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Event flyer for Sunday's Flyleaf Books reading with T.C. McCarthy and Michael J. Sullivan!Posted: 30 July, 2012 Filed under: flyers, Uncategorized 2 Comments
OK. Let's see these flyers posted all over the Triangle, please?
Color PDF: orbit-2012-august-v1
Black and white PDF: orbit-2012-august-v1-bw
Facebook event link: https://www.facebook.com/events/326070144135719/
If handing out or stacking on a giveaway table, the handout PDF handout-2012-july-v4 (b/w version: handout-2012-july-v4-bw) are still the way to go. Thanks guys!
End-of-July roundup!Posted: 28 July, 2012 Filed under: Uncategorized Leave a comment
Some quick-hitting notes for the end of July:
- Tickets for tomorrow's (Sunday) Raleigh Browncoats charity screening of Serenity (the Firefly movie) are SOLD OUT — they will not be available at the door, etc. Looking forward to seeing people out there! Come out and get in on the charity raffle, which will include issues 1-7 (the complete run… so far!) of Bull Spec.
- Local publisher Light Messages is publishing Siberian author Irina Lopatina's fantasy novel White Raven: The Sword of Northern Ancestors on Monday, July 30. Until then, there's still a 30% off pre-order offer.
- Also Monday (July 30) at 7 pm is another of the Duke Young Writers Camp readings at The Regulator Bookshop in Durham. While students' work is all over the map, with one of the classes being "Phantasmagoria: Writing Strange Fiction" my guess is we'll see at least one take on the fantastic.
- Wednesday, August 1, a local feature-length horror film, "Jiggly Baby 3" will premiere at the Raleigh Grande Theatre at 7 pm. More info including a trailer: http://www.jigglybaby.com/
- Friday, August 3, the North Carolina Museum of Natural Sciences is hosting a screening of three short films based on the late Ray Bradbury's work. The event starts at 5, with the films starting at 7.
- And don't forget that next weekend (August 4-5) is a huge weekend for speculative fiction in NC, with two major events: an absolutely start-studded "extravaganza" at Asheville's Malaprop's Bookstore Nathan Ballingrud, Tobias Buckell, Will Hindmarch, Naomi Novik, Karin Lowachee, and Ann and Jeff VanderMeer, moderated by Shared Worlds director Jeremy L.C. Jones) and Bull Spec's own "summer literary speculative fiction festival" comprising a writers meet-and-greet on Saturday evening (e-mail Sam for details) and the reading and signing at Chapel Hill's Flyleaf Books on Sunday from 2 to 4 with featured regional authors T.C. McCarthy and Michael J. Sullivan.
Today (Monday July 23): Special Star Trek: The Next Generation episode screenings across the Triangle (and NC, and…)Posted: 23 July, 2012 Filed under: events, Uncategorized Leave a comment
As I mentioned in the June newsletter, tonight (Monday July 23) Star Trek: The Next Generation is back on the big screen to celebrate its 25th anniversary with two hand-picked episodes, with three Triangle-area theaters among many state- and nation-wide, including Crossroads 20 in Cary, Brier Creek 14 (at 7 pm), and North Hills 15.
August 4-5: Science Fiction across the state!Posted: 13 July, 2012 Filed under: events 1 Comment
There are two events I'd like to tell you all about, both taking place the weekend of August 4-5.
The first is on Saturday, August 4, at Asheville's Malaprop's Bookstore/Cafe, from 7 to 9 pm. Continuing a "tradition" which started last year of the staff and visiting instructors from Wofford College's Shared Worlds teen writing camp, Malaprop's is hosting a Fantasy and Science Fiction Extravaganza with Nathan Ballingrud, Tobias Buckell, Naomi Novik, Will Hindmarch, Karin Lowachee, and Ann and Jeff VanderMeer, moderated by Shared Worlds director Jeremy L.C. Jones:
The second is one I hope you've all heard about and are excited about already, on Sunday, August 5, at Chapel Hill's Flyleaf Books, from 2 to 4 pm. This is also the second in a "series" which began last year, as the VanderMeers (along with Ekaterina Sedia, SJ Chambers, Scott Eagle, Jeremy L.C. Jones, and more including Durham's own Mur Lafferty) came down to Durham's Fullsteam Brewery (in partnership with local bookstore The Regulator Bookshop) after their Malaprop's reading last year. This year I'm hosting a second "Bull Spec summer literary speculative fiction festival", this time at Flyleaf Books, with South Carolina science fiction author T.C. McCarthy and Virginia fantasy author Michael J. Sullivan.
New local event announcement: Epic fantasy author Steven Erikson to visit Flyleaf Books.Posted: 9 July, 2012 Filed under: events | Tags: events, flyleaf books, steven erikson Leave a comment
It never really fails that as soon as I get a new flyer put together, and some copies printed, a new event comes along. Well, no surprise, as the author of the Malazan Book of the Fallen series, Steven Erikson, is coming to Flyleaf Books on Monday, September 24, to read and sign the first novel in a new fantasy trilogy set in the same world. That book is Forge of Darkness:
"The Forge of Darkness introduces readers to Kurald Galain, the warren of Darkness, and tells an epic tale of a realm whose fate plays a crucial role in shaping the world of the Malazan Empire. It's a conflicted time in Kurald Galain, the realm of Darkness, where Mother Dark reigns. But this ancient land was once home to many a power… and even death is not quite eternal. The commoners' great hero, Vatha Urusander, is being promoted by his followers to take Mother Dark's hand in marriage, but her Consort, Lord Draconus, stands in the way of such ambitions."
Well, on the positive side, I haven't sent out the July newsletter yet. On that front, I'm still working out the details for a writers-oriented event on the evening of Saturday, August 4, preceding the Sunday August 5 event at Flyleaf Books with TC McCarthy and Michael J. Sullivan. Stay tuned…
Event flyer, mid-July updatePosted: 6 July, 2012 Filed under: flyers Leave a comment
While there are more events going on than fit onto one page just now, here's the current event handout/flyer. Spread it far and wide!


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Richard Malotky: Blame your cave-dwelling ancestors
If you are alive, the meter is running. If life is a long series of decisions and their consequences, where we end up is the sum over histories of that dynamic.
Why do we do the things we do? That question is an endless source of fascination for me ... and a guilty pleasure as well.
When I think about most behavior, I can't help but think about paleobiology. The word refers to how things were with humans long ago. Many behaviors we have in the 21st century have their roots in paleobiology.
One hundred thousand years ago people had different concerns than most of us today. They didn't have "climate control" or indoor plumbing. Arguably, they were much more concerned with day-to-day survival than we are.
The humans most likely to survive and pass on their DNA were the ones best adapted to get all their needs.
Shelter, water, food and successful reproduction were really all that mattered. Modern humans have the same basic needs, but culture and technology have made our struggle a bit more nuanced.
Almost all of our emotional road map harkens back to these days. Fear, when the sabertooth tiger is suddenly standing in your way (or your boss has just threatened you with early retirement). Happiness, when you find the perfect cave just before the storm hits (or find that great pair of jeans on the sale rack).
Aggression, when you find someone else in your cave and you are hoping to get out of the snowstorm. And cooperation, when you both realize the cave has room for two, and the other person is warm.
As always with natural selection, the genes that were passed on were the genes that adapted best to the changing conditions. Many of the reasons people do the things they do harken back to this legacy.
One of the most problematic conditions I see at the office everyday is chronic anxiety. Anxiety is generated biochemically in the brain by the nerves that make up a collection of structures called the limbic system.
Like most parts of the brain, the limbic system is pretty amazing. Classically including the hippocampus and para-hippocampal gyrus, as well as the amygdala, this anxiety and fear center was originally designed to help us avoid and escape predators. (There are lots of other specific anatomic structures in the limbic system, each with specific functions. It's almost as if the closer you look the more you see.)
These nerves are designed to be down-regulated by the frontal and pre-frontal cortex. This inhibition requires the right balance of the molecules that the nerves use to communicate with each other.
Anxiety and fear happen when the executive part of the brain cannot inhibit the limbic system, and it is allowed to run the show.
Untreated, chronic anxiety can contribute to or cause many illnesses. Hypertension, stomach acid issues, irritable bowel, and weakened immune system are just the tip of the iceberg.
In fact, I am hard pressed to name any illness that anxiety can't exacerbate. Add to that the cultural hesitation to speak about these issues with friends or family and this illness is peculiarly insidious.
Although none of us meet sabertooth tigers on the trail anymore, we still have this very sensitive system that sparks "fight or flight." It is hard wired into us, and the reason is paleobiology.
Anyway, lots of folks ask how to deal with the problem of uncontrolled anxiety. Doctors, of course, have all kinds of drugs for this stuff, and sometimes they are necessary.
But I have seen folks aided by lots of other things, too. Go figure, but strong and loving relationships can really help. I know it's not empirically provable. I just know it helps.
The other thing that I have seen time and time again to really help is to achieve physical fitness. And I am not talking about those nice folks who walk the River Trail three times a week but are still 20 pounds overweight.
No, I am talking about the hardbodies, the aerobics instructors, the athletes, the folks who get or approach physical exhaustion every day. Say what you want, these folks have better blood flow to their brains.
Better blood flow means healthier brain chemistry, all else being equal. Why wouldn't we want that?
Bottom line, if you have untreated anxiety problems, get brave and go talk to your doctor about it. Or, if you want, try the hard body treatment if possible/plausible. And all of us could work on those loving relationships.
And lighten up on yourself, already. Blame it on your cave ancestors. It's all their fault anyway.
Record Searchlight contributing columnist Richard Malotky can be reached at email@example.com.
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subset: commoncrawl


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- Ajay Devgn (441 pics) ... Karan
- Manisha Koirala (139 pics) ... Varsh G. Mehra
- Sanjay Dutt (304 pics) ... Shravan 'S.D.' Dhariwal
- Suman Ranganathan (19 pics) ... Suman
Mehbooba is a Bollywood romance film written, produced and directed by Afzal Khan. The story of the movie is based on a love-triangle, lead protagonists being Ajay Devgn, Sanjay Dutt and Manisha Koirala. Music of the film was composed by Ismail Darbar. The film was released in India on July 11, 2008. The film was shot in 2000, but got delayed and released in 2008, 8 years after it was shot.


