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Apparently their are enough parking lots
The question remaining is whether Bell has agreed to rat on one or several others in order to solidfy his deal
While not the ultimate cure-all solution, it would be a major start if the gun laws that make military weapons and such readily advailable on the streets were changed. Curtainment of freedoms? Freedoms are being curtained on a daily basis. One thing is certain if more victims were white we would not be having this mail-a-tron.
We all know that a tightening of the gun laws that make it easy for practically anyone to purchase weapons would be far more effective than raising the bonds of ppl arrested for gun charges. The bonds are already excessive which explains why jails are always overcrowded, if defendants were making bond such would not be the case.
The laws that permit open air gun dealerships are the largest contributor to the glut of guns that are on the streets.
The law does not require an actual admission of guilt in entering a plea of guilty. Instead a person is stating for the record that either they are in fact guilty OR the plea is entered IN THEIR BEST INTERESTS (which is exactly what he said). This is merely another example of the government's bullying tactics unleashed.
I cannot believe the NOPD has actually made an arrest that has to be the only crime solved so far this year
FORCED! You mean like in forced labor/slavery. The fact that this country continues is proof of the non-existence of god. What righteous god would allow evil to governed the world.
You are forced to buy auto insurance, forced to accept any agreements proposed by cellphones companies, computers etc etc etc
This is a criminal matter (Assuming it actually took place) throughout the world including the GREAT STATE of LOUISIANA there are many instances of child abuse for whatever reason. To take this instance and attempt to further demonize a people is both mean and unjust. The American people do not care anything about Afghan people or any other people. Articles such as this are published from time to time because it helps with the war/robbery effort. The American people are the most hateful on the planet earth and must have an object to direct its hatred.
The law permits the widespread availibility of guns and weapontry in the area. It's almost as though it is a plan.
In response to: "Any idea what exactly it was he was doing that's so different from other police chiefs?" There are highly successful police chiefs, and there are some that aren't so successful. I think that more often that not Pennington is spoken of as an example that effective planning is likely to produce positive results.
Chief Serpent's intent is to cover his own incompetence by hopefully distracting the public from demanding that, at least some of these crimes, are solved. His aim is to numb the public. If the head of the NY crime family is murdered the police has a responsibility to gather evidence and then present it before the proper judical authority for litigation. There is no perspective, murder is murder and though we do tend to be more outraged at some crimes than others, the law must be enforced fully for all.
Many people speak about parents knowing where there kids are: Well and good and exactly as it should be; but if you are one or two of those parents working 10 or 12 hour shifts, with 12 or 14 hours tied up in work related activities. It becomes extremely difficult to know where your kids are. Some people with these gigantic homes are unaware of what there kids are doing under their roof. New Orleans is a very destitute place to live, and a case in point is every time policemen are arrested for crimes the first thing uttered is that it is proof that the police need a raise. Give them some more money and they won't feel it necessary to steal and committ mayhem. What's good for the Police is good also for the citizens as well.
If John Gotti (the only alleged mobster I know) were to fall victim to a murderer it remains incumbent upon the police to gather the facts and present them in a court of law so that the prepertrator is held accountable. What Serpas hope to accomplish is to put value on some lives and lessen the value on others. The police, if the past is any indication, are too busy stealing, selling drugs etc. to thoroughly investigate crimes. THEY ARE NOT DOING THEIR JOBS. It is impossible that most of these crimes are free of evidence.
Somewhere behind the scene, peeking from under a rock, I can assure you that insurance companies are at the controls. Speeding tickets no matter how benign result in higher premiums and more profits
The discussion is always limited to "how much time should we give the users or drug dealers?" The idea of going after the distributors, the ones who supply, organize and profit from the drug trade, is never spoke about. How can drugs and the crime that results from the drug trade be managed if the flow of drugs is unmanaged? My experience is that the police in many instances are the actual force behind the movement of drugs. What we have is a city with virtually no employment base, no fortune 500 companies, a dysfunctional educational system, a thorough and completely corrupt/murderous police department. The results are no accident.
"There is no indication in the record that the prosecutor's remarks so inflamed the jury that it influenced the verdict," states Judge Walter Rothschild. Yeah right! Like someone is going to make a statement to the extent that the proscutors remarks inflamed them and then have the statement placed in the record. Pretentious bastards.
Quite a step down for Odom & Gasol. New Orleans has the culture but money making opportunities are few.
How did this become "news?" It is not, defendants plead guilty every day without being required to do anything other than state for the record whether or not they or in fact guilty of the charges. This is a CAMPAIGN whose aim is to throw logs on the fire while the real criminals i.e. Connick, Nagin, Foti, School Board, Police Dept. etc do as they please.
The Mayor must not have much to do. You would think that if anyone in the city had a legitimate reason to be excused from jury duty it would be the Mayor but I guess not. But even though the evidence doesn't support it the guy will be convicted - ten get you one
The question: Will the reaction to CP3 departure produce the hatred that LBJ's did? Probably not, fans don't seem to mind when management is involved in the movement of players; but fans HATE to see a player make a move on his own, which is what Chris Paul is doing.
He got caught stealing $6,000 he has stolen quite a bit more


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Jakarta Globe
Solo. Jakarta governor candidate Joko Widodo's signature checkered shirts are rising in popularity in the run-up to the Idul Fitri holiday, with store owners reporting higher sales.
"Along with the momentum heading into the second round of the gubernatorial election, people outside Jakarta are getting more enthusiastic about Jokowi's checkered shirts during the fasting month," business owner Arjuna Suparto, who sells the shirts, told Antara state news agency in Solo, referring to Joko by his popular nickname.
Arjuna said orders for the shirts had increased sharply during Ramadan. His supply of the shirts has nearly run out he said, with about 30 people buying them daily, not counting customers who place orders from other cities.
"Ahead of Idul Fitri this year, we have sold almost 2,000 shirts and are anticipating even higher demand," he said. "In a day we can only produce 30 shirts, but to boost our supply we're hiring more people to sew them this month."
He said the shirts, which he sells for between Rp 100,000 and Rp 125,000 ($10 to $13), are popular in Jakarta; Yogyakarta; Semarang, Central Java; Cirebon, West Java; Palangkaraya, Central Kalimantan; Samarinda, East Kalimantan; and Papua.
Jokowi, who is currently the mayor of Solo, began selling the checkered shirts in a bid to raise funding and win over young voters for his gubernatorial campaign in the capital. He garnered 43 percent of the vote in the July 11 election, while incumbent Fauzi Bowo got 34 percent. The runoff election is on Sept. 20.

subset: commoncrawl


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COSBY — University High made it an all District 1 semifinal round with a 69-66 overtime win Saturday night against Cosby in the Region 1-A quarterfinals.
Marcus Taylor scored 24 points and Seth Hilbert had 17 points, seven assists and committed just one turnover to lead the Junior Bucs. UH sealed the win at the foul line.
"I'm really proud of our guys gutting out a win in a hostile environment," UH head coach Justin Penley said. "We got down on the scoreboard late but kept fighting. Marcus hit some huge shots and Seth played great, just like you would like to see from a senior point guard."
Calen Archer had 10 points and 10 rebounds for UH, and Marshall Hurley netted 12 points.
Cosby hit a pair of free throws to force overtime. Tate Parton scored 30 points for the Eagles, who finished the year at 17-10.
University High improved to 18-10 and plays Cloudland in the region semifinals on Tuesday at Chuckey-Doak Middle School.
Hampton 69
Hancock County 53
HAMPTON — Cody McClain tossed in 21 points as the Bulldogs cruised to victory in the Region 1-A quarterfinals.
Hampton won its 20th game of the season and earned another shot at Unaka, which has won the last three meetings, including 64-58 last week in the district semifinals. The teams will meet Tuesday night at Chuckey-Doak Middle School.
Stanley Valentine had 12 points and seven rebounds against Hancock. Wesley Murray chipped in with 11 points, and Cheyenne Camillo added 10.
Hampton (20-13) led 41-30 at the half and wasn't seriously threatened the rest of the way.
Unaka 71
Clinch 31
ELIZABETHTON — The Rangers held the Wildcats to six first-half baskets and rolled in the 1-A quarterfinal.
Danny Bales led Unaka with 10 points and Logan Carrier had nine. Michael Nave, Jeffery Yerkes and Billy Bales each scored eight. The Rangers led 45-17 at the break.
Unaka plays Hampton in Tuesday's semifinal. Clinch finished the year at 1-14.
Cloudland 81
Washburn 37
ROAN MOUNTAIN — Taylor Whitehead and Zac Potter scored 17 points apiece as the Highlander cruised in the 1-A quarterfinal.
Devin Whitehead added 15 points and Cloudland led 49-20 at halftime. The Highlanders (23-10) play UH in Tuesday's semifinal.
Sullivan East 80
Greeneville 77, OT
BLUFF CITY — The Patriots survived the Greene Devils' fourth-quarter rally to reach the Region 1-AA semifinals.
Sullivan East led by 22 after three quarters, but Greeneville outscored the Patriots 35-16 in the final frame to force overtime. East got late free throws from Jonathan King, Jordan James and Corben Sutherland in overtime for the win. Greeneville had a chance to tie it up again, but the 3-point shot missed.
David Casaday sank five 3-pointers to led East with 30 points. Austin Fleenor scored 18 points and King finished with 15.
Greeneville, which ended the year at 21-11, got 24 points from Landon Duncan, 21 from Trevor Wright and 16 from Hayes Culbreath.
Berean Christian 60
Tri-Cities Christian 50
Caleb Atkins scored 20 points and grabbed 10 rebounds as the Eagles lost in the TAACS Eastern Regional.
Holden Joseph had 13 points and Noah Rosebalm added 11 for Tri-Cities, which will play Thursday in Nashville in the TAACS state championship.
Tri-Cities Christian (girls) 48
Berean Christian 39
Emily Fox sank three 3-pointers and was named the tournament MVP as the Lady Eagles advanced to TAACS state tournament.
Alicia Cook scored 13 points and Fox finished with 11 points against Berean in the Eastern Region Championship. Becca Cox, Sarah Cox and Lindsey Hofer were also named to the all-tournament team.
Fox hit six 3-pointers and Sarah Cox made 5 in Tri-Cities win on Friday night in the semifinals. The Eagles play next week in Nashville.


