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A slew of batting titles. Corkscrew stance. Humble. A gentleman. All-around good guy.
Stan the Man.
Stanley Frank Musial, the St. Louis Cardinals star who was one of the greatest players in the history of baseball, died Saturday. He was 92.
"I never heard anybody say a bad word about him - ever,'' Willie Mays said in a statement released by the Hall of Fame.
The Cardinals announced Musial's death in a news release and said he died at his home in Ladue, a St. Louis suburb, surrounded by family. The team said Musial's son-in-law, Dave Edmonds, informed the club of the slugger's death.
Earlier Saturday, baseball lost another Hall of Famer when longtime Baltimore Orioles manager Earl Weaver died at age 82.
Musial, the Midwest icon with too many batting records to fit on his Hall of Fame plaque, was so revered in St. Louis that two statues in his honor stand outside Busch Stadium - one just wouldn't do him justice. He was one of baseball's greatest hitters, every bit the equal of Ted Williams and Joe DiMaggio even without the bright lights of the big city.
Musial won seven National League batting crowns, was a three-time MVP and helped the Cardinals capture three World Series championships in the 1940s.
He spent his entire 22-year career with the Cardinals and made the All-Star team 24 times - baseball held two All-Star games each summer for a few seasons. He had been the longest-tenured living Hall of Famer.
"Stan will be remembered in baseball annals as one of the pillars of our game,'' Hall of Fame President Jeff Idelson said. "The mold broke with Stan. There will never be another like him.''
A pitcher in the low minors until he injured his arm, Musial turned to playing the outfield and first base. It was a stroke of luck for him, as he went on to hit .331 with 475 home runs before retiring in 1963.
Widely considered the greatest Cardinals player ever, Musial was the first person in team history to have his number retired. Ol' 6 probably was the most popular, too, especially after Albert Pujols skipped town.
"I will cherish my friendship with Stan for as long as I live,'' Pujols wrote on Twitter. "Rest in Peace.''
At the suggestion of a pal, actor John Wayne, Musial carried around autographed cards of himself to give away. He enjoyed doing magic tricks for kids and was fond of pulling out a harmonica to entertain crowds with a favorite, "The Wabash Cannonball.''
Scandal-free and eager to play every day, Musial struck a chord with fans throughout America's heartland and beyond. For much of his career, St. Louis was the most western outpost in the majors, and the Cardinals' vast radio network spread word about him in all directions.
Farmers in the field and families on the porch would tune in, as did a future president - Bill Clinton recalled doing his homework listening to Musial's exploits.
"We have lost the most beloved member of the Cardinals family,'' team chairman William DeWitt Jr. said.
Musial's public appearances dwindled in recent years, though he took part in the pregame festivities at Busch Stadium during the 2011 postseason as the Cardinals won the World Series. And he was at the White House in February 2011 when President Barack Obama presented him with the Presidential Medal of Freedom, America's highest civilian honor for contributions to society.
At the ceremony, President Obama said: "Stan remains to this day an icon untarnished, a beloved pillar of the community, a gentleman you'd want your kids to emulate.''
He certainly delivered at the plate.
Musial never struck out 50 times in a season. He led the NL in most every hitting category for at least one year, except homers. He hit a career-high 39 home runs in 1948, falling one short of winning the Triple Crown.
"Major League Baseball has lost one of its true legends in Stan Musial, a Hall of Famer in every sense and a man who led a great American life. He was the heart and soul of the historic St. Louis Cardinals franchise for generations,'' Commissioner Bud Selig said. "As remarkable as `Stan the Man' was on the field, he was a true gentleman in life. All of Major League Baseball mourns his passing.''
In all, Musial held 55 records when he retired in 1963. Fittingly, the accolades on his bronze Hall plaque start off with this fact, rather than flowery prose: "Holds many National League records ...''
He played nearly until his 43rd birthday, adding to his totals. He got a hit with his final swing, sending an RBI single past Cincinnati's rookie second baseman - that was Pete Rose, who would break Musial's league hit record of 3,630 some 18 years later.
Of those hits, Musial got exactly 1,815 at home and exactly 1,815 on the road. He also finished with 1,951 RBIs and scored 1,949 runs.
All that balance despite a most unorthodox left-handed stance. Legs and knees close together, he would cock the bat near his ear and twist his body away from the pitcher. When the ball came, he uncoiled.
Unusual, that aspect of Musial.
Asked to describe the habits that kept him in baseball for so long, Musial once said: "Get eight hours of sleep regularly. Keep your weight down, run a mile a day. If you must smoke, try light cigars. They cut down on inhaling.''
One last thing, he said: "Make it a point to bat .300.''
As for how he did that, Musial offered a secret.
"I consciously memorized the speed at which every pitcher in the league threw his fastball, curve, and slider,'' he said. "Then, I'd pick up the speed of the ball in the first 30 feet of its flight and knew how it would move once it has crossed the plate.''
It worked pretty well, considering Musial began his baseball career as a pitcher in the low minors. And by his account, as he said during his induction speech in Cooperstown, an injury had left him as a "dead, left-handed pitcher just out of Class D.''
Hoping to still reach the majors, he turned to another position. It was just the change he needed.
Musial made his major league debut late in 1941, the season that Williams batted .406 for the Boston Red Sox and DiMaggio hit in a record 56 straight games for the New York Yankees.
Musial never expressed regret or remorse that he didn't attract more attention than the cool DiMaggio or prickly Williams. Fact is, Musial was plenty familiar in every place he played.
Few could bring themselves to boo baseball's nicest superstar, not even the Brooklyn Dodgers crowds that helped give him his nickname, a sign of weary respect for his .359 batting average at Ebbets Field.
Many, many years before any sports fans yelled "You're the man!'' at their favorite athletes, Stan was indeed the Man.
Dodgers pitcher Preacher Roe once joked about how to handle Musial: "I throw him four wide ones and then I try to pick him off first base.''
Brooklynites had another reason to think well of Musial: Unlike Enos Slaughter and other Cardinals teammates, he was supportive when the Dodgers' Jackie Robinson broke baseball's color barrier in 1947. Bob Gibson, who started out with the Cardinals in the late 1950s, would recall how Musial had helped establish a warm atmosphere between blacks and whites on the team.
"I knew Stan very well,'' Mays said. "He used to take care of me at All-Star games, 24 of them. He was a true gentleman who understood the race thing and did all he could.''
Like DiMaggio and Williams, Musial embodied a time when the greats stayed with one team. He joined the Cardinals during the last remnants of the Gas House Gang and stayed in St. Louis until Gibson and Curt Flood ushered in a new era of greatness.
"Sad to hear about Stan the Man, it's an honor to wear the same uniform,'' current Cardinals slugger Matt Holliday tweeted.
The only year Musial missed with the Cardinals was 1945, when he was in the U.S. Navy during World War II. He was based in Pearl Harbor, assigned to a unit that helped with ship repair.
Before and after his military service, he was a star hitter.
"St. Louis has been lucky to have a player like Stan Musial. He will always be Mr. Baseball,'' Hall of Fame Cardinals manager Whitey Herzog said. "It's a very big loss. You can go around the world and you'll never find a better human being than Stan Musial.''
Musial was the NL MVP in 1943, 1946 and 1948, and was runner-up four other years. He enjoyed a career remarkably free of slumps, controversies or rivalries.
"Stan was a favorite in Cooperstown, from his harmonica rendition of `Take Me Out to the Ball Game' during Hall of Fame Induction Ceremonies, to the reverence he commanded among other Hall of Fame members and all fans of the game. More than just a baseball hero, Stan was an American icon and we will very much miss him in Cooperstown,'' Hall of Fame chairman Jane Forbes Clark said.
The Cardinals were dominant early in Musial's career. They beat DiMaggio and the Yankees in the 1942 World Series, lost to the Yankees the next year and defeated the St. Louis Browns in 1944. In 1946, the Cardinals beat Williams and the visiting Red Sox in Game 7 at Sportsman's Park.
