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A bipolar lead for use in sensing cardiac depolarization signals and for applying electrical stimulation to cardiac tissue comprises a pair of elongated conductors contained within a lead body, the lead body terminating at its distal end in an enlarged head fabricated from an insulating plastic material. The head has a generally planar surface and projecting perpendicularly from that surface is a corkscrew electrode which is adapted to be screwed into myocardial tissue. Also supported on the planar surface of the head so as to surround the corkscrew electrode is a toroidal electrode formed from helically wound conductive wire. One of the conductors passing through the lead body connects at its distal end to the corkscrew electrode which the other conductor attached to the toroidal electrode. The toroidal configuration of the helically wound wire provides substantially increased surface area when compared to a flat disk electrode and, moreover, offers the ability of tissue to grow into the interior regions of the toroidal electrode for improved anchoring, higher amplitude of the sense depolarization signals and a higher slew rate for the signal. Another feature of the invention involves filling the interior of the hollow torus structure with a wool-like material formed from platinum or other inert conductive material for even further increasing the amount of electrode surface in contact with tissue.
1. A bipolar, positive fixation myocardial screw-in lead comprising:
(a) an elongated flexible plastic lead body having a proximal end and a distal end;
(b) first and second elongated flexible conductors extending through said lead body from said proximal end to said distal end, said first and second conductors being insulated from one another within said lead body;
(c) an enlarged insulating electrode supporting lead head affixed to said distal end of said lead body, said lead head having a generally planar exterior surface;
(d) a first conductive, generally rigid, helically-shaped electrode of open convolutions having one end supported by said head and extending normally to said planar exterior surface and terminating in a free end and being electrically connected to said first conductor;
(e) a second conductive, generally rigid, helically-shaped electrode of substantially open but closely spaced convolutions sufficient to allow tissue ingrowth and formed as an annulus of generally round cross-section and supported on said planar exterior surface surrounding said first electrode, said second electrode being electrically connected to said second conductor.
2. The bipolar lead as in claim 1 wherein said second electrode comprises a conductive wire of circular cross-section wound as a coil to thereby present a corrugated surface contour.
3. The bipolar lead as in claim 2 wherein said first electrode is partially covered with an insulating material except proximate said free end.
4. The bipolar lead as in claim 3 and further including connector means electrically connected individually to said first and second conductors for connecting said lead to implantable cardiac tissue stimulating apparatus.
5. The bipolar lead as in claim 4 wherein the ratio of the surface area of said second electrode to the tissue subtended is in the range of from about 5 to about 20.
6. The bipolar lead as in claim 2 and further including a mass of conductive fibers contained within the interior of said coil.
7. The bipolar lead as in claim 2 wherein one of said first and second electrodes is surface treated to increase the effective surface area thereof.
I. Field of the Invention
This invention relates generally to pacing and sensing leads for use with implantable cardiac stimulators, such as pacers and automatic implantable cardiac defibrillators (AICD), and more particularly to a bipolar screw-in type myocardial electrode system offering improved performance over prior art designs.
II. Discussion of the Prior Art
In the U.S. Pat. No. 4,010,758 to Ronald H. Rockland et al and entitled "Bipolar Body Tissue Electrode", there is described a myocardial screw-in bipolar tissue stimulating lead comprising a pair of elongated flexible conductors insulated from one another and extending from a proximal connector to an enlarged electrode supporting head at the distal end of the lead. Projecting outwardly from the head structure is a rigid helix formed from wire and which resembles a corkscrew. Surrounding the helical electrode is an apertured disk, resembling a common flat-washer, but of a suitable electrode material. The helix extends through the opening in the disk in non-contacting relationship. In use, it is intended that the Rockland electrode be screwed into epicardial tissue to the point where the flat disk electrode abuts the surface of the myocardium.
The lead described in the Rockland patent is intended strictly for stimulating cardiac tissue. That is to say, the proximal connector is intended to be coupled to a pulse generator, such as an implanted pacemaker which then functions to deliver a stimulating voltage between the corkscrew electrode and the surrounding disk electrode to the tissue located therebetween. No mention is made in the patent of using that arrangement as a sensing electrode whereby cardiac depolarization signals may be picked up and delivered to the implantable pacemaker for controlling the operation thereof.
In prior art, AICD systems of the type manufactured and sold by Cardiac Pacemakers, Inc. (applicant's assignee), it has been the practice to often utilize two monopolar positive fixation leads, e.g., corkscrew tips cooperating with myocardial tissue, for sensing ECG signals produced upon depolarization of that tissue and using the resulting signals, so detected, in determining whether normal sinus rhythm, tachycardia or ventricular fibrillation is in progress whereby the implanted pulse generator can be commanded to apply an appropriate shock or other stimulation to the heart over separate electrodes to restore sinus rhythm. It is also most important to proper operation of an AICD system that the sensing apparatus recover substantially instantaneously from a previous shocking episode whereby the pulse generator circuitry can determine whether defibrillation has, in fact, taken place or whether it will be necessary to recharge the device's capacitors in anticipation of the need for another shock to be administered. It is also known that antitachycardia pacing schemes may be employed to electrically treat tachycardia. Also, the heart may require short term back-up pacing following conversion attempts. In both cases, the electrode configuration used does not necessarily have to be designed or optimized for long term, chronic stimulation. In such cases, a lead designed for sensing may be suitable for delivery of these short term therapies.
In that the insertion of a positive fixation corkscrew electrode into the myocardial tissue is, at least, modestly traumatic, it is desirable, where possible, that only a single puncture be made. Thus, a bipolar electrode structure, rather than the use of two monopolar electrodes, is advantageous. To those familiar with the literature, it is known that a small surface area electrode favors pacing performance while a large surface area electrode favors sensing performance. These conflicting requirements, most recently pointed out by Sinnaeve, et. al., (PACE, volume 10, 1987, p. 546-554), makes the design of a single electrode, optimized for both purposes, especially difficult.
The present invention is deemed to be an improvement over the electrode arrangements disclosed in the Rockland U.S. Pat. No. 4,010,758. Specifically, by substituting a toroidal helically wound wire for the flat apertured disk electrode in Rockland, it is found that surprising performance advantages result. Specifically, the use of helically wound torus with the corkscrew electrode permits substantial tissue ingrowth between contiguous turns immediately following the implantation thereof whereas in the prior art structure, as disclosed in the Rockland patent, it may take several weeks for the electrode/tissue interface to mature. Because of the possibility for intimate tissue ingrowth into the interstice of the helically wound wire torus electrode, more stable cardiac depolarization signals can be monitored. Not only that, the slew rate for the cardiac depolarization signals being sensed is significantly higher than can be obtained using the Rockland electrode structure with its flat non-porous disk electrode which contacts the myocardial tissue.
In accordance with a further feature of the present invention, it is possible to fill the interior of the torus with a multiplicity of fine metallic fibers to form a fabric resembling steel-wool. With the myriad of porous openings afforded in this wool-like material, even greater surface area is made to engage the ingrowing tissue, thus enhancing the lead performance.
The bipolar, positive fixation, myocardial screw-in lead of the present invention comprises an elongated flexible plastic lead body having a proximal end and a distal end. First and second elongated flexible conductors extend through the lead body from the proximal end to the distal end in a way that insures that the two conductors are insulated from one another. An enlarged insulating electrode supporting lead head is affixed to the distal end of the lead body and has a generally planar exterior surface. The rigid helix or corkscrew electrode has one end supported by the lead head and it projects perpendicularly to the planar exterior surface and is electrically connected to the first conductor. The second conductive electrode of the bipolar pair is a generally rigid toroidal winding of generally circular cross-section and it is supported on the planar exterior surface of the lead head so as to surround the corkscrew electrode. The toroidally wound electrode is electrically joined to the second conductor in the lead body.
In use, the lead head may be appropriately gripped with an insertion tool which supports the elongated conductors in such a fashion that the helical tip or corkscrew can be rotated and screwed into tissue to the point where the annular helix also contacts myocardial tissue but without torquing the elongated conductors. In this way, the corkscrew remains implanted in the myocardial tissue when the electrode supporting head is released from the tool.
The foregoing features, objects and advantages of the invention will become apparent to those skilled in the art from the following detailed description of a preferred embodiment, especially when considered in conjunction with the accompanying drawings in which like numerals in the several views refer to corresponding parts.
FIG. 1 is a perspective view of a bipolar myocardial screw-in lead in accordance with a first embodiment of the invention;
FIG. 2 is an enlarged side view of the distal end portion of the lead of FIG. 1;
FIG. 3 is a plan view of the electrode head in accordance with a second embodiment; and
FIG. 4 is a cross-sectional view taken along the line 4--4 in FIG. 3.
Referring now to FIG. 1, there is indicated generally by numeral 10 apparatus for sensing ECG potentials developed during depolarization and repolarization of the cardiac tissue and stimulating cardiac tissue. The system is seen to include an implantable pulse generator 12 which, for purposes of this invention, may be a low power stimulator of the type commonly used for pacing patients having bradycardia or, alternatively, it may comprise any one of a number of types of electrical stimulators now used in treating episodes of tachycardia or may also be an implanted automatic implantable cardiac defibrillator. The pulse generator 12 includes a molded plastic header 14 having at least one bore 16 formed therein for receiving a proximal lead terminal therein. The sensing and stimulating lead in accordance with the present invention is indicated generally by numeral 18 and is seen to include an elongated flexible plastic lead body 20 which may be formed from materials such as silicone rubber, polyethylene, polyurethane, polypropylene or other known materials which have been used for a number of years in fabricating pacing leads. Routed through the lead body 20 are a pair of conductors 22 and 24 (FIG. 2) which are terminated at their proximal end by a terminal pin 26 which is designed to be inserted within the bore 16 of the stimulator 12. While in FIG. 1, an in-line terminal 26 is illustrated, those skilled in the art can appreciate that separate terminal pins can be associated with each of the conductors 22 and 24 so as to fit into separate bores in the header 16.
