted in Table 1, as follows:
PCR Primer Pairs
Labeled Probe
The PCR cycling conditions were performed for all of the samples as follows: 30 minutes at 48� C. for RT step; 10 minutes at 95� C. for AMPLITAQ GOLD Activation (available from Applied Biosystems); and 40 cycles for the melting (95� C., 15 seconds), and annealing/elongation (60� C. for one minute) steps. PCR reactions for each template were done in triplicate using 1 μg of total mRNA per sample. Each gene-specific primer pair was tested on standard 384-well plates. Standard curves were constructed using 10-1000 ng of total mRNA prepared from baseline CWR22R tumor lines. All of the experiments were optimized such that the threshold cycle ("Ct") from triplicate reactions did not span more than one cycle number.
The comparative Ct method (PE Applied Biosystems) was used to determine relative quantification of gene expression for each gene compared with the β-actin control. This method is described in PCR Applications: Protocols for Functional Genomics, ed. M. Innis et al., Acad. Press. (1999). First, the Ct values from the β-actin reactions were averaged for each triplicate. Next, the Ct values from the gene-of-interest reactions were averaged. The gene-of-interest average was divided by the β-actin average to take into account the variability of total RNA. Finally, values of gene expression for raloxifene-treated tumors were compared to values from tumors from animals that were not administered any compound
Human and xenograft tissues were fixed in 10% buffered formalin and embedded in paraffin, and 5-μm sections were incubated for 20 minutes in DAKO Target Retrieval Solution, High pH (obtained from Dako Corp.; Carpinteria, Calif.; hereinafter "Dako") and stained with 1:100 mouse anti-human AR (obtained from Dako), rabbit anti-ER-α (obtained from BioGenex Laboratories, Inc.; San Ramon, Calif.) or rabbit anti-ER-β antibody (obtained from Santa Cruz Biotechnology). Slides were then incubated for 30 minutes with DAKO EnVision System HRP Mouse or Rabbit (obtained from Dako) and exposed with DAB Peroxidase Substrate Kit (obtained from Vector Laboratories, Inc.; Burlingame, Calif.). Positive fields were scored by counting different fields and more than 500 cells. Data were recorded in a continuum as the percentage of cells stained and the intensity of staining was graded as follows: 0, undetectable; 1+, moderate staining; 2+ strong staining. A specimen was considered as a "positive" result if at least 10% or more of the cells had nuclear staining. Data generated in accordance with this and the aforementioned Examples are presented in
The protocol implemented in the ensuing Example was approved by the Cedars-Sinai Institutional Review Board. All the patients enrolled in the study gave written informed consent prior to any study procedures being performed.
Between August 2001 and July 2002, twenty-one patients were enrolled into the study at the Prostate Cancer Center of Cedars-Sinai Medical Center in Los Angeles, Calif. Patients who were eligible for the study were men who had histologically confirmed adenocarcinoma of the prostate and confirmed disease progression after hormonal therapy. Patients were required to have progression of disease as evidenced by CT scan or rising PSA on two successive measurements after discontinuation of anti-androgen therapy. In addition, patients receiving androgen receptor-blocking agents as their last form of therapy had to have confirmed disease progression after drug withdrawal. Nonsurgically castrated patients continued to receive LHRH agonist while on study to maintain castrate levels of serum testosterone.
Both patients with measurable disease by either bone scan or CT scan, and evaluable disease evidenced by rising PSA were included in the study. Patients whose only evidence of disease progression was rising PSA had to have an increasing PSA on any two determinations drawn at two least weeks apart, with a greater than 20% increase from the baseline value. Other eligibility criteria included: Karnofsky performance status >70%, life expectancy >12 weeks (with at least four weeks since major surgery or radiation therapy), and at least 12 weeks for treatment with strontium-89, rhenium, or samarium-153. Required laboratory values included white blood cell ("WBC") count greater than 3000 μL, granulocytes greater that 1,500 μL, platelets greater than 100,000/μL, hemoglobin greater than 9.0 g/dL, creatinine less than 1.5 times the upper limit of normal ("ULN"), aspartate transaminase ("AST") and alanine transaminase ("ALT") less than two times the UNL, sodium between 130 and 148 mmol/L, potassium between 3.3 and 5.2 mmol/L, chloride between 90 and 110 mmol/L, and calcium between 8.0 and 10.5 mg/dL. Patients with a history of uncontrolled or severe cardiovascular disease (e.g., inadequately uncontrolled hypertension, congestive heart failure, angina, or myocardial infarction within the previous year), a history of thromboembolism, a history of biliary colic or untreated cholethiasis were excluded. Patients with brain metastasis, clinical signs of brain involvement or leptomeningeal disease, dementia, psychoses, or other significant impairment of mental status were excluded. Patients with a history of another malignancy during the past five years (other than non-melanomatous skin cancer or in situ stage T1a bladder cancer), patients with active infections requiring antibiotics, or patients on concurrent commercial or investigational antineoplastic therapies were excluded. No concomitant use of prostata or saw palmetto was permitted.