Musial, mostly a left fielder then, starred with Terry Moore in center and Slaughter, another future Hall of Famer, in right, making up one of baseball's greatest outfields. Later on, Musial would switch between the outfield and first base.
Musial never played on another pennant winner after 1946. Yet even after the likes of Mays, Mickey Mantle and Hank Aaron came to the majors, Musial remained among baseball's best.
The original Musial statue outside the new Busch Stadium is a popular meeting place before games and carries this inscription: "Here stands baseball's perfect warrior. Here stands baseball's perfect knight.''
"Everybody's a Musial fan,'' Herzog once said.
Musial gave the press little to write about beyond his grace and greatness on the field. He didn't date movie stars, spike opponents or chew out reporters or umpires.
In 1958, he reached the 3,000-hit level and became the NL's first $100,000-a-year player. Years earlier, he had turned down a huge offer to join the short-lived Mexican League. He never showed resentment over the multimillion dollar salaries of modern players. He thought they had more fun in his days.
"I enjoyed coming to the ballpark every day and I think we enjoyed the game,'' Musial said in a 1991 Associated Press interview. "We had a lot of train travel, so we had more time together. We socialized quite a bit and we'd go out after ballgames.''
He was elected to the Hall of Fame in 1969, his first year of eligibility.
"It was, you know, a dream come true,'' Musial once said. "I always wanted to be a ballplayer.''
After retiring as a player, Musial served for years in the Cardinals' front office, including as general manager in 1967, when the Cardinals won the World Series.
In the 1970s, he occasionally played in Old-Timers' Day games and could still line the ball to the wall. He was a fixture for decades at the Cooperstown induction ceremonies and also was a member of the Hall's Veterans Committee. Often, after the Vets panel had voted, he'd pull out a harmonica conveniently located in his jacket pocket and lead the other members in a rendition of "Take Me Out to the Ball Game.''
Into the 2000s, Musial would spend time with the Cardinals at spring training, thrilling veterans and rookies alike with his stories.
Ever ready, he performed the national anthem on his harmonica at least one opening day at Busch Stadium. Musial learned his music during overnight train trips in the 1940s and in the 1990s was a member of a trio known as "Geriatric Jazz'' and collaborated on a harmonica instructional book.
Stanley Frank Musial was born in Donora, Pa., on Nov. 21, 1920, son of a Polish immigrant steelworker. He began his minor league career straight out of high school, in June 1938, and soon after married high school sweetheart Lillian Labash, with whom he had four children.
Musial fell in 1940 while trying to make a tough catch and hurt his left arm, damaging his pitching prospects. Encouraged by minor league manager Dickie Kerr to try playing the outfield, he did so well in 1941 that the Cardinals moved him up to the majors in mid-September - and he racked up a .426 average during the final weeks of the season.
In his best year, 1948, he had four five-hit games and batted .376, best in the National League. He also led his league that year in runs scored (135), hits (230), total bases (429), doubles (46), and triples (18).
In 1954, he set a major league record with five home runs in a doubleheader against the New York Giants. He hit .300 or better in 16 consecutive seasons and hit a record six home runs in All-Star play, including a 12th-inning, game-winning shot in 1955.
In 1962, at age 41, he batted .330 and hit 19 home runs. In his final game, on Sept. 29, 1963, he had two hits at Busch Stadium against the Reds and the Cardinals retired his uniform number.
He was active in business, too. He served as a director of the St. Louis-based Southwest Bank. He was co-owner of a popular St. Louis steakhouse, "Stan Musial and Biggie's,'' and a bowling alley with former teammate Joe Garagiola (leading to a bitter fallout that eventually got resolved). He later ran Stan the Man Inc., specializing in merchandise he autographed. Musial was known for handing out folded $1 bills.
A prominent Polish-American, he was a charter member of the National Polish-American Sports Hall of Fame and was warmly regarded by his ancestral country, which in 2000 dedicated Stan Musial Stadium in Kutno, Poland. Musial also was involved politically, campaigning for John F. Kennedy in 1960 and serving as Lyndon Johnson's director of the President's Council on Physical Fitness.
Musial's versatility was immortalized in verse, by popular poet of the times Ogden Nash, who in "The Tycoon'' wrote of the Cardinals star and entrepreneur:
"And, between the slugging and the greeting,
To the bank for a directors' meeting.
Yet no one grudges success to Stan,
Good citizen and family man,
Though I would love to have his job
One half tycoon, one half Ty Cobb.''
The Cardinals said Musial is survived by his four children, Richard, Gerry, Janet and Jean, as well as 11 grandchildren and 12 great grandchildren.
Musial's wife died in May 2012.
Funeral arrangements had not yet been finalized, the Cardinals said. The team set up a memorial site around one of Musial's statues at Busch Stadium.
Cardinals legend Stan Musial dies at 92
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When it comes to shooting, the Claremore Lady Zebras would rather drain three pointers than free throws.
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The Baltimore Ravens most formidable offensive threat these days is Justin Tucker, a quirky fellow whose skill set transcends kicking a football with uncanny accuracy.
Despite scoring only one touchdown in each of its last two games, Baltimore won twice because Tucker kicked four field goals against the New York Jets and five more in a 22-20 victory over Pittsburgh. -
NFL: Vikings QB Cassel on track to start for Ponder
Matt Cassel stepped on the platform, grasped the podium with both hands, looked around and grinned.
''It's nice being up here. I've never been up here before. It's a pretty nice setup,'' Cassel said as he surveyed the makeshift interview area the Minnesota Vikings have set up next to their indoor practice field. -
NFL: Rodgers limited as QB questions linger for Packers
Aaron Rodgers would rather not let the ''Will he-or-won't he'' questions linger until Sunday.
The Green Bay Packers' franchise quarterback expects a decision Friday -Saturday tops - whether he'll be medically cleared to face the Atlanta Falcons in a game crucial to the team's dwindling playoff prospects. - More Sports Headlines
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Somebody's child support payments are about to skyrocket. As BOSSIP reported, Ciara and Future are now engaged and it looks like the father of four (?) did a good job picking that ring. Via US Weekly reports: The 28-year-old


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Irish court: No 'right to die' for paralyzed woman
April 29, 2013 @ 11:55 am
DUBLIN (AP) - A paralyzed Irish woman who wants to die cannot legally commit suicide with her partner's help, Ireland's Supreme Court ruled Monday in a case that moved some in the courtroom to tears.
The seven-judge court said nothing in the country's Catholic-influenced 1937 constitution could authorize the deliberate taking of a life on humanitarian grounds. It said lawmakers could pass such a law to permit 59-year-old Marie Fleming to die at a time of her choosing, but no such statute existed yet.
Fleming, a former University College Dublin lecturer who is unable to move from the neck down because of advanced multiple sclerosis, testified that her life had been reduced to irreversible agony and that she feared choking to death because she couldn't swallow.
Her lawyers argued that suicide was not a crime in Ireland, therefore a disabled person unable to end his or her own life should receive that help to be equal under the law. They also contended that Fleming's right to personal autonomy under the European Convention on Human Rights was being violated.
But Chief Justice Susan Denham said EU law permits nations to set their own policies on euthanasia, and the Irish constitution contains "no explicit right to commit suicide or to determine the time of one's own death."
As Denham read the judgment, Fleming's partner, Tom Curran, and the couple's three adult children cried and held hands. Fleming herself could not come to the courthouse because, Curran said, she was battling a chest infection that itself might prove lethal.
Outside afterward, Curran said he would help his partner die regardless of criminal penalties if she decided to proceed. After telephoning her to say the verdict was as they both had expected, Curran said the couple was determined to end her life at their home in County Wicklow south of Dublin. If charged and convicted of assisting suicide, Curran would face a maximum prison sentence of 14 years.
"It's very difficult to understand how a person with a disability can be deprived of something that's legally available to everybody else. For that not to be discriminatory under the constitution, that's something we fail to understand. The constitution is there to protect people like Marie and to give them solace that they will be looked after," Curran said.
