Mayo Clinic recognizes that innovation has no inherent barriers, but rather, is an endless endeavor. That premise was one of the hallmarks behind the creation of Mayo Clinic Ventures, which is the doorway to Mayo Clinic's intellectual assets. Today, Mayo Clinic Ventures is a mission-driven, global leader in research and technology commercialization, known for its rigorous approach to bringing inventions to the market. It is not a traditional tech transfer office — distinct in that it not only licenses Mayo Clinic's intellectual property but also forms product development collaborations, actively mines Mayo Clinic for ideas, teaches entrepreneurism, starts companies, runs a business accelerator and participates in a $100 million venture and growth fund that supports economic development.
From the beginning, we recognized that industry saw value in working with Mayo Clinic experts for mutually beneficial opportunities. To date, the group has received more than 5,900 disclosures, filed 5,500 patents and signed 2,600 licensing agreements. An unprecedented 47% of disclosures are commercialized.
You can make medical history with us. The seeds of innovation that will evolve and advance medicine over the next several decades may already be present at Mayo Clinic today, and available for licensing.
To work with Mayo Clinic Ventures is to work with some of the most esteemed medical scientists in the world. The finest minds, focused on a responsibility to make medicine better, collaborate across specialties to solve complex research questions. Such a close integration makes it possible to quickly bring proven diagnostics and therapeutics to patients. Through industry collaborations, Mayo Clinic's innovative technologies are spread worldwide.
Mayo Clinic research personnel are conducting some 8,000 IRB-approved human studies at any given time. Our scientists publish more than 5,500 research and review articles in peer-reviewed journals each year. An annual research budget of $365 million includes Mayo's own investments in research, philanthropic support, royalties from technology commercialization and external funding.
These robust research efforts — and the resulting discoveries — come about as a result of Mayo's integrated medical group practice. Because Mayo Clinic is so large, we have not only specialties and subspecialties, but also sub-subspecialties. We combine this expertise in patient care with medical research. Along with full-time scientists, these leaders in medicine identify research questions — and answers that may not be unraveled anywhere else.
Mayo Clinic starts with the need first and works its way backward. So the probability of coming up with something that is translatable to the real world is higher simply because Mayo Clinic uses research and education as the scientific underpinning for improvements in patient care. "We have a disciplined, systematic approach for taking discoveries and translating them into clinical practice, whether it's a new device, drug treatment, therapy, health informatics or even health information," says Clark.
All this means a greater likelihood that Mayo Clinic discoveries will address actual patient needs, which will enhance a discovery's commercial appeal.
For example, Mayo will create a new device or technology that makes it easier to do a specific surgery. If that benefits our patients, there is likely a market for it. There is a discipline at Mayo Clinic for moving a discovery not just into practice, but also into the marketplace. Because we have an expectation that discoveries and research will be relevant to patient care, we bring forward significant opportunities for commercialization.
Mayo Clinic strives to get the discoveries into the marketplace so they can benefit patients all over the world. It's not science for science's sake — it is science for the patients' sake.


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Homepage NewsJCR Eurasia Rating affirms BKT as ''AAA (Alb)''
JCR Eurasia Rating, has evaluated the consolidated structure of "Banka Kombetare Tregtare Sh.A." affirmed the ratings as "AAA (alb)" on the Long-Term National Issuer Credit Rating and the Short-Term National Issuer Credit Rating at 'J1+ (alb)' with 'Stable' outlooks. On the other hand, the Long Term International Foreign and Local Currency Issuer Credit Ratings have been affirmed as 'BB' positioned in line with the country ceiling of the primary country of operations, Albania with 'Stable' outlooks.
Banka Kombetare Tregtare Sh.A. (referred to as "the Bank" or "BKT") is a consolidated entity comprising banking operating in Albania, Kosovo and Albania Leasing. The history of the Bank dates back to 1993 in its current name, when it was founded after the merger of the Albanian Commercial Bank and the National Bank of Albania. The Bank is owned by Çalık Holding A.Ş., a leading Turkey based conglomerate which acquired BKT in 2009.
As the oldest and largest commercial bank in Albania, the Bank offers a wide range of products and services to the public & private sectors as well as retail banking services for individuals.
The Bank maintains its leading position in the highly concentrated Albanian banking sector, consistently ranked first with respect to assets and net income. Due to its considerable asset size and scale of its operations, BKT is a systemically important bank in Albania. The Bank is well-capitalized maintains sound profitability indicators.
As of December 31, 2021, BKT operates principally in the Republic of Albania through 61 branches and 2 custom agencies, in addition to 22 branches in Kosovo, organized under subsidiary BKT Kosovo Sh.A. The Bank had a workforce of app. 1,333.
JCR Eurasia Rating affirms BKT as ''AAA (Alb)''
JCR Eurasia Rating, has evaluated the consolidated structure of "Banka Kombetare Tregtare Sh.A." affirmed the ratings as "AAA (alb)"
Safety Advices
We would like to bring to your attention a few safety advices for you to have a safe navigation on the internet:
National Commercial Bank reports increased net profit for the first quarter of year 2022
BKT reports that the net profit for June 2022 for BKT Albania only, increased to 53 million USD compared to June 2021 net profit of 39 million USD.

redpajama_set_name: RedPajamaCommonCrawl


Keeping your dog's nails trimmed to the correct length will keep your pet more comfortable and is essential to his health and well-being.
Nail guard minimizes over cutting. Keeping your dog's nails trimmed to the correct length will keep your pet more comfortable and is essential to his health and well-being. It is recommended that you trim your dog's nails every 4-6 weeks. The nail clipper features a nail guard that minimizes over cutting. Available in sizes to suit all dog breeds.


NMA is a member of the NSW Settlement Partnership (NSP), funded by the Department of Social Services through Settlement Services International (SSI).
Develop and deliver capacity building programs, and group activities to address the needs of the community.
Assist local services to develop and implement policies and practices to encourage the access of CALD communities and individuals.


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Plant Conservation Programs
Native Plant Restoration Nursery
Desert Discovery Garden
Mojave Desert Seed Bank
Living Collection
Friends of the Mojave Desert Seed Bank
Latino Conservation Week
Desert Indoors
Desert Discovery Field Studies
Reading the Landscape
MDLT blog
Meet Friends of MDLT
MDLT strives to help everyone who lives, works, and plays in the California desert to embrace the significance of this magical landscape. Outreach & Public Engagement Activities Include: guided hikes, outdoor education, outreach at local fairs and festivals, lectures and workshops, signature programs & special events, and Reading the Landscape for artists creating consciously in the desert.
Check out our YouTube channel for informational videos!
Citizen science is the collection and analysis of data relating to the natural world by members of the general public, typically as part of a collaborative project with professional scientists.
Desert Defenders
The Mojave Desert Land Trust launched its Desert Defenders campaign in response to a 2017 executive order instructing the Department of the Interior to review national monuments designated by the Antiquities Act. When our desert is under attack, we fight back.
These after-school experiential learning labs focus on important environmental themes while providing a chance for students to safely explore and learn as citizen scientists. This immersive program helps students become inspired advocates for the desert they call home.
In compliance with the Governor's Shelter-in-place order, Mojave Desert Land Trust is closed to the public. We are dedicated to helping students and parents negate the impacts of the "Stay-at-Home Order" on student education. As such, we have created a list of resources and compiled ideas that students...
Desert Seek & Find
Calling all families! From April 20th through April 24th, MDLT will be hosting a Seek & Find to help you learn more about the earth and our Mojave desert.
Artists have long played a role in telling the story of the Mojave -- but in telling one story, we must ensure we are not ending another.
Trump administration proposes 11th-hour plan to strip California desert protections
The Guardian The outgoing Trump administration is proposing to strip away protections for millions of acres of California desert, threatening damage to Joshua trees, desert tortoises and landmarks. "It's a bit baffling at the 11th hour that something like this would hit the street," said Geary Hund, the executive director for the Mojave Desert Land Trust, a…
Mojave Mercantile
Great gift ideas for friends and family. Proceeds support desert conservation efforts!
Become A Friend of the Mojave Desert Seed Bank
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Sign up for our email newsletter to learn about upcoming events and ways to connect with the desert you love. We send about one email per week and you can unsubscribe at any time.
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At Your Library: Family Mini-Golf Is Back!
$3.00 per person or $9.00 per family!
Funds raised by the Friends of the Dracut Library support library programming, the Museum Pass Program, College Scholarships, and other Parker Library activities.


You're now one step closer to making the perfect egg salad.
Delicious, nutritious and super-simple to make, are an easy go-to snack or healthy breakfast option. But when we bite into their core, the egg yolk has often been cooked too long or too little, leaving much to be desired.
Fear no more, egg-lovers! Alexis Kornblum of discovered the perfect cooking trick to ensure your hard-boiled eggs are . Her comprehensive graphic takes you through her genius process, which includes steaming eggs rather than dropping them directly into a boiling pot of water. Kornblum says that this technique is used to cook the eggs evenly.
She also places the cooked eggs into an ice bath directly after to ensure they peel easily.
Place one inch of water into your boiling pot.
Insert steamer basket into that same pot.
Add desired number of eggs into the steamer, cover and cook for six minutes (soft-boiled) or for 11 minutes (hard-boiled).
Immediately remove and place eggs into a bowl of ice-cold water.
Kornblum suggests many uses for these , including egg salad, a salad topper, on-the-go snack, deviled eggs and in a sandwich/open-faced sandwich.
Whichever you prefer, this technique will almost certainly .