Affixed to the distal end 28 of the lead body is an enlarged electrode supporting head 30 which is preferably molded or otherwise formed from plastic and which includes a generally planar surface 32 (FIG. 2).
Extending perpendicularly from the planar surface 32 is a helix 34 formed from a generally rigid wire and terminating in a sharpened tip 36. The electrode 34 may be covered over a portion of its surface with an insulating coating 38 so that only a small segment proximate the tip 36 remains exposed bare metal.
The structure thus far described is substantially identical to the same arrangement illustrated in the aforereferenced Rockland patent. In accordance with the present invention, however, the flat circular disk electrode in the Rockland device is replaced with a toroidally wound wire electrode 40 which is appropriately boned with a suitable medical grade adhesive or by some other means to the electrode supporting surface 32 of the head 30. The toroid 40 is positioned so as to surround the corkscrew electrode 34 in on-contacting relationship. In the arrangement shown in FIGS. 1 and 2, the toroid 40 has its adjacent convolutions abutting one another and because the convolutions are formed from conductive wire having a circular cross-section, the electrode surface will be non-planar and somewhat corrugated in appearance. This results in a significantly greater area of surface contact with tissue when contrasted with a flat apertured disc. It has been determined that a ratio of the surface area of the electrode 40 to that of the tissue subtended by the electrode lies in the range of from 5 to 20.Moreover, the minute spaces present between abutting convolutions allow for improved tissue migration and ultimate anchoring of the annular electrode to the myocardial surface which it abuts when the open-turn helical electrode 34 is advanced, by screwing, into the tissue. As is known in the prior art, a dacron screen as at 42 may also be affixed to the lead head 30 to enhance anchoring, via tissue ingrowth. Furthermore, the enhanced anchoring due to the presence of this tissue ingrowth would reduce any relative motion between the annular electrode and the heart tissue and therefore reduce or eliminate erosion of the tissue by the electrode.
Referring next to FIGS. 3 and 4, an alternative embodiment of the invention comprises a lead structure again having a corkscrew-shaped helical electrode 34 projecting normally from a planar surface 32. Surrounding the rigid helix 34 is a helically wound bare wire coil whose adjacent turns are non-abutting and thus resemble a stretched coil spring. This electrode is identified by numeral 44 and stuffed within its interior is a filamentary mass which resembles steel-wool in its appearance. The filaments may be platinum, a platinum alloy or other metal commonly used in fabricating implantable body contacting electrodes. The distance between adjacent turns on the helically wound wire electrode 44 is sufficient to allow exposure of the conductive filaments comprising the mass 46 to tissue ingrowth and intimate contact with body fluids while preventing migration of the material 46 outside of the bounds defined by the convolutions of the helically wound wire 44. The partial cross-sectional view of FIG. 4 is helpful in visualizing the composite annular electrode heretofore described. The filamentary mass may also be needed to increase the surface area of the electrode as some surface area may be covered during some assembly processes, such as gluing or welding. Increased surface area can also be achieved by well-known methods of roughening, texturizing, and or "blacking" as done to platinum. This can be incorporated on either or both of electrodes 34 and 40.
It can be seen, then, that the present invention provides a single bipolar sutureless myocardial lead which can be used with either a bradycardia pacemaker or with a AICD device for sensing cardiac rate. Being a bipolar device, it replaces the two unipolar sutureless myocardial leads commonly used with implantable defibrillating systems. By replacing the two leads by a single device, the implant procedure is simplified while trauma to the heart is reduced. Moreover, the bipolar lead may only require a single pin type proximal connector, thus freeing up space on the header of the pulse generator.
Still further, the concentric nature of this electrode configuration makes placement of this lead on the surface of the heart less critical than the two leads. This is due to the fact that sensing by a concentric device is essentially independent of the direction of the cardiac depolarization wavefront. This is not the case for sensing by two unipolar devices.
This invention has been described herein in considerable detail in order to comply with the Patent Statutes and to provide those skilled in the art with the information needed to apply the novel principles and to construct and use such specialized components as are required. However, it is to be understood that the invention can be carried out by specifically different equipment and devices, and that various modifications, both as to the equipment details and operating procedures, can be accomplished without departing from the scope of the invention itself.
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The best argument for an all-day program for the homeless landed on the Patriot's doorstep yesterday morning.
We spend a lot of time worrying these days about how we're going to keep our young people on Cape Cod. The answer is in the life of David Scudder, who died at age 59 April 16 after a long illness.
Stopping the rise of drug addiction and the subsequent deadly overdoses is going to take people who aren't willing to stop.
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Profile of Kenji Prince
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What The Heck Is Dwarfism
Achondroplasia effects roughly two out of each 100,000 reside births and is related with advancing paternal age (over 35 years old). While life span and intelligence are normal, in infancy kids often have low tone and are slow to meet developmental milestones, like crawling and walking. In addition, infants with achondroplasia are at risk of death due to spinal cord and/or upper airway obstruction. In childhood, obesity can be an issue. This disorder can be inherited or occur spontaneously. If one parent has the gene, the kid features a 50% likelihood of inheriting achondroplasia. If both parents have the gene, the child features a 75% likelihood of inheriting the disorder. During pregnancy, the disorder can be diagnosed via ultrasound and there will probably be much more amniotic fluid than anticipated. After birth, the infant's head might show indicators of hydrocephalus and/or have clubbed feet. The average height of a man with achondroplasia is 4'3.5" tall and the typical height of a lady using the disorder is 4'0.5" tall. Human growth hormone doesn't function to improve height in individuals with achondroplasia. Signs and symptoms of this situation include an abnormal appearance of the hand with a big space between the lengthy finger and also the ring fingers, decreased muscle tone, bowed legs, brief arms and legs, very large head size in relation to physique size, spinal stenosis, spinal kyphosis (hunchback), spinal lordosis (swayback), and very brief stature. Aside from treating the person symptoms of the disorder, there is no healthcare treatment for the situation itself. To improve height, some advocate leg-lengthening procedures. Leg-lengthening is an very controversial treatment that entails numerous surgeries, pain and feasible infections. Many adults with achondroplasia view the leg-lengthening process as unnecessary at very best and as an affront to their humanity at worst. The prognosis for individuals who have this disorder is excellent. As adults, regardless of medical conditions, individuals with this condition function as teachers, lawyers, physicians, actors, accountants or any quantity of other careers. They get [http://adjustableheell.insanejournal.com shoe lifts], have children and take part in their communities just like people without achondroplasia.


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Big Brother 12: Final HoH Competition Rounds 1 and 2 Results| September 9, 2010 at 7:45 PM EDT
Tonight on Big Brother 12 the results from the first round of the final HoH will be revealed along with the live second round. If you can't wait to see who won the endurance comp from round 1 then you can find those spoilers here! While we wait for the results be sure to Fan us on Facebook and join in the fun there!
Meanwhile, join us in the Big Brother chat room as we watch tonight's show! Can't wait to see what happens.
If you haven't signed up for the Live Feeds Free Trial then why are you waiting?
Big Brother 12 Final HoH – Round 1:
- Enzo lasted a wimpy 19mins 14secs in the endurance comp
- Lane lasted 2hrs 35mins in the comp
- Hayden wins Round 1
Oh boy! Julie just promised us scenes loaded with drama at the Jury House coming up on tonight's show. Okay, that whole segment of Matt telling Ragan and then Ragan fighting with Rachel was awesome. Definitely worth rewinding and watching a second time.
Big Brother 12 Final HoH – Round 2 – "It's Alive":
- It's the face-morph competition and they have 2 minutes to complete.
- Lane goes first, gets them all correct, and completes in 1m 13s.
- Enzo is up next, gets them all correct, but takes 1m 43 secs to complete!
- Lane wins Round 2!
Hayden and Lane will face off in Round 3 on Wednesday's finale show!
Once the live show is over the live feeds will turn back on. You won't want to miss what happens next and the only way to watch it uncut and unedited is with the Big Brother 24/7 uncensored feeds.
Be sure to sign-up for the free Big Brother email updates, visit the Big Brother Forum, follow us on Twitter, join us on Facebook, and get our Mobile Apps.
Matthew Boyer
Latest posts by Matthew Boyer (see all)
- Big Brother 17: Da'Vonne Rogers Uncovers Twin Twist - July 6, 2015
- Big Brother 17 Live Feeds Week 2: Monday Daytime Highlights - July 6, 2015
- 'Big Brother 17′ Spoilers: Week 2 Veto Ceremony Results - July 6, 2015


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Date: 1877 ca.
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Guardian lions, or foo dogs, historically fronted the entrances of Chinese imperial palaces and temples, serving as symbolic protectors. While the original statues are massive, this diminutive, but still fierce, pair are just the right size to stand guard over a mantel or bookshelf.