"We will now go back to Wicklow and live our lives until such time as Marie makes up her mind that she's had enough. And in that case, the court will have an opportunity to decide on my future," he said.
The family's lawyers say they could appeal their case to the European Court of Human Rights in Strasbourg, France. But Curran said that might prove to be too great an ordeal for his partner.
Most of the world, like Ireland, has not legalized assisted suicide for terminally ill patients. Belgium, Luxembourg, the Netherlands and Switzerland have legalized the practice as have the U.S. states of Montana, Oregon and Washington, all under restricted circumstances.
When Fleming testified in court in December _ she still can speak, though this ability is fading, with life-threatening choking episodes common _ she said she contracted multiple sclerosis 24 years ago and gradually lost her ability to move. The incurable disease attacks the central nervous system and often proves fatal. Fleming said doctors told her she would eventually become mute and most likely die from asphyxiation.
She said she had seriously considered killing herself three years ago, when she could have done this on her own because her arms still had movement, but Curran persuaded her to desist. She said she now regrets that decision.
When she testified, the judges left their benches to sit beside her, because her voice was so frail. She described a daily regimen involving seven caregivers, having to be slapped in the back to stop sudden struggles against suffocation, and 2 1/2-hour daily efforts to be showered that left her exhausted. She described recurring sensations of pain so searing that, she said, "I'm afraid my head will split open."
"When you have to be showered, toileted and fed, you start to feel like a nobody," she testified. "I want to go peacefully, in my own home, with the people I love around me."
The government-appointed Irish Human Rights Commission testified in support of her claim, while the government itself opposed her bid. And Catholic conservatives, opposed to euthanasia, welcomed the verdict.
"It's very important that we don't create a right to assisted suicide, because of the signal it sends out. We might normalize suicide," said David Quinn, director of a Catholic think tank in Dublin called the Iona Institute.
(Copyright 2013 The Associated Press. All rights reserved. This material may not be published, broadcast, rewritten or redistributed.)
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Announcing Considerable, an art show of sculpture, video, and installation in Gallery G107 and Closet Gallery (Sculpture Studio), the Sculpture Pad, and the Video Screening Room (Ahmanson Hall lower level) on Tuesday, December 10, 4:30-6:45 pm.
Graduate Public Practice and the 18th St Arts Center present a conversation with
Carolina Caycedo, Dana Yahalomi and Suzanne Lacy about social and political
actions demonstrated in an art practice and public performance.
Dana Yahalomi is founder and leader of Public Movement, a performative
research body that stages public political actions; Carolina Caycedo is an
L.A.-based artist whose work engages the public, and Suzanne Lacy,
Chair of Otis' MFA Public Practice program, creates large-scale
public performances and installations. -
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Sign up for Continuing Education courses with the early bird discount at the Spring 2014 Open House. Classes begin Feb 1.
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September03LecturesFine Arts lecture Julien Ceccaldi11:15AM Ahmanson Hall ForumOpen to the PublicFine Arts presents visiting artist Julien Ceccaldi, French Canadian artist from Montreal. Born in Canada in 1987, he currently works with many mediums like drawing, painting, and installations. He completed his BFA at Concordia University in 2009, and since then has shown his work around the world, including Mathew Gallery in Berlin, Bodega Gallery in Philadelphia, FOFA Gallery in Montreal, and Redbird Gallery in Montreal. He also produces unique pieces painting on garments and accessories which are hand-painted and presented as works of mass production. The narratives portrayed on the clothes and in his comics are centered on muscular manga heroines attempting to create the facade of thriving, desirable selves.
Series organized by Soo Kim, Director of Photography.2013-09-03 11:15 2013-09-03 11:15September03LecturesFine Arts lecture Julien Ceccaldi11:15AM 2013-09-03 11:15 | Ahmanson Hall Forum9045 Lincoln Blvd L.A. 90045Open to the PublicS M T W T F S 123456789101112131415161718192021222324252627282930Otis College of Art and Design
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hiphopfightsback: Madvillain(Source: real-hiphophead) Reblogged 2 days ago from hiphopfightsback (Originally from real-hiphophead) 491 notes
New #jormawhittaker record sounds great! Great work, @joyfulnoiserecs! (at le hotel bonesettier) # jormawhittaker Posted 2 days ago
Bonesetters "Figure It Out" test pressing! Listening to Day of the Dead! So glad we're so close! Preorder the vinyl through @instorerecordings and @rhedrholl! #thebonesetters #vinyl #music #indianapolis #indiana #dayofthedead #preorder #record (at le hotel bonesettier) # preorder indianapolis record music vinyl thebonesetters dayofthedead indiana Posted 2 days ago
bonesetters: Today's the day folks! We are happy to announce our next record, 'Figure It Out', will be put out on January 31st, 2014 by a brain trust of In Store Recordings and Rhed Rholl Recordings! Listen to our first single, Day of the Dead, above and preorder at one of these fine links:ISR: http://www.instorerecordings.com/product/preorder-the-bonesetters-figure-it-outRRR: http://rhedrholl.bigcartel.com/product/bonesetters-figure-it-out-preorder This is my band. We are releasing an album. You can pre-order it here! Good days ahead. # bonesetters record announcement vinyl rhed rholl in store recordings records band music indianapolis nashville indiana tennessee Reblogged 2 days ago from bonesetters 5 notes
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The Mr. Frank Churchils
Posted by Carrie on October 06, 1997 at 23:36:20:
Hello, I've been over at the P&P board for about a month now but also have been enjoying your Emma board.
I have the impression that the Emma with G. Paltrow (sorry, I don't have the numbers down yet) is the preferred Emma. For a few reasons, I have to say I prefer the Emma which aired on A&E.
I have to agree with another post that while (very) nice to look at the Mr. Knightly with G.P. is so nice to look at how could Emma have possibly not noticed him before? The other Mr. Knightly while not a "baberaham lincoln", was more appropriate for the part. He is the type where one's affection for him might creep up on you rather than hit you like a train (as in the case of Mr. Northram).
Also, the "Frank Churchills" in both movies, don't even begin to compare, for me. The "Frank" with G.P. made me think of a 13 year old boy wearing his father's clothes. I did not find him impressive, capable of such intrigues or inspiring any passions at all. Now the other "Frank", seemed much more appropriate for the roll. He was much more "manly" and yet maybe not too manly, so as to undertake such a ploy. (Handsome enough for Jane to undertake such a ploy also)
So, anyway, these are my musings. Sorry, I'm sure this has all been discussed before. I really enjoy reading Emma. For some reason I've tended to underestimate it each time I've read it (only twice), and always enjoy it very much.
Posting followups to old messages is disabled; instead go to the main index and post a new message which mentions this one.


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Book Recommendation In her debut guide to practical self-love and spirituality, You Are More Than Good Enough: A Journey to Freedom, Joy, and … [Continue reading...]
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How to be Successful in the Dating Game So it's the beginning of 2012 and you're still single. Have you been dating someone where things are just … [Continue reading...]
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Efficacy, safety and pharmacokinetics of candesartan cilexetil in hypertensive children from 1 to less than 6 years of age.
ABSTRACT Few antihypertensive drugs are available in appropriate formulations for infants.
We investigated candesartan cilexetil liquid suspension in a 4-week, randomized double-blind dose-ranging study followed by a 1-year open-label treatment phase (NCT00244621). The drug was administered at 0.05, 0.2 or 0.4 mg/kg per day in 93 hypertensive children aged 1-5 years, of whom 74 had underlying renal disorders.