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Sam Hahn Player Profile
Sam Hahn
Scoring Average: 77.7
12/4/2021 Tournament of Champions (Boys 16-18) presented by Radisson Hotels Americas
Walt Disney World -- 12/4/2021 (Started On 10)
+4 +6 +6 +6 +8 +8 +8 +9 +10 +2 +1 +1 +2 +1 +1 +1 +2 +3 +10
Round 2:70 (-2) Walt Disney World - Palms
Walt Disney World -- 12/5/2021
-1 E E +1 E -1 -2 -2 -2 -1 -1 -1 -1 -2 -2 -2 -2 -2 -2
Place: T3
Round 1:81 (+9) Bristow Manor Golf Club
E E +1 +1 +1 +2 +3 +3 +3 +3 +5 +6 +6 +6 +8 +8 +8 +9 +9
E E -1 -1 -1 E -1 -1 -1 -1 -1 -1 E E E E E +1 +1
7/31/2021 College Prep Series at UVA
Round 1:79 (+8) Birdwood Golf
Birdwood Golf -- 7/31/2021
+1 E +1 +3 +3 +3 +3 +3 +3 +3 +3 +3 +4 +4 +5 +5 +6 +8 +8
Birdwood Golf -- 8/1/2021
3/13/2021 Richmond Junior Open
Round 1:73 (+2) Providence Golf Club
Providence Golf Club -- 3/13/2021
1/23/2021 Pinehurst Junior Open
Round 1:82 (+11) Pinehurst Resort & Country Club - #5
Pinehurst Resort & Country Club -- 1/23/2021
Round 2:80 (+9) Pinehurst Resort & Country Club - #5


Calorie-scorching cardio dance workouts that help turn your metabolism into a fat-burning furnace.
Help kick your metabolism into overdrive with this pulse-pounding dance routine set to songs like "Save A Horse (Ride A Cowboy)" and step up the fat burn.
You'll have to dig a little deeper into moves like Body Roll and Savannah Stomp as Autumn works every muscle to tighten and tone your entire body.
"Cowboy Up!" Autumn's going to teach you her original choreography in this line dance that you can take straight to the dance floor.
Autumn planned this rotation to fire up your metabolism for maximum calorie burn and fat loss—to help you reveal your hottest body ever.
Results vary depending on starting point, goals, and effort. Exercise and proper diet are necessary to achieve and maintain weight loss and muscle definition.
© 2016 Beachbody, LLC. All rights reserved. Beachbody, LLC is the owner of the Country Heat, Beachbody, and Team Beachbody trademarks, and all related designs, trademarks, copyrights, and other intellectual property.


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Christian and Muslim Leaders Plea for Peace
Churches Together in Britain and Ireland and The Muslim Council of Britain have today issued this joint statement:
Over recent months, there have been many expressions of concern from both Christian and Muslim leaders about the developing crisis over Iraq. They encouraged all involved to weigh carefully the human costs and other likely consequences of war, pleaded for the UN process to be respected in the interests of upholding international law, and counselled that another way of ensuring Iraq's compliance with UN Resolutions might be identified and agreed – while being firm in their abhorrence at the nature of the Saddam Hussein regime. This resort to war reflects, therefore, our collective failure.
The military action that began today is not something that either faith community wanted to see. It is entirely contrary to their hopes and prayers. As representatives of Churches Together in Britain and Ireland and The Muslim Council of Britain, we stand together in our desire to see military action ended as quickly as possible.
In this time of crisis and deep disappointment, it is vitally important that, despite the occasional unhappy use of 'crusade' language by some American political leaders, none should see the conflict as one between faiths.
Both here and in Iraq more than one faith community is present. Relationships between our own religious communities could suffer from rising tension in the wake of hostilities developing between what, sadly, many in the world see as the 'Christian West' and 'Muslim East'. We must exercise the utmost caution to prevent opportunist elements from exploiting this state of affairs. Indeed, now that war has started, there is an even greater responsibility for Christians and Muslims to maintain bonds of harmony one with another and to pray for all caught up in the conflict.
Advice on contacting local churches and mosques can be sought from The Muslim Council of Britain and Churches Together in Britain and Ireland.
Signed on behalf of CTBI
Dr David Goodbourn
General Secretary of Churches Together in Britain and Ireland
Signed on behalf of MCB
Iqbal AKM Sacranie
Secretary General of The Muslim Council of Britain
1. Churches Together in Britain and Ireland is the umbrella body for all the major Christian churches in Britain and Ireland. It liaises with ecumenical bodies in Britain and Ireland as well as ecumenical organizations at European and world levels. Its work includes Church Life, Church and Society, Mission, Inter Faith Relations, International Affairs and Racial Justice. It provides a forum for joint decision-making and enables the churches to take action together. See www.ctbi.org.uk
2. The Muslim Council of Britain (MCB) is an umbrella organisation dedicated to work for the common good and for the betterment of the community and country. The MCB is a body that is made up of over 475 major national, regional and local organisations and institutions. It includes mosques, education and charitable bodies, cultural and professional bodies, relief agencies and women and youth groups. It encompasses the diverse range of linguistic and geographical cultures that make up the mosaic of the British Muslim community. For further information contact admin@mcb.org.uk or refer to http://www.mcb.org.uk
Churches Together in Britain and Ireland (CTBI)
Anne van Staveren
CTBI Communications Officer
020 7523 2137 or 07 939 139 881
www.ctbi.org.uk
PO Box 52, Wembley, Middlesex, HA9 0XW
Zahra Williams
Media Officer
Tel: 020 8903 9024 or 077 3421 9338 Fax: 020 8903 9026
Email: media@mcb.org.uk Website: http://www.mcb.org.uk


'Nobody Cares' Anyway, So How Does That Make Brian Williams 'Courageous'?
There's no equivocating or debating the fact that NBC News made the right decision to ditch the royal wedding and ship Brian Williams back stateside to cover the tornado outbreak.
But NBC News did not do a "brave" thing by bringing him home, as Salon proclaimed. NBC News did the right thing. And calling Brian Williams an "American media patriot" feels more to me like overblown self-congratulation from journalists than recognition of true courage.
So bringing your main anchor back to cover a big story in favor of a story viewers don't care about is courageous?


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155 is het natuurlijke getal volgend op 154 en voorafgaand aan 156.

Natuurlijk getal

redpajama_set_name: RedPajamaWikipedia


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A Baby at 62! Why Are Scientists So Surprised?
By Candy Sagon, February 08, 2013 08:00 AM
She is 62, and the smarty-pants scientists were sure her fertile days were long over. But then she (literally) gave them the bird by hatching a new little albatross chick.
Her name is Wisdom, and she's a beautiful charcoal-gray and snowy-white Laysan albatross (see a typical one, pictured at left) who lives at the Midway Atoll National Wildlife Refuge near the Hawaiian Islands.
Although the average Laysan albatross dies at less than half her age, Wisdom is proof you should never underestimate an older female.
She has raised chicks five times since 2006, and as many as 35 in her lifetime, according to a story this week in the Washington Post. And, although albatrosses mate for life, she's also shown that she can get a younger mate when necessary. She's already done it at least twice, scientists say. (To see a U.S. Fish and Wildlife Service photo of Wisdom and her newest mate, click here.)
Just as astonishing, she has likely flown up to 3 million miles since she was first tagged in 1956, report the scientists who have tracked her for the U.S. Geological Survey (USGS).
While the many grandmothers helping to raise and shepherd their grandchildren may not be quite as amazed, wildlife experts seemed stunned by Wisdom's accomplishments.
"If she were human, she would be eligible for Medicare in a couple years, yet she is still regularly raising young and annually circumnavigating the Pacific Ocean. Simply incredible," said Bruce Peterjohn, chief of the Bird Banding Laboratory at the USGS Patuxent Wildlife Research Center in Laurel, Md.
Equally impressive is legendary ornithologist Chandler Robbins, who was nearly 40 when he first put a little aluminum band around Wisdom's ankle in 1956 to help track her. In 2001, when Robbins was in his 80s and still working for the USGS, he returned to the atoll and "amid the thousands of albatrosses that nest there, picked up a bird with a tag that traced all the way back to one with a signature he recognized - his own," wrote Post reporter Darryl Fears.
That's when scientists got excited and gave Wisdom her name, estimating her age then at nearly AARP-ready, or about 49, Fears wrote. But she could be several years older - and Robbins, now 94 and retired, is sifting through the tangled data. "I'm trying to straighten out the record," he told the Post. "It takes a lot."
Wisdom is seen as a symbol of hope for her species, wildlife experts say. Nineteen of 21 albatross species are threatened with extinction, thanks in large part to humans. Longline fishing has depleted their numbers, because they get hooked and drown. The birds also swallow plastic debris in the ocean, notes the USGS; this is life threatening to the chicks. Scientists hope that by learning more about a healthy albatross, like Wisdom, they can learn more about the health of our oceans.
Photo: puuikibeach /flickr
albatross endangered birds older females candy sagon grandparents raising grandchildren older mothers birth stories women's health fertility


Zia Cooke, a South Carolina commit and ESPN's seventh-ranked prospect from the 2019 class, put on a show Saturday, dropping a career-high 43 points in the fifth game of her senior season. The highlight reel from the game featured pretty much everything you'd want from a high school mixtape: step-back jumpers, and-one baskets in the paint, no-look passes, and, of course, a devastating crossover.
Cooke's feat is even more impressive by the fact that it came in a 80-73 win over the previously undefeated East Kentwood, but this is to be expected for her. The Toledo Blade selected her for its 2018 player of the year, and she was a Division II first-team All-Ohio selection last season. In March, Cooke led Rogers High School to a Division II state championship, its first girls basketball title since 1981.
Cooke is the top player in South Carolina head coach Dawn Staley's No. 1-ranked recruiting class. She should be pretty fun to watch when she makes her way to Columbia.


Facebook blurb (50 words): Ukraine, 1933, during HOLODOMOR: the famine-genocide of Ukraine. Every day, in order to survive, the child has to travel long way to a place where she can receive a bowl of soup. One day kids are granted a cookie. 4 years old decides to save this treat to her mom.
Technique: oil pastel on backlit acetate, animated under the camera.
My short animation "Holodomor. Cookie" based upon the personal story – story of my grandmother as a young child about the day when she lost her mom. The film is set in times of Holodomor ("murder by hunger") – famine and genocide generated in Ukraine in 1932-1933 by Soviet Republic that killed more than 11 million people.
The main idea of film aimed to pass to spectator the feeling of very last minutes for mother and daughter they spent together, their love and empathy toward each other during very difficult times.
Technique used for film is oil pastel on backlit acetate was chosen to convey a sense of authenticity through strong and appealing texture. The song used in the film is a traditional Ukrainian lullaby, performed by the daughter of the main protagonist.