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The president of Enviren Worldwide, Inc. says that there are many reasons for retailers to consider cart sanitation systems.
Grocery Headquarters: Has the recent H1N1 flu epidemic raised awareness of the need for sanitizing carts?
D. Todd Feller: H1N1 has certainly brought on more concerns. However, awareness of the need for cleaner, safer shopping experiences is increasing daily because of two other factors: First is the increase in cases of food-borne illnesses, which have been on the rise in the last few years. Second, the largest demographic of our population is retirees and pre-retirees who are on medication or have illnesses which lower or weaken their immune systems, making them more susceptible to germs and bacteria.
Why should retailers get involved?
There are multiple reasons retailers should get involved, but I'll mention the top three:
First, it's the store's responsibility to provide safe, clean carts. Right now, most stores pressure wash carts once or twice a year; that's not enough to keep carts clean and safe. Our systems make it easy and cost-effective to have every shopping cart cleaned as often as after every use.
The second reason would be the environmental part. Enviren's system is self-contained and is totally environmentally friendly.
The third reason is the marketing opportunity. Having an Enviren Cart Cleansing System in your store shows your customers that you care about their health and safety. More customers will come to your store to shop after you have installed an Enviren system. It also helps retain current customers.
How does the Enviren system impact a store's costs and operational efficiency?
The way it's designed, it takes no longer to run carts through our system than it would to simply put them back into the cart-corral area without sanitizing. So there's no time wasted. As far as costs, in almost every case we've seen, the Enviren system actually saves the store money because it eliminates the need for wipes—plus, pressure washing is almost never required. As stated earlier, the system also really makes money for the store by attracting customers and increasing their loyalty.
Talk some more about the system's environmental benefits.
Being green while staying cost-efficient was one of our top priorities. One reason our system is more eco-friendly than pressure washing and sanitizing wipes is because the Enviren system is totally self-contained. It doesn't have a drain, and it doesn't send anything into the storm sewer or run-off systems. Another reason is that no water line is needed. The EnvirenMist solution is placed directly into the system and then applied to the carts. Pressure washing and other systems require a lot of water, which most of us are now trying to conserve.
How does a retailer get started with the Enviren system?
Enviren has three options for stores. You can buy a system outright; the cost varies on the number of units ordered, but to answer directly, if you order just one the cost is $13,000. We also have a three-year or five-year lease-purchase program that has an interest rate of 3.5%, with a dollar buyout at the end. The third program is a monthly rental. Enviren handles servicing the system, so the stores have nothing to worry about. The service cost varies based on the number of carts at a store, but the average is $75 per month, which encompasses all maintenance and operating costs, including formula.
What's the best setup for installing one of these systems?
Placement of the system can be virtually anywhere, but probably the most effective is inside the vestibule, right by the cart-corral area. This way, every time a cart is returned, it can be run right through and sanitized in seconds. Placement there at the front of the store also lets your customers see what you are doing for them.
How have customers reacted to the Enviren system so far?
The biggest surprise to me has been all of the store managers that have told me how many times a day they're stopped and thanked by customers for putting in an Enviren system. They've told me they never realized this was so important and on the minds of so many customers.
How can retailers let consumers know about their cart sanitation efforts?
Enviren has many ways to inform customers that their carts are clean and safe. We can replace existing handles with our handles, which read: "This cart has been sanitized and cleaned for your family's safety." Then there's the visibility of the Enviren system itself, right in the front where the customers get their carts. We also work with stores on signage in the cart area.
Letting the customers know about the system's safety and effectiveness goes a long way toward building confidence and establishing loyalty.


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There's controversy because two recipients of the World Food Prize now work for corporations, but their research was developed in academia and has made a world of difference.
The Opinion section is produced by the Editorial Department to foster discussion about key issues. The Editorial Board represents the institutional voice of the Star Tribune and operates independently of the newsroom.
Poll: Do you support or oppose the multi-national deal with Iran over nuclear weaponry?


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Disney's JOHN CARTER
View Single Post
March 23 2012, 01:29 AM
Vice Admiral
Location: Sac, Ca
Re: Disney's JOHN CARTER
Asbo Zaprudder wrote:
As has been said elsewhere, the essential factor missing from
John Carter
is a credible and charismatic lead actor. I doubt many people outside the US can name anything that Taylor Kitsch has been in. He does a reasonable job in the role, but I think he was miscast.
I'm afraid even with a bigger name actor it still would have been dismissed by most people as just a cheesy Prince of Persia/Attack of the Clones knockoff.
The style and art design of the movie just looked painfully tired and derivative, and there's no trailer you could cut that would have changed that.
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If you suffer from arthritis then this Free helpful guide will be something that you should check out. Start by Going Here or clicking on the banner above and within a few simple steps you'll have the free guide. The free guide includes the following helpful information: Pain relief techniques, Arthritic knee treatments, Other forms of arthritis, Diet and exercise tips And more!
Arthritis Guide eBook Freebie
June 27th, 2013 freestuffunlimited


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Thread: pro-rata?
Hi i am applying for a job i have the interview mon but iv'e just re-read the advertisement 4 it and it says £14,585 per annum pro rata (fixed) what does this mean? the job is advertised for 16 hours 15 min a week....does it mean that would be the annual salery if it was full time? if so i don't get why wouldn't they just put the actuall salary what it would be part time? and what does the fixed bit mean??? ahhhh i'm so confused!!
Pro rata means exactly what you said - if you were working full time, this would be the salary!! I agree and think they should just put what you will be getting! But I think it's an incentive so if you take the job you know it has the potential to earn you the pro rata amount!
Good luck x
the pro rata means that the full time wage is £14.585 and you will get paid for the 16hr and 15 mins you work. If they calculate full time as 35 hrs, then you will get about 43% (roughly) of the advertised rate.
the fixed means that there is no annual increment. for example in my job, for the first 5 yrs you get an annual increment on top of the April payrise, on the anniversary of your start date. So if you are there for eg 18 months, your pay will remain the same (not taken into account the usual April payrise though)
hth ?


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The last couple of days have been not so great for my family. We are all sick with a painfully lingering flu. Mommy wasn't insistent that flu shots were necessary..but boy am I regretting it now.
It is only wednesday and I have:
- Not used a coupon.
- went to Rite Aid and CVS for medicine with no ECB's or UP rewards.
- Broke our weekly grocery budget in take out.
- finally found a reason to use the
scratchyfree toilet paper from Rite Aid. (as extra filling for my boys diapers, because they have explosive uh..stuff coming out of their diapers)
So..yes, I paid full price for medicine this week. It wasn't painful because I know the end result would mean a ok-happy momma


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For immediate release
Jan. 13, 2004
Abilene Christian University has achieved the highest level of accreditation for the College of Business Administration. The Board of Directors of AACSB International -- the Association to Advance Collegiate Schools of Business recently accredited the bachelor and master degree programs in the College of Business Administration, completing a five-year process of seeking accreditation.
"This is huge," said Dr. Rick Lytle, College of Business Administration dean. "Our program is now ranked with the best business schools in the nation. There is no higher level than this."
The AACSB International accreditation is the premier business school accreditation worldwide and places ACU among the top 17 business schools in the state, with schools such as Trinity University, Baylor University, the University of Texas, Texas Christian University, Southern Methodist University, Texas A&M University, Texas Tech University and others. Only 466 schools in the world are AACSB accredited, and only 392 have both undergraduate and graduate accreditation.
ACU and Pepperdine University are the only Church of Christ-related schools to be accredited by AACSB, and ACU is one of only two schools in the Council for Christian Colleges and Universities to receive the accreditation.
"Moving from our national ACBSP business accreditation to AACSB global accreditation is comparable to an intercollegiate athletics program moving from NCAA Division III to NCAA Divison I.," Lytle said.
The accreditation provides new opportunities for students, including the AACSB honors program, increased graduate school acceptance and engagement with other top business schools. Faculty will have the opportunity to present at AACSB national conferences and will have access to AACSB resources and research opportunities.
The process began five years ago when ACU decided to seek AACSB accreditation. ACU's College of Business completed a self-study and assessed what areas needed to be improved to meet the AACSB standards.
Since that time, the College of Business Administration has made improvements including:
Reduced student-faculty ratio from 31-1 to 17-1 (adding 15 new faculty members)
Increased competency requirements for students
More focused curriculum
Increased technology resources
Introduction of the Career Development Center to assist with advising, internships and jobs
Increased resources for faculty research, travel and professional development.
If you are a member of the media who would like more information about this release, please contact Wendy Kilmer, media relations coordinator.
Recent news releases
Last Update: December 17, 2007
Questions to (firstname.lastname@example.com)
Copyright © 1995-2006 Abilene Christian University. All rights reserved.


