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Frontier Drum and Bugle Corps - Wikipedia
Manuel Guerrero & Roger Treacher
Crimson and chocolate tunic, black pants and shoes, crimson gauntlets, black gloves, crimson and white sash with silver trim, and black aussie hats with a black and silver plume
Frontier Drum and Bugle Corps was an all age Drum Corps Associates A Class summer drum and bugle corps based in Denton, Texas (USA).
Frontier operated under the umbrella of the Frontier Performing Arts Association (FPAA),[1] which, in addition to Frontier, operated Texas Independent Winterguard,[2] Open Range brass ensemble,[3] the Sky Ryders Alumni Drum and Bugle Corps,[4] and Outlaw mini-corps.[5] Frontier left the field in 2008. Several attempts were made to reform the group, but none succeeded.
1.3 Repertoires
4 Seasons of note
In its first two years, the corps uniform consisted of khaki pants and tops with a black belt and cross-belt, a uniform reminiscent of the 27th Lancers. Since 2007, Frontier wears a chocolate and crimson uniform with brass buttons and white gauntlets and gloves.[6] For 2008, the uniform was supposed to be changed to incorporate silver buttons, red gauntlets with black gloves, and a red sash with silver sequins.
The corps performed using 2-valved and 3-valved bugles.
Repertoires[edit]
Frontier has programmed music from a wide variety of musical genres, including jazz, classical, Broadway, folk, and movie tunes.[7]
The corps logo was the word Frontier with a shooting star crossing it from left to right. The corps song was Bridge Over Troubled Water by Simon and Garfunkel.
Frontier's membership drew on a large population of displaced drum corps veterans, but welcomed adults with any musical and/or visual experience. Members came from as near as the Dallas metro area and other parts of Texas to as far as Oklahoma, Kansas, Arkansas, Louisiana, and California. The corps eventually died because it was spread too thin.
Frontier is an associate member of DCA and a charter member of DCA-Central. Frontier was always trying to create something new and in turn, ran itself into the ground by expanding before it was ready.
Frontier was formed in the fall of 2004 by executive director Chris Green.
In the arts world, Frontier enjoyed a close relationship with the world-famous Turtle Creek Chorale men’s chorus, performing in several concerts and television broadcasts. With the Chorale, corps members participated in recording sessions for the nationally distributed compact disk "Songs of Our Nation",[8][9] an award-winning documentary entitled ”Power of Harmony”,[10] as well as the 2006 Christmas concert.[11]
Frontier also performed in exhibition at the annual Texas Drum Corps Preview,[12] the Denton Arts & Jazz Festival[13] in Denton, Texas,[14] at a roller derby game of Assassination City,[15] and at home games of the Dallas Diamonds[16] women’s professional football team.
From 2005 to 2008, Frontier competed at the DCA World Championships, Brass on the Bayou[17] sponsored by Gulf Coast Sound, as well as annual contests sponsored by Minnesota corps Govenaires and Minnesota Brass, Inc..
In 2007, Frontier also competed at local DCI contests.
Frontier sponsored an annual competition in the Dallas/Fort Worth area called Brass Hysteria.[18]
Seasons of note[edit]
In its inaugural season, the corps received a score of 70.713 and finished 16th, performing its debut show Lasso the Sun.
With their show, entitled Fire, Frontier improves nearly 10 points from its inaugural season, finishing 14th and posting a semifinals score of 80.288[19] while performing in less-than-ideal conditions in the rains of Hurricane Ernesto. In recent times, the only all-age corps to post a more significant improvement from one year to the next was the Bushwackers Drum and Bugle Corps, who improved 10.3 points from 2000 to 2001.
Frontier takes a step forward with the introduction of its new (and current) uniform. The corps makes its DCI debut at the Lake Highlands Festival of Drums & Bugles on July 19. The 2007 production, 1968, comprises music released in that year, including The Age of Aquarius from the musical Hair and Bridge Over Troubled Water (song), which has become the corps song.
The 2008 production, entitled There And Back Again, will take viewers on a musical journey, beginning with the modern classical piece Ride by Samuel Hazo and continuing with a lush arrangement of I'll Be Seeing You based on the version by New York Voices. Then the corps takes a jazzy turn with the classic Caravan, and finally returns Home to the strains of Michael Bublé's hit single of the same name.
^ http://www.frontierperformingarts.org/
^ http://www.txindependentguard.org/
^ http://www.openrangebrass.org/
^ http://www.skyrydersalumni.org/
^ http://www.theoutlaws.org/
^ "Help Frontier Get New uniforms In 2007". Drum Corps Planet. 2006-09-25. Retrieved 2006-09-25.
^ http://www.corpsreps.com/corpsreps.cfm?view=corpsdet&corps=651&corpstype=Senior
^ https://www.amazon.com/dp/B000P58PFM/
^ "Frontier Featured On Nationally Released CD". Drum Corps Planet. 2006-07-21. Retrieved 2006-07-21.