It's almost a Western tradition to be lured by the mysteries and legends of the East. Legend of Asia, founded in Beijing, is happy to participate. With exceptionally high-quality Asian-influenced furniture and antique reproductions, the company has succeeded in fusing the time-honored beauty of traditional Asian art with modern lifestyles


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First Posted: 5/19/2013
(AP) Associated Press journalists open their notebooks at the 2013 Cannes Film Festival:
In the Coen brothers' "Inside Llewyn Davis," Justin Timberlake sings music set to a very different beat than "Suit and Tie."
Timberlake plays a bearded pop folkie in the film, which was to premiere Sunday night at the Cannes Film Festival, about the music scene of early 1960s Greenwich Village. Oscar Isaac stars as a more serious but less successful folk musician than Timberlake's smiley Jim Berkey.
Speaking to reporters Sunday, Timberlake called Berkey "part of the transition that is sort of the underbelly of the time." The film summons the period of New York folk just before Bob Dylan arrived in the early '60.
"Obviously, it's on the surface, a different style from the music that I make in real life," said Timberlake. "But listen, man. I grew up in Tennessee, the home of the blues, the birthplace of rock 'n' roll Memphis and a lot of country music. So my first musical lessons were given to me by my grandfather an old Gibson guitar. He taught me how to fingerpick."
Timberlake helped write the music to the film's most comical song, "Please, Mr. Kennedy," which he sings with Isaac and Adam Driver of "Girls." The oft-repeated chorus goes: "Please, Mr. Kennedy, don't shoot me into outer space."
Timberlake got reflective about the curious mix of talent, luck and timing that goes into a music act breaking out. In contrast to the success Timberlake has had in music and acting, the characters of "Llewyn Davis" are those for whom things never click.
"I've been in the right place and met the wrong people, and I've been in the wrong place and met the right people," the former boy band singer said. "Usually, the second one ends up being the thing that can catapult someone's career."
Timberlake suggested disregarding how one's work is received.
"There's a lot of analysis now, a lot of analytics on what might be success and what might be failure," he said. "I don't know that I would measure the success or failure of it by how it's perceived because once it's done, it's sort of out there. You have to let it live in the ether."
Jake Coyle, http://twitter.com/jake_coyle
Young British actor George MacKay is making a splash at Cannes literally, amid the weekend's torrential downpours with his compelling central performance in mythic maritime drama "For Those In Peril."
Set in a fishing town on the stark Scottish coast, Paul Wright's debut feature stars 21-year-old MacKay as sole survivor of a boat accident that killed five others, including his elder brother. MacKay carries the intense and poetic film as a young man struggling to cope with loss, even as his survival alienates him from his bereaved neighbors.
"You got our film and our weather, too," MacKay joked, sitting in a wind-whipped beachside cafe during interviews for the film in Cannes.
Playing in Cannes' Critics' Week competition, the movie has garnered strong reviews for its exploration of guilt, masculinity and mythology.
It's a mature and meaty role for MacKay, who got his movie start aged 10 as one of the Lost Boys in P.J. Hogan's 2003 adaptation of "Peter Pan," shot at Warner Bros' studios on Australia's Gold Coast.
"It was mad. They built a pirate ship it was extraordinary. I think, the fact that we were 10, I don't think we realized how ridiculous the scale (was)," said MacKay, who also appeared alongside Clive Owen in 2009 family drama "The Boys Are Back."
"For Those in Peril" was a much smaller-scale operation, shot over six weeks in a small town in northeast Scotland and, for several key sequences, in the cold North Sea.
The boundlessly enthusiastic MacKay says even the frigid water scenes were made bearable by "lots of cups of tea … lots of towels, lots of food."
"We were kept safe," he said. "We were out in the middle of the ocean doing it and we had the water safety guys come very dramatic shooting across in their little (boat), whack you out and wrap you in towels. It was all good."
And the town had a bonus: "Best fish and chips you've ever had."
Jill Lawless, http://Twitter.com/JillLawless
Associated Press


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Bald Eagles have returned to nest in New York City! NYC Audubon announced on Friday that the city's first active Bald Eagle pair in 100 years has taken up residence on Staten Island, an encouraging sign for a species that was once nearly extinct. Fun fact: "Local birders have named the male Vito." »
Watch This Heroic Bald Eagle Keep Her Eggs Warm In A Snow-Covered Nest
Though the live camera feed of her nest in Pennsylvania's Codurus State Park reveals that she's gotten some relief from the snow, this image (captured March 5) shows a bald eagle mother keeping her eggs warm ... despite what was clearly some deeply inconsiderate weather. »
You will fall in love with these two bald eagles caring for their eggs,…
Live Video streaming by Ustream Few birds are as fierce and beautiful as the bald eagle, a predator who is both a mascot of the United States and (tragically) one of the victims of this country's expansion into the birds' traditional habitats. Still, many bald eagles survive — sometimes by adapting to human… »
ATTENTION: We are T-minus nine days to eaglet hatching
It's crunch time, folks. The time when you set aside everything else in your life that needs doing and spend every waking hour glued to your monitor, hoping — nay, praying — that you'll get a chance to witness the hatching of a brand new baby bald eagle, live on camera. »
Drop everything — the Bald Eagle Cam is back!
Have you ever wanted to spy on a bald eagle, watch one hatch, or watch one learn to fly? Then it's time to put everything going on in your life on hold... at least for the next few months. The Decorah Bald Eagle Cam — aka the most powerful time-devouring procrastination tool on the entire internet — is back. »


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Bill and Rosemary Phillips of Kingsport are pleased to announce the engagement of their daughter Hillary Anne Phillips to Michael David Ebling, son of Paula Ebling of Gainesville, Fla., and the late David Ebling, formerly of Gainesville, Fla.The bride-elect graduated with honors from Sullivan South High School in 2007, where she was president of the band and a Student Council officer. She is a senior at East Tennessee State University, where she is pursuing a biology major and a German minor. She is an active member in the American Medical Student Association and in President's Pride. She is the granddaughter of Harold Alspaugh of Magnolia, Ark.; the late Joyce Alspaugh, formerly of Magnolia, Ark.; and the late Ken and Virginia Phillips, both formerly of Kingsport.The bridegroom-to-be graduated from Gainesville High School, Gainesville, Fla., in 2006, where he was a National Merit Commended Scholar. He graduated summa cum laude from Sewanee University in May 2010, where he was a member of Phi Beta Kappa. He is earning a master of arts degree in teaching at Peabody College of Vanderbilt University, Nashville. He is the grandson of Paul Ebling of Gainesville, Fla.; the late Pauline Ebling, formerly of Gainesville; and the late Walter and Jane Whidden, both formerly of Gainesville.The couple plans to be married in a May 2011 garden ceremony in the Great Smoky Mountains.
Laura Beth McMurray of Kingsport, and Larry Wayne Ricketts Jr. of Gate City, Va., plan to be married in an open-church ceremony at 3 p.m., Dec. 4, 2010, at Homeland Baptist Church.The bride-elect is the daughter of Jack and Judy McMurray of Kingsport, and the granddaughter of the late Bascom and Bonnie Calhoun, formerly of Gate City.The bridegroom-to-be is the son of Barbara McConnell and stepson of Ron McConnell of Arkadelphia, Ark. He is the grandson of Eliza Garland of Gate City, and the late Guy Garland Sr., formerly of Gate City.
Glenn and Gladys (Gray) Haynes of Kingsport, formerly of Scott County, Va., will celebrate their 60th wedding anniversary with a reception to be held in their honor from 2 to 4 p.m., Nov. 14, 2010, at Christ Fellowship Church, 260 Victory Lane, Kingsport.The couple was married Nov. 18, 1950, in Weber City, Va., with the Rev. Herman Quillen officiating.They are the parents of Deborah Winegar of Church Hill; Darla Cline of Sparta, Tenn.; David Haynes of Kingsport; and Donna Jones of Kingsport.They have five grandchildren and two great-granddaughters.Mr. Haynes retired from Mead Corp. after 43 years of service. Mrs. Haynes is a homemaker.They invite all their family and friends to attend. Your presence is the only gift requested.
Robert J.B. Anderson and Susan Elizabeth Collins were married on Columbus Day, Oct. 12, 1942, and they joyously celebrated their 68th wedding anniversary at ages 88 and 86, respectively, in their home Oct. 12, 2010.Their twin 10-year-old granddaughters, Myla and Mattea Anderson, wanted to celebrate in "the days gone by" style. It was a wonderful opportunity for the couple to be nostalgic.The bride wore a long, flowing off-white gown and a wide-brimmed hat that belonged to her husband's maternal grandmother, Augusta, who died in 1929. She crocheted her red, white and blue apron for the event. The bridegroom matched in tuxedo style with bowtie and hat. The family joined in the celebration wearing bonnets and hats and dress attire fitting the occasion. That theme carried through to a sit-down dinner for the couple and special friends, Thelma and Bernie Benkey. Myla and Mattea served them.Cameras and video rolled capturing the cutting of their anniversary cake and warm wishes to the happy couple. They spoke of the memories and how the Lord had blessed them even through hardships. The entire event was one of reflection and thankfulness of God and for their families and many friends. They are especially thankful for and blessed with four children, four grandchildren and one great-grandson. They are the parents of Linda and Charles Rothwell, Carolyn Sakowicz, Norma Cato, and Bobby and Nancy Anderson . They are the grandparents of Stephanie Sakowicz, Leigh Sakowicz Basham and husband Joseph Basham, Myla Anderson and Mattea Anderson. They are the great-grandparents of Bryson Basham.