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Alert04.26.2013
PRESS RELEASE: ACLU OF Connecticut and Quinnipiac University Reach Settlement in Historic Title IX Case
John Morgan, Quinnipiac University, (203) 582-5359; john.morgan@quinnipiac.edu
Sandra Staub, ACLU of Connecticut, (860) 523-9146 or (860) 471-8471; sstaub@acluct.org
Sally Laroche, Pullman & Comley, (203) 330-2007; slaroche@pullcom.com
HAMDEN, Conn., April 26, 2013: Quinnipiac University has announced a major new commitment to women's sports at the university, including expansion of women's athletic opportunities, additional athletic scholarships for female athletes, and improved support of its women's teams. The announcement comes as part of a settlement in the case of Biediger, et al. v. Quinnipiac University, U.S. District Court (D.Conn.) Case No. 3:09-cv-621 (SRU), in which the plaintiffs asserted that the University had not complied with Title IX of the Education Amendments of 1972, which bars gender discrimination in collegiate athletics. The parties have filed a proposed Consent Decree resolving the case, subject to court approval.
Sandra Staub, Legal Director of the ACLU Foundation of Connecticut, commented: "This litigation advanced the cause of equality for female collegiate athletes across the nation, and the settlement will bring tremendous benefits to female athletes at Quinnipiac University. The parties have worked hard to achieve this agreement."
The ACLU Foundation of Connecticut, along with cooperating counsel Jonathan Orleans and Alex Hernandez of Pullman & Comley, LLC and Kristen Galles of Equity Legal in Alexandria, Virginia, filed the class action law suit in 2009 after Quinnipiac announced its intent to eliminate the women's volleyball team. During four years of litigation, the plaintiffs prevailed in five separate reported decisions in the U.S. District Court for the District of Connecticut and the United States Court of Appeals for the Second Circuit Court, ruling that Quinnipiac was not in compliance with Title IX in the operation of its varsity athletic program.
As part of the settlement, Quinnipiac will retain all of its existing women's teams (including volleyball), will allocate more scholarships to female athletes, and will improve the benefits provided to most of its women's teams. Quinnipiac has already added varsity women's golf and rugby and expanded its women's track program. Other highlights include:
· Quinnipiac will treat two more of its women's teams as "sports of emphasis," which will lead to more scholarships, more coaches, and better facilities.
· It will increase its commitment to the new varsity sport of women's rugby by increasing scholarships, raising the level of competition, adding coaches, and substantially improving its field.
· It will increase its commitment to women's track by increasing the number of scholarships, coaches, and competitions, as well as building an indoor track & field facility that meets NCAA competition standards.
· It will authorize the maximum number of competitions for all of its teams.
· It will spend at least $5 million improving the facilities used by women's varsity teams, including locker rooms.
· It will spend about $450,000 annually improving its women's athletics program by, among other things, increasing coaching salaries, hiring more coaches and academic support staff, and providing greater access to athletic training and conditioning services.
· It will allocate up to $175,000 during each of the next 3 years for additional improvements for women's sports.
· It will hire a "Referee," mutually agreed upon by the parties and confirmed by the Court, to monitor its progress.
Kristen Galles, one of the plaintiffs' attorneys, commented, "This was a particularly important case because the courts clarified the meaning of key terms such as 'substantial proportionality,' the 'competition test,' and 'varsity sport' under Title IX."
"We're very pleased with the multitude of benefits and increased opportunities this settlement will provide for female athletes at Quinnipiac," said Jonathan Orleans, another of the plaintiffs' attorneys. "We look forward to working with the University as it implements the terms of the settlement."
Jonathan B. Orleans


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March 16, 2011 10.56 am This story is over 129 months old
Council extends parking enforcement deal
Responsibility: Police will enforce parking in Lincoln with money from the City Council while the County Council prepares to take over.
By Daniel Ionescu Founder & Editor
After scrapping all six parking warden positions in Lincolnshire, two of which in Lincoln, Lincolnshire Police agreed to continue using funding from City of Lincoln Council to enforce on-street parking in the city.
The council currently pays Lincolnshire Police £48,000 per year to enforce parking restrictions throughout Lincoln, but following restructuring, the force decided to de-establish the role of traffic wardens in January.
The move was in anticipation of Lincolnshire County Council taking over civil parking enforcement responsibilities across the county, but the authority is not ready to assume the responsibilities until later this year.
This meant that from April there would be no dedicated parking wardens to enforce on-street parking restrictions in Lincoln and across the county besides Lincolnshire Police officers and PCSOs.
However, following discussions between the City of Lincoln Council and Lincolnshire Police, it has been agreed that the police will continue to enforce parking restrictions throughout Lincoln.
The City Council will provide another £48,000 to Lincolnshire Police for on-street parking enforcement in the new financial year, but it is unclear how the service will be delivered since the parking wardens were fired.
Lincolnshire Police Chief Inspector Mark Housley said the force will work with the City Council to find a solution, so that all forms of parking restrictions, including residents' parking zones, will be enforced in Lincoln over the next year.
"It has not been decided what form that will take, but we have de-established the role of traffic wardens within the force and that decision will not be reversed.
"As soon as a decision has been made on how the service will be delivered we will communicate it with the wider public," Housley added.
City Councillor Marc Jones instigated the discussions with Lincolnshire Police and says he is happy with the result.
"I know residents and businesses have expressed concern that parking does continue to be enforced," Jones said.
"We've always been clear that funding will be made available as long as we are confident that effective enforcement is happening, particularly where we have residents' parking schemes."
Meanwhile, at the County Council, preparations to take over civil parking enforcement are underway, said Brian Thompson, Divisional Highways Manager:
"We are currently carrying out a financial revaluation to ensure there is best value for taxpayers, ahead of an application to the Department for Transport to take on Civil Parking Enforcement later this year."
Lincolnshire County Council says it is preparing a parking policy that will guide actions on enforcement matters and also on-street parking provision.
The authority is yet to consult those involved in the implementation and operation of parking, including the police, neighbouring local authorities, the DVLA and the Traffic Enforcement Centre.
Source: City of Lincoln Council | Related Report: Lincolnshire Echo
Nursing & Care Homes, Residential Conversions
4 bedroom Town House for sale
2 bedroom Barn Conversion to let
Long-Established Florist Business For Sale