Response to therapy was assessed after the first two months of therapy and then monthly thereafter. Toxicity was assessed monthly at each study visit. A complete response ("CR") required resolution of all signs of disease for a duration of at least one month (i.e., normalization of PSA; resolution of all indicator lesions by physical examination or radiographic studies with no appearance of new lesions; decline of serum PSA to <0.1 ng/ml in patients who had had a prostatectomy and <0.5 mg/ml in patients who had had prostatic radiotherapy; all abnormal biochemical parameters must have returned to normal, and during this time there should have been no cancer-associated deterioration in weight, performance status, or symptoms). A partial response ("PR") required a decrease by >50% of the sum of the products of the perpendicular diameters for all measurable lesions lasting at least one month, no appearance of new lesions, and a reduction in serum PSA by >50% on two consecutive occasions at least one month apart. For patients being evaluated by bone metastases, a PR required a reduction in serum PSA by >50% on two consecutive occasions at least one month apart an improvement in bone scan (reduction in intensity or size of one or more metastatic foci and no new foci of radionuclide uptake unless due to osteoclastic healing documented on plain radiograph, CT scan, or MRI scan). During this time there should have been no cancer-associated deterioration in weight, performance status, or symptoms. Progressive disease ("PD") was defined by any of the following: (1) increase >25% in the sum of the products of the perpendicular diameters of bidimensionally measurable lesions in the sum of the transverse diameters of unidimensionally measurable lesions, (2) the appearance of new lesions, and (3) by the increase in serum PSA >50% over baseline as documented on two successive measurements >28 days apart. For patients with bone metastases, a PR could also be defined by an increase in size and intensity of radionuclide uptake of lesions previously seen on baseline bone scan or the appearance of two or more new foci of abnormal uptake (unless due to osteoclastic healing as described above) or any indication for radiotherapy to bone areas after the patient has begun treatment with raloxifene. For PD to be scored by PSA criteria alone, a confirmatory PSA determination was required and obtained two weeks after the value representing a >50% increase. Patients who had improvement in one objective parameter while meeting the criteria for PD by another parameter were scored as having PD. Patients who did not experience a response or exhibit PD were scored as having stable disease ("SD"), if they remained clinically stable for a period of at least three months.
At baseline, each patient was asked if he had bone pain related to the prostate cancer. Patients who answered affirmatively were asked to complete the Wisconsin Brief Pain Inventory at baseline and at each monthly follow-up visit thereafter.
Treatment consisted of 60 mg oral raloxifene daily (obtained from Eli Lilly & Company; Indianapolis, Ind.). Treatment was administered with monthly lab draws and follow-up visits with the physician. To counteract the increase risk of deep vein thrombosis that the estrogenic properties of raloxifene poses, patients were administered a regimen of low dose COUMADIN (warfarin sodium; available from DuPont Pharma; Wilmington, Del.). Patients received 1 mg oral COUMADIN daily (or 0.5 mg oral COUMADIN daily if patients were already taking aspirin).
Patient characteristics are listed in Table 2. A total of twenty-one patients with prostate cancer were enrolled into the study with a median age of 73 years. Patients had a median Karnofsky performance status of 90% (range, 70-100%).15/21 (71%) patients had evidence of bone disease. Six patients (28.6%) had evidence of measurable disease, nine patients (42.8%) had evaluable/non-measurable disease with bone metastases, and six patients (28.6%) had rising PSA levels only. A majority (67%) of patients had Gleason scores 8-10 at the time of biopsy. Prostate specimens were from either biopsies (14, 67%) or prostatectomy's (7, 33%). The median time from diagnosis of prostate cancer to study entry was 83.3 months (range, 16.6-209.5 months).