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Rudy Acuña: Pundit after pundit predicts that the entrance of large numbers gay and Latino voters will end the culture wars that divide the country. There is only one problem — progressives forget that the "Young Grow Old."
GOP Rolls Dice on Immigration Reform
What Activists (Should Have) Learned in 2012
Randy Shaw: Activists are in far better spirits than one year ago. Progressives see that the public is on their side, and, unlike in the aftermath of the 2008 elections, are staying engaged in the major policy struggles that elections are supposed to be all about.
Latino Voters: How Obama's Team Got 75%
Record Latino Support For Obama's Re-Election
Arizona Latino Voter Suppression
Mario Solis-Marich: Over 80,000 ballots are still uncounted in Maricopa County, Arizona — the county that could reelect anti- Latino Sheriff Joe Arpaio
Adiós, Mitt
4 Key Swing States to Obama with High Latino Vote
Latinos Voting Early, Enthusiastic in Final Week
Why Pollsters Missed the Latino Vote – 2012 Edition
Florida: Mother of All Battleground States
Latino Vote Uphill Climb for Romney
President Obama's Latino Kryptonite Gay Marriage?
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Latest Headlines
Heatley Suspended for 2 Games
Posted on 16 Mar 2011 by Alex Wasserstrom.
As mentioned in my previous post, Dany Heatley has been suspended for 2 games for his elbow to the head of Dallas Stars forward Steve Ott. The video clearly shows Heatley extending his elbow and making contact with the head of Ott. The San Jose Sharks will be without Heatley for their games on Thursday and Saturday night against Minnesota and St. Louis respectively.
Continue Reading
3 Trades I would make if I were Bob
Posted on 30 Jul 2009 by Corey Krakower.
I am not convinced that the Canadiens are done. There are still changes that need to be made to this team and assets they have that can be attractive to other teams. They could use a little more puck moving ability and speed from their defense, better secondary scoring and some more size up front. In the spirit of addressing those needs; here are the 3 trades I would make if I were Bob Gainey. ...


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The Horror Show coming to blu ray next year?
Is this official? Go down the list to see:
Dude, this news was already broke.
Oh, my bad.
Quite a lineup though isn't it? And you can add things like The Burning, The Fog, The Howling and all those others just announced. They gotta lower those damn prices though or I'll have to take out a second mortgage!
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What You Should Know
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Bio2Tox is a wrinkle treatment serum that claims to be a safe alternative to Botox, boasting of dramatic results within 3 minutes. These include a reduction in the appearance of wrinkles and fine lines. Included in the Bio2Tox serum is a mixture of Collagen and Elastin Hydrolysates, along with soothing botanical extracts and minerals. It seems to be targeted towards middle-aged to elderly consumers, and is designed for use by both men and women. Bio2Tox claims their serum will eliminate wrinkles and fine lines permanently within 3 months of use, and supposedly this can be gained by applying the Collagen-rich formula to problem areas daily. They also provide pictorial testimonials attesting to these claims.
Currently the availability of Bio2Tox is unknown; any information available appears outdated and it may be discontinued. Nevertheless, Bio2Tox will be evaluated in the likelihood it becomes available again, but the chances of finding this serum in your local retail store are very minimal. This lack of information makes it difficult to find an appropriate price range, but it is suggested it is not an expensive product. Any other information is not available at this time.
Product Details
According to Bio2Tox, the ingredients included in their serum are Collagen and Elastin Hydrolysates, Aloe Vera, Botanical Extracts, Glycerin, and Natural Gum and Minerals. Each ingredient is included to supposedly moisturize the skin while tightening sagging skin and increasing elastin growth. In retrospect, very few of its ingredients offer any immediate skin-related benefits. Collagen and Elastin Hydrolysates, more commonly known as Hydrolyzed Collagen, are the chemical forms of Collagen, and are more absorbent forms of this important structure. It is commonly used in cosmetic creams to enhance the moisturization of a product along with increasing elastin in the skin. This may make skin firmer and smoother, although there are not many studies conducted on this ingredient's skin-related benefits.
Glycerin, another key ingredient in Bio2Tox, works as an additional moisturizer, but its benefits end there. Natural Gum does not offer any benefits, and is mostly used to thicken creams. It appears some ingredients may help moisturize the skin and might help decrease the presence of sagging skin, but it may not completely reduce the appearance of wrinkles permanently.
The Good
- Contains a form of Collagen that also moisturizes, in addition to promoting elastin growth in skin cells.
- Bio2Tox is designed for use by both men and women.
The Bad
- Bio2Tox may be discontinued and its availability is currently unknown.
- There is very little information about Bio2Tox available, and they do not address any safety concerns.
- No price points could be located.
The Bottom Line
Bio2Tox does appear to contain a couple of useful ingredients which may moisturize the skin, but its product is not very radical in formulation. Finding this serum may be half the battle though, and the lack of information available may cause consumers to look for a different product.


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Quick Links
Shop All Jewelry
BER10042 In Stock
Our Designer Inspired Oval Bead Dangling Bali Style Earrings are universally appealing. The earring starts with a silver color loop post that is etched with a cobblestone design and hangs 3 chains with a silver teardrop bead with the same cobblestone texture. The cobblestone design is on a black background to heighten this design detail. Overall these silver color bali style earrings measure 2.5" in length from the post backing. These can be statement earrings or easily mixed with your other silver jewelry pieces.
Eve's Addiction.com wants you to be a happy customer. We want you to be completely satisfied with the sterling silver jewelry that you receive from us, as we only sell high quality silver and cubic zirconia cz jewelry. We do understand that you may not like your purchase for some reason.
You may return or exchange your jewelry within 60 days of purchase if you are not satisfied with it. The jewelry must be returned in its original condition for a refund or exchange. Engraved, personalized, photo, monogram, name and initial, chocolate and clearance items are not returnable or exchangeable.


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|Tolkien Gateway is 10 years old. Sign up today to edit TG and help us grow for years to come.
The river Ringwil was a short and foaming river of West Beleriand that flowed east through the hilly High Faroth north of Nargothrond until it joined the Narog.[1] Where it met the Narog a secret door was built, which was used by Lúthien to escape from Nargothrond when Celegorm and Curufin held her prisoner.


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HAZARD — A Perry County man was arrested last week after he allegedly fled from police twice, once after they responded to robbery call at a gas station in the Grapevine community earlier this month.
Police received a report of the alleged robbery on August 10 at the Willie Miller BP in Grapevine. Randy Napier with the Hazard Police Department responded as mutual aid to the Kentucky State Police. When Napier arrived to the area near the Coal Ridge Trailer Park, he noticed someone in the weeds.
According to a warrant issued following the robbery, the man was later identified as 26-year-old Albert Noble, of Bulan.
As Napier called out to the man telling him to stop, he ran up a steep hill. Napier reported that he followed Noble and was able to catch up with him, where a fight broke out as Napier attempted to arrest him.
The two men fell down the hill during the altercation, and as they rolled down, Napier said he felt the man reach for his weapon. Noble was able to stop rolling down the hill before Napier and get way with the hand cuffs that were being used to arrest him.
On August 21, Napier obtained a warrant for Noble, who lives on Pigeon Roost Road, and went to his home to serve the warrant. According to the citation, Noble fled the scene as the officer pulled up to the home. Napier yelled for him to stop several times before shooting a taser at him.
The citation says that Napier is not sure if the taser connected, though Noble eventually fell down a steep embankment when he hit his head on the pavement.
Noble was taken to the hospital in Hazard where he was treated for his head wound. Napier placed Noble under arrest at the hospital and transported him to the Kentucky River Regional Jail in Hazard.
Noble has been charged with a bevy of offences, including first-degree fleeing or evading police, second-degree fleeing or evading police, third-degree assault of a police officer, first-degree wanton endangerment of a police officer, resisting arrest, second-degree disorderly conduct, menacing, theft by unlawful taking under $500, third-degree criminal mischief, and attempting to disarm a police officer.


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Josephson is a much sought-after lecturer on ethical issues. A graduate of UCLA and UCLA Law School, he was a law professor with an academic career spanning over 20 years. During that time, he was founder and CEO of a publishing company and a national chain of bar preparation courses. Josephson has been profiled in Time, The Wall Street Journal and the Los Angeles Times. He has a daily radio commentary in southern California and has appeared on ABC's Primetime Live, Nightline, and PBS's Bill Moyer 's World of Ideas.
In his visit to the Athenaeum, Josephson will also discuss his recent book, The Power of Character: Prominent Americans Talk about Life, Family, Work, Values, and More (1998).
Michael Josephson's lecture is part of the Athenaeum series Integrity, Commitment, and Achievement.


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Air Venturi Safety Glasses, Clear Anti-Fog Lenses...
4.0(11 reviews)
From: Air Venturi
1-year limited warranty
Average Customer Review5.0 (5 reviews)
Create an online reviewand share your thoughts with other customers
Things I liked:nice fit and great clarity.
Things I would have changed:nothing so far
What others should know:I have bought many pairs of safety glasses to shoot indoors and this is finally the pair that I can see well with inside.
Things I liked:Nose piece is flexible, comfortable, and grips well. Offers plenty of coverage up, down, and side to side. Anti-fog works for cool weather steamy face and breath. Decent for bike riding too.
Things I would have changed:Make the adjustable ear stalks so they can move one position shorter. Anti-fog coating causes bleary streaking in drizzle and rain (rather than droplets). Nose piece slips when wet from rain or sweat.
What others should know:Best for shooting and working with hand/power tools, but these are pretty versatile and I use them riding bicycles too.
Things I liked:Works great for my wife.
Things I would have changed:For my wife nothing, but these would need to be a little larger for me.
Show Other ReviewsCreate an online review and share your thoughts with other customers
CheckoutSubtotal (USD):
does not include shipping and tax


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Scooped: Charoset Sorbet
Sorbet really is a perfect passover dessert. Light and refreshing, it's a great palate cleanser after a heavy meal. It's dairy-free, and doesn't require matzo meal as a poor substitute for flour. This sorbet is incredibly simple, a delicious marriage of grape and apple, slightly sweeter and a touch more tart than the charoset on your Hillel sandwich. More


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AoM responds to Ian Lang's assertions over at the cesspool known as AskMen.com. Sample assertion:
Finally, do you think your dad would enjoy lying in a field with you making daisy chains and contemplating what it means to be a man? No. He would tell you to work hard, that life doesn't ever get easier and to stop being such a pussy.
Snip from the response:
Yes, a man should be a man of action. That is the end of his creation. But what is the means to that end? What kind of actions should he take? What is driving that action? What is the purpose of that action? What kinds of goals and priorities, values and morals should a man have? Contemplation is needed to answer these questions. Contemplation leads to right action.
Read the whole thing here.