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cGMP PDE 5 inhibitors for inhalation in the treatment of sexual dysfunction
Treatment of sexual dysfunction by inhalation of a cGMP PDE 5 inhibitor, especially 5-[2-ethoxy-5-(4-methylpiperazinylsulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 4-phenylmethylamino-6-chloro-2-(1-imidazolyl)quinazoline, 4-phenylmethylamino-6-chloro-2-(3-pyridyl)quinazoline, 1,3-dimethyl-6-(2-propoxy-5-methanesulfonylamidophenyl)-1,5-dihydropyrazolo[3,4-d]pyrimidin-4-one or 1-cyclopentyl-3-ethyl-6-(3-ethoxy-4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-one.
Naef, Reto (Rheinfelden, CH)
A61K9/12; A61K31/519; A61K9/00; A61K9/72; A61K31/00; A61K31/517; A61K45/00; A61P15/00; A61P15/10; A61P43/00
20040176283 Methods and compositions for the design of synthetic vaccines September, 2004 Robinson et al.
20060052350 Crystalline forms of 1,24(S)-dihydroxy vitamin D2 March, 2006 Ploutno et al.
20070248554 Hair Style Control Agent October, 2007 Ishii et al.
20070244154 Substituted Tricyclic Benzimidazoles October, 2007 Brehm
20090118369 Use of CIS-9, Trans-11 Isomer of Conjugated Lineoleic Acid May, 2009 Bell et al.
20100087473 FREEZE-DRIED INJECTABLE PHARMACEUTICAL COMBINATION OF SEMISYNTHETIC VINCA ALKALOIDS AND CARBOHYDRATE STABLE AT ROOM TEMPERATURE April, 2010 Leverd et al.
20030125278 IMMUNIZATION OF ANIMALS BY TOPICAL APPLICATIONS OF A SALMONELLA-BASED VECTOR July, 2003 Tang et al.
20090275665 Enhanced biological potential of greater than 99% pure form of 1, 7-bis(4-hydroxy-3-methoxyphenyl)-3,5-heptanedione over corresponding 95% pure form-therapeutic and agricultural applications thereof November, 2009 Majeed
20020156084 Use of N-benzyl piperazine and analogues as quality of life enhancers October, 2002 Valent
20030068364 Pro-liposomal encapsulated preparations (iv) April, 2003 Garces et al.
20050054673 Combination of phenylcarboxylic acid amides with beta-adrenoreceptor blockers and their use for the treatment of atrial arrhythmias March, 2005 Wirth et al.
HAGHIGHATIAN, MINA
NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH, INC. (Cambridge, MA, US)
1. 1-20. (canceled)
21. A method of treating sexual dysfunction which comprises administering by inhalation an effective amount of an inhibitor of cGMP PDE 5 in an atomisable composition or a finely divided particulate form to a subject in need of such treatment, wherein said inhibitor is selected from the group consisting of 5-[2-ethoxy-5-(4-methylpiperazinyl-sulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one, 4-phenylmethylamino-6-chloro-2-(1-imidazolyl)quinazoline, 4-phenyl-methylamino-6-chloro-2-(3-pyridyl)-quinazoline, 1,3-dimethyl-6-(2-propoxy-5-methane-sulfonylamidophenyl)-1,5-dihydropyrazolo[3,4-d]pyrimidin-4-one and 1-cyclopentyl-3-ethyl-6-(3-ethoxy-4pyridyl)-pyrazolo[3,4-d]pyrimidin-4-one.
22. A method according to claim 21, in which said atomisable composition is an aerosol comprising said inhibitor in solution or dispersion in a propellant or a nebulizable composition comprising a dispersion of said inhibitor in an aqueous or aqueous/organic medium.
23. A method according to claim 21, in which said inhibitor in finely divided particulate form is inhaled together with a particulate carrier.
24. A medicament comprising 5-[2-ethoxy-5-(4-methylpiperazinylsulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 4-phenylmethylamino-6-chloro-2-(1-imidazolyl)-quinazoline, 4-phenylmethylamino-6-chloro-2-(3-pyridyl)quinazoline, or 1,3-dimethyl-6-(2-propoxy-5-methanesulfonylamidophenyl)-1,5-dihydropyrazolo[3,4-d]pyrimidin-4-one in an atomisable composition or a finely divided particulate form.
25. A medicament according to claim 24, in which the atomisable composition is an aerosol comprising said inhibitor in solution or dispersion in a propellant or a nebulizable composition comprising a dispersion of said inhibitor in an aqueous or aqueous/organic medium.
26. A medicament according to claim 24, in which said inhibitor in finely divided particulate form is inhaled together with a particulate carrier.
27. A method of treating sexual dysfunction which comprises administering by inhalation an effective amount of 5-[2-ethoxy-5-(4-methylpiperazinylsulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one in an atomisable composition or a finely divided particulate form to a subject in need of such treatment.
28. A medicament comprising 5-[2-ethoxy-5-(4-methylpiperazinylsulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one in an atomisable composition or a finely divided particulate form.
This is a continuation of U.S. application Ser. No. 09/883,572, filed Jun. 18, 2001 which is a continuation of International Application No. PCT/EP99/10250, filed Dec. 21, 1999, the contents of which are incorporated by reference.
This invention relates to the use of organic compounds, in particular inhibitors of cyclic guanosine 3′,5′-monophosphate phosphodiesterases (cGMP PDEs), in inhalable form for the preparation of a medicament for the treatment of sexual dysfunction, including male erectile dysfunction and female sexual dysfunction.
WO 94/28902, WO 96/16644 and WO 96/16657 describe the use of selective inhibitors of cyclic guanosine 3′,5′-monophosphate phosphodiesterases (cGMP PDEs), particularly cGMP PDE 5 inhibitors, in the treatment of sexual dysfunction. These references state that, for human use, the inhibitors are administered orally or, where the recipient suffers from a swallowing disorder or from impairment of drug absorption after oral administration, parenterally, sublingual and buccal administration being suggested as means of parenteral administration.
It has now surprisingly been found that compounds effective in the treatment, i.e. curative or prophylactic treatment, of sexual dysfunction exhibit maximum concentration in plasma in a very short time following administration by inhalation, i.e. by delivery to the lung, indicating a more rapid onset of action for the compounds when administered by this route.
Accordingly, the present invention provides, in one aspect, the use of a cGMP PDE 5 inhibitor in inhalable form for the preparation of an inhalable medicament for the treatment of sexual dysfunction.
In another aspect, the invention provides a method of treating sexual dysfunction which comprises administering by inhalation an effective amount of an inhibitor of cGMP PDE 5 to a subject, particularly a human subject, in need of such treatment.
In a further aspect, the invention provides an inhibitor of cGMP PDE 5 in inhalable form for use in the treatment of sexual dysfunction.
The cGMP PDE 5 inhibitor for use in accordance with the invention may be a pyrazolopyrimidinone or an aminoquinazoline derivative. Examples of such inhibitors include:
a pyrazolopyrimidinone as disclosed in EP-A-0463756, EP-A-0526004, WO 94/28902, WO 96/16657 or WO 98/49166;
a 5-substituted pyrazole [4,3-d]pyrimidin-7-one as disclosed in EP-A-0201188;
a griseolic acid derivative as disclosed in EP-A-0214708 and EP-A-0319050;
a 2-phenylpurinone derivative as disclosed in EP-A-0293063;
a phenylpyridone derivative as disclosed in EP-A-0347027;
a fused pyrimidine derivative as disclosed in EP-A-0347146;
a condensed pyrimidine derivative as disclosed in EP-A-0349239;
a pyrimidopyrimidine derivative as disclosed in EP-A-0351 058;
a purine compound as disclosed in EP-A-0352960;
a quinazolinone derivative as disclosed in EP-A-0371731;
a phenylpyrimidone derivative as disclosed in EP-A-0395328;
an imidazoquinoxalinone derivative or its aza analogue as disclosed in EP-A-0400583;
a pyrimidopyrimidine derivative as disclosed in EP-A-0442204;
a 4-aminoquinazoline derivative as disclosed in EP-A-0579496;
a 4,5-dihydro-4-oxo-pyrrolo[1,2-a]quinoxaline derivative or its aza analogue as disclosed in EP-A-0584487;
a polycyclic guanine derivative as disclosed in WO91/19717;
a nitrogenous heterocyclic compound as disclosed in WO93/07124;
a 2-benzyl-polycyclic guanine derivative as disclosed in WO94/19351;
a quinazoline derivative as disclosed in U.S. Pat. No. 4,060,615;
a 6-heterocyclyl pyrazolo [3,4-d]pyrimidin-4-one as disclosed in U.S. Pat. No. 5,294,612;
a benzimidazole as disclosed in Japanese Kokai 5-222000;
a cycloheptimidazole as disclosed in European Journal of Pharmacology, 251, (1994), 1.
a N-containing heterocycle as disclosed in WO94/22855;
a pyrazolopyrimidine derivative as disclosed in EP-A-0636626;
a 4-aminopyrimidine derivative as disclosed in EP-A-0640599;
an imidazoquinazoline derivative as disclosed in EP-A-0668280;
an anthranilic acid derivative as disclosed in EP-A-0686625;
a 4-aminoquinazoline derivative as disclosed in U.S. Pat. No. 5,436,233;
a tetracyclic derivative as disclosed in WO95/19978;
a quinazoline compound as disclosed in EP-A-0669324;
a fused pyridazine compound as disclosed in EP-A-0722936;
an imidazoquinoline compound as disclosed in EP-A-0758653;
a substituted pyrazoloquinolinamine as disclosed in WO96/28159;
a substituted pyrazolopyrimidinone as disclosed in WO96/28429;
an indole derivative as disclosed in WO96/32379; or
a benzimidazole derivative as disclosed in WO97/03070.
The invention includes, but is not limited to, the use of any compound within the scope of the documents listed above, particularly the specific compounds described therein, more particularly the specific compounds disclosed in the Examples and, where the document is a patent, the claims of those documents.
Preferred compounds for use in the present invention include pyrazolopyrimidinone cGMP PDE 5 inhibitors as disclosed in WO94/28902, more preferably
5-(2-ethoxy-5-morpholinoacetylphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
5-(5-morpholinoacetyl-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
5-[2-ethoxy-5-(4-methyl-1-piperazinylsulphonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
5-[2-allyloxy-5-(4-methyl-1-piperazinylsulphonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
5-[2-ethoxy-5-[4-(2-propyl)-1-piperazinyl-sulphonyl]phenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
5-[2-ethoxy-5-[4-(2-hydroxyethyl)-1-piperazinyl-sulphonyl]phenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
5-{5-[4-(2-hydroxyethyl)-1-piperazinylsulphonyl]-2-n-propoxyphenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
5-[2-ethoxy-5-(4-methyl-1-piperazinylcarbonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
and 5-[2-ethoxy-5-(1-methyl-2-imidazolyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.
Other preferred compounds for use in the present invention include pyrazolopyrimidinone and quinazolinone cGMP PDE 5 inhibitors as disclosed in WO96/16657, more preferably 1-ethyl-5-[5-(n-hexylsulphamoyl)-2-n-propoxyphenyl]-3-methyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
1-ethyl-5-(5-diethylsulphamoyl-2-n-propoxyphenyl)-3-methyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one;
5-(5-(N-cyclohexylmethyl-N-methylsulphamoyl)-2-n-propoxyphenyl]-1-ethyl-3-methyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
6-(5-bromo-2-n-propoxyphenyl)-3-methyl-1-n-propyl-1,5-dihydro-4H-pyrazolo(3,4-d]pyrimidin-4-one;
3-methyl-6-(5-morpholinosulphonyl-2-n-propoxyphenyl)-1-n-propyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one;
6-[5-(2-carboxyvinyl)-2-n-propoxyphenyl]-3-methyl-1-n-propyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one;
6-[5-(2-t-butoxycarbonylvinyl)-2-n-propoxyphenyl]-3-methyl-1-n-propyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one;
3-methyl-6-[5-(2-morpholinocarbonylvinyl)-2-n-propoxyphenyl]-1-n-propyl-1,5-dihydro-4H-pyrazolo [3,4-d]pyrimidin-4-one;
3-methyl-6-[5-(2-morpholinocarbonylethyl)-2-n-propoxyphenyl]-1-n-propyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one;
2-{2-ethoxy-5-[4-(2-hydroxyethyl)-1-piperazinylsulphonyl]phenyl}-8-methylquinazolin-4-(3H)-one;
2-{5-[4-(2-hydroxyethyl)-1-piperazinylsulphonyl]-2-n-propoxyphenyl}-8-methylquinazolin-4(3H)-one;
8-methyl-2-{5-[2-(4-methyl-1-piperazinylcarbonyl)-ethenyl]-2-n-propoxyphenyl}quinazolin-4(3H)-one;
8-carbamoyl-2-{2-ethoxy-5-[4-(2-hydroxyethyl)-1-piperazinylsulphonyl]phenyl}quinazolin-4(3H)-one;
8-ethylcarbamoyl-2-{2-n-propoxyphenyl)quinazolin-4(3H)-one;
2-[2-ethoxy-5-(4-ethoxycarbonylpiperidino-sulphonyl)phenyl]-8-n-propylpyrido[3,2-d]pyrimidin-4(3H)-one;
2-[5-(4-carboxypiperidinosulphonyl)-2-ethoxyphenyl]-8-n-propylpyrido[3,2-d]pyrimidin-4(3H)-one;
2-{2-ethoxy-5-[4-(2-hydroxyethyl)-1-piperazinyl-sulphonyl]phenyl}-8-n-propylpyrido[3,2-d]pyrimidin-4(3H)-one;
and 2-{2-ethoxy-5-[(bis-3-pyridylsulphonyl)amino]-phenyl}-8-n-propylpyrido[3,2-d]pyrimidin-4(3H)-one.
Other preferred compounds for use in the present invention include pyrazolopyrimidinone cGMP PDE5 inhibitors as disclosed in WO98/49166, more preferably
5-{5-[4-(2-hydroxyethyl)piperazin-1-ylsulphonyl]-2-n-propoxyphenyl}-3-n-propyl-1-(pyridin-2-yl)methyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimi din-7-one;
1-(1-methylimidazol-2-yl)methyl-5-[5-(4-methylpiperazin-1-sulphonyl)-2-n-propoxyphenyl]-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin -7-one;
5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-propoxyphenyl]-3-n-propyl-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-propoxyphenyl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-propoxyphenyl]-3-n-propyl-2-(pyridazin-3-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one ;
5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-propoxyphenyl]-3-n-propyl-2-(pyridazin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one ; and
5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)phenyl]-3-n-propyl-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
5-[5-(4-methylpiperazin-1-ylsulphonyl)-2-n-propoxyphenyl]-1-(1-methyl-1,2,4-triazol-5-yl)methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]p yrimidin-7-one;
1-benzyl-5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)phenyl]-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
2-benzyl-5-[2-ethoxy-5-(4-methylpiperazin-1-sulphonyl)phenyl]-3-n-propyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-propoxyphenyl]-1-(2-morpholin-4-ylethyl)-3-n-propyl-1,6-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyr imidin-7-one;
5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-propoxyphenyl]-2-(2-morphin-4-ylethyl)-3-n-propyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-propoxyphenyl]-2-(2-methanesulphonamidophenyl)-3-n-propyl-2,6-dihydro-7H-pyrazolo[4,3-d]-pyrimid in-7-one;
5-[5-(4-methylpiperazin-1-ylsulphonyl)-2-n-propoxyphenyl]-3-n-propyl-2-pyrimidin-2-yl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
2-cyclobutylmethyl-5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)phenyl]-3-n-propyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-propoxyphenyl]-2-(1-oxidopyridin-2-yl)methyl-3-n-propyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin- 7-one;
Further preferred compounds for use in the present invention include:
4-aminoquinazoline derivatives as disclosed in U.S. Pat. No. 5,436,233, more preferably 4-phenylmethylamino-2-((1-imidazolyl)methyl)-quinazoline, 4-phenylmethylamino-2-((1-imidazolyl)methyl)-quinazoline, 6-chloro-4-phenylmethylamino-2-(1-imidazolylmethyl)quinazoline, 6-chloro-4-phenylamino-2-(1-imidazolylmethyl)-quinazoline, 6-chloro-4-(3-carboxyphenyl)amino-2-(1-imidazolylmethyl)quinazoline, 4-phenylmethylamino-2-(2-(3-pyridyl)vinyl)quinazoline, 4-phenylmethylamino-6-chloro-2-(1-imidazolyl)quinazoline and 4-phenylmethylamino-6-chloro-2-(3-pyridyl)quinazoline;
pyrazolopyrimidine derivatives as disclosed in EP0636626, more preferably 1,3-dimethyl-6-(2-propoxy-5-acetamidophenyl)-1,5-dihydropyrazolo[3,4-d]pyrimidin-4-one;
1-ethyl-3-methyl-6-[2-propoxy-5-(4-methyl-2-thiazolyl)phenyl]-1,5-dihyropyrazolo[3,4-d]pyrimidin-4-one;
1-ethyl-3-methyl-6-[2-propoxy-5-(2-(3-pyridyl)-4-thiazolyl)phenyl]-1,5-dihydropyrazolo[3,4-d]pyrimidin-4-one;
1,3-dimethyl-6-(2-propoxy-5-(2-methyl-4-thiazolyl)phenyl]-1,5-dihydropyrazolo[3,4-d]pyrimidin-4-one;
1,3-dimethyl-6-(2-propoxy-5-(3-phenyl-1,2,4-triazol-5-yl)phenyl]-1,5-dihydropyrazolo[3,4-d]pyrimidin-4-one;
1,3-dimethyl-6-(2-propoxy-5-methanesulfonamidophenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;
pharmaceutically acceptable salts and solvates (e.g. hydrates) of such pyrazolopyrimidines;
arylpyrazolopyrimidinones as disclosed in WO96/28448, more preferably
1-cyclopentyl-3-ethyl-6-(2-propoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-one,
1-cyclopentyl-3-ethyl-6-[4-(1-imidazolyl)phenyl]pyrazolo[3,4-d]pyrimidin-4-one,
1-cyclopentyl-3-ethyl-6-[3-(2-(4-morpholinyl)ethoxy)phenyl]pyrazolo(3,4-d]pyrimidin-4-one,
1-cyclopentyl-3-ethyl-6-[2-ethoxy-4-(1-imidazolyl)phenyl]pyrazolo(3,4-d]pyrimidin-4-one, and
1-cyclopentyl-3-ethyl-6-[2-(CH2═CHCH2O)phenyl)pyrazolo[3,4-d]pyrimidin-4-one; and
6-heterocyclyl-pyrazolo[3,4-d]pyrimidin-4-ones as disclosed in U.S. Pat. No. 5,294,612, more preferably 1-tert-butyl-3-(3,4-dimethoxybenzyl)-6-(4-pyridyl)-pyrazolo(3,4-d]pyrimidin-4-one,
1-cyclopentyl-3-methyl-6-(4-quinolinyl)-pyrazolo[3,4-d]pyrimidin-4-one,
1-cyclopentyl-3-ethyl-6-(4-pyridyl)-pyrazolo(3,4-d]pyrimidin-4-one,
1-cyclopentyl-3-methyl-6-(4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-one,
1-tert-butyl-3-benzyl-6-(4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-one,
1-tert-butyl-3-methyl-6-(4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-one,
1-cyclopentyl-3-ethyl-6-(3-ethoxy-4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-one,
1-tert-butyl-3-pyridylmethyl-6-(4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-one,
1-cyclopentyl-3-ethyl-6-[2-(4-morpholinyl)ethoxy-4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-one,
1-cyclopentyl-3-trifluoromethyl-6-(3-ethoxy-4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-one,
1-cyclopentyl-3-ethyl-6-(3-methoxy-4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-one and
1-cyclopentyl-3-ethyl-6-(3-sec-butoxy-4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-one
Especially preferred compounds for use in the invention include 5-[2-ethoxy-5-(4-methylpiperazinylsulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo(4,3-d]pyrimidin-7-one, 4-phenylmethylamino-6-chloro-2-(1-imidazolyl)quinazoline, 4-phenylmethylamino-6-chloro-2-(3-pyridyl)quinazoline, 1,3-dimethyl-6-(2-propoxy-5-methanesulfonylamidophenyl)-1,5-dihydropyrazolo[3,4-d]pyrimidin-4-one and 1-cyclopentyl-3-ethyl-6-(3-ethoxy-4-pyridyl)-pyrazolo(3,4-d)pyrimidin-4-one.