Mr. and Mrs. James L. Carter (Jim and Charlotte) recently celebrated their 50th wedding anniversary with a family dinner and short Caribbean cruise to Nassau, along with some of the children and grandchildren.The couple was married June 4, 1960, and are the proud parents of five children, Margaret Beeler, whose husband was the late Anthony Beeler; Elizabeth Sherrard and her husband Dr. Rick Sherrard; Cathy Osborne and her husband Jack Osborne; J. Lawrence Carter Jr. and his wife Tisha, and John Carter and his wife Rachel. The are the proud grandparents of six grandchildren Erin Clark and her husband Jeremiah, Laura Beeler, Josh Osborne, and Jessica, Anna and Nora Carter.Jim is now retired from Eastman Kodak Co. after 33 years of service. He enjoys pickin' bluegrass music and currently performs with Shorthills Ramblers, which he formed, Southern Country Band and Just Friends band.Charlotte is a homemaker and Jim says "a great cook." She worked at Holston Valley Community Hospital as a ward clerk. She thoroughly enjoys reading and doing crossword puzzles.


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Methods of employing compositions containing 5-hydroxytryptamine-2 (5-HT2) receptor antagonists for the treatment of such venous conditions as varicose veins, venous insufficiency and wounds are disclosed.
1. A method for treating or preventing varicose veins comprising administering to an afflicted or susceptible patient a non-blood pressure-reducing 5-HT2 receptor antagonist at a therapeutically effective dose.
2. A method according to claim 1, wherein the 5-HT2 receptor antagonist is 2'[2-(1-methyl-2-piperidyl)ethyl]cinnamanilide hydrochloride; 2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-2,4-dihydro-4-(2-phenoxyethyl)-3H-1,2,4-triazol-3-onehydrochloride;8-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]-8-azaspiro[4,5]decane-7,9-dione hydrochloride; or any mixture thereof.
3. The method according to claim 2, wherein said 5-HT2 receptor antagonist is administered in admixture with a pharmaceutically acceptable carrier.
4. The method of claim 1 wherein said 5-HT2 receptor antagonist is administered topically or systemically.
5. The method of claim 2 wherein said 5-HT2 receptor antagonist is administered topically or systemically.
6. A method for treating or preventing venous insufficiency comprising administering to an afflicted or susceptible patient a non-blood pressure-reducing 5-HT2 receptor antagonist at a therapeutically effective does with the proviso that said patient is not afflicted with or susceptible to hemorrhoids.
7. A method according to claim 6, wherein the 5-HT2 receptor antagonist is 2'[2-(1-methyl-2-piperidyl)ethyl]cinnamanilide hydrochloride; 2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-2,4-dihdyro-4-(2-phenoxyethyl)-3H-1,2,4-triazol-3-onehydrochloride;8-[4-[4-(1,2-benziothiazol-3-yl)-1-piperazinyl]butyl]-8-azaspiro[4,5]decane-7,9-dione hydrochloride; or any mixture thereof.
8. The method according to claim 7, wherein said 5-HT2 receptor antagonist is administered in admixture with a pharmaceutically acceptable carrier.
9. The method of claim 6, wherein said 5-HT2 receptor antagonist is administered topically or systemically.
10. The method of claim 7, wherein said 5-HT2 receptor antagonist is administered topically or systemically.
11. A method for treating wounds comprising administering to an afflicted patient a non-blood pressure-reducing 5-HT2 receptor antagonist at a therapeutically effective dose.
12. A method according to claim 11, wherein the 5-HT2 receptor antagonist is 2'[2-(1-methyl-2-piperidyl)ethyl]cinnamanilide hydrochloride; 2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-2,4dihydro-4-(2-phenoxyethyl0-3H-1,2,4-triazol-3-onehydrochloride;8-[4-[4-(1,2-benziothiazol-3-yl)-1-piperazinyl]butyl]-8-azaspiro[4,5]decane-7,9-dione hydrochloride or any mixture thereof.
13. The method according to claim 12, wherein said 5-HT2 receptor antagonist is administered in admixture with a pharmaceutically acceptable carrier.
14. The method of claim 11 wherein said 5-HT2 receptor antagonist is administered systemically or topically.
15. The method of claim 12 wherein said 5-HT2 receptor antagonist is administered systemically or topically.
This is a continuation of International Application PCT/US93/01485 filed on Feb. 19, 1993 and which designated the U.S. and which is a continuation-in-part of Ser. No. 07/818,389 filed Jan. 9, 1992, now U.S. Pat. No. 5,266,571.
This invention relates to the treatment of and to compositions containing 5-HT2 receptor antagonists useful in treating such venous conditions as hemorrhoids, varicose veins, venous insufficiency and wounds. In particular it comprises use of a 5-hydroxytryptamine-2 receptor antagonist (5-HT2) at an effective therapeutic dose to treat a human or animal suffering from such a condition. The 5-HT2 receptor antagonist can also be administered prophylactically.
Serotonin or 5-hydroxytryptamine or 5-HT is a vasoconstrictor and a powerful stimulant of a variety of smooth muscles and nerves. A derivative of the amino acid tryptophan, 5-HT is formed predominantly in enterochromaffin or argentaffin cells of the intestinal tract. It is transported in the blood by platelets and is present in the brain and other tissues. Its pharmacological actions result in a variety of responses involving, inter alia, the cardiovascular, respiratory, and gastrointestinal systems, smooth muscles, exocrine glands, carbohydrate metabolism, sensory nerve endings, autonomic ganglia, the adrenal medulla, and the central nervous system.
Cellular reaction is determined by the type and number of receptors on the outer membrane of the cells. Consequently, one hormone can trigger different responses in different cells because it may have different receptors. Thus, the same hormone that can contract one smooth muscle cell, can also relax a skeletal muscle cell having a different receptor to the same hormone. This is true for 5-HT.
There are many receptors for 5-HT that control the various cellular responses which are mentioned above. To identify the different receptors to a specific hormone (e.g. 5-HT), several methods are used. For example, in labeling studies, the labeled hormone binds to a specific receptor. The antagonists are classified according to their ability to displace the labeled hormone from the receptor in question. Those that can displace it from a particular receptor are said to be antagonists to that receptor. Some antagonists can displace the hormone from one receptor without affecting its binding to another, and the degree of selectivity can thus be determined. In pharmacological studies, the ability of antagonists to antagonize some of the effects of the hormone thought to be related to one receptor or another are examined. A suitable example relates to the hormone histamine. Some antagonists (histamine-2 antagonists) can antagonize its acid secretory receptors with little or no effect on its lung receptors and thus inhibit acid secretion by the stomach without causing bronchodilatation. Other antagonists (histamine-1 antagonists) antagonize histamine's lung effects with almost no activity against its acid secretory effects. Biochemical studies are those in which the biochemical effects of the hormone in question can be antagonized selectively by one receptor antagonist or another.
Serotonin receptors are divided into several classes, one of which is referred to as the 5-HT2 receptor. A complete discussion of such receptors will be found in "The Peripheral Actions of 5-Hydroxytryptamine" edited by John R. Fozard (Oxford University Press, 1989). Receptors for 5-HT have been classified based on the responses they produce when stimulated by 5-HT. At present four main classes and several subclasses of 5-HT receptors are generally recognized. The four main classes are:
5-HT1 receptors: These receptors appear to mediate the relaxation of smooth muscles and increased heart rate.
5-HT2 receptors: These receptors appear to mediate vasoconstriction and platelet aggregation.
5-HT3 receptors: These receptors appear to mediate vomiting by action in the central nervous system.
5-HT4 receptors: These receptors mediate effects not covered by the other three receptors.
(P. A. van Zwieten et al. "Pathophysiological and Pharmacotherapeutic Aspects of Serotonin and Serotonergic Drugs," Clin. Physiol. Biochem. 8 (suppl 3), 1-18, 1990 Frazer et al. "Subtypes of Receptors for Serotonin" Ann. Rev. Pharmacol Toxicol. 30, 307-348, 1990)).
The Frazer article shows that serotonin has different receptors sometimes mediating opposite effects. Thus a multitude of different and sometimes opposite effects can be induced by 5-HT receptor antagonists. 5-HT receptor antagonists produce different pharmacological responses depending on the type and location of the 5-HT receptor they antagonize of block. They produce a variety of different responses in the central nervous system. Peripherally, such antagonists can sometimes produce antagonistic responses. This is similar in many respects to the Histamine antagonists. Histamine-1 (H-1) antagonists inhibit bronchioconstriction but have no effect on gastric acid secretion while Histamine-2 (H-2) antagonists inhibit gastric acid secretion with no effects on the lungs. Thus a general statement that histamine antagonists should be good for acid secretion or bronchio-spasm is meaningless.
5-Hydroxytryptamine (5-HT2) receptor antagonists are different from other 5-HT receptor antagonists in many respects in that 5-HT2 receptor antagonists:
a. Antagonize serotonin stimulation of intra-cellular calcium levels via stimulation of phosphoinostiide hydrolysis in smooth muscle, human and rabbit platelets and astrocytes.
b. Antagonize serotonin contraction of the canine and human basilar artery while producing no hypotension.
c. Antagonize the increased vascular permeability induced by 5-hydroxytryptamine
d. Antagonize the head shakes and twitches in rodents induced by serotonin.