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I'll be in the parks on Saturday (buying an ap). I need as much advice as possible to see all the new attractions also never seen World of Color yet. or you just plan a schedule for me. lol. All 3 annual passes will be blocked so I'm guessing it will be mostly clueless tourist.
any advice is needed.


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Travel around Rome or visit the Incas or Vikings in this fun strategy game. Cut the chains to make the colored balls fall in their matching color vessels. If you get stuck in one area, move unto another. Good luck solving the puzzles in this strategy game of Civiballs 2. This physics based puzzler will have you solving puzzles for hours.
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Randy Shaw: In accepting a Texas case of a white student challenging racial preferences, the United States Supreme Court is again set to reverse decades of court precedents and impose its own conservative agenda.
King Memorial: Now More than a Scar on the Nation's Conscience
MLK Would Oppose Today's Wars
China Needs Martin Luther King
We Twisted King's Dream, So We Live With His Nightmare
Finally, Black Civil Rights Movement is Dying
Rev. Irene Monroe: For many African Americans of younger generations, who are now the beneficiaries of the racial gains from the Movement, feeling the Movement's' slow death is like a welcoming boulder gradually being lifted from their shoulders, especially for those who are lesbian, gay, bisexual, transgender and queer.
Martin Luther King Day: They Never Heard Him Give a Speech
Kafi D. Blumenfield: "Injustice anywhere is a threat to justice everywhere." This generation of leaders has taken Dr. King's injunction to heart and they are taking action. They and their peers find common ground by connecting not only through race, gender, sexual orientation or citizenship status, but also, on higher ground, through shared aspirations and hope for the future.
The Pentagon and the King Legacy
William Lorenz Katz: Was not Martin Luther King, Jr. reaching beyond Vietnam when he warned of "approaching spiritual death" and called for "a significant and profound change in American life and policy" and insisted "we as a nation must undergo a radical revolution of values." Was he only speaking of Vietnam when he said, "War is not the answer?"
Racism in Review, A Look Back and a Look Ahead
With Friends Like These, Who Needs Glenn Beck? Racism and White Privilege on the Liberal-Left
The Unbearable Whiteness of Being
Paging Dr. King
Tom Degan: That's what I love about this guy! American history is littered with "Christian" religious leaders. Try as you might, you can't escape them. The thing that sets Reverend King apart from most of these guys is the fact that he wasn't a hypocrite. He never tried to twist the words of Jesus of Nazareth into anything other than what they were – a call to love one another and for kindness and gentleness. The Trappist monk Thomas Merton is another celebrated American Christian who took the gospel seriously. So was Dorothy Day. Please give me a day or two and I might be able to name more, but at the moment none come to mind. Both Merton and King died in 1968, Day in 1980. They're gone and they're not coming back.


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Gov. Dannel P. Malloy said Tuesday that he won't sign the revised education reform bill as approved Monday by the legislature's Education Committee, but he added that those who drafted it agree it's not finished yet.
"Everyone who spoke on the bill yesterday said this is not the final product," Malloy said at a news conference at the Capitol. Noting that someone had said that the bill was "written in pencil," Malloy added: "Well, I'm not going to sign a bill written in pencil, I can assure you."
Malloy said he will pursue the plans he had outlined in his original education bill, including linking a new teacher evaluation system with tenure and establishing a commissioner's network for low-performing schools.
The revised bill approved Monday by the Education Committee postponed any tenure reform, requiring the state education commissioner to report back in January 2013 on how the new evaluation system is working and on how it might be tied to tenure.


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No. 6 Wolfpack Edges App State 6-5
Feb. 21, 2014
Box Score | Box Score | Play-by-Play | Quotes
RALEIGH, N.C. - No. 6 NC State won its fourth-straight contest on Friday night at Doak Field at Dail Park, thanks to a nine strikeout performance by Carlos Rodon and a pair of run-scoring doubles by junior transfer Bubby Riley.


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How to Achieve Any Goal Once and For All
The no-fail guide to achieving any goal.
Plus free printable posters.
My post about inspiration received an overwhelming response–thank you to everyone who sent me personal stories!
Finding It
Why are some people so awesome and diligent at what they do?
According to a study conducted at the University College of London:
- You need an average of 66 days to form a habit.
- Depending on the difficulty and type of the habit, it can take anywhere from 18 to 254+ days for the habit to become automatic.
- For example, getting into the habit of drinking a glass of water everyday takes about 18 days, but doing 50 situps everyday takes more dedication.
- Missing one day doesn't reduce your chances of forming the habit. Don't give up.
"We are what we repeatedly do. Excellence then, is not an act, but a habit."
— Aristotle
Achieving Your Goal
- Break downthe goal and find out what you need to do to get there.
- For example, if someone wanted to lose 20 pounds, she will need to decrease the 'junk'/fatty foods and exercise at least 3 times a week.
- Your ultimate goalis to form a habit, something you do without thinking.
- Following the last example: Now that she has decided what to do, the next step is to form those habits so that those actions become automatic.
- Chances are, she's had a bad nutritional intake and a poor exercise routine for years– those have become her semi-permanent habits.
- She needs to break those old habits by forming new habits to reach her goal.
- At first, she'll need lots and lots of motivation to drop the junk food and exercise; her system has adjusted to years of unhealthy foods and a sedementary lifestyle– it's become natural and reflexive for her.
- She's almost forcing herself against her own will to form new habits.
- After a certain amount of time, it'll become natural for her to follow her new habits because they've become automatic.
- This habit-forming period is different for everyone.
- Motivate yourself to form the habit. Habits take time and dedication– it's all worth it in the end, when it becomes automatic.
- Have motivation in sight. Stick motivational quotes or inspiring imageson your walls, save them as your desktop background, and place them wherever you're most likely to wander away from your goal.
- See below for free motivational graphics that you can print!
- Remove distractions. Determine what distracts you or deters you from forming the habit.
- For example, if your goal is to practice 3 hours of piano everyday, but your computer distracts you from practicing, remove your computer from the practice room and make sure it's turned off while you practice– unplug the monitor, even– the harder it is to access your distraction, the more likely you're going to ignore it.
- Absorb yourself into your task. Think positively and involve your entire existence.
Print Your Own Motivation
- Due to popular demand (from an inspiring post), I've designed two motivational posters (on 8.5″ x 11″ paper) that you can print out and stick anywhere.
- Click on the thumbnail for the full-sized print image.
- These inspirational images are released under a Creative Commons license.
- I welcome personal stories and/or requests! Share your thoughts in your comment or email me.
Read the Comments or Add Yours
[…] proportion to the amount of positive messages that you consistently reflect on.Website content Anthony D Carter asked: Motivational quotes can inspire you to do great things. If you have ever fel…at motivation quotes can change your attitude instantly.Inspirational quotes give you motivation to […]
[…] It comes without thinking when you make it a habit. […]


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Lincoln is a 501(c)3, non-profit organization so all gifts to the School are tax deductible. There are many easy and convenient ways to support our unique educational mission as the nation's only All-Girls' Quaker School.
Become a member of our monthly giving club. To find out more, please click here.
Lincoln accepts gifts by personal check or credit card. Checks should be made payable to "Lincoln School" and mailed to:
Lincoln SchoolAttn: Development Office301 Butler AvenueProvidence, RI 02906
Join the Lincoln Foundation by making a planned gift to Lincoln School. These gifts include: bequests, charitable gift annuities, designation of Lincoln in your retirement and insurance plans, gifts of real estate, charitable reminder trusts, and charitable lead trusts among others.
If you are interested in discussing a gift to Lincoln, please contact:
Adrienne Morris Director of Development and Alumnae Relations301 Butler AvenueProvidence, RI401-331-9696 ext. email@example.com


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Follow Harry's journey from a headquarters hindering growth to a workplace where people and the business can prosper.Read More
The Vice President of Creative Design reflects on his 45-year tenure at the company and revisits his first—and now canonical—assignment on the job: a poster for the company picnic.Read More
Think money is the best way to motivate employees? Think again. Investing in a space that connects people to purpose is a bigger payoff for them and the bottom line.Read More