A single-dose pharmacokinetic profile was obtained in 10 patients. At 4 weeks, SBP declined dose dependently by 6, 9 and 12 mmHg in the three dose groups (P = 0.01), and DBP by 5, 8 and 11 mmHg (P = 0.03). During the 1-year follow-up, responder rates (both SBP and DBP < 95th percentile) ranged from 48.2 to 54.1%. Candesartan lowered the blood pressure regardless of age, sex, BMI or cause of hypertension. The pharmacokinetic profile was independent of age, sex and weight, and was similar to that in older children and adults. In participants with proteinuric renal disease (urinary albumin/creatinine ratio >30 mg/g), a 57% median decline in albumin/creatinine ratio was observed at 4 weeks, which was dose related (P = 0.007) and persisted with long-term administration. There were no notable electrocardiographic or laboratory abnormalities. A mild decline in estimated glomerular filtration rate observed at 4 weeks was not progressive with long-term dosing. Candesartan was generally well tolerated; two patients withdrew for adverse events (fatigue and worsening glomerulopathy). One patient died, probably from acute-on-chronic renal failure.
Candesartan cilexetil dose-dependently decreases blood pressure and albuminuria in hypertensive infants and is generally well tolerated.
- Daniel K Benjamin, P Brian Smith, Pravin Jadhav, Jogarao V Gobburu, M Dianne Murphy, Vic Hasselblad, Carissa Baker-Smith, Robert M Califf, Jennifer S Li[show abstract] [hide abstract]
ABSTRACT: Historically, drugs prescribed for children have not been studied in pediatric populations. Since 1997, however, a 6-month extension of marketing rights is granted if manufacturers conduct Food and Drug Administration-defined pediatric trials. In nearly half of the drugs studied, there were unexpected results in dosing, safety, or efficacy compared with adult studies, including failure of half of the antihypertensive dose-response trials, which are pivotal for deriving dosing recommendations. We sought to define design elements that might have contributed to these trial failures by combining patient-level data from 6 dose-ranging antihypertensive efficacy trials completed for pediatric exclusivity and submitted to the Food and Drug Administration from 1998 to 2005. We evaluated dosing, primary end point, and other components to assess underlying reasons for failure to show efficacy in children. Of 6 trials examined, 3 showed a dose response; 3 did not. Eligibility criteria were similar across studies, as were subject demographics. Successful studies showed large differences in doses, with little or no overlap between low, medium, and high doses; failed trials used narrow dose ranges with considerable overlap. Successful trials also provided pediatric formulations and used reduction in diastolic, not systolic, blood pressure as the primary end point. Careful attention to pediatric pharmacology and selection of primary end points can improve trial performance. We found poor dose selection, lack of acknowledgement of differences between adult and pediatric populations, and lack of pediatric formulations to be associated with failures. More importantly, our ability to combine data across trials allowed us to evaluate and potentially improve trial design.Hypertension 05/2008; 51(4):834-40. · 6.87 Impact Factor - SourceAvailable from: Arvind BaggaJoseph T Flynn, Kevin E C Meyers, Jose Pacheco Neto, Rejane de Paula Meneses, Aleksandra Zurowska, Arvind Bagga, Lionel Mattheyse, Victor Shi, Jitendra Gupte, Susan Solar-Yohay, Guangyang Han[show abstract] [hide abstract]
ABSTRACT: The efficacy and safety of valsartan were studied in 90 children (mean age: 3.2 years; 60% male; 30% black) with systolic blood pressure (SBP) > or =95th percentile. Nineteen percent received valsartan in addition to previous antihypertensive therapy. Subjects were randomly assigned to low-, medium-, or high-dose valsartan for 2 weeks (phase 1) and then reassigned randomly to placebo or to remain on the same valsartan dose for 2 additional weeks (phase 2). After this, subjects were enrolled into a 52-week, open-label phase during which valsartan was dosed to achieve SBP <95th percentile. Statistically significant reductions in SBP and diastolic blood pressure of approximately 8.5 mm Hg and 5.7 mm Hg, respectively, were observed at the end of phase 1 in all of the valsartan dose groups. SBP and diastolic blood pressure were also significantly lower during phase 2 in valsartan recipients compared with placebo recipients. SBP <95th percentile was achieved in 77.3% of subjects during the open-label phase. Adverse events were minor and occurred at similar frequencies in each of the 3 dose groups in phase 1 and at equal frequencies in the valsartan and placebo arms in phase 2. Serious adverse events and drug-related adverse events occurred infrequently during both the double-blind (2.2% and 5.6%, respectively) and open-label (14.8% and 6.8%, respectively) portions of the study. Valsartan treatment had no demonstrable negative effects on growth and development. In this study, the first trial of an antihypertensive agent conducted in children <6 years of age, valsartan effectively lowered SBP and diastolic blood pressure compared with placebo.Hypertension 06/2008; 52(2):222-8. · 6.87 Impact Factor - [show abstract] [hide abstract]
ABSTRACT: This 4-week randomized, double blind, placebo-controlled study (N=240), 1-year open label trial (N=233), and single-dose pharmacokinetic study (N=22) evaluated candesartan cilexetil (3 doses) in hypertensive children aged 6 to 17 years. Seventy-one percent were 12 years of age or older, 71% were male, and 47% were black. Systolic (SBP)/diastolic (DBP) blood pressure declined 8.6/4.8-11.2/8.0 mm Hg with candesartan and 3.7/1.8 mm Hg with placebo (P<.01 compared to placebo for SBP and for the mid and high doses for DBP; placebo-corrected 4.9/3.0-7.5/6.2 mm Hg). The slopes for dose were not, however, different from zero (P>.05). The response rate (SBP and DBP <95th percentile) after 1 year was 53%. The pharmacokinetic profiles in 6- to 12- and 12- to 17-year-olds were similar and were comparable to adults. Eight candesartan patients discontinued treatment because of an adverse event. Candesartan is an effective, well-tolerated antihypertensive agent for children aged 6 to 17 years and has a pharmacokinetic profile that is similar to that in adults.Journal of Clinical Hypertension 10/2008; 10(10):743-50. · 2.36 Impact Factor
Page 1
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Efficacy, safety and pharmacokinetics of candesartan cilexetil
in hypertensive children from 1 to less than 6 years of age
Franz Schaefera, Johan van de Walleb, Aleksandra Zurowskac,
Charlotte Gimpela, Koen van Hoeckd, Dorota Drozdze, Giovanni Montinif,
Ingretta V. Bagdasorovag, Jonathan Sorofh, Jennifer Suggh, Renli Tengh,
James W. Hainerh, for the Candesartan in Children with Hypertension (CINCH)
Background Few antihypertensive drugs are available in
appropriate formulations for infants.
Method We investigated candesartan cilexetil liquid
suspension in a 4-week, randomized double-blind
dose-ranging study followed by a 1-year open-label
treatment phase (NCT00244621). The drug was
administered at 0.05, 0.2 or 0.4mg/kg per day in 93
hypertensive children aged 1–5 years, of whom 74 had
underlying renal disorders.
Results A single-dose pharmacokinetic profile was
obtained in 10 patients. At 4 weeks, SBP declined dose
dependently by 6, 9 and 12mmHg in the three dose groups
(PU0.01), and DBP by 5, 8 and 11mmHg (PU0.03). During
the 1-year follow-up, responder rates (both SBP and
DBP<95th percentile) ranged from 48.2 to 54.1%.
Candesartan lowered the blood pressure regardless of age,
sex, BMI or cause of hypertension. The pharmacokinetic
profile was independent of age, sex and weight, and was
similar to that in older children and adults. In participants
with proteinuric renal disease (urinary albumin/creatinine
ratio >30mg/g), a 57% median decline in albumin/
creatinine ratio was observed at 4 weeks, which was dose
related (PU0.007) and persisted with long-term
administration. There were no notable electrocardiographic
or laboratory abnormalities. A mild decline in estimated
glomerular filtration rate observed at 4 weeks was not
progressive with long-term dosing. Candesartan was
generally well tolerated; two patients withdrew for
adverse events (fatigue and worsening glomerulopathy).