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|Publication number
|Publication type
|Application number
|Publication date
|Sep 28, 1999
|Filing date
|Oct 13, 1995
|Priority date
|Sep 19, 1994
|Fee status
|Also published as
|Publication number
|Leonard Cook
|Original Assignee
|Dupont Pharmaceuticals Company
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (4), Non-Patent Citations (17), Referenced by (43), Classifications (9), Legal Events (6)
|External Links: USPTO, USPTO Assignment, Espacenet
This application is a continuation of U.S. application Ser. No. 08/308,859 filed Sep. 19,1994 now abandoned.
This invention relates to a method of treating alcoholism and alcohol dependence in a mammal comprising administering to the mammal a therapeutically, effective amount of a synergistic combination of: (i) at least one opioid antagonist, and (ii) at least one selective serotonin reuptake inhibitor. This invention also relates to compositions and kits containing the same.
The present invention is based on the theory that an unexpected and surprising synergy will be found with a combination therapy involving opioid antagonists and selective serotonin reuptake inhibitors which has been neither disclosed nor suggested by the prior art. Such a therapy would provide a new and highly beneficial method for the treatment of alcohol dependence.
Disulfiram (Antabuse�) is the only FDh approved product that is currently available for adjunctive use in the treatment of alcohol abuse (T. W. Rall, in: Goodman and Gilman's The Pharmacological Basis of Therapeutics, A. G. Gilman et al., 8th Edition, Chap. 17, pp. 378-379, Pergamon Press, 1990). Disulfiram works by blocking the intermediary metabolism of alcohol. Most alcohol is normally metabolized to acetaldehyde which is further oxidized to innocuous byproducts which are excreted or recycled through energy-producing or other biosynthetic pathways. When alcohol is consumed in the presence of disulfiram, blood acetaldehyde concentrations increase to many-fold higher than normal values and produce markedly adverse behavioral and physiological responses that are collectively described as the "acetaldehyde syndrome." Psychological theory suggests that patients will avoid further consumption of alcohol to avoid these alarming and potentially life-threatening responses.
More recently, several investigators have reported that naltrexone is a useful adjunctive treatment following alcohol detoxification in alcohol-dependent human subjects (J. R. Volpicelli et al., Arch. Gen. Psychiatry, 49, 876, 1992; S. S. O'Malley et al. ibid., 49, 881, 1992). Naltrexone blocks alcohol craving and reduces total alcohol consumption without producing mood changes or psychiatric symptoms. The applicant suggests that naltrexone may be particularly useful in preventing alcohol relapse. Naltrexone, a well-known narcotic antagonist, is thought to work by blocking activation of the endogenous opioid reward system. Hence, naltrexone blocks the action of endorphins, enkephalins, and other endogenous opioids which may be released in response to alcohol consumption. Similar results have been obtained in studies in rats and monkeys where naltrexone, naloxone, nalmefene, and other opioid antagonists have been shown to block the apparent rewarding effects of alcohol and reduce total alcohol consumption (D. R. Brown and S. G. Holtzman, Pharmacol. Biochem. Behav., 11, 567, 1979; L. D. Reid and G. A. Hunter, Alcohol, 1, 33, 1984; C. L. Hubbell et al., Alcohol, 3, 39, 1986; R. D. Myers et al., Alcohol, 3, 383, 1986; C. L. Hubbell et al., Alcohol, 8, 355, 1991; D. V. Gauvin et al., Alcohol, 10, 37, 1993).
Medications that enhance brain serotonergic activity have also shown effectiveness in reducing alcohol consumption and are currently under evaluation for long-term treatment of alcoholism. For example, C. A. Naranjo et al., Clin. Pharm. Ther., 35, 374, 1984, and Clin. Pharm. Ther., 41, 266, 1987, have shown that the serotonin uptake inhibitors citalopram and zimeldine attenuate ethanol intake in nondepressed alcohol abusers. C. L. Hubbell et al., Alcohol, 8, 355, 1991, demonstrated that fluoxetine, another serotonin uptake inhibitor, attenuates alcohol intake in rats. In a review article, C. A. Naranjo et al., J. Clin. Psychiatry, 47, 16, 1986, indicate that several serotonin uptake inhibitors including zimelidine, citalopram, fluoxetine, and fluvoxamine decrease ethanol drinking in rats.
In the present invention, we claim an unexpected synergistic interaction between naltrexone, an opioid antagonist, and fluoxetine, a serotonin uptake inhibitor, on alcohol fluid consumption in rats. The synergism may be demonstrated where small combined doses of naltrexone and fluoxetine which are inactive by themselves are as effective as much higher doses of either drug alone. Alternatively, the data may show that the observed median effective doses (ED50 responses) for various fixed dose combinations of naltrexone and fluoxetine are significantly lower than can be accounted for by a simple additivity hypothesis. The data may show that the combination of a long-lasting opioid antagonist with a serotonin uptake inhibitor may provide a novel adjunctive treatment for alcohol abuse and alcoholism in man.
The present invention claims a method of treating alcoholism and alcohol dependence in a mammal comprising administering to the mammal a therapeutically effective amount of a synergistic combination of: (i) at least one opioid antagonist, such as naltrexone or nahmefene; and (ii) at least one selective serotonin reuptake inhibitor, such as fluoxetine or sertraline. The present invention is also directed to compositions and pharmaceutical kits containing the same. Such combination therapy may provide surprisingly efficient and effective methodology for use in the treatment of alcoholism and alcohol dependence.
The present invention provides a method of treating alcoholism and alcohol dependence in a mammal comprising administering to the mammal, in combination, a therapeutically effective amount of: (i) at least one opioid antagonist; and (ii) at least one selective serotonin reuptake inhibitor.
In the present invention, the applicant claims that the administration of an opioid antagonist (component (i)) in combination with a selective serotonin reuptake inhibitor (component (ii)) does result in an unexpected synergistic effect in the reduction of alcohol consumption. Thus, the reduction in alcohol consumption when an opioid antagonist is administered in combination with a selective serotonin reuptake inhibitor is greater than the additive effect of each agent when administered alone. This is a remarkable and unexpected effect in view of what is currently known in the literature. This synergistic combination is expected to greatly increase the efficacy of single agent or multiple agent treatments of alcoholism and alcohol dependence.
Thus, the present invention claims that an opioid antagonist may be administered in combination with a selective serotonin reuptake inhibitor, thereby reducing the doses of each drug required to achieve reduction in alcohol consumption. Moreover, the present invention claims that the use of the compounds of component (i) and component (ii) of the invention in combination results in a greater than additive effect. Thus, the combination treatment of the present invention of components (i), and (ii) permits the use of lower doses of each component, with reduced adverse, toxic effects of each component. It also provides for a greater window of efficacy, since the same maximum tolerated doses can be administered before toxic effects associated with each agent are observed. A lower dosage minimizes the potential of side effects of the compounds, thereby providing an increased margin of safety relative to the margin of safety for each component when used as a single agent.
As used herein, the term "opiate antagonist" refers to compounds or compositions which serve to block the action of endogenous or exogenous opioid compounds on narcotic receptors or narcotic receptor subtypes in the brain or periphery and include naltrexone (Trexan�) naloxone (Narcan�), nalmefene, naloxone methiodide, nalorphine, naloxonazine, naltrindole (NTI), naltrindole isothiocyanate, (NTII), naltriben (NTB), nor-binaltorphimine (nor-BNI), b-funaltrexamine (b-FNA), BNTX, cyprodime, ICI-174,864, LY117413, and MR2266. Other compounds and compositions are known and will be readily apparent to those skilled in the art, once armed with the present disclosure. Such opioid antagonists may serve to block the positive reinforcing effect of ethanol which results from the release of endogenous opioids upon consumption of alcohol.
The phrase "selective serotonin reuptake inhibitor", as used herein, denotes compounds which enhance brain serotonergic activity by blocking the neuronal reuptake and subsequent inactivation of serotonin at synaptic junctions between nerve cells. Such serotonin selective uptake inhibitor compounds include fluoxetine, sertraline, paroxetine, venlafaxine, fluvoxamine, nefazodone, citalopram, and zimeldine. Other compounds and compositions are known and will be readily apparent to those skilled in the art, once armed with the present disclosure. Such selective serotonin reuptake inhibitors may serve to reduce alcohol cravings by increasing endogenous levels of serotonin.
When terms narcotic antagonist or serotonin selective uptake inhibitor are used herein, it is to be understood that any of the pharmaceutically suitable salts thereof which have narcotic antagonist or serotonin uptake inhibiting properties in man and on other mammals are included by the term. Such salts include the hydrochlorides, hydrobromides, hydroiodides, sulfates, bisulfates, nitrates, citrates, tartrates, bitartrates, phosphates, malates, maleates, fumarates, succinates, acetates, terephthalates, and pamoates.
By "therapeutically effective amount" it is meant an amount of component (i), and component (ii) that when administered alone or in combination to a mammal is effective to treat alcoholism and alcohol dependence, such as by reduction of alcohol consumption end craving. Compositions of the invention present the opportunity of obtaining significant reductions in alcohol consumption with reduced dosages of the narcotic antagonist and serotonin selective uptake inhibitor components, thereby diminishing the side effects and possible toxicity which would result from the otherwise required amounts of the individual drug components.
By "administered in combination", or the like, when referring to component (i), and component (ii), of the present invention, it is meant that the components are administered concurrently to a mammal being treated. By concurrently, it is meant that each component may be administered at the same time or sequentially in any order at different points in time, however if not administered at the same time, they should be administered sufficiently closely in time so as to provide the desired treatment effect. Suitable dosing intervals and dosing order with such compounds will be readily apparent to those skilled in the art, once armed with the present disclosure. Preferably, all components are administered at the same time, and if not administered at the same time, preferably they are all administered less than one hour apart from one another.
In a composition of the invention, naltrexone and fluoxetine are combined and will be utilized at various dose ratios based on weight of naltrexone and fluoxetine in rats offered an opportunity to drink e sweetened ethanol solution or water. The ethanol drinking test e.g., C. L. Hubbell et al., Alcohol, 3, 39, 1986! is a standard procedure for detecting and comparing the ability of different classes of compounds to increase or decrease alcohol consumption in rats and has a good correlation with the ability of compounds to modify human alcohol drinking. Data for the rat, as presented in an isobologram, can be translated to other species where the orally effective alcohol modifying dose of the individual compounds is known or can be estimated. The method simply consists of reading the % ED50 DOSE for each dose ratio on the best fit regression analysis curve from the rat isobologram, multiplying each component by its effective species dose, and then forming the ratio of the amount of naltrexone to fluoxetine. This basic correlation for antagonist properties enables estimation of the range of human effectiveness E. W. Pelikan, The Pharmacologist, 1, 73 (1959)!.
Application of an equieffective dose substitution model and a curvilinear regression analysis utilizing all the data for the individual compounds and various dose ratios for the combinations establishes the existence of unexpectedly enhanced alcohol drinking suppressing activity of combinations of naltrexone and fluoxetine, i.e., the resulting activity is greater than the activity expected from the sum of the activities of the individual components.
The present invention also includes pharmaceutical compositions (that is, combination products), such pharmaceutical compositions (combination products) comprising, an opioid antagonist (such as naltrexone), and a selective serotonin reuptake inhibitor. Such compositions may be in solid, liquid, sustained release such as transdermal, transnasal, or depot dosage units and may further include a suitable pharmaceutical carrier.
The present invention also includes pharmaceutical kits comprising an opioid antagonist (such as naltrexone), together with a selective serotonin reuptake inhibitor. In the kit, the opioid antagonist and the selective serotonin reuptake inhibitor may each be presented in separate vials as compounds, and/or in separate vials as compounds in combination with a pharmaceutically acceptable carrier. Alternatively, the opioid antagonist and the selective serotonin reuptake inhibitor may be combined together in one or more vials, with or without a carrier. Thus, for example, the invention includes pharmaceutical kits comprising a separate vial comprising the opioid antagonist and a separate vial comprising the selective serotonin reuptake inhibitor, each vial also containing, if desired, a carrier.
The compositions and kits of the present invention may be employed in the treatment of alcoholism and alcohol dependence.
In the method of the present invention, the opioid antagonist (such as naltrexone) may be administered in combination with a selective serotonin reuptake inhibitor to achieve a synergistic decrease in alcohol consumption. Synergy occurs when the effect (such as reduction in alcohol consumption or craving) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds.
The method of the present invention provides for an enhanced effect of the two drugs when administered in combination. Thus, the claimed combination treatment allows for the use of lowered clinical doses and increases the window of efficacy. In view of the marginal effects associated with the presently approved therapies for treating alcoholism and alcohol dependence, the present invention provides an important advantage over current therapies.
Opioid antagonists useful in the methods, compositions and pharmaceutical kits of the present invention include, but are not limited to naltrexone and nalmefene. These and other opioid antagonists will be readily apparent to those skilled in the art, once armed with the present disclosure.
The preparation of naltrexone is described in U.S. Pat. No. 3,332,950 (H. Blumberg et al.), the disclosure of which is hereby incorporated herein by reference in its entirety. Naltrexone is available commercially as "Trexan�", for which product information, including dosage and administration, is given in Physicians' Desk Reference, 47th Edition, 1993, pp 956-958. The preparation of nalmefene may be carried out using preparatory methods such as those described in J. Fishman, U.S. Pat. No. 3,814,768; E. F. Huhn et. al., J. Med. Chem. 18, 259 (1975); P. C. Meltzer et al., European Patent Application No. 140,367 and U.S. Pat. No. 4,535,157.
Selective serotonin reuptake inhibitors useful in the method, compositions, and pharmaceutical kits of the present invention include, but are not limited to, fluoxetine, sertraline, paroxetine, venlafaxine, fluvoxamine, and nefazodone. These and other selective serotonin reuptake inhibitors will be readily apparent to those skilled in the art, once armed with the present disclosure.
The preparation of fluoxetine may be carried out in a number of different fashions, as will be evident to the skilled artisan. Such preparatory methods include, for example, those described in Malloy et al. GE Patent 2,500,110 and U.S. Pat. No. 4,314,081, the disclosures of each of which are hereby incorporated herein by reference in their entirety. Fluoxetine is available commercially as "Prozac�", for which the product information, including dosage and administration, is given in Physicians' Desk Reference, 48th Edition, 1994, pp. 877-880. The preparation of sertraline may be carried using preparatory methods such as those described in initials Welch, et al. European Patent Application 30,081 and U.S. Pat. No. 4,536,518, the disclosures of each of which are hereby incorporated herein by reference in their entirety. Sertraline hydrochloride is available commercially as "Zoloft�", for which the product information, including dosage and administration, is given in Physicians' Desk Reference, 48th Edition, 1994, pp. 2000-2003.
The present invention claims that therapeutic agents of component (i), and component (ii) described above, when administered in combination, exert a synergistic effect, particularly, reducing the consumption of alcohol. Such combination treatment may allow the use of lowered clinical doses with increase efficacy and a wider safety window.
Component (i) of the present invention may also be provided as a pharmaceutical composition comprising a therapeutically effective amount of an opioid antagonist and a pharmaceutically acceptable carrier. Component (ii) of the present invention may likewise be presented as a pharmaceutical composition comprising a therapeutically effective amount of a selective serotonin reuptake inhibitor and a pharmaceutically acceptable carrier. Mixtures of the components (i), and (ii) with or without a pharmaceutically acceptable carrier, are also within the ambit of the present invention.
Dosage and Formulation
The opioid antagonist (component (i)), and selective serotonin reuptake inhibitor (component (ii)) combination treatment of the invention can be administered by any conventional means available for the use in conjunction with pharmaceuticals, either as individual separate dosage units administered simultaneously or concurrently, or in a physical combination of each component therapeutic agent in a single or combined dosage unit. The active agents can be administered alone, but are generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
The dosage administered will, of course vary depending on the use and known factors such as the pharmacodynamic characteristics of the particular agent, and its mode and route of administration; age, health, and weight of the recipient; nature and extent of symptoms, kind of concurrent treatment, frequency of treatment, and the effect desired. The recipient may be any type of mammal, but is preferably a human.
For use in the treatment of diseases characterized by abnormally high consumption of alcohol, by way of general guidance, a daily oral dosage of active ingredient(s) can be about 0.001 to 1000 mg/kg of body weight. Ordinarily a dose of 0.1 to 500 mg/kg per day in divided doses one to four times a day or in sustained release form is effective to obtain the desired results.
The compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
In the methods of the present invention, the compounds herein described in detail can form the active ingredient, and are typically administered in a mixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as carrier materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamallar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
Compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.
Dosage forms (compositions) su table for administration contain about 1 milligram to 100 milligrams of active ingredient per unit. In these pharmaceutical compositions, the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.
The active ingredient may be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions. It can also be administered parenterally, in sterile liquid dosage forms.
Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfate, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.
Suitable pharmaceutical carriers and methods of preparing pharmaceutical dosage forms are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.
Useful pharmaceutical compositions (dosage forms) for administration of the compounds of this invention can be illustrated as follows:
A large number of unit capsules can be prepared by filling standard two-piece hard gelatin capsules each with 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.
Soft Gelatin Capsules
A mixture of active ingredients in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 milligrams of the active ingredient. The capsules are washed and dried.
A large number of tablets can be prepared by conventional procedures so that the dosage unit is 100 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.
An aqueous suspension can be prepared for oral administration so that each 5 ml contains 25 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S.P., and 0.025 mg of vanillin.
A parenteral composition suitable for administration by injection can be prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution is sterilized by commonly used techniques.
Each therapeutic agent component of this invention can independently be in any dosage form, such as those described above, and can also be administered in various ways, as described above. The component (i), and (ii) of the invention may be formulated together, in a single dosage unit (that is, combined together in one capsule, tablet, powder, or liquid, etc.) as a composition (combination product). When component (i), and (ii) are not formulated together in a single dosage unit, the opioid antagonist component (i) may be administered at the same time as the selective serotonin reuptake inhibitor component (ii) or in any order. For example, component (i) of this invention may be administered first, followed by administration of component (ii), or they may be administered in the reverse order. When not administered at the same time, preferably the administration of component (i) and component (ii) of this invention occurs less than about one hour apart. Preferably, the route of administration of component (i) and component (ii), of the invention is oral. The terms oral agent, oral release enhancer, oral compound, or the like, as used herein, denote compounds which may be orally administered. Although it is preferable that component (i), and (ii), of the invention are both administered by the same route (that is, for example, both orally) or in the same dosage form (that is, for example, as a tablet), the invention contemplates that they may each be administered by different routes (that is, for example, one component of the combination product may be administered orally, and another component may be administered intravenously) or in different dosage forms (that is, for example, one component as a tablet and another as a liquid).