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Making your home baby and child-proof
We all want to protect our children as much as possible. Whilst there's no guaranteed way to completely baby- or child-proof your home, there are lots of things you can do to reduce potential accidents. This is our guide to what to do at different stages of your baby's development. Remember, it's best to be prepared, so try and put safety measures in place in advance.
Home safety before your baby becomes mobile
You may think there are few threats to a baby who can't move about independently but there's still plenty to consider, as babies love to reach out and grab things. The three main areas of focus for parents with new babies should be:
Safety in the nursery
The Foundation for the Study of Infant Deaths (FSID), now known as The Lullaby Trust, recommends babies sleep in the same room as their parents for the first six months of life. This has been shown to significantly reduce the risk of cot death.
Set up your baby's cot as far from heat sources and windows as possible. If you can't avoid placing your baby's cot near a radiator, turn it right down or off so your baby can't get burnt or overheat. If your baby's cot has to be under a window, make sure you keep it locked or use a restrictor that stops it opening more than 10cm. Your baby may surprise you by climbing earlier than you expected.
Make sure there aren't dangling cords that your baby could choke on. Tie up light pulls and curtain or blind cords and, if you use a cot bumper, cut any tapes or ties as short as possible.
Remove mobile and hanging toys from the cot as soon as your baby can stand up, or make sure these are well out of reach.
Secure heavy furniture so that it can't topple forwards and crush your baby. Also, don't position the cot under shelves, as items might fall down into the cot.
Don't buy any second-hand or antique furniture that might be painted with lead-based paints as these are toxic and your baby could swallow peeling flakes. The most risky pieces are those from the early to mid-20th century.
If you have a cat, buy a cat net to fit over your baby's cot. Always keep animals out of your baby's room.
Safety in the bathroom
Wet babies are very slippery, so a baby bath seat is a great idea to keep him or her secure. It also lets you keep both hands free for washing your baby. Baby bath seats are usually made of towelling fabric over a metal frame and sit inside the bath with your baby safely reclining inside.
Cover the bath taps by tying a flannel around them. This will protect your baby from bumps and scalds.
Secure all bathroom cupboards with cupboard locks, even before your baby becomes mobile. Babies like to pull door handles and bathroom cupboards can contain all kinds of hazards.
Never leave your baby unattended in a bath, even in a baby bath seat. Babies can drown quickly in only a few centimetres of water.
Safety in the kitchen
Check your baby can't reach out and grab electrical cables and cords when they are in their highchair or bouncing seat, in case you turn your back for a second.
Don't position your baby near drawers, especially those containing sharp utensils. Always keep cupboards containing medicines or chemicals locked.
Keep the highchair or bouncing seat away from anything that could fall on to it, and well clear of any breakables, such as glasses.
Place the highchair or bouncing seat away from heat sources such as kettles, radiators, cooker fronts and the hob.
Home safety for older babies
Once your baby is rolling, crawling or bottom-shuffling, it won't be long before they're standing, presenting you with a whole new world of safety hazards.
Safety in the toilet
Now's the time to fit a toilet seat lock - an inquisitive, mobile baby who can stand up can also fall into a toilet, which is both full of germs and chemicals and a very hard surface to collide with.
Fit cupboard door locks in the bathroom to stop your toddler reaching cleaning products or toiletries.
Don't keep bleach or air freshener sprays down on the floor by the toilet.
Safety in the kitchen
Keep toddlers out of the kitchen by fitting a safety gate (conforming to safety standard BS EN 1930:2000).
If a safety gate into the kitchen is impractical, you'll need to make extra safety checks. As well as taking on board all the advice for a younger baby (see above), check for anything that's reachable from your baby's height.
Fit drawer locks to prevent exploring and stop them getting their fingers trapped. Anti-slam cushions will also stop your baby's fingers from being slammed in closing doors.
Fit a fridge and freezer lock.
When cooking, turn saucepan handles to the back of the stove.
Make sure all cords and cables are well out of reach.
Don't leave pet food dishes and bowls on the floor. Put them away as soon as your pet has finished eating and lock the cat flap whenever your baby is roaming.
Always secure your baby in a highchair when you're carrying hot food or dishes across the kitchen in case you trip.
Safety in the nursery
If you've bought a cot bed , have a detachable side rail ready for when your baby is ready for the bed (at about two or three years old).
Safety around the house
According to the NHS, falls account for around 44% of all children's injuries. Fit baby safety gates across your stairs. You'll need a fixed gate at the top of the stairs but pressure-fitted gates are fine for downstairs.
Fit baby safety gates across the doorways of any spaces you don't want your baby or toddler exploring. This could include the utility room, downstairs loo or conservatory. For more information, read our safety gates guide.
Make sure your baby can't fit through spaces between your banisters. If they can, board them up temporarily.
Fit electric plug covers to stop your child putting their little fingers inside them.
Keep all alcohol locked away and put childproof locks on cupboards with cleaning products, medicines and toiletries, breakables (such as glassware) and sharp implements.
Cut looped ties for window blinds or drapes to remove the risk of strangulation.
Place a fixed fire guard with a mesh top around open fires and keep matches and firelighters out of reach.
Secure rugs with a non-slip underlay.
Install corner protectors to all furniture with sharp edges.
Secure furniture that can topple over, such as bookcases, to the wall.
Clear all surfaces your baby could pull itself up to, such as coffee tables and counter tops, and cover a glass-topped coffee table with safety film.
Secure table lamp wires behind items of furniture or use a hide-a-cord device so they're not visible or accessible.
Keep hairdryers, hair straighteners and other electrical equipment well out of your baby's reach, along with cosmetics and toiletries.
Don't use floor-based electric or fan heaters when your child is in the room.
Get rid of toxic houseplants or place them up high out of reach. If the leaves shed, it's best to remove these plants from the house altogether.
If you use a tablecloth, fix it with clips to prevent it - and everything on it - from being pulled down.
Remember to keep all handbags, including visitors', out of reach as they can contain chemicals (such as perfume or hand wash) that could harm your baby. They may have small items in them like hairgrips and pen caps that could become lodged in a toddler's nose or mouth.
Lock all doors that lead outside, including balcony doors and French windows.
Baby safety tip
Crawl around on your hands and knees to get a baby's-eye view of your home and spot any potential hazards. Secure or remove anything that looks tempting to pull down and explore
Making the garden safe for your baby
Securely cover, or (better still) fill in ponds and other water features.
Empty paddling pools and upturn buckets when not in use.
Keep side gates locked.
Check regularly for any pet or other animal faeces. Clear faeces away and keep your baby from regularly soiled areas - fence or screen them off if possible.
Keep all tools locked away securely.
Always supervise your baby when they're exploring outside.
If your baby is sleeping outdoors, cover their crib, carrycot or pram with a cat net, which will also protect against flying insects.
Don't let your baby dig around in soil with their hands. They could swallow something toxic.


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The American Legion Riders National Advisory Committee [2], appointed by the national commander, is tasked with advising the Legion's Internal Affairs Commission on resolutions and other matters related to The American Legion Riders activities across the nation. The committee has also been tasked with providing information and assistance to the departments as needed.
Each member of the Advisory Committee has been assigned a region to assist Riders and department officers on questions arising from Riders within each department. To see the regional breakdown, click here [3].
To see the minutes from the last Advisory Committee meeting, click here [4].
[1] http://www.legion.org/print/222413
[2] http://www.legion.org/riders/contacts
[3] http://www.legion.org/documents/pdf/ALRRegional%20Assignments2014.pdf
[4] http://www.legion.org/documents/word/ALR Meeting2-6.doc


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Growing to Maturity
It was Jesus Himself who said that we must become like little children to enter the Kingdom of heaven. But we find in Paul's first letter to the Corinthians that we are to leave childish ways behind us. How …
‹ Previous 1 2 3 Next ›


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Animation, Corporate, Drone, Events, Hospitality, Real Estate, Testimonials, Trailers
We work with you to discover the things that distinguish your brand from the rest. From there, our team develops distinctive content tailored to fulfill your specific needs.
Bring us on board to write your script, shoot your video, animate your logo, or help you reach the audience you want to address.
Our production services range from script writing and on-location filming to post-production picture and sound editing.
We use search engine, social media, and mobile marketing campaigns to get eyes on your content and increase awareness of your brand.
Our aerial video platform allows us to capture incredible footage from far above the action.
We can use motion graphics to liven up your logo, explain your business model, instruct your employees, and more.
Just Peachy Pictures utilizes the latest in drone technology to deliver stunning, high-definition aerial video and stills.
View aerial reel below:
It's All About Passion
We love helping our clients, be they business professionals, creative types, or folks who work somewhere in between these worlds.


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Hi Current and Past PE Mommies,
Here's the update. All good news today. My AFI is up to 18:) Amazing! The baby is right on track for growth. They are estimating his weight at 3lbs 8oz. The perinatologist said that she is very happy with the way everything looks. We are still going day by day, but she said if he had to be born now, we'd be ok.
I cannot thank all of you enough for all your support over the last week. It was a very hard week. As I know, you all know, things are still very subject to change, but for today I'm just so thankful. So back to side lying and water drinking:)
Ann Marie
PE/low amniotic fluid
EDD: 4/7/04-boy-Luke Matthew
9 weeks bedrest
31 weeks tomorrow:)


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Weekend Weather Outlook: Nice Saturday, Icy SundayJanuary 25th, 2013 at 5:07 pm by Ken Brewer under Weather
THIS EVENING: Temperatures will stay fairly steady this evening. Clouds will linger for most of the evening. There could be some Lake Effect snow showers in extreme northern and northeastern parts of our area.
OVERNIGHT: Colder air will arrive late tonight and drop lows into the low to mid teens. The wind will push wind chill values close to zero.
SATURDAY: It will be the nicer day of the weekend by far. We will see a decent amount of sunshine early, then clouds will mix in by the afternoon and evening. Highs will reach the mid 20s.
SUNDAY: The leading edge of warmer air will overrun colder air at the ground. Add moisture, and we will see a wintry mix of mainly freezing rain and sleet develop by Sunday afternoon and Sunday night. Models indicate the possibility of .25″ of ice accumulation in places, so this will be an event to track carefully and we will do so throughout the weekend!
8-DAY FORECAST: After the weekend, it will really warm-up for the first part of the week. Highs will reach the upper 40s on Monday with scattered rain. More substantial rain and maybe even some rumbles of thunder are possible late Tuesday into early Wednesday. Colder air will arrive late Wednesday and we will see a brief shot of bitter cold air late next week.