In a yet further aspect, the invention provides a medicament comprising a cGMP PDE inhibitor as disclosed in WO94/28902, WO96/16657, WO98/49166, EP-A-0636626 or U.S. Pat. No. 5,436,233, particularly the preferred and especially preferred such inhibitors as described above, in inhalable form, especially 5-[2-ethoxy-5-(4-methylpiperazinylsulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 4-phenylmethylamino-6-chloro-2-(1-imidazolyl)quinazoline, 4-phenylmethylamino-6-chloro-2-(3-pyridyl)quinazoline, and 1,3-dimethyl-6-(2-propoxy-5-methanesulfonylamidophenyl)-1,5-dihydropyrazolo[3,4-d]pyrimidin-4-one in inhalable form.
The inhalable form of the cGMP PDE 5 inhibitor, i.e. the form suitable for delivery to the lung, may be, for example, an atomisable composition such as an aerosol comprising the active ingredient in solution or dispersion in a propellant or a nebulizable composition comprising a dispersion of the active ingredient in an aqueous, organic or aqueous/organic medium, or a finely divided particulate form comprising the active ingredient in finely divided form optionally together with a pharmaceutically acceptable carrier in finely divided form.
An aerosol composition suitable for use as the inhalable form of the medicament may comprise the active ingredient, for example a cGMP PDE inhibitor as disclosed in WO94/28902, WO96/16657, WO98/49166, EP-A-0636626 or U.S. Pat. No. 5,436,233, in solution or dispersion in a propellant, which may be chosen from any of the propellants known in the art. Suitable such propellants include hydrocarbons such as n-propane, n-butane or isobutane or mixtures of two or more such hydrocarbons, and halogen-substituted hydrocarbons, for example fluorine-substituted methanes, ethanes, propanes, butanes, cyclopropanes or cyclobutanes, particularly 1,1,1,2-tetrafluoroethane (HFA134a) and heptafluoropropane (HFA227), or mixtures of two or more such halogen-substituted hydrocarbons. Where the active ingredient is present in dispersion in the propellant, i.e. where it is present in particulate form dispersed in the propellant, the aerosol composition may also contain a lubricant and a surfactant, which may be chosen from those lubricants and surfactants known in the art. The aerosol composition may contain up to about 5% by weight, for example 0.002 to 5%, 0.01 to 3%, 0.015 to 2%, 0.1 to 2%, 0.5 to 2% or 0.5 to 1%, by weight of the active ingredient, based on the weight of the propellant. Where present, the lubricant and surfactant may be in an amount up to 5% and 0.5% respectively by weight of the aerosol composition. The aerosol composition may also contain ethanol as co-solvent in an amount up to 30% by weight of the composition, particularly for administration from a pressurised metered dose inhalation device.
A finely divided particulate form, i.e. a dry powder, suitable for use as the inhalable form of the medicament may comprise the active ingredient, for example a cGMP PDE inhibitor as disclosed in WO94/28902, WO96/16657, WO98/49166, EP-A-0636626 or U.S. Pat. No. 5,436,233, in finely divided particulate form, optionally together with a particulate carrier, which may be chosen from materials known as carriers in dry powder inhalation compositions, for example saccharides, including monosaccharides, disaccharides and polysaccharides such as arabinose, glucose, fructose, ribose, mannose, sucrose, lactose, maltose, starches or dextran and sugar alcohols such as mannitol. An especially preferred carrier is lactose. The carrier may be finely divided, e.g. finely divided but of larger particle size than the active ingredient, or may comprise a mixture of particles of similar size to the active ingredient and larger particles. The dry powder may be in capsules of gelatin or plastic, or in blisters, for use in a dry powder inhalation device, preferably in dosage units of 5 mg to 40 mg of the active ingredient. Alternatively, the dry powder may be contained in a reservoir in a multi-dose dry powder inhalation device.
In the finely divided particulate form of the medicament, and in the aerosol composition where the active ingredient is present in particulate form, the active ingredient may have an average particle diameter of up to about 10 μm, for example 0.1 to 5 μm, preferably 1 to 5 μm. The particle size of the active ingredient, and that of a solid carrier where present in dry powder compositions, can be reduced to the desired level by conventional methods, for example by grinding in an air-jet mill, ball mill or vibrator mill, microprecipitation, spray-drying, lyophilisation or recrystallisation from supercritical media.
Accordingly, in a yet further aspect, the invention provides a pharmaceutical composition comprising a cGMP PDE 5 inhibitor, optionally together with a pharmaceutically acceptable diluent or carrier, for use by inhalation in the treatment of sexual dysfunction.
The inhalable medicament may be administered using an inhalation device suitable for the inhalable form, such devices being well known in the art. Accordingly, the invention also provides a pharmaceutical product comprising a cGMP PDE inhibitor as disclosed in WO94/28902, WO96/16657, WO98/49166, EP-A-0636626 or U.S. Pat. No. 5,436,233 in inhalable form as hereinbefore described in association with an inhalation device. In a further aspect, the invention provides an inhalation device containing a cGMP PDE inhibitor as disclosed in WO94/28902, WO96/16657, WO98/49166, EP-A-0636626 or U.S. Pat. No. 5,436,233 in inhalable form as hereinbefore described.
Where the inhalable form of the active ingredient is an aerosol composition, the inhalation device may be an aerosol vial provided with a valve adapted to deliver a metered dose, such as 10 to 100 μl, e.g. 25 to 50 μl, of the composition, i.e. a device known as a metered dose inhaler. Suitable such aerosol vials and procedures for containing within them aerosol compositions under pressure are well known to those skilled in the art of inhalation therapy. Where the inhalable form of the active ingredient is a nebulizable aqueous, organic or aqueous/organic dispersion, the inhalation device may be a known nebulizer, for example a conventional pneumatic nebulizer such as an airjet nebulizer, or an ultrasonic nebulizer, which may contain, for example, from 1 to 50 ml, commonly 1 to 10 ml, of the dispersion; or a hand-held nebulizer such as an AERx (ex Aradigm, US) or BINEB (Boehringer Ingelheim) nebulizer which allows much smaller nebulized volumes, e.g. 10 to 100 μl, than conventional nebulizers. Where the inhalable form of the active ingredient is the finely divided particulate form, the inhalation device may be, for example, a dry powder inhalation device adapted to deliver dry powder from a capsule or blister containing a dosage unit of the dry powder, for example a dry powder capsule inhaler as described in U.S. Pat. No. 3,991,761, which may be modified by coating the capsule-piercing pins with a polymer as described in WO99/45987, or a multidose dry powder inhalation device adapted to deliver, for example, 5 mg to 25 mg of dry powder per actuation. Suitable such dry powder inhalation devices are well known, for example the device described in WO97/20589.
The invention is illustrated by the following Examples.
Gelatin capsules suitable for use in a capsule inhaler are prepared, each capsule containing a dry powder consisting of 10 mg of 5-[2-ethoxy-5-(4-methylpiperazinylsulfonyl)phenyl]-1-methyl-3-n-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (hereinafter Compound A) which has been ground to a mean particle diameter of 1-5 μm in an air jet mill and 10 mg of lactose monohydrate having a particle diameter below 212 μm. These capsules are used in the treatment of erectile dysfunction patients by inserting a capsule into the capsule chamber of the inhaler described in U.S. Pat. No. 3,991,761 and actuating the piercing devices to perforate the capsule and release the dry powder when air is inhaled through the capsule chamber by a patient.
EXAMPLES 2-34
Example 1 is repeated using the amounts of Compound A and lactose monohydrate shown below instead of the amounts used in Example 1:
Amount of Lactose
Example Amount of Compound A Monohydrate
2 10 mg 15 mg
8 15 mg 5 mg
10 15 mg 15 mg
15 20 mg 5 mg
EXAMPLES 35-54
Example 1 is repeated, but using 4-phenylmethylamino-6-chloro-2-(1-imidazolyl)quinazoline (hereinafter Compound B) as the active ingredient instead of Compound A used in that example and using amounts of active ingredient and lactose monohydrate as shown below:
Example Amount of Compound B Monohydrate
Example 1 is repeated, but using 1-cyclopentyl-3-ethyl-6-(3-ethoxy-4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-one (hereinafter referred to alternatively as Compound C) as the active ingredient instead of Compound A used in that Example and using amounts of active ingredient and lactose monohydrate as shown below:
Example Amount of Compound C Monohydrate
Example 1 is repeated, but using 1,3-dimethyl-6-(2-propoxy-5-methanesulfonylamidophenyl)-1,5-dihydropyrazolo[3,4-d]pyrimidin-4-one (hereinafter referred to as Compound D) as active ingredient instead of Compound A used in that Example, and using amounts of compound D and lactose monohydrate as shown below:
Example Amount of Compound D Monohydrate
Example 1 is repeated, but using 4-phenylmethylamino-6-chloro-2-(3-pyridyl)quinazoline (hereinafter referred to alternatively as Compound E) as active ingredient instead of Compound A used in that example, and using amount of Compound E and lactose monohydrate as shown below:
The absorption time for 5-[2-ethoxy-5-(4-methylpiperazinylsulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, hereinafter Compound A, following administration by inhalation is measured in a rodent pharmacokinetic model which simulates inhalation as a route of administration. Male Wistar:Han rats used for this model are supplied by Harlan UK Ltd at 105 days of age and approximately 350 g weight. They are fed ad libitum with a standard laboratory diet and housed under controlled conditions (12 hours light/dark cycle; 20° C.) for at least one week prior to the experiment.
Compound A is dissolved, at a concentration of 1.75 mg/ml in 0.9% saline which has been acidified with 1M aqueous HCI (5 μl), giving a clear solution of pH 5.0. To the solution is added 1M aqueous NaOH (2μl) to increase the pH to 6.0, resulting in a very fine suspension. The suspension is administered to the rats directly into the trachea via the mouth and vocal chords from a 1.0 ml plastic syringe and Penn-Century microsprayer. Each animal receives a 2.1 μmol/kg dose in 200 μl of suspension.
The following surgical procedure is used to prepare the animals for the experiment: the animals are anaesthetised, initially with 4% halothane, maintained with 2% halothane, both in a 1:1 oxygen: nitrous oxide mixture carrier. The anaesthetised animals are shaved on their ventral neck and craniodorsal back, then swabbed with a solution of 5% Hibitane in a 70% solution of ethanol in water. A 10 mm longitudinal incision is made in the ventral neck, the connective tissue, salivary glands, omohyoideus and sternohyoideus muscle are separated by blunt dissection and the left common carotid artery is exposed, cleared of the Vagus nerve and then elevated. The carotid artery is clipped and cannulated with a 150 mm length of pp50 Portex tubing attached to a 1 ml syringe with a 26 G blunt needle filled with heparinised saline (500 i.u./ml in 0.9% saline). 10 mm of cannula is inserted, tied in place using braided silk sutures proximal and distal to the insertion point, and the clip is removed. A 2 mm incision and subcutaneous tunnel is made in the craniodorsal neck between the scapula with a 100 mm 16 G curved gavage needle emerging adjacent to the cannulation site and right salivary gland. The cannula is clamped 20 mm above the insertion point with artery forceps covered with polythene tubing to avoid damaging the cannula. The syringe and needle are removed from the cannula and the free end passed through the gavage needle. The gavage needle is withdrawn and the syringe and needle are replaced on the cannula. The forceps are removed and the cannula is further withdrawn to form a gentle curve across the trachea, allowing the incision to be closed without interference, enabling free blood flow to be tested by drawing back the syringe. 50 μl of heparinised saline is administered. The ventral incision is closed with Michel clips (12 mm×2.5 mm). A small suture loop is formed 10 mm distal to the cannula exit point and the exteriorised cannula tied to it so that it lies along the midline of the back. The cannula is again tested for free blood flow and a further 50 μl of heparinised saline is administered. The cannula is clamped with modified artery forceps near to the securing suture and cut to a length of 20 mm. A dressmakers pin is inserted to seal the cannula and the forceps are removed. Buprenorphine (Vetergesic, Reckin and Colman) is administered (0.06 mg/kg i.m.) and the animals are placed in cages over a heated pad until fully ambulatory. Thereafter, they are placed in metabolism cages with free access to food and water. The patency of the cannula is assessed immediately before experimentation.
At 0 min, i.e. prior to dosing with Compound A, a 300 μl sample of blood is collected from the cannula into a 2.0 ml plastic syringe containing 60 μl aqueous 3.8% tri-sodium citrate. Samples are immediately transferred to a 1.9 ml Eppendorf tube and held on ice. Serial blood samples are withdrawn at ten time intervals up to 1440 minutes after dosing with Compound A. At each time point, the withdrawn blood sample is replaced with an equal volume of heparinised saline (10 i.u./ml in 0.9% saline). After the final blood sample, the rats are killed by an overdose of sodium pentobarbitone (Sagatal, Rhone Merieux, UK), followed by cervical dislocation.
Withdrawn blood samples are analysed as follows:
Chilled whole blood samples are centrifuged at 11,000 rpm (Hereaus Biofuge 15) for 6 minutes and the plasma supernatant collected. The plasma (100 μl) is placed into an extraction tube containing acetonitrile (300 μl). After shaking for 10 minutes and centrifuging for 12 minutes, 200 μl of supernatant is transferred from the extraction tube to an autosampler vial and diluted with water (200 μl). The resulting sample is analysed by LC-MS/MS (liquid chromatography—tandem mass spectrometry). Calibration samples are prepared by adding 1 μl of a 10 mM solution of Compound A in dimethyl sulfoxide to 2 ml of blank rat plasma to give a 5 μM plasma standard, and diluting this plasma standard with blank plasma to give final concentrations of 1.67 μM, 0.56 μM, 0.19 μM, 0.062 μM, 0.021 μM and 0.007 μM. Validation samples are prepared by appropriate dilution of the 5 μM plasma standard with blank rat plasma to give concentrations of 1, 0.5, 0.2, 0.1 and 0.05 μM. The calibration standard samples are analysed by LC-MS/MS as for the withdrawn plasma samples. Calibration curves (y=mx+b), represented by the plots of the peak area ratios (y) of Compound A versus the concentrations (x) of the calibration samples, are generated using weighted (1/x) linear least-squares regression as the mathematical model. Concentrations in the withdrawn, calibration and validation samples are calculated from the resulting peak areas and the regression equation of the calibration curve. Pharmacokinetic parameters are calculated by Win Nonlin (Professional version 1.5) using non-compartmental analysis. The results (mean for 6 animals) give a Tmax of 5 minutes, i.e. the concentration of Compound A in plasma reaches a maximum within 5 minutes after intratracheal administration.
The absorption time Tmax for Compound A, following administration as a dry powder (particle size 0-5 μM) is measured in a rodent pharmacokinetic model which simulates inhalation as a route of administration essentially as described in Example 93.
In this case compound A (citrate salt) is formulated as a dry powder by micronisation to give an average particle diameter of less than 5 μM and then carefully diluted in lactose to give a mixture which contains Compound A diluted by weight to 40%. A calculated nominal dose of 8.4 μmol/kg is administered to each of 3 male Wistar:Han rats by administration directly into the trachea via the mouth and vocal chords from a Penn-Century dry powder delivery device actuated via a 2 ml syringe containing air as a propellent.
The time to peak plasma concentration is determined as 2 minutes.
The absorption time Tmax for 1-cyclopentyl-3-ethyl-6-(3-ethoxy-4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-one, hereinafter referred to as Compound C, following administration by dry powder inhalation is measured in a rodent pharmacokinetic model which simulates inhalation as a route of administration essentially as described for Compound A in Example 93 with the following significant variations:
Compound C is formulated as a dry powder to give a 6% blend with lactose.
A calculated nominal dose of 2.1 μmol/kg is administered to each of 4 male Wistar:Han rats by administration directly into the trachea via the mouth and vocal chords from a Penn-Century dry powder delivery device actuated via a 2 ml syringe containing air as a propellent.
The absorption time T max is determined as 2 to 20 minutes.
The absorption time Tmax for 1,3-dimethyl-6-(2-propoxy-5-methanesulfonylamidophenyl)-1,5-dihydropyrazolo[3,4-d]pyrimidin-4-one hereinafter referred to as Compound D, following administration by dry powder inhalation is measured in a rodent pharmacokinetic model which simulates inhalation as a route of administration essentially as described for Compound C in Example 95 with the following significant variations:
Compound D is formulated as a dry powder to give a 6% blend with lactose.
Each of 3 animals receives a dose equivalent to 2.1 μmol/kg.
The absorption time for Compound D, T max, is determined as 10 minutes.
Previous Patent: Aryl substituted purine analogues
Next Patent: Inhibitors of nucleoside metabolism