5-HT can induce both contraction and relaxation in blood vessels. The type of responses produced depends on the type of receptor present. For example, 5-HT2 receptor stimulation contracted the porcine coronary arteries (Daniel J. Cushing and Marlene L. Cohen, "Comparison of the Serotonin Receptors That Mediate Smooth Muscle Contraction in Canine and porcine Coronary Artery" J. Pharmacol. Exptl. Therapy. 261, 856-862, 1992) but dilated the canine renal artery (Shoji et al. "Renal vasodilation Induced by DOL, a 5-HT2 Receptor Agonist, in the Canine Kidney" Europ. J. Pharmacol. 190, 247-250, 1990) Stimulation of 5-HT-receptors produced constriction in the canine Savenous vein (Else Muller-Schweinitzer, "Venoconstrictor Responses to Dihydroergocristine and Dihydroergotamine: Evidence for the Involvement of 5-HT1 Like Receptors" Cardiovascular Drugs and Therapy, 4, 1455-1460, 1990), the rabbit saphenous vein, (Dicky Van Heuven-Nolsen et al. "5-HT1 Like Receptors Mediate Contraction of the Rabbit Saphenous Vein" Europ. J. Pharmacol. 191, 375-382, 1990) but dilated the small arteriols in rat skeletal muscles (Nancy L. Alsip et al. "Multiple Serotonin Receptors on Large Arteriols in Striated Muscle" Blood Vessels, 28, 537-541, 1991). These are only example. For more examples see (Sahin-Erdemli et al. "5-HT1 like Receptors Mediate 5-hyroxytryptamine-induced Contraction of Guinea-pig Isolated Iliac Artery" Brit. J. Pharmacol., 102, 396-390, 1991; Fong M. Lai et al. "Characterization of Serotonin Receptors in Isolated Rat Intramyocardial Coronary Artery" J. Pharmacol., Exptl. Therapy., 256, 164-169, 1991; Hubert Dabire et al., "Hemodynamic Aspects and Serotonin," Clin. Physiol. Biochem. 8 (suppl 3), 56-63, 1990; M. J. Summer, "Characterization of the 5-HT receptor Mediating Endothelium-Dependent Relaxation in Porcine Vena Cava," Brit., J. Pharmacol., 102, 938-942 1991; B. N. C. Prichard and C. C. T. Smith, "Serotonin: Receptors and Antagonists-Summary of Symposium," Clin. Physiol. Biochem. 8 (suppl 3), 120-128, 1990, Lubo Zhang and Donald C. Dyer, "Characterization of Serotonergic Receptors Mediating Contraction of Ovine Umbilical Artery" J. Pharmacol., Exptl. Therapy. 255, 233-239, 1990).
In fact 5-HT can mediate both contraction and relaxation in the same tissue (Zeljko S. Radic et al., "Alterations in Serotonergic Receptor Expression in Experimental Vein Grafts;" J. Vascular Surgery 14, 40-47, 1991).
Tissues respond to hormones only if they possess specific receptors capable of recognizing and interacting with the hormone in question. The selective and sometimes opposite responses of different tissues to the same hormone, in this case 5-hydroxytryptamine (5-HT) or serotonin, is determined by the type and density of the receptors to the hormone that exist in the particular tissue. It is not possible to predict the activity of 5-HT receptor antagonists in a particular disease condition unless the tissue involved in that disease is tested. For example, 5-HT will not contract the colon vein of cats or dogs since the colon veins from both animals species have no 5-HT receptors. 5-HT will contract the human colon vein because the human colon vein contains 5-HT2 receptors that mediate contraction. (see example below). In the human colon, 5-HT2 receptor antagonists are expected to antagonize the increased contraction of the colonic veins induced by 5-HT (shown in the data) and decrease the vascular permeability that mediate the swelling and discomfort of hemorrhoids. Other 5-HT receptor antagonists (as 5-HT1 1A, 1B, 1C, 1D, 1P and 3) will not mediate these effects and are expected to have no beneficial effects in treating hemorrhoids, varicose veins, venous insufficiency and the healing of wounds.
In the past, before the inventor's present understanding of the different receptors and actions of 5-HT was discovered, it was customary to regard all 5-HT receptor antagonists as constituting one category and to assign common actions to all of them. This was what was done in South African Patent 85/2785 (Merck & Co). This reference as well as U.S. Pat. No. 4,665,075 (Vandenberk), European Patent 0037265 (Kennis), South African Patent 854161 (Merck) and U.S. Pat. No. 4,539,319 (Baldwin) suggest, without support, a connection between anti-serotonin activity and anti-hemorrhoidal effects. None of these references show any applicable data. Patents published in the 1980's generally assumed that anti-serotonin activity should translate into anti-hemorrhoidal effects mince the hemodynamic effects should, on theoretical grounds, be helpful. In addition, most anti-hypertensive drugs were thought to possess anti-hemorrhoidal activity. This has no basis in fact.
Specific 5-HT2 receptor antagonists produce several effects including inhibition of platelet aggregation and decreasing vascular permeability. 5-HT2 receptor antagonist compounds have traditionally been used as anti-anxiety agents, antidepressants, antipsychotics, anti-migraine agents or as modifers of certain other CNS functions. 5-HT2 receptor antagonists, do not cause vasodilation in the arteries and do not lower blood pressure. This is shown in the example below where the 5-HT2 receptor antagonist 2'[2-(1-methyl-2-piperidyl)ethyl]cinnamanilide hydrochloride do not lower blood pressure. This is so exemplified by ritanserine and ICI 169, 369 (Gerard J. Blauw et al., "Antihypertensive Treatment with Ketanserine Shows No Evidence of Vascular Serotonin-Receptor and alpha-Adrenoceptor Blockade" Drugs, 40 (suppl 4), 42-44 1990; P. A. van Zwieten et al. "The role of 5 hydroxytryptamine and 5-hydroxytryptaminerigic Mechanisms in Hypertension, "Brit J. Clin. Pharmacol., 30, 695-745, 1990: Bengt Persson, et al., "Antihypertensive Effects of Ketanserine and Ritanserine in the Spontaneously Hypertensive Rat," J. Cardiovasc. Pharmacol., 11 (suppl. 1. 522-524, 1988). The compounds disclosed in South African patent 85/2785 all lower blood pressure indicating that they could not be selective 5-HT2 receptor antagonists.
Serotonin is not a general endogenous vasoconstrictor. Its effects in the different blood vessels varies depending on the location and size of the vessel in question (P. A. van Zwieten et al., "Pharmacological Profile of Antihypertensive" Drugs with Serotonin Receptor and alpha-Adrenoreceptor Activity Drugs 40 (suppl 4) 1-8, 1990). Hemorrhoids is a disease of veins not arteries. Drugs that are expected to have beneficial activity in hemorrhoids must be able to antagonize the contractile effects of 5-HT on the colon vein. Hemorrhoids is a varicose dilation of veins in the superior or inferior hemorrhoidal plexus, resulting from a persistent increase in venous pressure" (Dorland's Illustrated Medical Dictionary, 25th Edition, W. B. Saunders, Philadelphia, 1974).
Hemorrhoids refer to a mass of dilated veins in swollen tissue situated near the anal sphincter. They are believed to result from a persistent increase in venous pressure, which may be due, in part, to a constriction of the large downstream colonic veins. Occlusion due to platelet aggregation and thrombus formation may also contribute to the symptoms of hemorrhoids by interrupting blood flow and increasing blood stasis and tissue congestion.
Varicose veins are enlarged, twisted superficial veins. Varicose veins partially result from incompetent venous valves that may be acquired or congenital.
Venous insufficiency results from increase tone (partial constriction) of the deeper veins (particularly in muscles) which impedes good circulation and results in blood pooling and stasis. This is turn results in pain, tenderness and edema. The problem appears to be related to inadequate draining of the leg veins due to constriction of the exit vein valves. 5-hydroxytryptamine (5-HT or serotonin) is released from the blood platelets when the blood sits around for a long time and is thought to mediate the contraction of the exit veins.
In wounds, 5-HT is released from blood platelets causing venous constriction and interfering with good drainage and circulation. Good drainage and circulation are needed for proper and fast healing of the wounds.
This invention is directed to compositions or medicines useful in treating or preventing such conditions as hemorrhoids, varicose veins, venous insufficiency and wounds. In particular it comprises use of a 5-hydroxytryptamine-2 receptor antagonist (5-HT2) to treat an animal or human, in need of such treatment. The 5-HT2 receptor antagonist can also be used prophylactically. The 5-HT2 receptor antagonist is used at an effective therapeutic dose. Preferred 5-HT2 receptor antagonists include 2'[2-(1-methyl-2-piperidyl)ethyl]cinnamanilide hydrochloride; 2-[3-[4(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-2,4-dihydro-4-(2-phenoxyethyl)-3H-1,2,4-triazol-3-one hydrochloride, 8-[4-[4-(1,2-benzisotriazol-3-yl)-1-piperazinyl]butyl]-8-azaspiro[4,5]decane-7,9-dione hydrochloride and any mixture thereof. The 5-HT2 receptor antagonist 2'-[2-(1-methyl-2-piperidyl)ethyl]cinnamanilide hydrochloride is disclosed and claimed in U.S. Pat. No. Re. 30, 811 (Dysktra et al. Mead Johnson & Company). The 5-HT2 receptor antagonist 2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-2,4-dihydro-4-(2-phenoxyethyl)-3H-1,2,4-triazol-3-one hydrochloride is disclosed in U.S. Pat. Nos. 4,339,317 and 4,497,773. The 5-HT2 receptor antagonist 8-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]-8-azaspiro[4,5]decane-7,9-dione hydrochloride is disclosed in German Patent DE 3,247,530 and U.S. Pat. No. 4,411,901.