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When trying to choose between a nutritionist and a dietitian, know that there are important differences in their qualifications, scope of expertise and legal status as practitioners.
Comparison chart
|A dietitian is a qualified health professional who helps promote good health through proper nutritional habits.
|A Nutritionist is someone who works with food and nutritional science, aiming to prevent diseases related to nutrient deficiencies. Nutritionists are ofter certified by professional organizations.
|Legal status
|In many states, legally considered an expert on nutrition. Registered with the Commission of Dietetic Registration (CDR). Licensed to practice diet and nutrition consultation.
|In many states, legally accepted as an expert. A Nutritionist may or may not be a qualified health professional.
|A registered dietitian in the US needs to have a bachelor's degree, complete an internship, take an exam and maintain ongoing education credits.
|Many Nutritionists have a Bachelor's, Master's, or a Doctorate in nutrition. Some may not have any formal education in this field.
edit Definitions
A Nutritionist is a health specialist who devotes professional activity to food and nutritional science, preventive nutrition, diseases related to nutrient deficiencies, and the use of nutrient manipulation to enhance the clinical response to human diseases. A Dietitian is an expert in food and nutrition. Dietitians help promote good health through proper eating. They also supervise the preparation and service of food, develop modified diets, participate in research, and educate individuals and groups on good nutritional habits .
edit Qualifications
In the US, a Registered Dietitian (RD) needs the following qualifications:
- a Bachelor's degree in nutrition or dietetics
- an internship for 6 to 12 months at a healthcare facility, foodservice company or nonprofit agency approved by the American Dietetic Association
- successful completion of a national exam conducted by the Commission on Dietetic Registration.
- Ongoing to retain their registration as a dietitian.
Nutritionists are not required to have any such qualifications. This means nutritionists have varying levels of education -- from someone with little or no education to an individual who has obtained a bachelor's, master's, or even a doctoral degree.
edit Legal status
A Dietitian holding a Bachelor's degree in dietetics or related areas is legally regarded as the expert in nutrition and dietary related matters. On the other hand, a Nutritionist may or may not have any educational qualification and is not a legally protected term in most parts of the world.
edit Video Explaining the Differences
In the following video, Ashley Sweeney, a registered dietitian, explains the differences between a registered dietitian and a nutritionist.
edit Types
The types of Nutritionists are: Nutrition Scientists and Public Health Nutritionists. The former are those individuals who use the scientific method to study nutrients, both as individual compounds and as they interact in food and nutrition while the latter are specialists who aid in diagnosing the nutritional problems of communities and in finding solutions to those problems.
The different types of Dietitians include:
Clinical Dietitians: They work in hospitals and other health care facilities to provide medical nutrition therapy to patients according to the disease processes, provide individual dietary consultations to patients and their family members and also conduct group education for other health workers, patients and the public.
Community dietitians: They work with wellness programs and international health organizations.
Foodservice dietitians: They are responsible for large-scale food planning and service.
Gerontological dietitians: They are specialists in nutrition and aging. They are Board certified in Gerontological Nutrition with the American Dietetic Association.
Research dietitians: They are mostly involved with dietary related research in the clinical aspect of nutrition in disease states, public aspect on primary, secondary and sometimes tertiary health prevention and foodservice aspect in issues involving the food prepared for patients.
Administrative Dietitians: They are managers or head of their departments and have a number of dietitians in the department.
Business dietitians: These serve as resource people for the media. Dietitians' expertise in nutrition is often taped for TV, radio, and newspapers -- either as an expert guest opinion, regular columnist or guest, or for resource, restaurant, or recipe development and critique.
Consultant dietitians: These work under private practice.