What Did We Learn From Victory Over Fulham?
Three games in a week ends unbeaten as the Eagles completed the double over Fulham, but what did we learn from the win?
1. Look at all the strikers! In the space of just a month Palace have somehow gone from being forced to play their wingers up front to having four centre forwards in the squad. Christian Benteke has looked fitter and sharper since returning from injury and his audacious bicycle kick reflected the confidence of a man who appears to have put the struggles of last season behind him. Benteke linked up well with Jordan Ayew, who had his best game in a Palace shirt and similarly looks like a player reborn. Then, of course, came Michy Batshuayi, who in his cameo appearance showed exactly why Palace were so keen to bring him in. The way he created space for himself to shoot in the box was something that we haven't seen from a Palace striker for some time, and a player with his goalscoring instinct should profit from playing alongside the likes of Benteke, Wilfried Zaha and Andros Townsend. Either way, Roy Hodgson now has a selection headache, but a very welcome one at that.
2. For all of the good things Palace now look capable of going forward, it is the back four who have been on top of their game for much of this season. With the exception of one moment in the first half, James Tomkins and Mamadou Sakho were once again flawless at the heart of the defence, not allowing Fulham a single shot on target and comfortably dealing with the threat of Aleksandar Mitrovic. Given Palace's wastefulness in front of goal this season there has been added pressure on the back four to remain watertight. Now, with Palace's attacking options deepened, the hope is that the forward men can return the favour and alleviate some of that pressure.
3. Jeffrey Schlupp has been made somewhat of a scapegoat this season, but rarely has he let Palace down when called upon. Much of the frustration with Schlupp is likely born out of the fact that he tends to be picked ahead of Max Meyer, who some believe should be starting in midfield every week. Schlupp may not be as technically gifted as the German is on the ball, but in the games that he's started has proved to be more effective going forward and now has four goals to his name this season. Schlupp joined the club primarily as a left back or a left winger – the fact that his manager has found a different way to utilise him is no reason for the 26-year-old to be unfairly maligned. Perhaps now it's time to cut Schlupp some slack.
4. Palace finally look like a team capable of winning without Zaha. Fulham might not have been the most testing of opposition, but wins against the West Londoners and Leicester have at least done away with the myth that Palace's squad has no talent beyond the Ivorian winger. Previous performances without Zaha have been lethargic and absent of cutting edge, but Roy Hodgson deserves credit for the way he set Palace up against Fulham. The Eagles were happy to let Fulham have the ball and invited the away side to try and break them down, consequently leaving space for Palace to break into when they won the ball back. Fulham might have enjoyed the lion's share of possession, but Palace were much more effective with it.
5. It's time for Palace to start looking up instead of down. The gap to the bottom three is still only four points, but with a strong squad and some winnable games coming up the Eagles should be looking to secure their Premier League status as soon as possible. There is no doubt that Palace have been underachieving so far this season, and now that Hodgson is equipped with a fully fit slate of players and a couple of reinforcements there can be no excuses for not pushing towards the top half of the table.