As will be appreciated by a medical practitioner skilled in the art, the dosage of the combination therapy of the invention may vary depending upon various factors such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration, the age, health and weight of the recipient, the nature and extent of the symptoms, the kind of concurrent treatment, the frequency of treatment, and the effect desired, as described above.
The proper dosage of component (i), and component (ii) in this invention will be readily ascertainable by a medical practitioner skilled in the art, based upon the present disclosure. By way of general guidance, typically a daily dosage may be about 10 milligrams to about 1.5 grams of each component. By way of general guidance, when the compounds of component (i) and component (ii) are administered in combination, the dosage amount of each component may be reduced by about 70-80% relative to the usual dosage of the component when it is administered alone as a single agent for the treatment of alcoholism and alcohol dependence, in view of the synergistic effect of the combination.
The combination products of this invention may be formulated such that, although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized. In order to minimize contact, for example, where the product is orally administered, one or more of the active ingredients may be enteric coated. By enteric coating one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines. Another embodiment of this invention where oral administration is desired provides for a combination product wherein one or more of the active ingredients is coated with a sustained-release material which effects a sustained-release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients. Furthermore, the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine. Still another approach would involve the formulation of a combination product in which the one or more components is coated with a sustained and/or enteric release polymer, and the other(s) component is also coated with a polymer such as a low viscosity grade of hydroxypropyl methylcellulose or other appropriate materials as known in the art, in order to further separate the active components. The polymer coating serves to form an additional barrier to interaction with the other component.
Dosage forms of the combination products of the present invention wherein one active ingredient is enteric coated can be in the form of tablets, such that the enteric coated component and the other active ingredients are blended together and then compressed into a tablet or such that the enteric coated component is compressed into one tablet layer and the other active ingredient is compressed into an additional layer. Optionally, in order to further separate the two layers, one or more placebo layers may be present such that the placebo layer is between the layers of active ingredients. In addition, dosage forms of the present invention can be in the form of capsules wherein one active ingredient is compressed into a tablet or in the form of a plurality of microtablets, particles, granules or non-perils, which are then enteric coated. These enteric coated microtablets, particles, granules or non-perils are then placed into a capsule or compressed into a capsule along with a granulation of the other active ingredient.
These as well as other ways of minimizing contact between the components of combination products of the present invention, whether administered in a single dosage form or administered in separate forms but at the same time or concurrently by the same manner, will be readily apparent to those skilled in the art, based on the present disclosure.
Pharmaceutical kits useful for the treatment of alcoholism and alcohol dependence, which comprise a therapeutically effective amount of a compound of component (i), and a compound of component (ii), in one or more containers, are also within the ambit of the present invention. Sterilization of the container may be carried out using conventional sterilization methodology well known to those skilled in the art. Component (i), and component (ii) may be in the same container or in separate containers. The containers of materials may comprise separate containers, or one or more multi-part containers, as desired. Component (i), and component (ii), may be separate, or physically combined into a single dosage form or unit as described above. Such kits may further include, if desired, one or more of various conventional pharmaceutical kit components, such as for example, one or more pharmaceutically acceptable carriers, additional vials for mixing the components, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, may also be included in the kit.
The examples described below may be used to demonstrate the synergistic effect of an opioid antagonist, such as naltrexone, administered in combination with a selective serotonin reuptake inhibitor. The tests described below may demonstrate that a representative opioid antagonist, naltrexone, acts synergistically with a representative selective serotonin reuptake inhibitor, fluoxetine, resulting in reduction of total alcohol consumption in a model of sustained ethanol drinking behavior in rats.
The methods for testing individual compounds for their ability to modify alcohol intake are essentially the same as described by C. L. Hubbell et al. in Alcohol, 3, 39 (1986). Male Sprague-Dawley rats are obtained from Charles River Breeding Laboratories. For 14-30 days, rats are given a 2 hour daily opportunity to drink a sweetened 10-20% ethanol solution or water. Rats are deprived of water for the remaining 22 hours each day. Rats eventually drink considerable amounts of ethanol solutions equivalent to about 1.0 to 3.0 g/kg of pure ethanol equivalent each day. After stable levels of alcohol intakes are achieved, various pharmacological preparations are tested for their effects on the intake of sweetened alcohol solutions. For the next; few days, designated groups of rats are administered various oral doses of naltrexone, fluoxetine, fixed-dose combinations of naltrexone and fluoxetine, or water (vehicle) 10-30 minutes before their opportunity to drink ethanol solutions. In similar experiments, data may also be obtained using rats prepared by the "Samson" sucrose-fading procedure (D. V. Gauvin et al., Alcohol, 10, 37, 1993). In this procedure, rats are offered a 30 minute opportunity to drink sweetened ethanol solutions each day and are not water deprived for the remaining period each day. To induce a stable level of alcohol consumption, the concentration ratios of the sucrose-ethanol solutions are varied over days by increasing the ethanol concentration from 5% to 20% w/v and reducing, eventually to zero, the sucrose concentration. On day 1 only, rats are deprived of water for 16 hours prior to the introduction of 20% sucrose solutions. Thereafter, access to food and water is ad libitum except during the 30 minute ethanol-sucrose access test period each day. Rats are eventually maintained on 20% ethanol solutions during the daily test period. Test compounds are administered as described above.
All rats are dosed sequentially by the oral route with solutions or suspensions of naltrexone HCl and/or of fluoxetine HCl. A dosing volume of 1 to 10 ml/kg is used for each sequential solution or suspension. All doses are coded and the test is performed under a code not known to the observer.
The data for each experimental group are from 3-7 separate studies. The reduction in alcohol consumption is quantified by determining the dosage of individual drugs or fixed-dose drug combinations which reduce alcohol consumption by 50% from pre-drug values for each rat or each group of rats. This dosage as described herein is referred to as the ED50 dose. All ED50 values and their 95% confidence limits are determined numerically by the computer-assisted methods of Finney D. J. Finney, "Probit Analysis," Third Edition, Cambridge University Press, Cambridge, England, 1971!, Tallarida and Murray R. J. Tallarida and R. B. Murray, "Manual of Pharmacologic Calculations with Computer Programs," Second Edition, Springer-Verlag, New York, 1987!, or Litchfield and Wilcoxon (J. T. Litchfield, Jr., and F. Wilcoxon, J. Pharmacol. Exp. Ther., 96, 99, 1949).
The nature of the analgesic interaction (addition, potentiation, or antagonism) is determined by graphing the results in a Loewe isobologram (S. Loewe, Pharm. Rev., 9, 237, 1957). Regression analysis is used to evaluate the statistical significance of the isobologram using an equi-effective dose substitution model (Appendix II). All tests of statistical significance are carried out at a 95% confidence level (P≦0.05).
The isobologram is a quantitative method for measuring interactions between drugs where dose-effect relationships are depicted in a multi-dimensional array with lines connecting dose pairs that are equieffective in relationship to a common pharmacological endpoint. In this instance, the alcohol drinking test is used to estimate a common level of suppressant activity for the two component drugs separately and for each fixed dose-ratio combination. In the isobolographic figure, areas of dose addition, synergism, and/or antagonism are clearly defined by reference to the theoretical "ED50 Addition Line." According to Loewe's isobolographic theory, ED50's falling under the curve (between the ED50 Addition Line and the origin) would represent unexpectedly enhanced suppressant activity and combination ED50's located above the line would represent unexpectedly diminished suppressant activity.
Most importantly, the isobolographic technique permits a full range of doses and dose combinations to be examined where the proportion of the first drug to the second actually varies from 0 to infinity, and to determine, by virtue of the graphical display, whether any one or more of the paired drug combinations displays unique pharmacological properties in comparison to the entire body of data generated. The isobologram is also valuable for organizing the data in a form which is easily amenable to statistical assessment of observed differences.
The nature of the analgesic interaction (addition, potentiation, or antagonism) between naltrexone and fluoxetine is determined by graphing equi-effective (ED50) amounts of naltrexone alone, fluoxetine alone, and of each fixed-dose combination in a Loewe isobologram (S. Loewe, Pharm. Rev., 9, 2:37, 1957). Regression analysis is used to evaluate the statistical significance of the isobologram using an equi-effective dose substitution model. The effects of two compounds are additive if the response to a dose of the two in combination does not change when a portion of one is removed from the mixture and replaced by an equipotent portion of the other. If such substitution increases the response, the mixing together of the compounds is said to potentiate their effect.
Consider ED50 doses of mixtures of X units of compound B with Y units of compound A, whose ED50 doses are b and a, respectively. Given the hypothesis of additivity, all doses of mixtures satisfying the straight line relation, ##EQU1## will be ED50 doses to test the hypothesis of additivity, ED50 doses of mixtures are estimated through probit analysis of data from experiments run at various rations of A to B. Linear and curvilinear regression models are fitted to the data to estimate the amounts of A in respective ED50 doses, given the amount of B, (or, conversely, the amount of B, given A). If a curvilinear regression fits the data significantly better than a straight line regression, the hypothesis of additivity is refuted and potentiation exists.
Values of Y calculated from the straight line of Equation 1, and values of Y calculated from the curvilinear regression are plotted against X on an ED50 isobologram to describe the potentiation response.
It is convenient to standardize the units of dose such that 100 units of either compound alone is its respective estimated ED50 dose. The additivity hypothesis, then, will be represented by a straight line from 100 on the Y-axis to 100 on the X-axis on the isobologram, and Equation (1) becomes:
The regression is fitted to the data by the method of least squares. Residual squared deviations about the line of best fit are minimized in directions along lines from the origin through respective data points on the isobologram, these lines making angles with X-axis, tan-1 (Y/X). This is accomplished by a transformation prior to the regression analysis. Its inverse is applied to transform the coordinates of the regression curve back to the X,Y coordinates of the isobologram.
Let Dr be an ED50 dose of a mixture of A and B, where r is the fraction of compound B in the mixture; i.e. ##EQU2##
It follows from Equation 1 that ##EQU3##
From the additivity hypothesis, the logarithms of the ED50 doses at various mixture ratios are a straight line function of (Log Dr). To test the hypothesis, polynomial regressions, as follows, are fitted to ED50 estimates from experimental data obtained at various mixture ratios: ##EQU4## The additivity hypothesis is refuted if a polynomial of degree higher than one fits the data significantly better than the straight line equation: ##EQU5##
Since X and Y are uniquely determined by Fr and r, the coordinates of the regression are transformed readily to the coordinates of the isobologram.
If data are scaled to ED50 dose levels of 100 standard dose units, Equation (2) becomes
Fs =log 100=2. (2.1)
The additivity hypothesis implies that Fs is independent of rs, and may be tested by analysis of the regression model ##EQU6## the subscripts, s, indicating that the data are scaled. A statistically significant regression will refute the hypothesis.
The model of least squares utilizes jointly the information contained in all of the separate data points. Statistical significance of the curvilinearity of the regression model establishes the existence of potentiation (or antagonism) of the compounds in the biological system studied. The parameters in the model describe its intensity over the range of mixture ratios, from 0 to 1, the nature of which is seen readily when the regression is plotted on the isobologram. This method is used to determine the best-fitting ED50 regression line through ED50 data points representing equivalent levels of alcohol suppressing activity for each of the naltrexone-fluoxetine dose-ratios and for naltrexone and fluoxetine alone. As shown in an isobologram plot, the calculated quadratic polynomial "ED50 Regression Line" fits the data significantly better than the straight "ED50 Addition Line" using stringent 95% confidence limits. Thus, consistent with Loewe's isobolographic model, the hypothesis of analgesic additivity is refuted and potentiation of alcohol drink suppressing activity is established for all combinations of naltrexone and fluoxetine.
The results may be used to demonstrate that groups of rats receiving effective doses of naltrexone or fluoxetine each consume significantly less ethanol on each day tested compared to vehicle-treated rats. Effective oral doses of naltrexone generally range from 0.1 to 10 mg/kg and effective doses of fluoxetine generally range from 1 to 100 mg/kg. In rats administered fixed-dose combinations of naltrexone and fluoxetine, ethanol drinking may be significantly reduced using lower doses of naltrexone and fluoxetine than represented by their individual proportions in the fixed-dose mixture, hence a synergistic interaction would exist between naltrexone and fluoxetine which produces a greater reduction in alcohol consumption than can be accounted for based on addition of their individual effects.
The disclosures of all of the references cited herein are hereby incorporated herein by reference in their entirety.
Various modifications of the invention in addition to those shown and described herein will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims.
|Cited Patent
|Filing date
|Publication date
|Mar 25, 1987
|Oct 11, 1988
|Bristol-Myers Company
|Method for treatment of alcohol abuse
|Nov 14, 1991
|Nov 22, 1994
|Reid Larry D
|Method for treating alcohol abuse and alcoholism
|May 7, 1992
|Nov 12, 1992
|Dynagen Inc
|A controlled, sustained release delivery system for treating drug dependency
|Feb 28, 1994
|Sep 15, 1994
|Nagle John S
|Method for treating emotional or mental illness and emotional or mental illness concomitant with seizures
|Benjamin and Buot Smith, J. Am. Acad. Child Adolesc. Psychiatry, Naltrexone and Fluoxetine in Prader Willi Syndrome 32:4, Jul. 1993.
|Benjamin and Buot-Smith, J. Am. Acad. Child Adolesc. Psychiatry, Naltrexone and Fluoxetine in Prader-Willi Syndrome 32:4, Jul. 1993.
|Bohn, The Psychiatric Clinics of North America, Alcoholism 16:4, 1993.
|C. A. Narango et al., Clin. Pharm. Ther., 1984 35:374.
|C. A. Narango et al., Clin. Pharm. Ther., 1987 41:266.
|C. A. Narango et al., J. Clin. Psychiatry., 1986, 47:16.
|C. L. Hubbell et al., Alcohol, 1986, 3:39.
|C. L. Hubbell et al., Alcohol, 1991, 8:355.
|D. R. Brown & S. G. Holtzman, Pharmacol. Biochem. Behav., 1979, 11:567.
|D. V. Gauvin et al., Alcohol, 1993 10:37.
|Ferrero, et al., Medicine & Hygiene, Acquisitions Therapeutiques 1993 ( II ) 52: 93 6.
|Ferrero, et al., Medicine & Hygiene, Acquisitions Therapeutiques 1993 (II) 52: 93-6.
|J. R. Volpicelli et al., Arch. Gen. Psychiatry, 1992 49:876.
|L. D. Reid & G. A. Hunter, Alcohol, 1984, 1:33.
|R. D. Myers et al., Alcohol, 1986, 3:383.
|S. S. O Malley et al., Arch. Gen Psychiatry, 1992, 49:881.
|S. S. O'Malley et al., Arch. Gen Psychiatry, 1992, 49:881.
|Citing Patent
|Filing date
|Publication date
|Oct 30, 2001
|Apr 25, 2006
|Pain Therapeutics, Inc.
|Inhibitors of ABC drug transporters at the blood-brain barrier
|Apr 21, 2004
|May 20, 2008
|Orexigen Therapeutics, Inc.
|Compositions for affecting weight loss
|Apr 23, 2004
|Sep 16, 2008
|Orexigen Therapeutics, Inc.
|Method for treating obesity
|Jan 11, 2005
|Sep 30, 2008
|Orexigen Therapeutics, Inc.
|Compositions of an anticonvulsant and an antipsychotic drug and methods of using the same for affecting weight loss
|Feb 17, 2006
|Dec 9, 2008
|Orexigen Therapeutics, Inc.
|Compositions for affecting weight loss
|Nov 4, 2003
|Feb 9, 2010
|Purdue Pharma L.P.
|Tamper-resistant oral opioid agonist formulations
|Mar 23, 2010
|Purdue Pharma L.P.
|Tamper-resistant oral opioid agonist formulations
|Aug 31, 2005
|May 11, 2010
|Duke University
|Compositions of an anticonvulsant and mirtazapine to prevent weight gain
|Nov 4, 2003
|May 18, 2010
|Purdue Pharma L.P.
|Tamper-resistant oral opioid agonist formulations
|Sep 5, 2008
|Jul 13, 2010
|Duke University
|Method for treating obesity
|Nov 30, 2010
|Purdue Pharma L.P.
|Tamper-resistant oral opioid agonist formulations
|Jan 3, 2012
|Orexigen Therapeutics, Inc.
|Layered pharmaceutical formulations
|Dec 19, 2011
|Nov 27, 2012
|Orexigen Therapeutics, Inc.
|Layered pharmaceutical formulations
|Jul 16, 2010
|May 13, 2014
|Orexigen Therapeutics, Inc.
|Methods for administering weight loss medications
|Nov 21, 2006
|Aug 26, 2014
|Orexigen Therapeutics, Inc.
|Compositions and methods for increasing insulin sensitivity
|Feb 4, 2013
|Nov 11, 2014
|Pharmorx Therapeutics, Inc.
|Compositions and methods for minimizing or reversing agonist-induced desensitization
|Jun 4, 2007
|Dec 23, 2014
|Orexigen Therapeutics, Inc.
|Sustained release formulation of naltrexone
|Jul 2, 2014
|Mar 3, 2015
|Orexigen Therapeutics, Inc.
|Compositions and methods for weight loss in at risk patient populations
|Nov 26, 2014
|Aug 18, 2015
|Orexigen Therapeutics, Inc.
|Sustained release formulation of naltrexone
|Mar 2, 2015
|Sep 1, 2015
|Orexigen Therapeutics, Inc.
|Compositions and methods for weight loss in at risk patient populations
|Mar 20, 2014
|Sep 8, 2015
|Orexigen Therapeutics, Inc.
|Methods for administering weight loss medications
|Dec 19, 2014
|Nov 24, 2015
|AntiOP, Inc.
|Intranasal naloxone compositions and methods of making and using same
|Oct 30, 2001
|Apr 17, 2003
|Schoenhard Grant L.
|Inhibitors of ABC drug transporters at the blood-brain barrier
|Aug 13, 2002
|Aug 14, 2003
|Oy Contral Pharma Ltd
|Method of treating alcoholism or alcohol abuse
|Apr 23, 2004
|Oct 7, 2004
|Duke University
|Method for treating obesity
|Jun 7, 2004
|Dec 16, 2004
|Grant Zimmermann
|System and method for multidimensional evaluation of combinations of compositions
|Apr 21, 2004
|Dec 16, 2004
|Eckard Weber
|Compositions for affecting weight loss
|Feb 15, 2005
|Jun 30, 2005
|Gadde Kishore M.
|Method for treating obesity
|Nov 4, 2003
|Aug 18, 2005
|Benjamin Oshlack
|Tamper-resistant oral opioid agonist formulations
|Feb 15, 2005
|Sep 29, 2005
|Gadde Kishore M
|Method for treating obesity
|Sep 7, 2005
|Jan 12, 2006
|Gadde Kishore M
|Method for treating obesity
|Nov 4, 2003
|Feb 23, 2006
|Benjamin Oshlack
|Tamper-resistant oral opioid agonist formulations
|Apr 19, 2005
|May 11, 2006
|Eckard Weber
|Compositions for affecting weight loss
|Oct 3, 2005
|Jul 20, 2006
|Krishnan K R R
|Compositions of an anticonvulsant and an antipsychotic drug and methods of using the same for affecting weight loss
|Nov 21, 2006
|Jun 7, 2007
|Mckinney Anthony A
|Compositions and methods for reducing food cravings
|May 5, 2006
|Aug 7, 2008
|Gadde Kishore M
|Method for treating obesity
|Nov 4, 2003
|Dec 11, 2008
|Purdue Pharma L.P.
|Tamper-resistant oral opioid agonist formulations
|Nov 4, 2003
|Dec 18, 2008
|Purdue Pharma L.P.
|Tamper-resistant oral opioid agonist formulations
|Dec 27, 2007
|Jul 2, 2009
|Mylan Inc.
|Formulation and method for the release of paroxetine in the large intestine
|Jun 3, 2009
|May 6, 2010
|Daniel Wermeling
|Pharmaceutical compositions comprising an opioid receptor antagonist and methods of using same
|Oct 21, 2009
|Jul 1, 2010
|Pharmorx, Inc.
|Compositions and methods for minimizing or reducing agonist-induced desensitization
|Mar 26, 2010
|Jul 15, 2010
|Krishnan K Ranga R
|Compositions of an anticonvulsant and mirtazapine to prevent weight gain
|Apr 21, 2004
|Dec 26, 2007
|Orexigen Therapeutics, Inc.
|Compositions for affecting weight loss
|U.S. Classification
|514/397, 514/811, 514/649, 514/651
|International Classification
|Cooperative Classification
|European Classification
|Nov 2, 1998
Owner name: DUPONT PHARMACEUTICALS COMPANY, DELAWARE
Free format text: CHANGE OF NAME;ASSIGNOR:DUPONT MERCK PHARMACEUTICAL COMPANY, THE;REEL/FRAME:009586/0702
Effective date: 19980701
|Feb 11, 2002
Owner name: BRISTOL-MYERS SQUIBB PHARMA COMPANY, NEW JERSEY
Free format text: CHANGE OF NAME;ASSIGNOR:DUPONT PHARMACEUTICALS COMPANY;REEL/FRAME:012607/0038
Effective date: 20011001
|Dec 25, 2002
|Fee payment
Year of fee payment: 4
|Apr 18, 2007
|Maintenance fee reminder mailed
|Sep 28, 2007
|Lapse for failure to pay maintenance fees
|Nov 20, 2007
|Expired due to failure to pay maintenance fee
Effective date: 20070928