One patient died, probably from acute-on-chronic renal
Conclusion Candesartan cilexetil dose-dependently
decreases blood pressure and albuminuria in hypertensive
infants and is generally well tolerated. J Hypertens 28:000–
000 Q 2010 Wolters Kluwer Health | Lippincott Williams &
Journal of Hypertension 2010, 28:000–000
Keywords: candesartan cilexetil, pediatric hypertension, pediatric renal
Abbreviations: A/C ratio, albumin/creatinine ratio; ACEIs, angiotensin-
converting enzyme inhibitors; ARBs, angiotensin receptor blocking agents;
AUC, area under the plasma concentration curve; CI, confidence interval;
CINCH, Candesartan IN Children with Hypertension; Cmax, maximum
plasma concentration; FDA, US Food and Drug Administration; GFR,
glomerular filtration rate; IQR, interquartile range; RAS, renin–angiotensin
system; SD, standard deviation; SDS, standard deviation scores; t1/2, half
life; tmax, time to Cmax
aDivision of Pediatric Nephrology, Center for Pediatrics and Adolescent
Medicine, University of Heidelberg, Heidelberg, Germany,bPediatric Nephrology,
UZ Ghent, Ghent, Belgium,cDepartment of Pediatric and Adolescent
Nephrology, Medical University of Gdansk, Gdansk, Poland,dPediatric
Nephrology, University Antwerp, University Hospital Antwerp, Edegem,
Belgium,eDepartment of Pediatric Nephrology, Jagiellonian University
Medical College, Krakow, Poland,fPediatric Nephrology, University
Children's Hospital, Bologna, Italy,gCity of Children Clinical Hospital #7,
Kyiv, Ukraine andhClinical Development Cardiovascular, AstraZeneca LP,
Wilmington, Delaware, USA
Correspondence to Dr Franz Schaefer, Division of Pediatric Nephrology, Center
for Pediatrics and Adolescent Medicine, Im Neuenheimer Feld 430, 69120
Heidelberg, Germany
E-mail: firstname.lastname@example.com
Received 13 August 2009 Revised 15 December 2009
Accepted 17 December 2009
Although hypertension in older children and adolescents
is typically classified as primary in cause, in young chil-
dren and infants an elevated blood pressure (BP) is
usually secondary to an underlying comorbid condition
[1]. In either case, expert groups recommend the low-
ering of elevated BP by employing antihypertensive drug
therapy when necessary [1]. Increasingly, clinical trials
are indicating that the BP-lowering effects of antihyper-
tensive agents in children areconsistent withtheireffects
in adults, but there have been some exceptions [2–5].
Furthermore, there are very few reported controlled
clinical trials in very young hypertensive children in
which the hypertension is usually a secondary condition
and is often more severe. Thus, careful study of anti-
hypertensive agents in pediatric populations is important
to guide pharmacological treatment and particularly for
the young hypertensive child.
The study of antihypertensive drugs which inhibit the
renin–angiotensin system (RAS), including angiotensin-
converting enzyme inhibitors (ACEIs) and angiotensin
Original article1
0263-6352 ? 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI:10.1097/HJH.0b013e328336b86b
Page 2
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
receptor blocking agents (ARBs), is particularly germane,
as these agents are also employed to treat some childhood
renal diseases [6,7] and their safety requires evaluation as
insufficiency in susceptible patients [8].
Candesartan is an ARB that selectively inhibits the
angiotensin type 1 receptor by binding tightly to and
dissociating slowly from the receptor site [9]. It is admi-
nistered orally as candesartan cilexetil, which is hydro-
lyzed to candesartan upon absorption from the gastroin-
testinal tract. It lowers BP with once-daily dosing in
adults within a dose range of 2–32mg [10]. In children
6–17 years of age, it lowers SBP and DBP by about 8.6–
11.2/4.8–8.0mmHg over a similar dose range [11].
The Candesartan IN Children with Hypertension
(CINCH) program evaluated candesartan in hyperten-
sive children of 1–17 years of age. A tablet formulation
was studied in 6–17-year-olds and a liquid (suspension)
in 1 to <6-year-olds. The current report describes the
results of following studies in 1 to <6-year-olds: a 4-week
dose ranging study, a 1-year clinical experience study and
a single-dose pharmacokinetic substudy. The study [11]
in children of 6–17 years of age was reported previously.
The CINCH program was designed to comply with a US
directed by the FDA, the program excluded children
under 1 year of age, given the potential for RAS-inhibit-
ing drugs to impair renal maturation in the incompletely
developed kidney [12].
Study design
The 4-week dose-rangingstudy was randomized, double-
blind and parallel-group in design, and was conducted in
18 sites in the United States/Puerto Rico and 20 sites in
Europe. The protocol permitted enrollment of children
from 1 to 6 years of age, weighing 10–40kg, receiving no
antihypertensive treatment or receiving a stable dose of
up to two antihypertensive agents (ACEIs and ARBs
Potentially eligible patients first entered a 1-week single-
blind placebo period, after which those found study-
eligible (SBP or DBP more than the 95th percentile of
the height-corrected age and sex-specific normal BP
distribution [1] but not exceeding the 95th percentile
by >20/10mmHg) were randomly allocated to one of
three dose levels of candesartan (0.05, 0.20 or 0.4mg/kg)
in a 1:1:1 ratio. Study drug was administered as a liquid
oral suspension with the concentration adjusted for each
child to a standard volume (5ml for children<25kg,
10ml for those >25kg); all children received half the
final dose during the first week (2.5 or 5.0ml). Relative to
a tablet formulation, the liquid suspension induces a
slightly higher maximum peak concentration but it is
equivalent with regard to area under the plasma concen-
tration curve (AUC).
The study protocol excluded persons with hypertension
secondary to endocrinopathies and uncorrected coarcta-
tion oftheaorta,aswellasthosewithbilateralrenalartery
stenosis, uncompensated nephrotic syndrome, insulin-
dependent diabetes mellitus and significant valvular
heart disease. Patients with an estimated glomerular
filtration rate (eGFR) of less than 30ml/min per
1.73m2were also excluded. Clinic visits for BP and safety
assessments occurred at weekly intervals.
The long-term (1-year) open-label clinical experience
study enrolled patients who completed participation in
the 4-week dose-ranging study. Investigators could begin
candesartan 0.2mg/kg per day, and adjust the dose as
necessary and as tolerated to a maximum of 0.4mg/kg.
The use of supplemental antihypertensive agents was
permitted if needed. Follow-up visits were every 4 weeks
for two visits, then every 8 weeks for five visits, then
1 month to the last visit.
For the pharmacokinetic substudy, 10 patients (five boys
and five girls) weighing between 11 and 22kg received a
single dose of candesartan 0.2mg/kg, then had serial
blood samples collected over 28h for determination of
candesartan plasma concentrations for pharmacokinetic
BPs were taken with the child in a resting sitting position
using an oscillometric device (Dinamap; GE Medical
Systems, Milwaukee, Wisconsin, USA) and each deter-
mination represented the mean of three consecutive
readings taken at least 1min apart. Laboratory tests
(hematology, chemistry and urinalysis) and electrocardio-
graphic findings were collected at the screening visit,
week 4 of the dose-ranging study and at weeks 28 and 56
in the long-term study. Freshly voided morning urine
specimens were collected for albumin, protein and crea-
tinine at baseline, week 4 and week 56.
Study participants (parents or guardians) provided
written informed consent prior to participating in the
study, and the protocol was approved by each investi-
gator's ethics committee or institutional reviewboard and
regulatory authority as per local regulations.
Statistical methods
In the dose-rangingstudy, change from baseline in sitting
SBP served as the primary efficacy measure; the primary
analysis evaluated the change as a function of relative
dose(1:4:8)bylinear regressionusingtheintent-to-treat
population. Change in DBP was analyzed similarly.
Median percentage change in albumin/creatinine (A/C)
ratio was evaluated by a nonparametric test for corre-
Journal of Hypertension
2010, Vol 28 No 00
Page 3
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The sample size in the dose-ranging study was based on
the FDA written request that the 1 to less than 6-year-old
population should represent one-quarter of the patients
in the overall program (1 to <17-year-olds). The sample
size in the overall program was sufficient to detect an
(a¼0.05. 1?b¼0.80). Participants completing the dose-
ranging study were eligible to enter the long-term study.