text:
GOP challenges recess appointments
Senate Republicans are teaming up with famed GOP lawyer Miguel Estrada.
By Seung Min Kim
Senate Republicans are teaming up with famed GOP lawyer Miguel Estrada to challenge President Barack Obama's controversial appointments to the National Labor Relations Board.
Estrada is a former attorney for the Solicitor General's office whose 2001 nomination to the D.C. Circuit was ultimately derailed by a Democratic-led filibuster two years later – a battle that became a cause célèbre for conservatives.
"Given Miguel's own experience with the confirmation process, it might make particularly a good case for him to represent us in this particular undertaking," Senate Minority Leader Mitch McConnell (R-Ky.) told reporters on Tuesday.
Aided by Estrada, Republican senators will be filing a friend-of-the-court brief in Noel Canning vs. the National Labor Relations Board — a Washington state case challenging a ruling from the NLRB that the company violated labor laws. Nearly 40 Senate Republicans said in February that they would join in on a court case, but had declined to identify one at the time.
"If the president can do what he did with the recess appointments, I believe he could be making appointments right now by just deciding 'they're not there, it's lunchtime, let's make some appointments and they'll meet the constitutional standard,' " Sen. Roy Blunt (R-Mo.) said Tuesday.
Obama infuriated Republicans in January when he bypassed the traditional Senate confirmation process and appointed Richard Cordray to lead the Consumer Financial Protection Agency and filled three vacancies on the labor board. Republicans had said the Senate was technically in session and subsequently, Obama would not have the power to make recess appointments.
The Obama administration had repeatedly defended its actions as legal, saying the Senate was not actually in session when it was convening a series of brief, pro forma sessions – designed to prevent Obama from making recess appointments. White House spokesman Eric Schultz reiterated that on Tuesday, saying in an e-mail: "We are confident that the president's authority to make recess appointments will be upheld by the courts."
When asked about the GOP's move, Senate Majority Leader Harry Reid (D-Nev.) simply replied: "How do I describe 'I don't care?' Because I don't."
Recess,
Solicitor General,
Recess Appointments,
Senate Republicans