text: We are now just $350 away from reaching our KickStarter goal of $7,500. If you have already donated, please consider chipping in another small amount or reposting/sharing this link on your wall. If you haven't donated, please take a minute to check out our KickStarter page. If you decide not to donate, reposting or sharing this link would also be a big help. Thank you for all your help!


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Emily Jaeger, right, a Youth Tobacco Prevention board member for the state of Wisconsin, received the 'Youth Leader of the Year' award from the 5 Counties for Tobacco-Free Living Coalition. Emily is a WLA junior. She is shown with her mother Kathy.
- Filed Under
Emily Jaeger, a Winnebago Lutheran Academy junior and also a Youth Tobacco Prevention board member for the state of Wisconsin, received the "Youth Leader of the Year" award from the 5 Counties for Tobacco-Free Living Coalition at their annual Legislative Breakfast.
Jaeger received the award for promoting and supporting youth tobacco prevention activities in her school and in the community. She commented, "I was really surprised and honored to receive this award. My goal is to get the message out to as many youth as possible - that tobacco products are both very addictive and very harmful, even the ones that are available in candy flavors.
"I want my peers to know that they do have a choice. I don't force them to do anything. I hope that they make the informed decision to not use tobacco because this could come back to hurt them and their loved ones. I don't want my peers or their family members to experience the same kind of pain that I have endured from watching someone that I loved so much, die from tobacco use."