For both the dose-ranging study and the long-term
clinical experience study, therapeutic response was
defined as both SBP and DBP less than the 95th per-
centile and was expressed as a response rate (RR), which
was the simple proportion of responders in the intent-to-
treat population.
The pharmacokinetic parameters included maximum
plasma concentration (Cmax), time to Cmax(tmax), AUC
calculated by the trapezoidal rule with extrapolation to
infinity and half-life (t1/2) calculated as 0.693/kel. The
effect of age and body weight on the pharmacokinetic
parameters was also examined.
Longitudinal growth (height and weight) and BMI were
evaluated by standard deviation scores (SDS) relative to
age and sex-specific population distributions [13]. GFR
was estimated by the new Schwartz et al.'s [14] formula.
A planned analysis also combined the data from the 4-
week dose-ranging study in 1 to less than 6-year-olds and
the data from the previously reported 4-week data in 6 to
less than 17-year-olds into a linear regression analysis of
change in BP as a function of relative dose (1:4:8).
Laboratory methods
Hematology, chemistry and urinalysis tests (including
microalbumin/creatinine ratio) were preformed by a cen-
tral laboratory (Quintiles, Marietta, Georgia, USA and
Livingston, Scotland, UK). Serum creatinine was deter-
mined by an enzymatic assay (Roche Diagnostics, Basel,
Switzerland). Plasma candesartan concentrations were
analyzed by Quintiles, Sweden, based on established
methods [15].
Study population
Of the 118 patients screened, 93 were randomized
and received study treatment. All 93 were included in
the intent-to-treat analysis [n¼29 in the low-dose
(0.05mg/kg), 32 in the medium-dose (0.20mg/kg) and
32 in the high-dose group (0.40mg/kg)]. Seven patients
for an adverse event) and for these patients a week 4 BP
value was imputed using the last available observation.
Of the 93 randomized patients, 45 were from the United
States and Puerto Rico and 48 from European study
centers. The distribution of age, sex, ethnic background,
anthropometric variables, underlying diseases and base-
line BP characteristics appear in Table 1. In almost three
quarters of the patients, the hypertension was secondary
to an underlying cause, primarily renal disease. The
kidney disorders included renal hypoplasia or dysplasia,
reflux or obstructive uropathy (n¼36), polycystic kidney
disease (n¼14), nephrotic syndrome (n¼5), hemolytic
vascular disorders and infections (n¼13).
Candesartan in hypertensive infants Schaefer et al.3
Table 1
Demographic and baseline characteristics
Low dose
Medium dose
High dose
Men, n (%)
Race, n (%)
Age (years)
Height (cm)
Weight (kg)
BMI (kg/m2)
BMI > 95th percentile, n (%)
Renal disease, n (%)
GFR <60ml/min per 1.73m2, n (%)
Albumin/creatinine ratio >30mg/g, n (%)
SBP (mmHg)
DBP (mmHg)
Type of hypertension, n (%)
DBP only
SBP only
Antecedent antihypertensive therapy, n (%)
18 (62.1) 22 (68.8)20 (62.5)60 (64.5)
20 (69.0)
6 (20.7)
3 (10.3)
6 (20.7)
23 (79.3)
3 (10.3)
12 (41)
25 (78.1)
5 (15.6)
2 (6.3)
10 (31.3)
23 (71.9)
4 (12.5)
11 (34)
26 (81.3)
6 (18.2
0 (0)
5 (15.6)
23 (71.9)
3 (0.9)
9 (28)
71 (76.3)
17 (18.3)
5 (5.4)
21 (22.6)
69 (74.2)
10 (11)
32 (34)
2 (6.9)
7 (24.1)
6 (20.7)
14 (48.3)
10 (34.5)
0 (0)
7 (21.9)
7 (21.9)
18 (56.3)
15 (46.9)
1 (3.10
6 (18.8)
8 (25.0)
17 (53.1)
14 (43.8)
3 (3.2)
20 (21.5)
21 (22.6)
49 (52.7)
39 (41.9)
aThe 'no-hypertension group' represents a difference in the study site's determination of the 95th percentile (using BP charts) vs. the percentiles calculated by a central
program. GFR, glomerular filtration rate.
Page 4
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Baseline mean (?SD) eGFR was 89?44ml/min/1.73m2;
eGFR of less than 90ml/min/1.73m2. Median baseline
urinary A/C ratio was 36mg/g [interquartile range (IQR)
Thirty-nine patients had been treated with antihyper-
tensive agents prior to entering the study; 23 continued
antihypertensive agents during the 4-week dose–
response period, most commonly calcium channel block-
ers or diuretics.
Antihypertensive efficacy
Dose–response period
BP declines were apparent within the first week of
candesartan treatment and by the end of 4 weeks, mean
SBP declined by 6–12mmHg in the three dose groups in
a monotonic and dose-related fashion (P¼0.014); DBP
similarly declined (5.2–11.1mmHg, P¼0.03) (Fig. 1).
The proportion of patients achieving both SBP and DBP
less than 95th percentile were 27.6% [95% confidence
interval (CI) 11–44], 50% (95% CI 33–67) and 65.6%
(95% CI 49–82) for the low, medium and high-dose
groups, respectively.
The reductions in BP appeared independent of age (1 to
<2 vs. 2 to <6 years), sex, race or cause of hypertension
(primary vs. secondary). BP reduction was slightly, but
insignificantly more marked in children exceeding the
95th BMI percentile than in nonobese children. Also,
the BP response at 4 weeks did not differ between the
54 children that were naive to antihypertensive pharma-
cologic treatment (?10.2?9.7mmHg for SBP and
?8.7?11.2mmHg for DBP) and the 39 patients who
received such antecedent treatment (?7.5?8.3mmHg
for SBP and ?7.5?8.3mmHg for DBP; P¼0.18 and
P¼0.53, respectively).
Long-term open-label period
A total of 85 patients enrolled in and 81 completed the 1-
year clinical experience study (one discontinued for an
adverse event and three for other reasons).
The mean administered candesartan dose remained rela-
tively constant at 0.2mg/kg (range 0.06–0.41mg/kg).
The prescribed candesartan dose was increased at least
once for 61 patients and decreased at least once for 25. In
addition, 14 patients received concomitant antihyper-
tensive treatment at some point during the open-label
period; 11 carried over background antihypertensive
therapy from the double-blind period. Twelve patients
between their participation in the double-blind period
and long-term periods. The supplemental agents in the
long-term period included calcium channel blockers
(n¼7), thiazide diuretics (n¼2), b-blockers (n¼3) and
other agents (n¼1 per agent).
BP (mean?SD) control remained constant at 103?10.6/
61.7?8.0, 103?9.9/63?8.9, 102?10.3/61.6?9.2 and
102?9.7/62.5?8.4mmHg at week 4 (end of double-
blind period), week 20, week 36 and week 56, respect-
ively. The fraction of patients with full SBP and DBP
control (responder rate) was 51.8% (95% CI 41–62),
48.2% (95% CI 38–59), 51.8% (95% CI 41–62) and
54.1% (95% CI 44–65) at weeks 4, 20, 36 and 56,
respectively. The antihypertensive RR appeared inde-
pendent of age (1 to >2 vs. 2 to <6 years), sex, race or
cause of hypertension (primary vs. secondary). The
response was slightly more marked in children exceeding
the 95th BMI percentile than in nonobese children,
although significance was not reached (see Fig. 2). Com-
pliance with study treatment according to the difference
in dispensed and returned study medication was greater
than 80% for 96% of the study participants.