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Drug-delivery stents capable of providing release of two or more drugs such as everolimus and estradiol are provided. The stents can be used for treating a disease such as restenosis and vulnerable plaque.
1. A drug delivery stent, comprising:
a primer;
a reservoir layer comprising estradiol;
an intercoat;
a second reservoir layer comprising everolimus encapsulated in nano- and/or micro- particles and unencapsulated everolimus.
2. The drug delivery stent of
3. The drug delivery stent of
burst and/or pulsed and sustained release of everolimus; and
sustained release of estradiol.
4. The drug delivery stent of
5. The drug delivery stent of
6. A method of treating a disorder in a patient comprising implanting in the patient the stent of
7. The method of
the everolimus is released from an 18 mm stent at a rate of about 15 μg to about 40 μg per day for at least one day after implantation.
8. The method of
9. The method of
the everolimus is released from a 13 mm stent at a rate of about 10 μg to about 27 μg per day for at least one day after implantation.
10. The method of
the everolimus is released from an 8 mm stent at a rate of about 6 μg to about 17.2 μg per day for at least one day after implantation.
This is a divisional application of U.S. application Ser. No. 10/881,540, filed on Jun. 29, 2004now abandoned, the teaching of which is incorporated herein by reference in its entirety.
1. Field of the Invention
This invention relates to drug combinations, formulations, and methods of application for the treatment or prevention of vascular disorder such as restenosis and/or vulnerable plaque. More superficially, the invention relates to application of everolimus and estradiol such as by a stent.
2. Description of the Background
Plaques have been associated with stenosis and restenosis. While treatments of plaque-induced stenosis and restenosis have advanced significantly over the last few decades, the morbidity and mortality associated with vascular plaques have remained significant. Recent work suggests that plaques may generally fall into one of two different general types: standard stenotic plaques and vulnerable plaques. Stenotic plaque, which is sometimes referred to as thrombosis-resistant plaque, can generally be treated effectively by the known intravascular lumen opening techniques. Although the stenosis the plaques induce may require treatment, these atherosclerotic plaques themselves are often a benign and effectively treatable disease.
Unfortunately, as plaque matures, narrowing of a blood vessel by a proliferation of smooth muscle cells, matrix synthesis, and lipid accumulation may result in formation of a plaque which is quite different than a standard stenotic plaque. Such atherosclerotic plaque becomes thrombosis-prone, and can be highly dangerous. This thrombosis-prone or vulnerable plaque may be a frequent cause of an acute coronary syndrome.
Coronary heart disease is generally thought to be caused by the narrowing of coronary arteries by atherosclerosis, the buildup of fatty deposits in the lining of the arteries. The process that may lead to atherosclerosis begins with the accumulation of excess fats and cholesterol in the blood. These substances infiltrate the lining of arteries, gradually increasing in size to form deposits commonly referred to as plaque or atherosclerotic occlusions. Plaques narrow the arterial lumen and impede blood flow. Blood cells may collect around the plaque, eventually creating a blood clot that may block the artery completely.
The phenomenon of "vulnerable plaque" has created new challenges in recent years for the treatment of heart disease. Unlike occlusive plaques that impede blood flow, vulnerable plaque develops within the arterial walls, but it often does so without the characteristic substantial narrowing of the arterial lumen which produces symptoms. As such, conventional methods for detecting heart disease, such as an angiogram, may not detect vulnerable plaque growth into the arterial wall. After death, an autopsy can reveal the plaque congested in arterial wall that could not have been seen otherwise with currently available medical technology.
The intrinsic histological features that may characterize a vulnerable plaque include increased lipid content, increased macrophage, foam cell and T lymphocyte content, and reduced collagen and smooth muscle cell (SMC) content. This fibroatheroma type of vulnerable plaque is often referred to as "soft," having a large lipid pool of lipoproteins surrounded by a fibrous cap. The fibrous cap contains mostly collagen, whose reduced concentration combined with macrophage derived enzyme degradations can cause the fibrous cap of these lesions to rupture under unpredictable circumstances. When ruptured, the lipid core contents, thought to include tissue factor, contact the arterial bloodstream, causing a blood clot to form that can completely block the artery resulting in an acute coronary syndrome (ACS) event. This type of atherosclerosis is coined "vulnerable" because of the unpredictable tendency of the plaque to rupture. It is thought that hemodynamic and cardiac forces, which yield circumferential stress, shear stress, and flexion stress, may cause disruption of a fibroatheroma type of vulnerable plaque. These forces may rise as the result of simple movements, such as getting out of bed in the morning, in addition to in vivo forces related to blood flow and the beating of the heart. It is thought that plaque vulnerability in fibroatheroma types is determined primarily by factors which include: (1) size and consistency of the lipid core; (2) thickness of the fibrous cap covering the lipid core; and (3) inflammation and repair within the fibrous cap.
While the known procedures for treating plaque have gained wide acceptance and shown good efficacy for treatment of standard stenotic plaques, they may be ineffective (and possibly dangerous) when thrombotic conditions are superimposed on atherosclerotic plaques. Specifically, mechanical stresses caused by primary treatments like percutaneous transluminal coronary intervention (PTCI), such as stenting, may actually trigger release of fluids and/or solids from a vulnerable plaque into the blood stream, thereby potentially causing a coronary thrombotic occlusion. For example, rupture of the fibrous cap that overlies the thrombogenic necrotic core is presently believed to play an important role in acute ischemic events, such as stroke, transient ischemic attack, myocardial infarction, and unstable angina (Virmani R, et al. Arterioscler Thromb Vasc Biol. 20: 1262-1275 (2000)). There is evidence that fibrous cap can be ruptured during stent deployment. Human data from various sources have indicated that lipid rich and/or positively remodeled and/or echolucent lesions in sysmptomatic coronary atherosclerosis have higher likelihood for restenosis (See, for example, J. Am. Coll. Cardiol. 21(2):298-307 (1993); Am. J. Cardiol. 89(5):505 (2002); Circ. 94(12):3098-102 (1996)). Therefore, there is a need for stabilization of thin fibrous cap by building-up additional fibrous mass in a controlled manner without triggering occlusive restenosis.
The drug formulations and delivery methods of the present invention address issues of restenosis, vulnerable plaque and other disorders.
Described herein is a coating formulation for controlled release of two or more drugs for treating a medical condition. The coating is capable of a variety of combinations of release of the two or more drugs.
The release profiles of the drugs are tailored to meet various therapeutic needs. Therapeutic intervention of a drug may vary as a function of time because the mechanistic target of the drug may be a function of time. For example, anti-proliferative drugs may need to be released between 5 days to 30 days after implantation, and anti-inflammatory or antiplatelet drugs may need to be delivered acutely during the implantation procedure followed by a sustained release up to 2 months after implantation. Antimigratory drugs may need to be released within 1-4 weeks. The coating described herein, in one embodiment, is capable of providing a pulse or fast release of a first drug followed by a sustained release the first drug. The coating can further provide a fast release and/or followed by a sustained release of a second drug over a defined period.
A stent having a coating formulation defined herein can be used to treat or prevent a disorder such as atherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof.
In one embodiment a drug release profile or drug formulation is disclosed for the treatment of vascular disorder or related disorder. More specifically, the vascular disorder is restenosis and/or vulnerable plaque. The term "treatment" includes prevention, reduction, delay or elimination of the referred to disorder. In some embodiments, treatment also includes repairing damage caused by the disorder or the mechanical intervention, e.g., stenting. The mode of deliver of any one or the combination of the drugs can be local or systemic. Local administration can be by a stent (e.g., coated stent or biodegradable or bioabsorbable stent), a drug delivery particle or other known methods of local drug delivery. Systemic administration can be accomplished orally or parenterally, including intravascularly. For example, in one embodiment, a first drug can be delivered by a stent and the other by a catheter at the site of treatment. The delivery can be simultaneous or in sequence. In one embodiment, one of the drugs can be delivered before the other while there is some or a significant overlap between the deliveries of both. Preferably, the drug treatment is via a stent.
Therapeutic intervention of a drug may vary as a function of time because the mechanistic target of the drug may be a function of time. For example, anti-proliferative drugs may need to be released within a period of time between 3 days to 30 days after implantation, and anti-inflammatory or antiplatelet drugs may need to be delivered acutely during the implantation procedure followed by a sustained release up to 2 months after implantation. Antimigratory drugs may need to be released within 1-4 weeks.
For stent applications, the release profiles of the drugs can be tailored by using different types of coating material in mixed, bonded, or layered format; modifying the coating material; or positioning of the coating layers on the stents. Coating layers can include any combinations of a primer layer, a reservoir layer, a topcoat layer and a finishing coat layer. Any of the layers can include a biocompatible polymer as described below. For example, any of the layers, such as the barrier polymer can be a biocompatible polymer capable of controlled release of a drug by virtue of very low equilibrium water uptake. The term "very low equilibrium water uptake" can be defined as having a water permeability of less than about 1% by weight. Generally, a barrier formed of a hydrophobic biocompatible polymer would have a very low equilibrium water uptake. Polymers fall within this category include, for example, polystyrene, poly(butyl methacrylate) (PBMA), poly(D,L-lactic acid) (PDLLA), poly(L-lactic acid) (PLLA) or poly(D,L-lactic acid-co-glycolic acid) (PDLLAGA). In one embodiment, a layer, such as the barrier polymer, can be formed of a bioabsorable polymer such as polycaprolactone (PCL), poly(ester amides) (PEA), polyhydroxyalkanoate (PHA), or poly(3-hydroxybutyrate) (PHB), vinylidene fluoride based homopolymers such as polyvinylidene fluoride (PVDF) and copolymers such as poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF-co-HFP). Vinylidene fluoride based polymers are commercially available under the trade name Kynar™ and Solef™.
In one embodiment, the coating can have any one or combination of a pulse, burst or sustained release profile. For example, the coating can be made to have a pulse or burst release of a drug, followed by a sustained release of the same drug. The drug can be a bioactive agent as defined below. Preferably, the drug is an anti-proliferative 40-O-(2-hydroxy)ethyl-rapamycin (known by the trade name of everolimus, available from Novartis as Certican™), estradiol such as 17-beta-estradiol, other estrogen receptors, anti-proliferative drugs, immunosuppresant drugs, anti-inflammatory drugs, anti platelet drugs, antimigratory drugs, anti-thrombotic drugs, drugs that regress plaque such as high density lipoprotein (HDL)-mimetics, agents that promotes endothelial cell growth, prohealing drugs and combinations thereof.
As used herein, the term "pulse release" generally refers to a release profile of a drug that features a sudden surge of the release rate of the drug. The release rate surge of the drug would then disappear within a period. A more detailed definition of the term can be found in Encyclopedia of Controlled Drug Delivery, Edith Mathiowitz, Ed., Culinary and Hospitality Industry Publications Services.
In some embodiments, the term "fast release" refers to a release profile of a drug that features a release rate in the range between about 15 μg and about 40 μg per day (typically for one to three days) (or between about 45 μg and about 120 μg in three days) for a 18 mm stent, about 10 μg to about 27 μg per day (typically for one to three days) for a 13 mm stent, and about 6 (6.7) μg to about 17.2 μg per day (typically for one to three days) for a 8 mm stent. Equivalent profiles can be derived by one having ordinary skill in the art for stents having other sizes. The term "fast release" is used interchangeably with the term "burst release."
As used herein, the term "sustained release" generally refers to a release profile of a drug that can include zero-order release, exponential decay, step-function release or other release profiles that carry over a period of time, for example, ranging from several days to several weeks or years. The terms "zero-order release", "exponential decay" and "step-function release" as well as other sustained release profiles are well known in the art (see, for example, Encyclopedia of Controlled Drug Delivery, Edith Mathiowitz, Ed., Culinary and Hospitality Industry Publications Services). In some embodiments, sustained release refers to 2 to 15 μg per day for a selected number of days or weeks.