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Architect's Knowledge ResourceDocuments
AIA Design Voice
By Eva Schone, AIA, LEED AP
Never doubt that a small group of thoughtful, committed citizens can change the world.
Indeed, it is the only thing that ever has. -Margaret Mead
Early on in my career as a young architect it became evident to me that my personal mission and goals are strongly interlinked with those of my professional life and this realization caused me to turn apparent challenges into potential opportunities and to find ways to actively contribute to my community.
I see it as my personal responsibility and obligation to contribute to society through my work as an architect. I want to apply my education and creative skills and talents to assist in solving some of the problems we face as a society and as a community. When I entered the work force full-time after graduate school in 2004, I realized quickly that it would be very challenging to establish myself in the work place as a capable and dedicated young architectural intern, prepare for the licensing exams after long work weeks, to live a decently healthy life style, as well as to contribute to my community. But I also knew that I did not want to limit my community service to the required IDP hours or wait many years to give back to my community – I want community service to be a significant and consistent part of my career. When relocating to Austin in 2006 I made it one of my top priorities to find a firm that was supportive of my mission and goals. I earned my architectural license in Summer of 2008 and when I joined the AIA as a licensed architect shortly thereafter, it was important to me that I felt represented by my professional organization. After attending several community meetings and workshops related to affordable housing and community building, the time seemed right to approach the local AIA chapter together with my boss and a couple of like-minded architects to propose a "Community Action Group" – a group of architects and designers who's goal it would be to give back to the community - with an initial focus on affordable housing. AIA Design Voice was born and initiated in January 2009.
It is the mission of AIA Design Voice (AIA DV) to enable the greater design community to connect and collaborate with organizations and individuals interested in and engaged in housing advocacy, development and community building in Austin. AIA DV wants to be a valuable resource and action group that furthers the community involvement of the AIA chapter. AIA DV works with the community organizations in developing a program, assisting in outlining specific goals and tasks and estimating the amount of volunteer time required. The information gets distributed to AIA members and community forums as a call for volunteers. Interested design professionals with matching interests, skills, and available time frames contact AIA DV which matches them up with the community organization in need. In year one of AIA DV, volunteers assisted a non-profit with space planning and subsequent installation of space dividers for a two-week long Back-to-School event which served 150 families a day. The event took place in an empty big box building and AIA DV supported community leaders in receiving permission for the temporary use of the building. We also collaborated with an affordable housing advocacy organization to design and build a physical model that is used to discuss neighborhood planning, density, and open space. We are working with high school students interested in architecture to give them close up looks at the world of architecture. We have collaborated with other AIA Austin committees on presentations for a summit on affordable housing and we are in the process of assembling a resource database of affordable housing projects and best practices. We are enthusiastic supporters of Public Architecture's national 1% Pro Bono Program and will log AIA DV hours through their website. We would be very happy to share our organizational setup and experiences with other AIA chapters.
In conclusion and based on my personal experiences, observations, and discussions with like-minded individuals inside and outside of the profession, I believe that it is vital to make volunteering in the design field more accessible, manageable, and to provide more opportunities to contribute 15 or 20 hours at a time so that volunteers have a positive (non-burn-out) experience and most importantly want to volunteer again. AIA Design Voice has been especially popular with current architectural interns, reinforcing the notion that many of the younger generation want to make community service a priority throughout their professional careers. I believe it is fair to say that AIA Design Voice has already greatly contributed to the awareness of the community that architects can and want to be more active participants in shaping and improving our community and that our problem-solving and design skills are as applicable to seemingly mundane tasks as they are to complex design challenges.
A lot of people are waiting for Martin Luther King or Mahatma Gandhi to come back – but they are gone. We are it. It is up to us. It is up to you. - Marian Wright Edelman
About the Author: A German native, Eva immigrated to the USA in 1998 and is currently a project architect with Hurt Partners Architects in Austin, Texas. She co-founded AIA Design Voice, a community action group based out of the AIA Austin chapter.
(AIA Design Voice logo by graphic design competition winner Marina Petric, Austin)