Antiproteinuric efficacy
The majority of children with chronic kidney disorders
presented with variable degrees of proteinuria. Signifi-
cant albuminuria (>30mg/g creatinine) was observed in
32 children. In these children, median albuminuria was
104mg/g creatinine (IQR 429, total range 31–5327) and
decreased by a median of 56.7% (IQR 70%) during the
double-blind period (18, 61 and 69% at the low, medium
and high dose; P¼0.007). The antialbuminuric effect of
Journal of Hypertension
2010, Vol 28 No 00
Fig. 1
0.05 mg/kg
n = 29
0.2 mg/kg
n = 32
Candesartan dose
Change in SBP (mmHg)
Change in DBP (mmHg)
0.4 mg/kg
n = 32
Mean (SD) change from baseline in SBP (upper panel) and DBP (lower
panel) during double-blind intervention period. P value for dose
response by linear regression.
Page 5
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candesartan in the initially albuminuric children per-
sisted during the open-label period; at week 56, a 59%
median (IQR 59%) reduction relative to baseline was
preserved (see Fig. 3). The changes in urinary A/C ratio
were not correlated with the changes in BP.
Pharmacokinetic study
Quantifiable plasma candesartan concentrations were
obtained in 10 participants following a 0.2mg/kg cande-
sartan cilexetil dose. The mean (?SD) AUC was
3.2?1.0h and t1/25.7?1.4h. No correlation between
Cmaxor AUC and age, or body weight was observed. The
pharmacokinetic parameter values were consistent with
those determined for the liquid suspension in adult
volunteers and the t1/2values were consistent with those
for the tablet formulation both in adults and in hyper-
tensive children 6–17 years of age [11].
Candesartan was generally well tolerated; two patients
discontinued treatment because of an adverse event
(abdominal pain or worsening renal insufficiency). One
2-year-old child with steroid-resistant nephrotic syn-
drome died. This Ukrainian child had a 15-month history
of nephrotic proteinuria largely unresponsive to immu-
nosuppressive medications, consistent with focal-seg-
mental glomerulosclerosis. Serum creatinine increased
after start of candesartan therapy from 0.6 to 1.1mg/dl
but stabilized subsequently. After 6 months of unevent-
ful treatment with good BP control, lowered proteinuria
and improved clinical condition, the child developed
acute diarrhea and expired at home within 14h. Post-
mortem analysis showed pulmonary and brain edema.
The fatal course was possibly due to acute-on-chronic
renal failure provoked by incidental diarrhea-induced
hypovolemia during chronic ARB treatment. In addition,
a 3-year-old with nephrotic syndrome thrombosed the
venacavaandunderwentsuccessful openthrombectomy.
The most commonly reported adverse events overall
included upper respiratory tract infections, urinary tract
infections and gastroenteritis symptoms. There were no
notable adverse findings in laboratory parameters or
electrocardiographic data. Mean serum creatinine and
serum potassium levels did not change significantly.
Mean (?SD) eGFR declined by 5.4?20ml/min per
from baselineto
(P<0.05), with no further decline from week 4 to week
56 (?2.1?27ml/min per 1.73m2, not significant). The
wide variability of eGFR change was explained by large
random fluctuations calculated in patients with very low
week4 of treatment
Candesartan in hypertensive infants Schaefer et al.5
Fig. 2
Responders (%)
n = 16
n = 69
n = 55
n = 30
n = 15
n = 70
n = 75
n = 10
n = 21
n = 64
1 to < 2 2 to < 6Men WomenBlackOther< 95 > 95 Primary Secondary
Sex RaceBMI
Mean and 95% confidence intervals of responder rate (patients with SBP and DBP below 95th percentile) at the end of 1-year open-label
intervention period in different population subgroups.
Fig. 3
4 weeks
Median % change in A/C ratio
1 year
n = 12
0.05 mg/kgCandesartan dose 0.20 mg/kg0.40 mg/kgAll doses All doses
n = 11
n = 9
n = 32
n = 26
Median percentage change from baseline in albumin/creatinine ratio in
children with baseline albuminuria less than 30mg/g creatinine during
double-blind period and after 1-year open label period. P for dose
response in double-blind period by nonparametric correlation testing.
Boxes denote interquartile range. A/C, albumin/creatinine.
Page 6
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serum creatinine values. When patients with eGFR more
than 120ml/min per 1.73m2were excluded, the mean
change from baseline to week 4 was ?4.1?10.8ml/min
per 1.73m2(P<0.005). The changes in eGFR were not
associated with patient age, baseline eGFR and the
presence of a renal diagnosis or chronic kidney disease.
Among the 22 patients with CKD stage 3 (eGFR 30–
60ml/min per 1.73m2), eGFR declined insignificantly
by 1.5?4.3ml/min per 1.73m2from baseline to week 4.
The only child with a marked initial eGFR decline (from
61 to 33ml/min per 1.73m2) was the patient who later
developed a lethal complication as reported above.
Baseline mean (?SD) SDS of height (?0.1?1.4) and
BMI (0.9?1.5) implied that the children were approxi-
mately of normal height, and some patients were mildly
overweight at baseline. Height and BMI SDS did not
change significantly over the course of the study.
Combined efficacy results of studies in 1 to less than
6-year-old and 6 to less than 17-year-old participants
In the preplanned regression analysis of the 4-week dose-
ranging data from the study of children 1 to less than
6-year-old combined with the 4-week dose-ranging data
(active doses only) from children 6 to less than 17 years of
age, the declines in both SBP and DBP were both
monotonic and both were significantly dose related
(P¼0.01 for SBP, P¼0.049 for DBP).
as a liquid suspension lowers elevated BP in 1 to less than
6-year-old hypertensive children in a dose-dependent
manner over a dose range of 0.05–0.4mg/kg. Moreover,
candesartan exerts a dose-dependent antialbuminuric
effect in infants with proteinuric kidney disorders. Both
the antihypertensive and the antiproteinuric effects were
persistent during 1 year of observation. Candesartan was
well tolerated, with a side-effect profile consistent with
adult experience.
The BP findings are consistent with those in older
children (6 to <17 years of age) treated with a tablet
formulation. Although in the 6 to less than 17-year-olds,
all doses proved superior to a concurrent placebo control
group, the test of dose response was not statistically
significant due to a plateau effect at the highest dose
[11]. In that study, dose separation may have been com-
promised by the use of only two weight strata per dose. In
the infant trial reported here, the variability of drug
exposurewas minimizedbynormalizing doseto theexact
body weight in each participant. When taken together,
the two trials indicate that candesartan exerts a dose-
related antihypertensive effect for children 1–17 years of
age. The trials also indicate that the antihypertensive
effect of candesartan is maintained for long term and that
it can be additive to other agents.
There are few reports of antihypertensive trials of reason-
able size in very young hypertensive children. The most
relevant report published to date is for the ARB valsartan
[16]. This trial also included three dose levels and BP
declined up to 8.6/6.4mmHg, but no dose–response
relationship was established. A recent review [3] indicted
the choice of too narrow dose ranges as the major cause of
flat dose–response curves. Although this factor cannot
explain the superior dose response observed with cande-
sartan, as an eight-fold dose-escalation scheme was
applied in both studies, it is more likely that the use
of fixed tablet sizes with only two weight strata across the
infantile age range in the valsartan trial may have caused
significant overlap in drug exposure between the dose
In contrast to the preponderance of 'primary', typically
obesity-related, hypertension in older children and ado-
lescents [11], hypertension was secondary to renal dis-
orders in three quarters of this infant population. Con-
genital anomalies of the kidneys and urinary tract and
steroid-resistant nephrotic syndrome appear to be the
most common underlying causes of hypertension in this
age group.
Glomerular proteinuria is an important risk factor for
progressive renal failure not only in adult nephropathies
but also in children with hypoplastic/dysplastic kidney
disorders [17,18]. RAS antagonists are preferred antihy-
pertensive agents in adult and pediatric renal hyperten-
sion due to their marked antiproteinuric effect [19,20]. In
this study, almost 50% of hypertensive infants with renal
controlled trial evidence that angiotensin receptor block-
ade by candesartan reduces albuminuria in a dose-depen-
dent fashion in infants with proteinuric kidney diseases.