FIG. 1 illustrates the effect of 2'[2-(1-methyl-2-piperidyl)ethyl]cinnamanilide hydrochloride (MPEC) on hemorrhoidal pain as compared to a control;
FIG. 2 illustrates the effect of MPEC on hemorrhoidal itching as compared to a control;
FIG. 3 illustrates the effect of MPEC on hemorrhoidal bleeding as compared to a control;
FIG. 4 illustrates the effect of MPEC on hemorrhoidal tenderness as compared to a control;
FIG. 5 illustrates the effect of MPEC on hemorrhoidal fullness as compared to a control; and
FIG. 6 illustrates the effect of MPEC on hemorrhoidal throbbing as compared to a control.
In a series of experiments using rings of human colon veins representative 5-HT2 receptor antagonists were found to produce highly surprising results in blocking the contractile effects of 5-HT on the human colon. Human colonic vein rings were isolated from discarded human colon tissue following surgery (colostomy). The rings were prepared immediately after surgery and were suspended in buffered physiological saline. The contractions produced by the rings in response to the addition of 5-HT in vitro were measured. The effects of three selected 5-HT2 receptor antagonist compounds on antagonizing 5-HT contractile effects were also determined.
The following tables list the three compounds used and the activity of each in blocking the contractile effects of 5-HT on the human colon in vitro. Table A also includes the activities of the three compounds on four receptors to determine receptor selectivity.
Compound I as used herein has the chemical formula: 2'[2-(1-methyl-2-piperidyl)ethyl]cinnamanilide hydrochloride, and has the following structural formula: ##STR1## compound II as used herein has the chemical formula: 2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-2,4-dihydro-4-(2-phenoxyethyl)-3H-1,2,4-triazol-3-one hydrochloride, and has the following structural formula: ##STR2## Compound III as used herein has the chemical formula: 8-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]-8-azaspiro[4,5]decane-7,9-dione hydrochloride, and has the following structural formula: ##STR3##
TABLE A______________________________________Receptor Blocking Profile (1C - 50; nm) [nM ==nanomolar or 1 � 10-9 M]Receptor Compound I Compound II Compound III______________________________________5-HT2 3.4 17.0 1.75-HT1 22,000.0 >1,000.0 12.5Dopamine-2 >1000.0 >1000.0 8.4Alpha-receptor >1000.0 160.0 47.0______________________________________
The IC-50 is the concentration that inhibits agonist binding to the receptor by 50%. The better the blocker a compound is, the smaller is the concentration thereof needed to block the receptor, i.e., the smaller the IC-50, the better receptor blocker or antagonist the compound is.
The activity is determined as follows: Rings of human colon veins are prepared and hung in a tissue bath. The contractions of the rings are monitored. Adding 5-HT causes the rings to contract. Pre-addition of increasing concentrations of the antagonist result in lesser contractions. The amount of antagonist causing a 50% inhibition of the contractions is then calculated.
The receptor blocking profile is determined as follows: Labeled 5-HT is mixed with a purified preparation containing the receptor. The amount of labeled material that attaches itself to the receptor and cannot be washed off is calculated. In a series of other similar tubes, the same quantity of labeled 5-HT is mixed with increasing concentrations of the antagonist which will antagonize the binding of 5-HT to the receptor. Decreasing quantities of the labeled material will bind to the receptor. The concentration of the antagonist that inhibits the binding of 50% is then calculated.
TABLE B______________________________________Activity against 5-HT on the human colon invitro______________________________________IC-50 2 � 10-9 (I) 10-8 (II) 10-9 (III)______________________________________
As is evident from the above data, although the compounds I, II, and III possess widely different activities against the different receptors tested, their activities in blocking the contractile effects of 5-HT on human colon rings correlated best with their 5-HT2 blocking potencies.
Since these three compounds differ significantly from each other chemically, one can conclude that their antagonism of the effects of 5-HT on the human colon is due primarily to their function in blocking the 5-HT2 receptors in that tissue. Thus, other 5-HT2 receptor antagonists, irrespective of their chemical structure or other properties, should antagonize 5-HT and block its contractile effects on the human colon.
An experiment was performed and established that 2'[2-(1-methyl-2-piperidyl)ethyl]cinnamanilide hydrochloride (MPEC) does not lower blood pressure. This is a classical pharmacological experiment designed to test the effects of new drugs on blood pressure:
Beagle hounds of either sex weighing 8-20 kg were acclimated (18�-29� C., humidity 30-70%) for a minimum of 21 days with automatically controlled illumination (12 hours light/12 hours dark) prior to use. Each animal received approximately 300 grams of Purina Lab Canine Diet #5006 daily which was adjusted as needed for each animal to maintain appropriate body weight. Husbandry practices and veterinary care were in accordance with the Guide for Care and Use of Laboratory Animals (NIH Publication No. 85-23) Animals were fasted on the morning of the experiment and anesthetized with pentobarbital sodium 35 mg/kg i.v. Each animal was intubated with cuffed endotracheal tube to maintain respiration with Bird Mark 7 respirator. Arterial blood pressure (right femoral artery) was measured with Statham P23Db or P23Gb pressure transducer (Gould Statham Instruments, Halo Rey, PR). Heart rate was calculated from the pressure recordings. Other parameters were also monitored. The right femoral vein was cannulated for administration of supplemental anesthesia, and the left femoral vein for administration of vehicle or test drug. When give intravenously, MPEC in a dose of 1 mg/kg elicited no effect on blood pressure or heart rate. A dose of 10 mg/kg w as lethal in both dogs tested.
The effects of MPEC on patients with hemorrhoids was studied. This was a double-blind study. The drug was applied as a 1% cream three times a day. Patients maintained a symptom diary each day. The diary included evaluation of each symptom on a 10 point scale. The results described represent the improvements in the scale between days 1 and 5. The results are depicted in accompanying FIGURES, FIGS. 1-6. The actual numbers of score improvements were as follows:
______________________________________Parameter Placebo MPEC % Improvement______________________________________Pain 0.71 2.14 301.4Itching 1.42 2.00 140.8Bleeding -0.43 1.43 >1000.0Tenderness 0.86 2.71 315.1Fullness 0.80 4.50 562.5Throbbing 0.80 1.75 218.8______________________________________
The results also support the conclusion that MPEC is working in hemorrhoids via 5-HT2 receptor blockade since the main effect appears to be on fullness and bleeding. It is expected that a product blocking 5-HT2 receptors in the colon veins will help with the drainage and will reduce the feeling of fullness that patients with hemorrhoids feel. Since there will be less blood trapped in the swollen veins, less bleeding is also expected. None of the medications presently available on the market have an effect on these two parameters.
The 5-HT2 receptor antagonists of this invention may be used topically or systemically, and they may be taken orally, in liquid, powder, table or capsule form; parenterally, by intravenous, subcutaneous, or intramuscular injection; transdermally, topically by direct application in the form of a cream, gel, or ointment; rectally by suppository or enema; or by inhalation therapy. The 5-HT2 receptor antagonists of this invention may be prepared and used in any suitable solid or liquid form, e.g. powder, cream, paste, table, lozenge, gel, chewing gum, solution, suspension, emulsion, salve, aerosol or the like. They may also be incorporated into wound dressings such as bandages, adhesive strips, and other forms designed to be used for wounds. These pharmacological agents may be administered in admixture with a pharmaceutically acceptable carrier or a dermatologically acceptable carrier for the topical preparations.
The compositions contain the active ingredient in an amount ranging from less than 1% to over 99%, with the remainder being a pharmaceutically acceptable or dermatologically acceptable solid or liquid carrier, which may contain other conventional excipients. Example of such carriers and excipients include fillers, binders, flavors, sweetners, bulking and coloring agents, antioxidants, anionic, nonionic, cationic, zwitterionic, and amphoteric surface active detergents, sudsing, dispersing and emulsifying agents, buffering and pH adjusting agents, water and organic solvents, humectants, thickeners, preservatives, stabilizers, mold release agents, disintegrates, anti-disintegrants, lubricants and the like. Examples of conventional pharmaceutically acceptable carriers and excipients are profusely disclosed in the prior art including discussions in U.S. Pat. No. 4,515,772 (Parran et al. Procter & Gamble), U.S. Pat. No. 4,966,777 (Gaffar et al., Colgate-Palmolive Company), and U.S. Pat. No. 4,728,512 (Mehta et al. American Home Product.), which discussion are incorporated herein by reference thereto.
The topical compositions typically contain from 0.1 to 20 weight % of a 5-HT2 receptor antagonist. Preferably, they contain from 0.5 to 10 weight %. More preferably, from 1-5 weight %.
Transdermal compositions typically contain from 0.1 to 20 weight % of a 5-HT2 receptor antagonists. Preferably, they contain from 0.5 to 10 weight %. More preferably, from 1-5 weight %.
Suppositories typically contain from 0.1 to 20 weight % of a 5-HT2 receptor antagonist. Preferably, they contain from 0.5 to 10 weight %. More preferably, from 1-5 weight %.
Wound dressings typically contain from 0.1 to 20 weight % of a 5-HT2 receptor antagonist. Preferably, they contain from 0.5 to 10 weight %. More preferably, from 1-5 weight %.