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Recent Existence Results for Second-Order Singular Periodic Differential Equations
1 Department of Mathematics, College of Science, Hohai University, Nanjing 210098, China
2 Department of Mathematics, Pusan National University, Busan 609-735, South Korea
3 Departamento de Análisis Matemático, Facultad de Matemáticas, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain
Boundary Value Problems 2009, 2009:540863 doi:10.1155/2009/540863Published: 8 June 2009
We present some recent existence results for second-order singular periodic differential equations. A nonlinear alternative principle of Leray-Schauder type, a well-known fixed point theorem in cones, and Schauder's fixed point theorem are used in the proof. The results shed some light on the differences between a strong singularity and a weak singularity.


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POSTED: 10:30 a.m. HST, Mar 4, 2013
LAST UPDATED: 11:35 a.m. HST, Mar 4, 2013
Tesoro Corp. has told state officials that it expects to lay off 210 workers in May when it shuts down its refinery in Kapolei, more than the 180 to 200 employees previously estimated by the company.
Tesoro announced on Jan. 8 that it planned to close the refinery and convert it into an import, storage and distribution terminal.
The updated layoff count was included in a letter Tesoro sent Feb. 28 to the state Department of Labor and Industrial Relations. Federal law requires employers to provide notice at least 60 days in advance of any mass layoffs of 100 workers or more.
"Approximately 210 employees will be separated from employment. At this time the company anticipates that a group of affected employees will be terminated sometime during a 14-day period beginning on May 1, 2013," according to the notification letter written by Thomas Weber, vice president of Tesoro's Kapolei refinery.
"This announcement and the above timetable are based on the best information currently available," Weber wrote. "however, various factors may still affect these plans and the timing of employee separations."
Tesoro is seeking a buyer for the terminal, as well as its local network of 31 gas stations.
San Antonio-based Tesoro put the underperforming refinery up for sale in January 2012, but was not able to find a buyer.
The Tesoro plant is the state's largest of two refineries with a capacity of 94,000 barrels a day. It employs 240 people. The other refinery, operated by Chevron, has a capacity of 54,000 barrels a day.
For the longer term, Tesoro already sees the writing on the wall that less bunker fuel will be purchased by HECO and less revenue will be generated because Hawaii's renewable/alternative energy goals and priorities will replace a good chunk of their business by 2030.
Hawaii may be less energy dependent on petroleum but at what cost?