At the highest tested dose (0.4mg/kg), proteinuria was
reduced by more than two-thirds. The antiproteinuric
effect persisted over 1 year of observation. The antipro-
teinuric effect of candesartan did not appear to correlate
with BP changes. This is consistent with the fact that in
many pediatric kidney disorders proteinuria occurs inde-
pendently of hypertension. Although severe hyperten-
sion is usually associated with proteinuria, children with
massive proteinuria may present with no or mild hyper-
tension such as in idiopathic nephrotic syndrome. Recent
studies [21,22] in proteinuric adults have suggested that
the maximal antiproteinuric effect of candesartan may
only be achieved at doses exceeding the maximal BP-
lowering doses by far (up to 128mg, i.e., 1.4mg/kg per
day). ARB dose titration studies aimed at minimizing
proteinuria may become a germane subject of future
research in pediatric nephropathies.
Furthermore, the recently concluded Efficacy of Strict
BlooodPressureControland ACEInhibitioninPEdiatric
Patients with Chronic Kidney Disease (ESCAPE) trial
Journal of Hypertension
2010, Vol 28 No 00
Page 7
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[23] observed a gradual loss of antiproteinuric efficacy of
the ACEI ramipril during extended administration in
children with chronic kidney disease. Residual protei-
nuria on treatment was predictive of renal survival. It has
beenhypothesized that compensatoryACE-independent
intrarenal angiotensin II formation might be responsible
seen whether downstream RAS blockade by ARBs will
provide superior long-term proteinuria control, and even-
tually renal survival, in children and adults with chronic
kidney disease.
Our results demonstrate a good tolerability and safety
profile of candesartan, particularly when one considers
the extensive comorbidities in infants with hyperten-
sion. A small decline in GFR occurred in the early
treatment period, which was expected in view of the
known effects of RAS antagonists on glomerular hemo-
dynamics. The short-term effect on GFR was not associ-
ated with progressive renal functional loss during
further follow-up. Also, neither an increased incidence
of hyperkalemic episodes nor a trend toward higher
serum potassium levels was noted in this population.
ARBs in infants with kidney disorders, as also suggested
by the valsartan study. Although these findings are
reassuring, it should be recognized that neither study
included children with advanced or end-stage chronic
kidney disease, and statistical sensitivity was limited in
both studies by relatively small sample sizes and short
follow-up. Furthermore, acute renal failure is a recog-
nized rare complication of RAS-inhibiting agents in
adults and this same admonition must be considered
relevant for children, particularly in conditions associ-
ated with unstable intravascular volume such as nephro-
tic syndrome and polyuria. The observed fatal course of
an infant with nephrotic syndrome and incidental diar-
rhea highlights the need for close attention to kidney
function and strict stopping criteria for RAS antagonist
therapy in this vulnerable population.
Regarding the general safety profile, both the candesar-
tan and the valsartan trials noted no apparent effect on
longitudinal growth, and the safety experiences were
similar in that they largely reflected the cooccurrence
of childhood illnesses. Serious adverse effects could
be attributed to underlying comorbid illnesses.
The pharmacokinetic substudy indicated that the single-
dose plasma concentration profile with candesartan sus-
pension in infants is consistent with that of the tablet
formulation studied in older children as well as with the
pharmacokinetic profile in adults, and supports once-
daily dosing down to 1 year of age. The profiles also
suggest that little, if any, dosage adjustment is needed
should a child graduate from the suspension to the
tablet formulation.
ARB with proven dose-dependent antihypertensive and
age. Together with its good tolerability and safety profile
and age-independent pharmacokinetic properties, the
drug qualifies as an important pharmacological treatment
of arterial hypertension across the pediatric age range.
This study was sponsored and funded by AstraZeneca
LP, Wilmington, Delaware, USA. We are indebted to all
study investigators, study coordinators and most of all the
patients and their families for their commitment to this
trial. This trial is registered at www.clinicaltrials.gov
(identifier NCT00244621).
F.S., J.v.d.W., A.Z., C.G., K.v.H., D.D., G.M. and I.V.B.
have received research funding from AstraZeneca. J.Su.,
J.So., R.T. and J.W.H. are employees of AstraZeneca.
List of Principal Investigators of CINCH Infant Trial:
Koen Van Hoeck, MD, U.Z. Antwerpen, Edegem,
Belgium; Johan Vande Walle, MD, U.Z. Gent, Gent,
Belgium; Michel Fischbach, MD, Ho ˆpitaux Universi-
taires de Strasbourg Ho ˆpital de Hautepierre, Strasbourg,
France; Jorg Do ¨tsch, MD, Universitatsklinikum Erlan-
gen, Erlangen, Germany; Gu ¨nter Klaus, MD, University
Hospital Marburg, Germany; Dirk E. Muller-Wiefel,
MD, University Hospital Hamburg–Eppendorf Univer-
sity Children's Hospital, Germany; Uwe Querfeld, MD,
Charite Children's Hospital, Campus Virchow, Berlin,
Germany; Franz Schaefer, MD, University Hospital for
Childrenand Adolescents,
Rostock, Germany; Gianluigi Ardissino, MD, Clinica
Pediatrica G.E.D. de Marchi, Milan, Italy; Maria Chiara
Matteucci, MD, Ospedale Pediatrico Bambino Gesu ´,
Rome, Italy; Giovanni Montini, MD, University of
Padua, Padova, Italy; Francesco Perfumo, MD and
Antonella Trivelli, MD, G. Gaslini Institute, Genoa,
Italy; Dorota Drozdz, MD, PA Children's Hospital,
Cracow, Poland; Aleksandra Zurowska, MD, Gdansk
University Medical School, Gdansk, Poland; Melvin
Bonilla-Felix, MD, University of Puerto Rico Medical
Sciences Campus CV Center, San Juan, Puerto Rico;
Malcolm A. Lewis, Royal Manchester Children's Hospi-
tal, Manchester, UK; Kjell Tullus, MD, Great Ormond
Street Hospital for Children, London, UK; Professor
Ingreta V. Bagdasorova, MD, City of Children Clinical
Hospital #7, Kyiv, Ukraine; Svitlana Trishnya, MD,
Crimean Republican Children Clinical Hospital, Crimea,
Ukraine; Carolyn Abitbol, MD, Jackson Memorial Hos-
pital Pediatric Dialysis Unit, Miami, Florida, USA; Billy
S. Arant, Jr., MD, Erlanger Health System Hypertension
Management Center, Chattanooga, Tennessee, USA;
Mazen Arar, MD, University of Texas Health Science
Center Children's Kidney Center, San Antonio, Texas,
Universita ¨ts-Kinderklinik,
Candesartan in hypertensive infants Schaefer et al.7
Page 8
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USA; Deane Baldwin, MD, Little Rock Pediatric Clinic,
Pediatric Clinical Trials International, Columbus, Ohio,
USA; Jeffrey Blumer, MD, University of Cleveland,
Cleveland, Ohio, USA; John Foreman, MD, Duke
Pediatric Clinical Research Program Children's Health
Center, Durham, North Carolina, USA; Randall Jenkins,
MD Northwest Pediatric Kidney Specialist, Portland,
Oregon, USA; Vijay S. Kusnoor, MD, Southeast Texas
Clinical Research Center, Beaumont, Texas, USA; Tej
Mattoo, MD, Children's Hospital of Michigan, Detroit,
Michigan, USA; Kenneth Miller, MD, Hope Children's
HospitalNephrology andHypertension Consultants, Inc,
Park Ridge, Illinois; Brenda Montane, MD, Nemours
Children's Clinic, Orlando Florida; Naomi Neufeld,
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Journal of Hypertension
2010, Vol 28 No 00


text:
It's been a whole week since she's worn them, so naturally I assumed that Kim Kardashian quit The Travelling Pants just like a bunch of people quit their relationships this Thanksgiving. But that shows what I know, because they're on the move again from Miami, FL to Los Angeles, CA. Here are some photos of whichever pair of pants it is that make her butt look widescreen (IMAX?).
Image credit to INF Daily.