In another embodiment, the coating may include two or more drugs. One of the drugs or both drugs can have any one or combination of the pulsed, burst or sustained delivery profile. The coating can have a delivery profile that features a burst delivery of one or more drugs together with a sustained delivery of the one or more drugs. In one embodiment, the coating can be made to have a profile of a burst release of a first drug and sustained release of the first drug and a second drug. Alternatively, the coating can be made to have a burst release of a first and a second drug followed by a sustained release of the first and the second drug. The release rate of the drugs can be tailored by coating concentration of a drug and the equilibrium water uptake of the barrier if the barrier is formed of a hydrophobic, nonabsorable polymer or the absorption rate if the barrier is formed of an absorbable polymer.
For example, the coating can have a burst release in the first three days after implantation of an immunosuppresant, followed by a sustained release of the immunosuppresant thereafter or a sustained release of an anti-inflammatory drug or an antiplatelet drug over a period of two months.
In another embodiment of the present invention, a coating can be made to provide a release profile that includes a pulse release of one or more drugs and optionally a sustained release of the same or different drugs. The art of formulation to provide a pulsed release profile is well developed (see, for example, Encyclopedia of Controlled Drug Delivery, Edith Mathiowitz, Ed., Culinary and Hospitality Industry Publications Services). In one example, the upper most stent coating or surface thereof can be concentrated with the drug. In another example, a drug can be encapsulated within microcapsules. The degradation of the microcapsule wall can generate a pulsed release of the drug.
In one embodiment, a coating providing a pulse release profile can be made from nano or microparticulate drug loaded particles (DrugP) formed of a drug encapsulated within a degradable polymer. The drugP can be nanoparticles or microparticles of the drugP having a size ranging for example, from about 0.5 nm to about 1000 nm, or from about 1 μm to about 100 μm. Representative drug particles can have a size of about 0.5 nm, about 2 nm, about 5 nm, about 10 nm, about 20 nm, about 50 nm, about 75 nm, about 100 nm, about 200 nm, about 500 nm, about 750 nm, about 1000 nm, about 2 μm, about 5 μm, about 10 μm, about 20 μm, about 50 μm, about 75 μm, or about 100 μm.
The drugs forming the drugP can be any one or more bioactive agents described below. Representative drugs can be anti-proliferative everolimus, estradiol (e.g., 17-beta-estradiol), other estrogen receptors, anti-proliferative drugs, immunosuppresant drugs, anti-inflammatory drugs, anti platelet drugs, antimigratory drugs, anti-thrombotic drugs, agents that promotes endothelial cell growth, drugs that regress plaque such as high density lipoprotein (HDL)-mimetics, prohealing drugs and combinations thereof. The encapsulating polymer can be any degradable biocompatible polymer having a range of hydrolysis rate. Representative polymers include, but are not limited to, poly(glycolic acid) (PGA), poly(D,L-lactic acid) (DLPLA), polyhydroxyalkanoates (PHA), poly(ester amides) (PEA), and polyether esters such as poly(butylene terephthalate)/poly(ethylene glycol) (PBT/PEG). The drugP can be formed by emulsion methods known in the art (see, for example, Hans Mollet, Formulation Technology: Emulsions, Suspensions, Solid Forms, Wiley-VCH, 2001). The drugP can be suspended in a solution of a polymer and optionally the drug forming the drugP particles and then sprayed on the stent. Hydrolysis of the encapsulating polymer will allow the drug to be released from the drugP. The drugP having a size ranging from about 0.5 nm to 2 nm or from about 1 μm to 4 μm would favor surface degradation over bulk degradation. A population distribution of drugP can result in the drug release in the coating matrix at times that appear as a pulsed dosing from the coating matrix impressed on a background release of the same drug or a different drug if a drug is optionally included in the coating solution in which the drugP is suspended. The background release can be the same drug, a different drug or no drug at all. The background release of drug can be tailored to have a different profile as well. In one embodiment, the background release is sustained release.
In a further aspect of the present invention, the coating can be made to simultaneously release an agent that reduces smooth muscle cell migration and/or proliferation and an agent that promotes endothelial cell growth. Simultaneous delivery means that there is at least some overlap in the release of the drug. Under this embodiment, at least one of the drugs can be released first such as by pulsed, burst, or sustained delivery so long as there is an overlap in delivery with the second drug. Smooth muscle cell proliferation has been identified as a cause of restenosis, and endothelial cell growth contributes to vessel healing (see, for example, Chandrasekar, et al., J. Am. Coll. Cardiol. 38: 1570-6 (2001)). A combination of an anti-proliferative agent and an agent that promotes endothelial cell growth allows one to treat restenosis through different channels and may have a synergistic effect on ameliorating restenosis.
Coatings capable of simultaneously releasing an anti-proliferative agent and an agent that promotes endothelial cell growth can have a variety of configurations. For example, the coating can have a layer that comprises a mixture of the two agents or have two layers, each of which comprises a polymer and either the anti-proliferative agent or the agent that promotes endothelial cell growth.
In one embodiment, a composition containing a drug such as drugP particles described above can be formed from a polymer and one of the anti-proliferative agent and the agent that promotes endothelial cell growth. The composition such as the drugP particles can be suspended in a solution of the polymer and the other agent of the anti-proliferative agent or the agent that promotes endothelial cell growth and then coated on to a stent. The resultant coating would provide a pulsed release of one agent and a background release of the other agent.
The ani-proliferative agent useful for forming the various formulations described herein includes any anti-proliferative agents that reduce smooth muscle cell migration and/or proliferation. In one embodiment, the ani-proliferative agent is rapamycin, rapamycin derivatives, paclitaxel, docetaxel, 40-O-(3-hydroxy) propyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole -rapamycin, ABT-578, everolimus and combinations thereof.
The agent that promotes endothelial cell growth useful for forming the various formulations described herein can be any agent that provides beneficial effect on endothelial cell growth. Exemplary agents promoting endothelial cell growth include, for example, vascular endothelial growth factor (VEGF), estradiol such as 17-beta-estradiol, agents that do not inhibit endothelial cell growth, and combinations thereof. Preferably, the endothelial cell growth promoting agent is estradiol, more preferably 17-beta-estradiol.
In one embodiment, the ani-proliferative agent is everolimus and the endothelial cell growth promoting agent is 17-beta-estradiol, and the simultaneous release of everolimus and 17-beta-estradiol can be achieved by three-layer coating on a stent. The first layer can be only a primer layer, the second layer can include a blend of everolimus and a polymer such as an EVAL polymer, and the third layer can have a blend of 17-beta-estradiol and a polymer such as an EVAL polymer.
In a further embodiment, a coating can be formed to include (1) a first drug that can be one of rapamycin, rapamycine derivatives, paclitaxel, docetaxel, 40-O-(3-hydroxy)propyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole -rapamycin, ABT-578, everolimus and combinations thereof, (2) a second drug that can be one of vascular endothelial growth factor (VEGF), estradiol such as 17-beta-estradiol, agents that do not inhibit endothelial cell growth, and combinations thereof. The first and second drugs can have any of the aforementioned release profiles such as the first drug can have a pulse, burst and/or sustained release profile, and the second drug can have a pulse, burst and/or sustained release profile. The first drug can have a burst release followed by sustained release while the second drug has a sustained release. Alternatively, the second drug can have a burst release followed by sustained release while the first drug has a sustained release. Preferably, the first drug is everolimus and the second drug is 17-beta-estradiol.
The coating can have different constructs. For example, the coating can have a first layer that comprises a first drug and a first polymer, and a second layer that comprises a second drug and a second polymer. The first polymer and the second polymer can be same or different. In addition, the first layer and the second layer can have a drug/polymer ratio between 1/99 and 99/1, e.g., a ratio between 10/90 and 90/10.
The coatings described above can be designed to have a topcoat or a finish coat that is capable of promoting accelerated-healing. This topcoat or finish coat can be made non-inflammatory and/or non-fouling. Non-inflammatory is defined as preventing inflammation or reducing inflammation to an acceptable degree. Non-fouling or anti-fouling is defined as preventing, delaying or reducing the amount of formation of protein build-up caused by the body's reaction to foreign material. The topcoat or finish coat can be combined with a tailored release of a drug or drugs at the finalcoat and/or the drug reservoir layers to further modulate the plaque stabilization and controlled healing. The accelerated-healing topcoat can be formed of one of polyester amide, Silk-elastin, elastin-epitoped supramolecular assembly of peptide amiphile or combinations thereof. The accelerated-healing topcoat can be made non-inflammatory, non-fouling by including a non-inflammatory, non-fouling material such as PolyActive™, PEG, hyaluronic acid and its derivatives, and heparin and its derivatives that can be a fragment heparin such as pentasaccharide, a derivative heparin or a complexed heparin. Heparin derivatives can be any functional or structural variation of heparin. Representative variations include alkali metal or alkaline—earth metal salts of heparin, such as sodium heparin (e.g., hepsal or pularin), potassium heparin (e.g., clarin), lithium heparin, calcium heparin (e.g., calciparine), magnesium heparin (e.g., cutheparine), low molecular weight heparin (e.g., ardeparin sodium) with a molecular weight of from about 4,000 to about 5,000 Daltons and high affinity heparin (see, e.g., Scully, et al., Biochem. J. 262:651-658 (1989)). Other examples include heparin sulfate, heparinoids, heparin based compounds and heparin having a hydrophobic counter-ion such as tridodecylmethylammonium and benzalkonium.
The coatings described herein can optionally have one or more bioactive agents, which may be the same or different from the drugs described in the above. Examples of such agents include synthetic inorganic and organic compounds, proteins and peptides, polysaccharides and other sugars, lipids, and DNA and RNA nucleic acid sequences having therapeutic, prophylactic or diagnostic activities. Nucleic acid sequences include genes, antisense molecules which bind to complementary DNA to inhibit transcription, and ribozymes. Other examples of drugs include antibodies, receptor ligands, and enzymes, adhesion peptides, oligosaccharides, blood clotting factors, inhibitors or clot dissolving agents such as streptokinase and tissue plasminogen activator, antigens for immunization, hormones and growth factors, oligonucleotides such as antisense oligonucleotides and ribozymes and retroviral vectors for use in gene therapy. Such agents can also include a prohealing drug that imparts a benign neointimal response characterized by controlled proliferation of smooth muscle cells and controlled deposition of extracellular matrix with complete luminal coverage by phenotypically functional (similar to uninjured, healthy intima) and morphologically normal (similar to uninjured, healthy intima) endothelial cells. Such agents can also fall under the genus of antineoplastic, cytostatic, anti-inflammatory, antiplatelet, anticoagulant, antifibrin, antithrombin, antimitotic, antibiotic, antiallergic and antioxidant substances. Examples of such antineoplastics and/or antimitotics include paclitaxel (e.g. TAXOL� by Bristol-Myers Squibb Co., Stamford, Conn.), docetaxel (e.g. Taxotere�, from Aventis S. A., Frankfurt, Germany) methotrexate, azathioprine, vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride (e.g. Adriamycin� from Pharmacia & Upjohn, Peapack N.J.), and mitomycin (e.g. Mutamycin� from Bristol-Myers Squibb Co., Stamford, Conn.). Examples of such antiplatelets, anticoagulants, antifibrin, and antithrombins include heparinoids, hirudin, recombinant hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclin analogues, dextran, D-phe-pro-arg-chloromethylketone (synthetic antithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membrane receptor antagonist, antibody, and thrombin inhibitors such as Angiomax � (Biogen, Inc., Cambridge, Mass.). Examples of cytostatic agents include angiopeptin, angiotensin converting enzyme inhibitors such as captopril (e.g. Capoten� and Capozide� from Bristol-Myers Squibb Co., Stamford, Conn.), cilazapril or lisinopril (e.g. Prinivil� and Prinzide� from Merck & Co., Inc., Whitehouse Station, N.J.), actinomycin D, or derivatives and analogs thereof (manufactured by Sigma-Aldrich 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233; or COSMEGEN available from Merck). Synonyms of actinomycin D include dactinomycin, actinomycin IV, actinomycin I1, actinomycin X1, and actinomycin C1. Other drugs include calcium channel blockers (such as nifedipine), colchicine, fibroblast growth factor (FGF) antagonists, fish oil (omega 3-fatty acid), histamine antagonists, lovastatin (an inhibitor of HMG-CoA reductase, a cholesterol lowering drug, brand name Mevacor� from Merck & Co., Inc., Whitehouse Station, N.J.), monoclonal antibodies (such as those specific for Platelet-Derived Growth Factor (PDGF) receptors), nitroprusside, phosphodiesterase inhibitors, prostaglandin inhibitors, suramin, serotonin blockers, steroids, thioprotease inhibitors, triazolopyrimidine (a PDGF antagonist), and nitric oxide. An example of an antiallergic agent is permirolast potassium.