^ https://www.amazon.com/dp/B000E60Q5Y/
^ "Turtle Creek Chorale to perform five concerts" (PDF). Dallas Morning News. 2006-12-15. Retrieved 2006-12-15.
^ "Texas Drum Corps Rock Austin". Drum Corps Planet. 2006-06-26. Retrieved 2006-06-26.
^ http://www.dentonjazzfest.com/
^ "Frontier To Perform At Denton Arts & Jazz Festival". Drum Corps Planet. 2006-03-11. Retrieved 2006-03-11.
^ http://www.acderby.com/
^ "Archived copy". Archived from the original on 2013-10-12. Retrieved 2014-01-28.
^ http://www.gulfcoastsound.org/brassonthebayou-index.html
^ http://www.brasshysteria.org
^ http://www.corpsreps.com/scores.cfm?view=scoreshow&showid=2006732
Frontier Performing Arts
Frontier historical scores
Frontier historical repertoires
Current DCA Open Class Corps
Current DCA Class A Corps
Retrieved from "https://en.wikipedia.org/w/index.php?title=Frontier_Drum_and_Bugle_Corps&oldid=854175239"
This page was last edited on 9 August 2018, at 13:25 (UTC).

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Patent US4931813 - Ink jet head incorporating a thick unpassivated TaAl resistor - Google Patents
A thermal ink jet head incorporates bubble-generating resistors, each with a relatively thick layer of unpassivated resistive material, such as TaAl. The thermal ink jet head includes an ink source, ink channels, respective orifices, and circuitry for providing the electrical energy which the resistors...http://www.google.com/patents/US4931813?utm_source=gb-gplus-sharePatent US4931813 - Ink jet head incorporating a thick unpassivated TaAl resistor
Publication number US4931813 A
Application number US 07/317,106
Publication number 07317106, 317106, US 4931813 A, US 4931813A, US-A-4931813, US4931813 A, US4931813A
Inventors Alfred I. Pan, Howard H. Taub, Harold W. Levie
Patent Citations (9), Referenced by (124), Classifications (7), Legal Events (3)
US 4931813 A
A thermal ink jet head incorporates bubble-generating resistors, each with a relatively thick layer of unpassivated resistive material, such as TaAl. The thermal ink jet head includes an ink source, ink channels, respective orifices, and circuitry for providing the electrical energy which the resistors convert to heat to form bubbles which expel ink through respective orifices. A range between 3,000 Å and 5,000 Å is preferred for the resistive material to minimize failure rate while avoiding thermal, electrical and manufacturing limitations of passivated resistors.
1. A print head for a thermal ink jet printer comprising:
ink source means for supplying ink;
orifice means for directing ink expelled therethrough toward a recording medium;
channel means for conveying ink from said ink source to said orifice;
circuit means for supplying a current in response to a control signal; and
a resistor structure coupled to said circuit means so that when said circuit means supplies a current said resistor structure converts electrical energy into heat, said resistor structure being arranged with respect to said channel means and said orifice means so that ink within said channel means can be expelled through said orifice in response to the generation of heat by said resistor structure, said resistor structure including a base structure having a substrate and a homogeneous TaAl resistive layer disposed to contact fluid within said channel means, said resistive layer being at least about 2000 Å thick.
2. The print head of claim 1 wherein said resistive layer is at least 3000 Å thick.
5. A print head for directing ink toward a recording medium in response to control signals, said print head comprising:
channel means for conveying ink from said source means to said orifice means;
a resistor structure coupled to said circuit means so that when said circuit means supplies a current said resistor structure converts electrical energy into heat, said resistor structure being arranged with respect said channel means and said orifice means so that ink within said channel means can be expelled through said orifice means in response to the generation of heat by said resistor structure, said resistor structure including a silicon substrate, a silicon dioxide thermal barrier layer, and a TaAl resistive layer disposed to contact said ink within said channel means, said TaAl resistive layer being at least about 3000 Å thick.
6. The print head of claim 5 wherein the thickness of said resistive layer is at most about 5000 Å.
7. In a print head for a thermal ink jet printer comprising:
ink source means for supplying ink capable of corroding TaAl;
a resistor structure coupled to said circuit means so that when said circuit means supplies a current said resistor structure converts electrical energy into heat, said resistor structure being arranged with respect to said channel means and said orifice means so that ink within said channel means can be expelled through said orifice in response to the generation of heat by said resistor structure, said resistor structure including a base structure having a substrate and a resistive TaAl layer;
said TaAl layer is disposed to contact ink within said channel means said is between about 3000 Å and 5000 Å thick;
whereby the operating life of said resistor structure, and thus of said print head, is enhanced.