Suitably the compositions of this invention consist of sufficient material to provide a dose of from 0.05-10 mg. per kg. of body weight, more suitably 0.2-6 mg/kg body weight. These compositions may be taken 1-3 times daily or as needed until the pain or symptoms of the condition have subsided.
It will be understood that the foregoing discussion including the examples, only illustrates the invention and its principles. However, many modifications and variations in the details of the disclosure will occur to those skilled in the art to which this invention relates and still remain within the scope and principles of the invention. For example, the illustrative embodiments of the invention deal primarily with several specific 5-HT2 receptor antagonists. It is apparent, however, that the principles of the invention can be applied to other 5-HT2 receptor antagonists as well.
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South Beach Fitness Festival
- Sports & Fitness
- 1200 Meridian Avenue, Miami Beach, FL, 33139
The Symphony of Yoga
Friday, January 11, 2013 from 7:00 PM to 9:00 PM (PST)
Join us and the New World Symphony for a monumental night of yoga and music. The evening kicks off with a $2.50 mini-concert inside the New World Symphony and then head downstairs to SoundScape park for an epic yoga class conducted by three of Miami's premier instructors - Paul Toliuszis, Christy Nones McKenzie and Rina Jakubowicz.
Tickets for the concert are at www.nws.edu/yoga. Class is complimentary and open to the public.
For more information : https://www.facebook.com/events/170678949741475/
Join millions of people on Eventbrite.
In order to purchase these tickets in installments, you'll need an Eventbrite account. Log in or sign up for a free account to continue.


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It is almost a truism that marketing has become highly technology-intensive. A nearly ubiquitous component of any marketing technology portfolio is email marketing. In fact, there is a high probability your company is already using some form of it, even though you might not be aware of it. A related component is marketing automation. Customers often talk of these in the same breath. In this article, we will look at this distinction in some detail and also summarize what marketers should know when evaluating these technologies.
Sep 16, 2013
Alive Software Inc. has released ePageCreator v. 5.5, a digital publishing application for Windows and Mac that lets you turn PDF, Flash, and image files into flipbooks that can be published to your website, blog, or CD/DVD, and to your customers' mobile device. ePageCreator creates ebooks, e-catalogs, and e-brochures from a single source file. The documents employ a realistic 3D page-flipping visual effect that displays your content professionally and memorably. Without needing a graphic artist, business managers can use ePageCreator's library of templates and backgrounds to design and publish electronic documents. The entire production and hosting work takes place on your PC or Mac, with no need to engage third-party artists, designers, or programmers. Alive Software says there are no limits to the number of electronic documents that can be created, and no hidden charges. ePageCreator builds standard Flash or HTML5 files for use on PCs, Macs, iOS devices, and Android phones and tablets. The software can also create ePub and .mobi files for e-readers such as the Kindle, iBook, Kobo, and Nook.


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Priya Rana Kapoor Releases PERMISSION TO LIVE YOUR LIFE
"Whose life are you living?" asks author and life coach Priya Rana Kapoor. "Do others' desires often precede your own? Do you wish you knew how to balance it all, have healthy relationships and end up feeling truly happy?"
Kapoor presents an encouraging, straightforward guide to help readers take control of their lives and find ultimate happiness in her new book, "Give YourSelf Permission to Live Your Life" (published by Balboa Press).
Kapoor believes the road to ultimate happiness begins with giving oneself permission to live life on one's own terms. Her book invites readers to embark on her trademarked Permission Journey, a step-by-step process designed to cultivate strength and courage.
Accompanied by candid anecdotes from the author's own experiences, "Give YourSelf Permission to Live Your Life" recounts Kapoor's struggles with illness, self-doubt and a chronic need to please. She shares how she got through it all and shows readers how they can do the same using breakthrough techniques that have benefitted a wide range of people from all walks of life.
Praise for "Give YourSelf Permission to Live Your Life":
"Priya has written an insightful and compassionate book for the individual who struggles with wanting to make everyone else happy, but who neglects their own self-worth and joy."
-Shawn Achor, New York Times bestselling author, "Before Happiness," "The Happiness Advantage"
"Give YourSelf Permission to Live Your Life"
By Priya Rana Kapoor
Hardcover | 6 x 9 in | 244 pages | ISBN 9781452593692
Softcover | 6 x 9 in | 244 pages | ISBN 9781452593685
E-Book | ISBN 9781452593678
Available at Amazon and Barnes & Noble
About the Author
Priya Rana Kapoor is a life coach, speaker and founder of the Give YourSelf Permission empowerment program. She has a master's degree in marriage and family therapy and a certificate in coaching. She divides her time between London and Los Angeles. More information is available at http://www.gyspermission.com and http://www.priyaranakapoor.com.
Balboa Press, a division of Hay House, Inc. - a leading provider in publishing products that specialize in self-help and the mind, body, and spirit genres. Through an alliance with indie book publishing leader Author Solutions, LLC, authors benefit from the leadership of Hay House Publishing and the speed-to-market advantages of the self-publishing model. For more information, visit balboapress.com. To start publishing your book with Balboa Press, call 877-407-4847 today. For the latest, follow @balboapress on Twitter.
About Author
- Casting Roundup: Sarah Chalke, Kim Raver Headline New Pilots
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- Pilot Season Roundup: Colm Feore, Daniel Stern, Dave Annable to Star in New Shows
- James Franco to Star in New Fox Comedy, WHY HIM?
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- Grammy Winner Kelly Clarkson Exclusively Premieres New Music from New Album on MTV, VH1 & CMT First
- CONSTELLATIONS' Jake Gyllenhaal and Ruth Wilson Set for THEATER TALK This Weekend


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Tag:Jesse Palmer
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Posted on: June 30, 2011 11:38 am
Former Texas QB to look for love on TV
Posted by Tom Fornelli
They're young, they're hot, they're single –- they're Dallas' Most Eligible. From beauty queens to pro-football players, this group of Texas socialites proves that everything's bigger in Texas –- including the drama. Some are looking for true love while others have perfected the art of the one-night stand, and somehow their love lives have all crossed paths at one time or another. Dallas serves as the sexy backdrop for this jaw-dropping series that follows a group of successful friends living it up in the lone star state.
If that's not enough to get you to watch the show, here's Nordgren's bio from Bravo's site as well. It sounds like Nordgren is going to get more playing time on the show than he ever did at Texas, where he threw only 14 passes in his career.
Matt is an all-American, blue-eyed Texan charmer. Formerly a quarterback at the University of Texas, Matt signed to play football professionally, until an injury shifted his path. Today, the ambitious 28-year old is partner in the family energy business, Nordco Inc., and is the founder of Nordco Consulting. Matt also devotes his time to various charities, primarily his own -- The Leadership Foundation and Gala -- which helps underprivileged children develop character and strength through sports and educational programs.
Here's hoping that television can show Matt and Courtney the love they truly have for one another in the scene where both of them have had too much to drink.
Category: NCAAF
Posted on: January 7, 2011 3:04 pm
Jim Harbaugh is ... The Bachelor
Posted by Jerry Hinnen
There's no doubt that were we writing in a bygone era, the football world's most desirable object of lust, Jim Harbaugh, would be described as the prettiest girl at the coaching cotillion. This being the year 2011, though, cotillions are out and reality TV is in, meaning that it was only a matter of time before somone -- in this case, Tauntr.com -- came up with something like this:
Jesse Palmer , eat your heart out. ("You all have a lot of money to offer?" If you have seen even one episode of The Bachelor --and it's not something we recommend -- you will recognize that line as unqualified genius.) We'd say the image of Dave Brandon in a cocktail dress would be enough to send Michigan fans running for the eye bleach, but the last few days have probably been enough to drive Wolverine supporters past the point of being surprised by anything.
If there's one other thing The Bachelor and the Harbaugh frenzy have in common, it's this: it's a sure bet the producers at its heart still have a twist or two coming down the stretch. We're all staying tuned.
HT: NBCSports . And it's about an ABC show. Maybe this post was a bad idea.
Category: NCAAF


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World Book
& EBooks
Book Sale and Craft Fair
Saturday, September 26 from 10 am-2 pm
Save the date for the annual used book sale and craft fair at the Hampton Falls Free Library. The Library will begin accepting donations of gently used books beginning Saturday, August 1. Crafters, click here for a downloadable registration form.
Storyteller Simon Brooks
Wednesday, July 8 from 6:30-7:30 pm
Storyteller Simon Brooks doesn't just tell stories. He acts them out. You will laugh; you will love the evening! We will be serving ice cream after the program. This event is sponsored in part by Bill Kenney.
Magician Norman Ng
Wednesday, July 15 from 6:30-7:30 pm
Always amazing, always fun! No sign-ups necessary. This event is sponsored by the Pimental family.
Land Managment Options
Tuesday, July 21 at 6:30 pm
Join Hampton Falls residents and NH Coverts Project volunteers Paul Melanson and Carol Moore for a presentation and discussion on forest management options and land conservation practices for landowners in Hampton Falls.
The Annual Talent Show
Wednesday, July 22 from 6:30-7:30 PM
Children in the Summer Reading Program can sign up to showcase their talent at the Annual Talent Show.
Adult Book Group
Tuesday, July 28 at 7:00 p.m.
This month's selection is The Martian by Andy Weir. Copies are available at the Library. New members are always welcome.
The Hampstead Stage Company "Robin Hood"
Wednesday, July 29 from 6:30-7:30 p.m.
The Hampstead Stage Company returns with a production of "Robin Hood." This event will be followed by the final raffle.