Other therapeutic substances or agents which may be appropriate include alpha-interferon, genetically engineered epithelial cells, antibodies such as CD-34 antibody, abciximab (REOPRO), and progenitor cell capturing antibody, prohealing drugs that promotes controlled proliferation of muscle cells with a normal and physiologically benign composition and synthesis products, enzymes, anti-inflammatory agents, antivirals, anticancer drugs, anticoagulant agents, free radical scavengers, steroidal anti-inflammatory agents, non-steroidal anti-inflammatory agents, antibiotics, nitric oxide donors, super oxide dismutases, super oxide dismutases mimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl(4-amino-TEMPO), dexamethasone, clobetasol, aspirin, pro-drugs thereof, co-drugs thereof, and a combination thereof. The foregoing substances are listed by way of example and are not meant to be limiting. Other active agents which are currently available or that may be developed in the future are equally applicable.
The stent coating formulation provided herein can include any biocompatible polymer. Representative examples of polymers that can be used to coat an implantable device in accordance with the present invention include, but are not limited to, poly(ester amide), polyhydroxyalkanoates (PHA) such as poly(3-hydroxyalkanoates), e.g., poly(3-hydroxypropanoate), poly(3-hydroxybutyrate), poly(3-hydroxyvalerate), poly(3-hydroxyhexanoate), poly(3-hydroxyheptanoate) or poly(3-hydroxyoctanoate), poly(4-hydroxyalknaote), e.g., poly(4-hydroxybutyrate), poly(4-hydroxyvalerate), poly(4-hydroxyhexanote), poly(4-hydroxyheptanoate), poly(4-hydroxyoctanoate) and copolymers including any of the 3-hydroxyalkanoate or 4-hydroxyalkanoate monomers described herein or blends thereof, polyesters, poly(D,L-lactide), poly(L-lactide), polyglycolide, poly(D,L-lactide-co-glycolide), poly(L-lactide-co-glycolide), polycaprolactone, poly(lactide-co-caprolactone), poly(glycolide-co-caprolactone), poly(dioxanone), poly(ortho esters), poly(anhydrides), poly(tyrosine carbonates) and derivatives thereof, poly(tyrosine ester) and derivatives thereof, poly(imino carbonates), poly(glycolic acid-co-trimethylene carbonate), polyphosphoester, polyphosphoester urethane, poly(amino acids), polycyanoacrylates, poly(trimethylene carbonate), poly(iminocarbonate), polyurethanes, polyphosphazenes, silicones, polyesters, polyolefins, polyisobutylene and ethylene-alphaolefin copolymers, acrylic polymers and copolymers, vinyl halide polymers and copolymers, such as polyvinyl chloride, polyvinyl ethers, such as polyvinyl methyl ether, polyvinylidene halides, such as vinylidene fluoride based homopolymer (PVDF) and copolymers such as poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP) known as Solef™ or Kynar™ polymers and polyvinylidene chloride, polyfluoroalkenes such as tetrafluoroethylene (Teflon™), polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics, such as polystyrene, polyvinyl esters, such as polyvinyl acetate, copolymers of vinyl monomers with each other and olefins, such as ethylene-methyl methacrylate copolymers, acrylonitrile-styrene copolymers, ABS resins, and ethylene-vinyl acetate copolymers, polyamides, such as Nylon 66 and polycaprolactam, alkyd resins, polycarbonates, polyoxymethylenes, polyimides, polyethers, poly(glyceryl sebacate), poly(propylene fumarate), epoxy resins, polyurethanes, rayon, rayon-triacetate, cellulose acetate, cellulose butyrate, cellulose acetate butyrate, cellophane, cellulose nitrate, cellulose propionate, cellulose ethers, carboxymethyl cellulose, polyethers such as poly(ethylene glycol) (PEG), copoly(ether esters) (e.g. PEO/PLA); polyalkylene oxides such as poly(ethylene oxide), poly(propylene oxide), polyalkylene oxalates, polyphosphazenes, phosphoryl choline, choline, poly(aspirin), polymers and co-polymers of hydroxyl bearing monomers such as 2-hydroxyethyl methacrylate (HEMA), hydroxypropyl methacrylate (HPMA), hydroxypropylmethacrylamide, PEG acrylate (PEGA), PEG methacrylate, 2-methacryloyloxyethylphosphorylcholine (MPC) and n-vinyl pyrrolidone (VP), carboxylic acid bearing monomers such as methacrylic acid (MA), acrylic acid (AA), alkoxymethacrylate, alkoxyacrylate, and 3-trimethylsilylpropyl methacrylate (TMSPMA), poly(styrene-isoprene-styrene)-PEG (SIS-PEG), polystyrene-PEG, polyisobutylene-PEG, polycaprolactone-PEG (PCL-PEG), PLA-PEG, poly(methyl methacrylate)-PEG (PMMA-PEG), polydimethylsiloxane-co-PEG (PDMS-PEG), poly(vinylidene fluoride)-PEG (PVDF-PEG), PLURONIC™ surfactants (polypropylene oxide-co-polyethylene glycol), poly(tetramethylene glycol), hydroxy functional poly(vinyl pyrrolidone), biomolecules such as collagen, chitosan, alginate, fibrin, fibrinogen, starch, collagen, dextran, dextrin, fragments and derivatives of hyaluronic acid, heparin, fragments and derivatives of heparin, glycosamino glycan (GAG), GAG derivatives, polysaccharide, elastin, alginate, and combinations thereof.
As used herein, the terms poly(D,L-lactide) (PDLL), poly(L-lactide) (PLL), poly(D,L-lactide-co-glycolide) (PDLLG), and poly(L-lactide-co-glycolide) (PLLG) are used interchangeably with the terms poly(D,L-lactic acid) (PDLLA), poly(L-lactic acid) (PLLA), poly(D,L-lactic acid-co-glycolic acid) (PDLLAGA), and poly(L-lactic acid-co-glycolic acid) (PLLAGA), respectively.
Although embodiments of local drug delivery has been described in reference to a stent (balloon or self expandable), other medical substrates that can be implanted in a human or veterinary patient are also applicable with the embodiments of the invention. Examples of such implantable devices include stent-grafts, grafts (e.g., aortic grafts), artificial heart valves, cerebrospinal fluid shunts, pacemaker electrodes, and endocardial leads (e.g., FINELINE and ENDOTAK, available from Guidant Corporation, Santa Clara, Calif.). The underlying structure of the device can be of virtually any design. The device can be made of a metallic material or an alloy such as, but not limited to, cobalt chromium alloy (ELGILOY), stainless steel (316L), high nitrogen stainless steel, e.g., BIODUR 108, cobalt chrome alloy L-605, "MP35N," "MP20N," ELASTINITE (Nitinol), tantalum, nickel-titanium alloy, platinum-iridium alloy, gold, magnesium, or combinations thereof. "MP35N" and "MP20N" are trade names for alloys of cobalt, nickel, chromium and molybdenum available from Standard Press Steel Co., Jenkintown, Pa. "MP35N" consists of 35% cobalt, 35% nickel, 20% chromium, and 10% molybdenum. "MP20N" consists of 50% cobalt, 20% nickel, 20% chromium, and 10% molybdenum. Devices made from bioabsorbable or biostable polymers could also be used with the embodiments of the present invention.
In accordance with embodiments of the invention, a coating of the various described embodiments can be formed on an implantable device or prosthesis, e.g., a stent. For coatings including one or more active agents, the agent will retain on the medical device such as a stent during delivery and expansion of the device, and released at a desired rate and for a predetermined duration of time at the site of implantation. Preferably, the medical device is a stent. A stent having the above-described coating is useful for a variety of medical procedures, including, by way of example, treatment of obstructions caused by tumors in bile ducts, esophagus, trachea/bronchi and other biological passageways. A stent having the above-described coating is particularly useful for treating atherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof. Stents may be placed in a wide array of blood vessels, both arteries and veins. Representative examples of sites include the iliac, renal, and coronary arteries.
For implantation of a stent, an angiogram is first performed to determine the appropriate positioning for stent therapy. An angiogram is typically accomplished by injecting a radiopaque contrasting agent through a catheter inserted into an artery or vein as an x-ray is taken. A guidewire is then advanced through the lesion or proposed site of treatment. Over the guidewire is passed a delivery catheter which allows a stent in its collapsed configuration to be inserted into the passageway. The delivery catheter is inserted either percutaneously or by surgery into the femoral artery, brachial artery, femoral vein, or brachial vein, and advanced into the appropriate blood vessel by steering the catheter through the vascular system under fluoroscopic guidance. A stent having the above-described coating may then be expanded at the desired area of treatment. A post-insertion angiogram may also be utilized to confirm appropriate positioning.
The embodiments of the present invention will be illustrated by the following set forth examples. All parameters and data are not to be construed to unduly limit the scope of the embodiments of the invention.
Penta™ stents (available from Guidant) can be coated according to the configurations defined in Table 1 to provide a fast release or a slow release of estradiol.
Penta™ stents can be coated according to the configurations defined in Table 2 to provide a fast release or a slow release of everolimus.
The following preclinical data are representative results from the drug-eluting stent (DES) implants of everolimus and 17-beta-estradiol in a hypercholesterolemic rabbit model of human thin-cap fibroatheroma (TCFA). The MULTI-LINK Penta™ 13 mm was the platform for all DES and metallic stents. Both a slow release and fast release formulation of each drug were tested and the results were evaluated at 28 days. In both
As shown in
Onto Vision 12 mm small stents (available from Guidant) can be coated according to the following configurations. An auto coater can be used to coat the abluminal surface of the stent.
Configuration A
Drug coating: coating with 200 μg of poly(D,L-lactic acid) (PDLLA)/estradiol, from 4.8% poly(D,L-lactic acid) (PDLLA), 4.8% estradiol, and 90.4% acetone, by 3 passes, drying at 35� C. for 8 hours, and then coating with 200 μg of DL-PLA/everolimus, from 4.8% DL-PLA, 4.8% everolimus, and 90.4% acetone, coating by 3 passes, drying at 35 � C. for 8 hours.
Configuration B
Primer: coating with 80 μg PDLLA, using one pass coating, from 9.6% DL-PLA in acetone solution, baking at 120� C. for 1 hr; and
Drug coating: coating with 200 μg of PDLLA/estradiol, from 4.8% PDLLA, 4.8% estradiol, and 90.4% acetone, by 3 passes, drying at 35 � C. for 8 hours, and then coating with 200 μg of PDLLA/everolimus, from 4.8% PDLLA, 4.8% everolimus, and 90.4% acetone, by 3 passes, drying at 35� C. for 8 hours.
Configuration C
Primer: coating with 80 μg PDLLA, using one pass coating, from 9.6% PDLLA in acetone solution, baking at 120� C. for 1 hr;
Drug: coating with 200 μg of estradiol, from 5% estradiol solution in acetone, using 3 pass coating;
Inter coat: coating with 80 μg PDLLA, using one pass coating, from 9.6% PDLLA in acetone solution, baking at 35� C. for 1 hr; and
Drug coat: coating with 200 μg of PDLLA/everolimus, from 4.8% PDLLA, 4.8% everolimus, and 90.4% acetone, by 3 passes, drying at 35 � C. for 8 hours.
Configuration D
Primer: coated with 80 μg PDLLA, using one pass coating, from 9.6% PDLLA in acetone solution, baking at 120� C. for 1 hr;
PDLLA /drug: coating with 300 μg of PDLLA /estradiol, from 4.8% PDLLA, 4.8% estradiol, and 90.4% acetone, by 4 passes, drying at 35� C. for 8 hours;
Pure everolimus: coating with 100 μg everolimus, from 10% drug solution in MEK (methylethylketone), by 2 passes, baking at 50� C. for 1 hr; and
Top coat: coating with 100 μg Polyactive™, using one pass coating, from a 5% solution of 5% Polyactive™, 76% chloroform, and 19% 1,1,2-trichloroethane.
Configuration E
Primer: coating with 80 μg PDLLA, using one pass coating, from 9.6% PDLLA in acetone solution, and baking at 120� C. for 1 hr;
Poly(ester amide) (PEA)/estradiol: coating with 200 μg of PEA/estradiol, from 5% PEA, 5% estradiol, 72% chloroform, and 18% 1,1,2-trichloroethane, by 3 passes, drying at 35� C. for 8 hours;
PEA/everolimus: coating with 200 μg of PEA/everolimus, from a solution that includes 5% PEA, 5% everolimus, 72% chloroform, and 18% 1,1,2-trichloroethane, by 3 passes, and drying at 35� C. for 8 hours; and
Top coat: coating with 100 μg Polyactive™, using one pass coating, from a 5% solution of 5% PolyactiveTM in 76% chloroform, and 19% 1,1,2-trichloroethane.
While particular embodiments of the present invention have been shown and described, it will be obvious to those skilled in the art that changes and modifications can be made without departing from this invention in its broader aspects. Therefore, the appended claims are to encompass within their scope all such changes and modifications as fall within the true spirit and scope of this invention.
Patent Citations
Non-Patent Citations
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July 29, 2015
A panel appointed by Gov. Arnold Schwarzenegger says California must build new dams and change how it channels water through the Sacramento-San Joaquin Delta.
The seven-member Delta Vision task force on Friday stopped short
of saying where dams should be built or whether water should be
piped around or through the delta to cities, farmers and wildlife.
The report comes after 10 months of deliberations. It says the state should study the various routes that could funnel water to Southern California and the San Francisco Bay Area.
Changing how California moves water is one of 12 strategies the panel is recommending to restore the ailing delta and secure the state's water supplies.
(Copyright 2007 by The Associated Press. All Rights Reserved.)
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