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The Movie Blu-ray
Includes: Movie
Rating: R
Release Date: 12/28/2010
Market: $19.98
Price: $14.99 (25% savings)
The year is 1614. Japan has been united under the Tokugawa Shoguns and the land is beginning to feel at peace. Two remote ninja clans, the Koga and Iga, are ancient enemies but have long been bound by a peace agreement forbidding them to fight. The heirs to the leadership of both clans have fallen in love, but a tragic fate awaits them. A cruel plot is set by the Shogun to wipe these two clans from existence by breaking the peace agreement and forcing the two clans to battle. Five Ninjas of each the Koga and Iga clans will battle against each other to the death. As a great war begins, it brings the two young heirs together again. But this time as enemies.
- Includes: Movie
- Format: Blu-ray
- Language: English,Japanese
- Subtitles: English
- Rating: R
- Aspect Ratio: 16x9
- Main Feature Video: 1080p High Definition (HD Native)
- Special Feature Video: 480 Standard Definition
- Main Feature Audio: Dolby TrueHD: English 5.1,Dolby TrueHD: Japanese 5.1
- Special Feature Audio: Dolby TrueHD: English 2.0,Dolby TrueHD: Japanese 2.0
- Main Feature Runtime: 102
- Special Feature Runtime: 80
- Region: A
- Number of Blu-ray Discs: 1
- Studio: Giant Ape
- VFX Behind the Scenes
- Storyboard Collection
- Director Storyboard Collection
- Weapons Introduction
- Shinobi Art – Manjidani
- Shinobi Action - Sumpu Castle Fight
- Original Trailers and TV Spots
- Trailers


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While reading The City of Ember, our class finished chapter 3. This chapter is about Doon's first day in the pipeworks. When he pushed open the heavy pipeworks door and walked in, the air smelled strongly of dampness and moldy rubber, which seemed to him a pleasant, interesting smell. When he first walks farther down the pipeworks, he is greeted by Lister Munk (PipeWorks Director.) Lister walks up to him and asks his boot size, large, medium, Or small. Doon answers medium, after a few minutes of Lister retrieving his gear such as tool belt, boots, and a yellow slicker (a plastic suit to stay dry.) Doon was ready to go in to the pipe cavern. Led by Arlin Froll, they descend down a stair case, she told him he would work in tunnel 97 today. He stared hearing a loud noise and thought it was the generator at first, but it turned out to be the river that flowed right under the city, it also supplies the water for the city. This was the first time Doon had ever so much flowing water. During lunch break, he snuck to the generator room (and he knew he was not supposed to be in there without permission from Lister) and waited until someone came out. After a while, a lady walked out and that's when he put his plan into action. Once he got in the generator room, it was nothing like he expected, it was so loud. He got frustrated because he didn't understand how the generator worked.
Written by Hayden Crawford and Connor Bardin


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Big Bear City, CA, April 4, 2013 - CATS, The Community Arts Theater Society of Big Bear Valley, will present the world premiere production of "MARK TWAIN and the SHAKESPEARE MYSTERY", written by and starring Robin Field, for a limited run at The CATS Warehouse Theater beginning April 5. Field has adapted Mark Twain's book "Is Shakespeare … [Read more...]
C.A.T.S. Presents Mark Twain And The Shakespeare Mystery
Holiday Fun In Big Bear Valley
Big Bear Lake, CA, November 17, 2012, 6am - This week Bear Mountain & Snow Summit officially opened for the season. Get any early start to the holidays and have some fun on the slopes with friends and family. The Community Arts Theater Society, CATS, presents Oliver at the Big Bear Lake Performing Arts Center. The show will run through … [Read more...]
CATS & Class Act Kidz Present A Musical Theater Day Camp
Big Bear Lake, CA, September 9, 2012 -- The Community Arts Theater Society (CATS), in association with Class Act Kidz, will offer a musical theatre day camp for kids during the fall school break. Camp will be held Monday through Friday, October 8 through October 12 from 9:00 AM to 3:00 PM each day. Students will learn every aspect of putting … [Read more...]
CATS Announces Auditions And Opportunities For 2012 Productions
Big Bear City, CA, April 26, 2012, 3:00pm - CATS, The Community Arts Theater Society, announces some auditions on April 28 for their 2012 season, as well as opportunities to get involved with the organization onstage or backstage. Some principal auditions for CATS fall production of "Oliver!" will be held on Saturday, April 28 by … [Read more...]
Grand Opening of New CATS Warehouse Theater and 2012 Season Performances
Big Bear City, CA, March 21, 2012, 1:00pm - The Community Arts Theater Society of Big Bear Valley, known as CATS, will present an original variety show, "BEARLY BROADWAY" written by Robin Field and Karen Sargent Rachels to commemorate the opening their 2012 season beginning on Friday, March 23rd through April 1st for seven performances. The … [Read more...]
Cats Announces Auditions For 2012 PRODUCTIONS
Big Bear City, CA, January 6, 2011, 3:00pm - CATS, The Community Arts Theater Society, announces auditions for upcoming shows. The all volunteer organization does not charge any fees for participation, but all who are interested in being in the shows must be able to schedule their time, and commit to the project as a part of the team. CATS will … [Read more...]
My Fair Lady Opens Friday
Big Bear, Ca June 22, 2011 1:00 pm - This weekend, Big Bear's Community Arts Theater Society opens their 12 performance production of the musical My Fair Lady. Veteran New York and television actor Robin Fields will star as Henry Higgins, with Jennifer Gail as Eliza Doolittle. The production is directed and choreographed by Karen Sargent … [Read more...]
CATS Casting for My Fair Lady
Orientation and first rehearsal for CATS summer musical production of My Fair Lady. No auditions necessary for adult, teen, and children's choruses. Additional small parts will be cast from the choruses. No cost to participate in the production, but interested parties must commit to the rehearsal and performance schedule. Orientation to be … [Read more...]


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Infographic Sundays – American Food Consolidation – Let's Eat Local!
Take a look at the consolidation of our food system. It's so sad, but I am hoping that we're on the cusp of change as the locavore movement gains more and more momentum. Eat Local. Shop Local. Support Local! If you're in Denver, this company, The Corner Store by Fooducopia, is a great way to shop, eat, […]Read More


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Management Today lists under 35
This week saw the launch of Management Today's 35 women under 35 in 2008. As we went through the list of generation Y we discovered 5 female internet heroes: Christina Domecq, Madeleine Milne, Sarah Curran, Sanchita Saha and Philippa Snare.
Christina Domecq is co-founder and chief executive of Spinvox, a voice-to-text messaging service that employs 300 globally and makes customers' lives easier . For her, being an entrepreneur is not a career option – it's a vocation. Se has set up three businesses, an IT consultancy and IT training, since the age of 20. In 2006 she was Ernst & Young's UK Entrepreneur of the Year.
Madeleine Milne joined eMusic in 2006. She launched its digital-music retail operation in Europe and developed it into the second- biggest business after iTunes.
This former Times journalist started the fashion retailer My-wardrobe.com in 2006. Selling collections from labels such as See by Chloe, she heads a team of 30, and last year launched the Design Incubator for new talent.
As founder and chief executive Sanchita Saha launched a social- networking site for London professionals City Socialising last year. It has since gone national, with plans to expand it into the Continent. On freeindex 83% of the reviews about the site are positive.
Philippa Snare joined Microsoft UK in 2000 and is now group director of the Windows Live commercial business. She built a £5m dotcom business in classified ads at Scoot before joining Yell to manage business development. She told Naymz her goal is to become one of the most professional, well respected and renowned women in the IT industry, known for being fair, effective, efficient and knowledgeable.
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text:
HIV is the virus that causes AIDS. It attacks the body's defence system preventing it from fighting illnesses and infections. HIV is not passed on by shaking hands, kissing, touching or hugging, sharing cups, cutlery, crockery or towels. HIV is not spread by sneezing or coughing or from tears or sweat. A person does not get infected with HIV from daily contact.
HIV can be passed on in the following ways:
A diagnosis of HIV affects you, your family, partner and friends. This site describes the help available and provides details of who to contact for further information and advice.
Social Services provides a confidential service for anyone regardless of gender, sexuality, lifestyle or racial origin in the surrounding area. Together we can help with:
You may feel the need to discuss your fears and anxieties. It may be difficult for you to talk about your thoughts and feelings with your family. We offer emotional and psychological support in a confidential and non judgmental environment.
Extra expenses may be associated with your illness. You may be entitled to various benefits or be eligible for financial help from other sources. You may also be given support with continuing to work.
You may have physical difficulties in coping with daily living, need help in the home or with travelling to hospital appointments. We will work with you to try to meet your needs for practical assistance.
If you think you, or someone in your family, might benefit from any service provided by Social Services and you would like us to contact you by phone or email, please click the following link and complete the Social Services Contact Us/Self Referral Online Form and someone will be in touch with you as soon as possible.
To make a referral, or for more information about the support available for adults with HIV, please contact the Adult Care Service via the Access Team.
The NHS Direct Information Page describes diagnosis, treatment, prevention and useful links on HIV and AIDS.
National AIDS Helpline 0800 567 123. For other languages 0800 717 2227.


text:
The Pilot Handbook app is based on the Federal Aviation Administration (FAA) titled Pilot's Handbook of Aeronautical Knowledge (FAA-H8083-25A). This app provides knowledge that is essential for pilots, student pilots, and instructors.
Many FAA Knowledge Exams' questions are taken directly from the information presented in these texts.
Pilot Handbook app includes information on:
The app includes over 500 illustrations and images. It also now includes over 60 aviation calculators integrated into the content and standalone.
Pilot Handbook is an encyclopedia of all aspects of aeronautical information.
Additional Screenshots


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The North Dakota Department of Transportation is looking for teen drivers to participate in a safety program.
Ford Driving Skills for Life, one of the nation's most comprehensive teen driver safety programs, allows participants to be involved in multiple traffic safety activities.Â
Participants with a permit between ages 15 and 17 will have the opportunity to drive through a challenging course with the North Dakota Highway Patrol and experience a variety of driving simulators for free.
The event is in Bismarck on Sept. 25 and is open to 75 students. To register, visit www.NDTeenDrivers.com.
The deadline to apply is 11:59 p.m. Sunday. Participants will be randomly drawn.


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K&N Round Style Air Filter for your BMW R1100S.
K&N air filters are designed to achieve high, virtually unrestricted air flow while maintaining filtration levels critical to ensure long engine life. And because it's washable and reusable, it will last indefinetly and could be the last air filter you will ever need!


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