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Monsters and Size Queens 2 - Scene 2
Get Your Gay Access Now!
DVD Title Monsters and Size Queens 2
Category Gay
Added September 22, 2014
Viewed 25,881 times
Favored 37 times Add to favorites
Duration 14m, 52s
Tags Cum on Hands, Cum on Stomach, Fingering, Handjobs, Solo Guy
- This scene does not have any comments yet!
We start off with Andrew, a hot dude who we see a picture of and then find out hes chilling. As we watch he starts flicking his hand over is butt and then turns over to pull out his shlong and start jerking off and playing with his balls. As we watch he continues to stroke his long hard dong and he then takes off his panties. He continues to stroke his meatstick for a while before he gets up, puts his thongs on, goes back inside, and pulls his cock back out to keep stroking on it. He takes off his underwear again and continues to stroke his penis good and hard probing his balls as he does. He finally blows his enormous load all over his abdomen.
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Monsters and Size Queens 2
September 22 2014
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- Scene 2 - Hot Guy Masterbates And Cums On Himself
- Scene 1 - Huge Cocked Guy Jerks Himself Off Good
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- Scene 4 - Athletic Hunk Stroking His Big Dick
- Scene 5 - Big Dick Stud Masturbating Poolside
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So your blog is not getting the results you want, right? Be it traffic, sales, affiliate sales, traction, authority - nothing happens!
So what's wrong? One of the main reasons why most blogs don't work is that they are not interesting enough for the readers.
In this crowded, competitive blogosphere the last thing you want is to have a dull blog. Even interesting blogs sink into the noise of the overwhelming number of blogs that are online.
There are hundreds, if not thousands, of blogs that are started every day. The competition is getting tougher by the minute.
You are in an era where you have to fight to get your readers' attention. And no, you … [Read more...]


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ABC House wants you to know there are ways you can help prevent child abuse in your community.
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£1,249 pcm
3 bed flat to rent
£2,200 pcm
3 bedroom flat to rent Seven Sisters Road, Finsbury ParkPlatinum Estates are delighted to offer modern and unique 3 bedroom ground floor garden flat located close to transport links. The property boasts a large kitchen and living room space, new modern fully fitted kitchen and bathroom. More details ›
£507 pw
3 bedroom flat to rent Seven Sisters Road, Manor HouseAlex Crown are pleased to present this brilliant and unique three bedroom garden flat located in Manor House N4. The property comprises of; three large double bedrooms, fully fitted kitchen, spacious lounge and a fully tiled bathroom. Wood flooring throughout. More details ›
£335 pw
3 bedroom flat to rent Ashmount Road, London, N15Three bedroom flat, Situated moments from the shops and amenities around Seven Sisters, this Three bedroom first floor flat provides spacious accommodation.Reception room two double bedrooms and a single bedroom kitchen, shower room and WC. More details ›
£550 pw
3 bedroom flat to rent Grace Lodge, 181 Clarence Road, London( Estates and Lets ) * Penthouse * Three double bedroom * Furnished to a high standard * Open plan kitchen * Wooden floors throughout * Balcony off main bedroom * MUST BE VIEWED More details ›
Added yesterday by Estates & Lets Ltd, London. Call: 020 8012 1661 Local call rate
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3 bedroom apartment to rent De Beauvoir Road,London,N1Spacious three bedroom maisonette with additional office/study. More details ›
£1,400 pcm
3 bedroom flat to rent Inglehurst Gardens, Gants Hill, IG4First floor 3 Bedroom flat. 2 Toilets. Close to Redbridge Junior School & Beal High School. Close to station. More details ›
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3 bedroom flat to rent Alexandra Grove, London, N4Beautiful very spacious 3 double bedroom split level flat with own garden/balcony situated within a converted Victorian terrace house which is presented in excellent condition throughout and benefits from a good location and off street parking. More details ›
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3 bedroom flat to rent Perth Road, LondonFirst Floor Ex-Warner This 3 bedroom first floor flat has a reception room It has fitted kitchen, bathroom with separate WC, own front door, rear garden, mostly double glazed, gas central heating (untested) and available now. The flat is close to Lea bridge road with access to Hackney easily ava... More details ›
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3 bedroom flat to rent Eastway, Hackney, E9LONG LET. A wonderful three bedroom flat arranged over two floors of a charming church conversion boasting bright and modern interiors throughout located in an excellent Hackney location. More details ›
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3 bedroom flat to rent Trelawney Estate, Hackney, Hackney Central, Mare Street, Paragon Road, London, E9Dimension Estates are delighted to offer a fantastic 3 bed x-local flat located just moments away from Hackney Central Overgrounnd. Situated in the heart of Hackney with many vibrant local amenities, pubs and restaurants. More details ›
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Joe Student
If you don't enjoy the things I write about — entertainment, nightlife, music, booze, gadgets, sports, Playboy models and more —you're probably dead. I enjoy when you read what I write. (And, yes, it's my real name. Stop asking.)
Peyton Manning tied an NFL record by throwing seven touchdown passes in a game, and the Denver Broncos beat the Baltimore Ravens, 49-27, in the opener of the 2013 NFL season in Denver on Thursday night.
The NFL begins its 2013 season this week with all 32 teams in action. Week 1 is stacked with intriguing games. Here's what we'll be watching:
You were innocent, but these animated images were not. Why you so pervy, old cartoons?
We don't know precisely what sort of training goes into becoming a "bikini athlete" — does one do beach towel squats? — but our Babe of the Day, Taylor-Jade Carroll, seems to excel at it.
Model and pageant winner Natalie Pack doesn't need a sash to demonstrate her beauty.
Laura Leary isn't just a gorgeous model represented by Wilhelmina in Los Angeles; she's also a community advocate.
Bryan Bickell and Dave Bolland scored within 17 seconds of each other late in the third period, and the Chicago Blackhawks beat the Boston Bruins, 3-2, in Game 6 of the Stanley Cup Finals on Monday night to win their second championship in four seasons.
You know all those plans you had to go swimming this summer? Forget them. After you see the fish a Virginia man caught earlier this month, you're not even going to want to take a shower without a spear gun.
Virginia fisherman Caleb Newton caught a three-foot-long, 17-pound, six-ounce Northern snakehead fish (also known a
To paraphrase the late Robert F. Kennedy, some people would ask 'Why put sloppy joe meat into a deep-fried, glazed donut shell?' but Charlie Boghosian asks 'Why not?' Boghosian, known to many fans of fair food (and presumably their cardiologists) as "Chicken Charlie," debuted a Krispy Kre
A truck carrying fireworks struck a moose on the Trans Canada Highway near Wawa, Ontario on Friday morning. The collision caused the vehicle's fuel tank to rupture and catch fire, and you know what happened next. Watch the video above for the impressive display (though the moose probably didn't enjoy it
Nikki du Plessis is a 23-year-old from Pretoria, South Africa. An international model, Nikki has done fashion, lifestyle, glamor and nude modeling both in her native country and the U.S. Having your body celebrated on several continents is something that can really buil
True skateboard freaks will skate over anything, even the baseball cathedral that is Yankee Stadium. But if they can look this good doing it, what's the harm, grandpa? Watch the video above to see some major league shredding
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Buy online front row tickets for all Concert, Theater and Sporting events, and tickets to all sold out major events.
Sport, Concert and Theater tickets are hot and Frontrow.com has tickets to all your favorite events, including the Miami Heat Games, College Football and Super Bowl. We can get you "In the door" or the best seats to all games and events. Talk to one of our specialists or order online 24/7. Frontrow.com has a solid reputation of 22 years in the business selling tickets. Front row can get you tickets for all the, Playoffs and all NBA Games.
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Front Row is a quality ticket broker for all concerts, theater, and sporting events. Front Row sells the finest Piccadilly Circus packages and tickets. If tickets you are searching for are not available, please check back as we always update and list new tickets in our huge inventory. Piccadilly Circus schedules are on our web site. Just click to see our real-time online concert, sport and theater tickets.
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City A.M.
Alight at Liverpool Street for Love
City A.M.
The commuter hub along with Tottenham Court Road and Piccadilly Circus have the greatest number of people without a significant other than any other station in London. For the greatest chance of finding a date, men should head to Goldhawk Road in west ...
ITV News
Parts of London Underground hotter than the Sahara Desert
ITV News
Sweltering commuters faced temperatures as high as 35C on London Underground today making it hotter than the Sahara Desert. . Credit: PA. The high was recorded on a Bakerloo line train between Piccadilly Circus and Oxford Circus at 2pm while the ...
and more »
Police restrains a lone demonstrator during London Pride
01/03. Caption. A protester is held on the ground by police officers and security guards for disrupting the London Pride parade at Piccadilly Circus. Police restrains a lone demonstrator during London Pride. ID:7963372. +add to lightbox · -remove from ...
and more »
Stereo Kicks Week: Watch acoustic performances of 'Love Me So' and GRL's ...
Oh it's been a bloody great week, hasn't it? Namely because we've mainly been staring at GIFs of Niall Horan's arse and eating double stuff Oreos, but also because it's been Sugarscape's Stereo Kicks Week and we've been doing all sorts of interviews ...
and more »
Accountancy Age
London's Criterion restaurant enters administration
Accountancy Age
ADMINISTRATORS from UHY Hacker Young have been called in by the owners of the opulent Criterion on Piccadilly Circus after the historic restaurant entered administration following a steep rent rise. Peter Kubik and Andrew Andronikou of UHY Hacker ...
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