The present invention relates to thermal ink jet printers, and more particularly, to a bubble-generating heating element for the print head of such a printer. It is a major object of the present invention to provide a relatively simple heating element with improved life properties.
The foregoing and other objects are achieved in a print head using heating element with a relatively thick unpassivated tantalum-aluminum (TaAl) resistor structure. The ink jet head includes an ink source an ink channel and an orifice through which ink droplets are directed toward a recording medium. An electrical circuit provides the current used by the heating element in generating heat which causes ink to be ejected from the channel and through the orifice.
FIG. 1 is a schematic perspective assembly view of a thermal ink jet head in accordance with the present invention.
A print head 10 for a thermal ink jet printer includes a source 12 for supplying ink, channels 14 for conveying ink, and an orifice plate 16 with orifices 18 through which droplets 20 are expelled from the channels 14, as shown in FIG. 1, and propelled toward a recording medium, as is known in the art. Heating element resistors 22 are positioned so that ink within a channel 14 can be expelled through a respective orifice 18 when the respective resistor 22 generates heat. The resistors 22 are arranged in series with respective pairs of conductors 24 which provide the current, the electrical energy of which is converted to thermal energy by the resistors 22 to heat the ink.
US5148191 * Feb 28, 1990 Sep 15, 1992 Canon Kabushiki Kaisha Ink jet head having heat generating resistor made of non-single crystalline substance containing ir, ta and al and ink jet apparatus having such ink jet head
US6142612 * Nov 6, 1998 Nov 7, 2000 Lexmark International, Inc. Controlled layer of tantalum for thermal ink jet printer
WO1996024764A1 * Feb 1, 1996 Aug 15, 1996 Siemens Aktiengesellschaft Fluid proportioning and atomizing device
U.S. Classification 347/62, 338/333
Cooperative Classification B41J2002/14387, B41J2202/03, B41J2/14129

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Spring Thaw: A Chris Matheson Cold Case Mystery Novella and Other Mystery Short Stories (Audiobook) by Lauren Carr | Audible.com
In today’s hectic world, many whodunit fans don’t have time to get their mystery fix diving into a whole novel. Lauren Carr’s Spring Thaw is for these fans - but that doesn’t mean whodunit fans who do have time can’t dive in as well.
Spring Thaw features retired federal agent Chris Matheson from Lauren Carr’s newest best-selling cold case series. When his late father’s former friend is indicted for the seven-year old murder of a church bishop, Chris renews old broken friendships to thaw out the cold case.
Featuring Mac Faraday from Lauren Carr’s popular Mac Faraday Mysteries, an estate auction turns into a deadly affair after Gnarly's antics cause Mac to purchase a gem of a dress, which isn't his color in "Killing Bid".
"Beauty to Die For" features the Lovers in Crime characters Joshua Thornton and Cameron Gates in a race against the angel of death to clear the name of a dying woman's son, who was framed for murdering Miss Pennsylvania.
"Countdown to Murder" returns to the Lovers in Crime where Cameron and Joshua try to solve the murder of a young pregnant widow before it happens.
Mystery fans will discover that every dog has his day, especially if that dog is Gnarly. In Lucky Dog, Gnarly helps Mac Faraday to solve the murder of a wealthy society girl.
Dog-loving mystery fans will get a special treat when they listen to "The Gnarly Rehabilitation Program". In this Gnarly mystery short, Bert and Ernie learn the hard way that crime does not pay when they dognap Gnarly.
Gnarly, the rambunctious German shepherd, is also featured in Lauren Carr’s Christmas short, "A Gnarly Christmas". It is Christmas day, and Gnarly has been up to his old tricks again. Now he's in the doghouse - or rather the boathouse - after stealing the Christmas feast! Moments after Archie and Mac leave Spencer Manor, Gnarly hears a call for help from Rocky the Maltese down the street. Four assassins for hire have invaded the home of Rocky's elderly owners. While the home invaders wait for instructions from a mysterious caller, Gnarly must plot to stop them. Can Gnarly save Christmas with only the help of an eight-pound Maltese dressed in an elf suit?
©2018 Terri Lynn Zaleski (P)2018 Terri Lynn Zaleski
Spring Thaw: A Chris Matheson Cold Case Mystery Novella and Other Mystery Short Stories is a collection of seven novellas by Lauren Carr. These novellas include:
Spring Thaw: A Chris Matheson Cold Case Mystery Short - Chris Matheson gets caught up in a cold case murder mystery of a bishop and his father's former friend is the accused.
Killing Bid: A Mac Faraday Mystery Short - Mac Faraday gets into a predicament because of his German shepherd, Gnarly.
Beauty to Die For: A Lovers in Crime Mystery Short - Joshua and Cameron has to help solve a murder of a beauty queen, Miss Pennsylvania.