Patient Baseline Characteristics
Percentage (%)
Number in Study
Age (yr)
Karnofsky Performance Status
Weight at Entry (kg)
Site of Disease
Lymph Nodes
Hemoglobin (mg/dl)
Alkaline Phosphatase (u/l)
Gleason Score
2 + 2
2 + 3
3 + 4
3 + 5
4 + 3
4 + 5
5 + 3
5 + 4
Time from diagnosis of prostate
cancer to study entry (months)
N/A = not applicable
Prior treatment is listed in Table 3. All patients received prior treatment with combined androgen blockade. 19 (95%) received secondary hormone therapy with thirteen (62%) patients receiving more than two hormonal therapies prior to the study. Previous non-hormonal treatments included local surgery (57%), local radiation (38%), and chemotherapy (33%). Patients received a median of 4.0 (range, 1-9) prior systemic treatments. All patients enrolled in the study failed their prior treatments and were determined to have AIPC.
Prior Treatments
Percentage (%)
Local Therapy
Systemic Therapy
Hormone Therapy
>2 Regimens
Mode of Castration
1 Regimen
>1 Regimen
Prior Systemic Treatments
N/A = not applicable
Previous clinical studies indicate that raloxifene is well tolerated and the most common adverse events reported were hot flashes and leg cramps (EVISTA package insert; Eli Lilly & Co.). Similarly, we observed that raloxifene was well tolerated with most drug related toxicities reported being mild (grade 1-2). Toxicities are listed in Table 4. The reported urinary tract infection ("UTI") (1) and hematuria (1) were thought to be related to the patient's underlying disease. Two grade 3 events were reported: a grade 3 arthralgia/myalgia thought to be related to the patient's recent injury, and a grade 3 elevated creatinine that was attributed to the patient's disease progression. A grade 4 hyperglycemia was reported, however, that patient had a documented grade 3 hyperglycemia prior to beginning treatment; the hyperglycemia was therefore not attributed to the study drug.
Patients Experiencing Drug-Related Toxicity*
Blood/Bone Marrow
Constitutional Symptoms
Hot flashes
Increased Alkaline
Increased SGOT
Bone Pain
Increased Creatinine
*divided by NCI's Common Toxicity Criteria, v2.0
Of the twenty-one patients enrolled, seventeen patients (81%) patients reached the first evaluation time point and were included in the efficacy analysis. Four patients did not reach evaluation time point; two withdrew from the study at their own request due to (1) emotional side effects, and (1) change in medical care. The third patient was withdrawn from the study due to non-compliance (1), and the fourth patient was withdrawn because he required radiation to bony areas for pain relief (although this fourth patient was included in the efficacy analysis and was considered as disease progression).
At the first evaluation time point, thirteen of the eighteen patients had progressive disease and were discontinued from the study, while five of eighteen patients had stable disease and were continued on raloxifene. Disease progression was defined as rising PSA (12) and required radiation to bony area (1). No progression of soft tissue or osseous disease was observed. Of the five patients with stable disease, four patients were discontinued due to progressive disease (i.e., rising PSA) at the second evaluation point. The other patient remained on study with stable disease. No improvement in soft tissue or bone disease was observed.
Median time to disease progression on raloxifene was 8.3 weeks (range, 2.9-24.71). At the time of analysis (November, 2002), the median potential off study follow-up time was 9.0 months. Median survival was 10.5 months. As of July, 2003, 19 of 21 (90%) patients are alive.
Of the twenty-one patients enrolled in the study, thirteen patients had existing prostate tissue available for analysis of ER-α, ER-β and AR expression. Moderate to strong expression of ER-β and AR was detected in all of the cases (100%, 13/13). Almost complete absence of ER-α nuclear staining was seen in all except for two out of thirteen (15%) patients. Fifty percent of the surrounding stromal tissue stained positive for both estrogen receptors in all of the patients. Due to the small number of available specimens no significant differences were detected between groups of patients that progressed during the first round of treatment and those that exhibited stable disease.
While the description above refers to particular embodiments of the present invention, it should be readily apparent to people of ordinary skill in the art that a number of modifications may be made without departing from the spirit thereof. The accompanying claims are intended to cover such modifications as would fall within the true spirit and scope of the invention. The presently disclosed embodiments are, therefore, to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than the foregoing description. All changes that come within the meaning of and range of equivalency of the claims are intended to be embraced therein.