text:
2023 Oscar Nominated Short Films: Live Action
Dates with showtimes for 2023 Oscar Nominated Short Films: Live Action
Run Time: 115 min.
Celebrate Awards Season at Gateway Film Center
As part of Awards Season at the Film Center each year, we are thrilled to present the Academy Award-nominated shorts program featuring the year's most spectacular Animation, Documentary, and Live Action short films.
The 2023 Awards Gala at Gateway Film Center is on Sunday, March 12! Join us as we raise our glasses with our community in celebration of the year's best films and most important filmmakers. Register here.
From 200 total qualifying films, these five are nominees in the Live Action Short Film category for the 95th Academy Awards. Winners will be announced at on Sunday, March 12.
More details soon!


text:
Flashback Friday #1: City of Bones by Cassandra Clare June 6, 2014
Filed under: Book Review,Books,Flashback Friday — Maura @ 12:00 am
Tags: 2007 release, 5 stars, angels, audiobook, author, blue bloods, book, book one, cassandra clare, cassie clare, debut, demons, diverse characters, diversity, ebook, faeries, fantasy, first book, flashback friday, harry potter, infernal devices, library, literature, low fantasy, march 2007 release, march release, mcelderry books, melissa de la cruz, mild spoilers, mortal instruments, mundane, paperback, paranormal, personal copy, reread, review, romance, series, shadow world, shadowhunter, shadowhunters, simon & schuster, simon pulse, supernatural, urban fantasy, vampires, villain, werewolves, YA, young adult
Flashback Friday is a feature I started here on The Whimsical Mama featuring books I read before I started blogging. Most reviews will come after rereading the book again. This is a biweekly feature. This week's selection is:
Pub date: 27 March 2007
Publisher: Margaret K McElderry Books, Simon & Schuster
Genre: Young Adult, Fantasy, Urban Fantasy, Paranormal
Format: paperback, personal copy,audiobook, via library
Status: Book one of The Mortal Instruments series
When fifteen-year-old Clary Fray heads out to the Pandemonium Club in New York City, she hardly expects to witness a murder― much less a murder committed by three teenagers covered with strange tattoos and brandishing bizarre weapons. Then the body disappears into thin air. It's hard to call the police when the murderers are invisible to everyone else and when there is nothing―not even a smear of blood―to show that a boy has died. Or was he a boy?
This is Clary's first meeting with the Shadowhunters, warriors dedicated to ridding the earth of demons. It's also her first encounter with Jace, a Shadowhunter who looks a little like an angel and acts a lot like a jerk. Within twenty-four hours Clary is pulled into Jace's world with a vengeance, when her mother disappears and Clary herself is attacked by a demon. But why would demons be interested in ordinary mundanes like Clary and her mother? And how did Clary suddenly get the Sight? The Shadowhunters would like to know…
Exotic and gritty, exhilarating and utterly gripping, Cassandra Clare's ferociously entertaining fantasy takes readers on a wild ride that they will never want to end.
I think it's fitting that my first review for Flashback Friday is starting with a binge reread of The Mortal Instruments in preparation for City of Heavenly Fire coming out. I picked up an ebook of City of Bones on sale from Amazon. Mary had recommended it to me in passing, so I decided to get it. Then I saw the announcement that Jamie Campbell Bower had been cast in the upcoming movie. I liked him in Sweeney Todd, Twilight, and Harry Potter, so I decided to read this series. I asked Mary about it again and she said to read it. I devoured the whole series and then The Infernal Devices. The Infernal Devices was read while snuggling my very clingy newborn. She's Team Jem like her mommy. (;
Anyway. Focus.
Once again, I was immediately sucked back into Cassie's incredible Shadow World. I've been to New York City once, but between The Mortal Instruments and Melissa de la Cruz's Blue Bloods, I feel that I know it much more than I learned in that single visit. I love that both star in a club scene. I'm much like Simon in not caring for clubs. I've only been a handful of times.
I think that Clary is a very strong and magnetic leading lady. She is thrown into a horrific situation and is able to relatively together. I'm sure it's part of her Shadowhunter legacy over her strengths as a 15/16 year old.
I absolutely love Simon. I think he's the true scene stealer of City of Bones. As a whole, I consistently love him. Yes, he irks me occasionally, but not as much as others. He's the best best friend Clary could ever want and most definitely needs. He has a lot thrown at him, but he remains calm and stays by Clary's side. A true friend for sure, sticking with her through thick and thin.
Jace is a strong personality to swallow. He's so full of himself that during a first read, it's easy to dislike him and wonder what the crap Clary is thinking. Multiple reads and it's still irritating, but you're more sympathetic to his issues.
Isabelle and Alec are introduced and set up to become excellent secondary characters. Isabelle is so sassy and I love it. Alec is well, Alec. Like Jace, he's on the rough side to handle in the first read and then he becomes so endearing.
On my list of villains, Valentine is definitely one of the better ones. Much like Voldemort in Harry Potter, he's a shadowy and feared name an dno one knows if he's alive or dead. I think not knowing is worse than Valentine himself in City of Bones. I find him a much more intimidating figure in City of Bones the book than the movie. As much as I love Johnathon Rhys-Meyers, I thought he was horribly miscast for Valentine.
For a debut novel, I think City of Bones is a well put together story. The world building and characters are incredible. It's full of actions and twists and turns. Every time I've read it, I've breezed through it. I highly recommend it and the series. I think it's worth the hype. Will all of the future spin off series set in the Shadowhunter universe be as great? I can't say. I do think this is a good paranormal series that can be enjoyed by young adult readers of all ages.
"Cassandra Clare was born overseas and spent her early years traveling around the world with her family and several trunks of fantasy books. Cassandra worked for several years as an entertainment journalist for the Hollywood Reporter before turning her attention to fiction. She is the author of City of Bones, the first book in the Mortal Instruments trilogy and a New York Times bestseller. Cassandra lives with her fiance and their two cats in Massachusetts."
You can find me online at
www.cassandraclare.com
I have a blog:
http://cassandraclare.livejournal.com/
and a Facebook:
http://www.facebook.com/Cassandraclare
and a Twitter:
www.twitter.com/cassieclare
Throwback Thursday #1: Blue Bloods by Melissa de la Cruz October 10, 2013
Filed under: Book Review,Books,Throwback Thursday — Maura @ 11:30 am
Tags: 2007 release, 4 stars, authors, blue bloods, book one, books, disney hyperion, fantasy, fiction, first book, hyperion, hyperion teens, literature, melissa de la cruz, murder, mystery, new york, new york city, nyc, paperback, personal copy, series, thriller, vampires, YA, young adult
Throwback Thursday is a meme I'm starting. TBT is when I'll review a book I read before I started blogging. This week's selection is:
Publisher: Hyperion
Genre: Young Adult Fiction, Fantasy
Format: paperback, personal copy
Status: Book one of the Blue Bloods series
When the Mayflower set sail in 1620, it carried on board the men and women who would shape America: Miles Standish; John Alden; Constance Hopkins. But some among the Pilgrims were not pure of heart; they were not escaping religious persecution. Indeed, they were not even human. They were vampires.The vampires assimilated quickly into the New World. Rising to levels of enormous power, wealth, and influence, they were the celebrated blue bloods of American society.
The Blue Bloods vowed that their immortal status would remain a closely guarded secret. And they kept that secret for centuries. But now, in New York City, the secret is seeping out. Schuyler Van Alen is a sophomore at a prestigious private school. She prefers baggy, vintage clothes instead of the Prada and pearls worn by her classmates, and she lives with her reclusive grandmother in a dilapidated mansion. Schuyler is a loner…and happy that way. Suddenly, when she turns fifteen, there is a visible mosaic of blue veins on her arm. She starts to crave raw food and she is having flashbacks to ancient times. Then a popular girl from her school is found dead… drained of all her blood. Schuyler doesn't know what to think, but she wants to find out the secrets the Blue Bloods are keeping. But is she herself in danger?
I came across Blue Bloods just after Masquerade was published in 2007. I would stroll up and down the aisles of the YA section at Barnes and Noble looking for new reads. I saw the cover of Blue Bloods and was immediately drawn in by the obvious vampire aspect. I mean, c'mon. There are bite marks on her neck. MUST be vampire involved! Honestly, I think this is when I came across Twilight, too, but put it back cause it didn't catch me. I thought what the heck, school's almost over so I'll pick it up. I started it the next school day. Wow. Back to B&N to get book 2! I actually "got in trouble" in my AP US History class for reading this one. My teacher told me if I was going to read in class at least make it look like I was paying attention. I said okay and set the book down on my desk and kept reading. (: Now, I wasn't being bad, I'm great with history. Can't remember what we were covering, but it was something I already knew well so… I read. (:
Let me introduce you to the big players:
Schuyler Van Alen – I love her. I identified so much with her! I wasn't part of the "cool kids" in HS. I never wanted to be, and I was okay with that. I loved my friends. I think the way she handles herself when she is thrust into the middle of the Committee is inspiring. She stays true to herself and never wavers.
Oliver Hazard Perry – Oh, Ollie. He's the best best friend a girl could hope for! His crush on Schuyler is adorable as well.
Bliss Llewellyn – I can kinda relate to Bliss being the new kid in school. I switched school systems in middle school.
Jack Force – Jack is the off limits hot jock in school. He's a year older than Schuyler and always seems unattainable. Schuyler nurses a secret crush she even tries to hide from Ollie. There's so much more to Jack than meets the eye and it just pulls you right in.
Mimi Force – Your stereotypical hateful Mean Girl. She's THE queen bee of the school and lords it over EVERYONE. She especially hates Schuyler because she might as well be a charity case. Mimi is so evil that you hope she has a redeeming aspect.
Everyone's world is thrown upside down when one of their fellow students is found dead. Schuyler is then among the new inductees of this year's crop of Committee recruits. It is revealed to her that she is a vampire, a fallen angel from heaven. Or so she thinks. She soon learns that she is a new creation. She's part human and part angel. This makes things extremely complicated as there has never been another like her. The Committee reveals that the girl who was found dead was killed and they don't know who did it.
The race is on to uncover a mystery that has been hidden from the Coven for generations. At each turn, things become clearer and more muddled. Schuyler teams up with Jack in trying to uncover the murderer. Certain things come to light that throw their suspicions down the drain. Schuyler's grandmother is attacked and she offers a piece to the puzzle that might help solve things. She says to find Schuyler's grandfather.
Blue Bloods is a quick and light read. It's full of NYC socialite drama with a dark twist. I never thought I would go for a book like this, but Melissa does such a fantastic job with the story line that some of the Mean Girls type drama actually makes it better overall.
The drama and intrigue continues in book two, Masquerade.
Recommended for: Those who have an interest in fallen angels, vampires, NYC, and lots of drama (but GOOD drama!)
Not recommended for: Those who don't care for drama or a new spin on vampires.


text: Lea-Beth Shapiro is an independent producer with experience in independent film, cable television, and network news. After graduating from New York University, she produced promos for USA Network and the Sci-Fi Channel and also worked for MTV before earning her Master's Degree in Broadcast Journalism from Columbia University. She then went on to work for NBC News and The Today Show. Lea-Beth relocated to Los Angeles to earn her Master's Degree in Film Producing at the American Film Institute. She is currently in pre-production on her third feature film and is looking forward to continuing the story of Rocco and Jasmine with more episodes of Fusion.


You're at the airport and the city centre is still a few miles away. So how do you go there? One company that offers shuttle transfers between airports and city centres is Terravision. But will you not have to wait long for your airport transfer to arrive? Will they drive you directly to the city centre? Will they be able to handle your luggage? Will the driver make sure that you arrive at the city centre safe and sound? How easy will it be to book a transfer via Terravision's website? And what will Terravision 's customer service department say if you ask for their help? The only people to tell you about these matters are the customers that have arranged a transfer via Terravision before. Read their reviews to know if they were satisfied with this service. Their opinions, ratings, experiences and other comments can help you to see if Terravision might be an option for your next city trip.
Terravision is a company that offers shuttle transports. They offer to transfer you and any luggage you might have from the airport to the city centre. That means you can get on the bus when you exit the airport terminal. They will bring you directly to the city centre. So they can bring you from Luton Airport to the city centre of London, from Eindhoven Airport to Amsterdam city centre or from Fiumicino Airport to Rome. Other transfers include Dublin Airport – Dublin, Bergamo Airport – Milan, Stansted Airport – London Victoria Station, Keflavik Airport – Reykjavik and some others. They charge no booking fee, so you won't have to pay extra for booking in advance. That also means you are sure of a spot on the bus. It's free to carry extra luggage with you. Besides airport transfers, they also offer city tours. So they can show you the best cities of Ireland, Norway, the Netherlands, Poland, Spain, Hungary, Greece, Portugal, Iceland, France, Belgium, Czech Republic, Sweden, Denmark and some other countries. They can show you places that you would miss if you visit the city or country on your own.
One of Terravision's bus tours.
You can book an airport transfer or a city tour via Terravision's website. Just select the departure date, arrival date and some other personal details. You can choose a one-way city tour or roundtrip. It's even possible to book a hotel via their website. If you run into some problems, Terravision will be available to help you out.
Have you ever been on a bus tour or arranged an airport transfer via Terravision? If so, we would like to know what your experience with this company was like. Did the bus take you safely to the city centre? Did their driver show you all the best places a city has to offer? Was it easy to make a booking via Terravision's website? And what is your personal experience with Terravision's customer service department? Please write a Terravision review and tell us everything.
i just used their services for one time till now but i am very impressed that they make my whole shifting luggage from here to there so easy and simple. Also, there is no hassle when you use their services. HIghly recommended.


MCA AMA, L.L.C. is a business entity registered in the state of New York under the legal form of DOMESTIC LIMITED LIABILITY COMPANY. It can be found in the register by the DOS ID 3347375. The company was established and set into the register at 11th April 2006 and its current status is ACTIVE. Company´s jurisdiction is in the state of NEW YORK in county SARATOGA. Process address of this entity is at 187 WOLF ROAD, SUITE 101, ALBANY, 12205, NEW YORK.
Entity Name MCA AMA, L.L.C.
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