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|Citing Patent
|Filing date
|Publication date
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|Aug 6, 2013
|John G. Stark
|Use of selective estrogen receptor modulator for joint fusion and other repair or healing of connective tissue
|Jul 3, 2013
|Jan 13, 2015
|John G. Stark
|Use of selective estrogen receptor modulator for joint fusion and other repair or healing of connective tissue
|Feb 24, 2011
|Arne Hengerer
|Method for normalizing the results of an in-vitro analytical method
|U.S. Classification
|International Classification
|Cooperative Classification
|European Classification
|Mar 8, 2004
Owner name: CEDARS-SINAI MEDICAL CENTER, CALIFORNIA
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:AGUS, DAVID B.;REEL/FRAME:015060/0420
Effective date: 20040227
|Apr 30, 2012
|Maintenance fee reminder mailed
|Sep 16, 2012
|Lapse for failure to pay maintenance fees
|Nov 6, 2012
|Expired due to failure to pay maintenance fee
Effective date: 20120916


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Last updated 9 hours ago
Sep 29 2008 | 9:04am ET
Private equity firm J.C. Flowers & Co. has raised a $2.5 billion buyout fund to invest in banks and financial firms battered by the Wall Street crisis.
The New York-based firm finished a first round of fundraising this month, and may raise additional capital if needed, Bloomberg News reports. Flowers last month won approval to buy the nationally-chartered First National Bank of Cainesville, Mo., which he said he may use to buy "troubled of failed depository institutions."
Flowers has considered making investments in at least two financial firms this year, advising Bank of America on its purchase of Merrill Lynch, as well as trying to invest in insurer American International Group before its bailout by the government this month.
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Jun 17 2016 | 1:05pm ET
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Joe Biden Just Joined Instagram, And His First Photo Is Perfect
Published 1:10 pm, Wednesday, April 16, 2014
Vice President Joe Biden joined Instagram on Wednesday, ahead of his trip to Pennsylvania with President Barack Obama to announce a new job-training program.
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Bill Gates talked to Reid Hoffman about being on Microsoft's board of directors (MSFT, LNKD)
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The top 10 travel destinations for private jet owners this July 4
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April 27, 2013 1:41:46 PM
May 2 - Kentuck Art Night (open studios; live music by Mary Tylosaur), 5-9 p.m., Kentuck Art Center, downtown Northport, Ala., 205-758-1257
May 3-5 - Tupelo Blue Suede Cruise classic car show (parade, live music, poker run, more), BancorpSouth Arena parking lot, Tupelo. 662-842-4242 or bluesc.com.
May 4 - Edwin McCain, Hoover Library Theatre, Hoover, Ala., 4 p.m. and 8 p.m. ($25). 205-444-7888 or thelibrarytheatre.com.
- Inaugural Cinco de Mayo Mississippi Festival, downtown Jackson (cultural dancers, concerts, parade) 11 a.m.-11 p.m. $10 advance/$15 at gate. cincodemayomississippi.com.
May 5 - The Band Perry, Thalia Mara Hall, Jackson ($25-43). 601-960-1537.
May 9 - Blues Brothers Revue, Riley Center, Meridian ($39-45). 601-696-2200 or msurileycenter.com.
May 11 - Crossroads Blues & Heritage Festival, Rosedale, Miss. rosedaleblues.com.
May 11-12 - 42nd Annual Gumtree Festival (visual arts, music, more), downtown Tupelo. 662-844-2787 or gumtreefestival.com.
- 8th Annual White Buffalo Pow Wow, Tupelo Buffalo Park. 662-844-8709 or tupelobuffalopark.com.
May 15-18 - 10th annual Tupelo Film Festival; 800-533-0611 or tupelofilmfestival.net.
May 17 - The Time Jumpers (Vince Gill, Dawn Sears, Kenny Sears, Ranger Doug Green), Riley Center, Meridian ($63-69), 602-696-2200 or msurileycenter.com.
May 18 - Natchez Trace Parkway 75th Anniversary Celebration (historical re-enactors, discovery walk, mock archaeological dig, more), free, Visitor Center at milepost 266 near Tupelo, 10 a.m.-2 p.m. 662-680-4027 of 800-305-7417.
June 1 - 16th annual Freedom Creek Blues Festival (Microwave Dave and the Nukes, "Birmingham" George Conner, Mississippi Blues Boys, more), 1438 Wilder Circle, downtown Aliceville, Ala., 11 a.m-until. $10. freedomcreek.org.
June 6-9 - Tupelo Elvis Festival (Cowboy Mouth, Montgomery Gentry, more). 662-841-6598 or tupeloelvisfestival.com.
June 6-July 7 - Oxford Shakespeare Festival, various locations, Oxford. 662-915-7411 or shakespeare.olemiss.edu.
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