Countdown to Murder: A Lovers in Crime Mystery Short - Joshua and Cameron finds themselves helping a pregnant widow.
Lucky Dog: A Mac Faraday Mystery Short - Mac gets the help from Gnarly to solve another murder.
The Gnarly Rehabilitation Program: A Gnarly Mystery Short - Gnarly gets abducted!
A Gnarly Christmas: A Gnarly Short Story - It is Christmas time and Gnarly gets himself into a little bit of trouble.
I enjoyed every one of these stories. Since I have just discovered Lauren Carr recently, I got a good taste of what her other series are about They are fun and entertaining stories with laugh out loud humor. My favorite story would have to be A Gnarly Christmas. That pup sure knows how to cause trouble. This one is the one that made me giggle throughout. So much fun!
Spring Thaw: A Chris Matheson Cold Case Mystery Novella and Other Mystery Short Stories gets a well deserved five plus stars from me. I cannot wait to read full length novels the series the stories are from. Most definitely worth a read. Highly recommended!
I received an audio version of this book from the author. This review is 100% my own honest opinion.
Mysteries with characters I already know & love
Spring Thaw and Other Mystery Short Stories contains several stories that have characters from the Mac Faraday, Chris Matheson, and Lovers in Crime series. Of course, since these are short stories the mystery occurs and is solved quickly. Lauren Carr's full-length novels are great, and I was pleasantly surprised at how much I enjoyed these stories as well. It's fun to read short stories about characters I already know, including the animals. Gnarly, Mac Faraday's German Shepherd, is such an amazing character he's always fun to read about.
I like the author's writing. She makes it seem that you actually know the characters. The narrator did a good job with pace and timing and his voices for the different characters were done very well.
Whether you are a fan of Lauren Carr or haven't read any of her books yet, if you like a mystery you'll like these stories. This would be a good book to read to get a taste of her writing.
I have "listened" to a handful of Lauren Carr's books. However, there are still many books that I have not "listened" too yet. This is a fun sampler of short stories. A nice introduction to new readers of Lauren Carr and her books. It gives the readers a chance to get to know some of her main characters from the various series. Of course, my favorite stories involved Mac Farady and Gnarly. I am a sucker for a good dog story or any story featuring animals. Than, there is Mac, who I have gotten to know pretty well now.
The first story in this audiobook is more like a full length story. It is the longest. There was a twist or two thrown into the storyline. Overall, while I may not have loved each story on their own or overall this audiobook, it is one to listen to. Another reader did mention that most of these stories were not new as they had been previously featured. So, fans of this author who have read the prior books have been warned. Although, they may not mind revisiting with old characters. Kind of like family.
Normally, I'm not really into short stories, because I am always left wanting more. More drama, more mystery, more everything. But these short stories were an absolute joy to listen to. The narrators did a fantastic job. I never had trouble keeping the characters straight during dialogue heavy scenes, nor did I feel the need to constantly speed up the playback.
The characters themselves were very well done, though not necessarily extraordinary. I don't think they are supposed to be, as the mystery is what is compelling each tale. The real stars for me were the dogs. Each story featured a different dog, and each dog had their own personality. If you are a dog lover, you know that no two dogs are alike. Each is unique with its own traits and quirks, just like humans. Often dogs will be written generically, with traits of loyalty, cuddling, and sometimes mischief. When a dog lover writes a dog, you can see the appreciation for the different types and instincts each dog has and just as much thought is put into their personality as any other character. I truly appreciated Lauren Carr's understanding and love of animals and the significant roles they play in our lives.
If you enjoy a good story with intrigue and plot twists, pick up this collection of stories. You will not be disappointed.
Great Stories! Great Narration!
I love this short story collection by Lauren Carr. I had previously read several of them, but think they fit this short story book so well. I so enjoy the books featuring Gnarly and Mac Faraday along with Chris Matheson and his motley crew of animals and Joshua Thornton/Cameron Gates with their pets as well. Each story in this book is a standalone that brings more dimension to the characters that I have grown to love. The author has a great way of writing humor into the books along with vivid imagery. Each story has some very unexpected twists and I love how the criminal is revealed. I so enjoy it when the villain is not obvious. Of this collection, I do not have a favorite story because each is so good, but I am partial to the Mac Faraday stories as that is the character that led me to discovering the author Lauren Carr. I am definitely hooked on reading more from this author. I highly recommend this book to discover more about some favorite characters in various series. Listening to this collection, I thought that Mike Alger did a wonderful performance. He has the perfect voice inflections for these stories and adds to the enjoyment. I requested this review copy audiobook and have voluntarily written this review.
So Amusing and Entertaining!
Lauren Carr’s collection of short stories is sure to keep you smiling through each story. Featuring characters from her bestselling series, fans will love visiting again. New readers will get a taste of the humor found in each book.
Animal lovers can’t resist Gnarly especially, and the many other pets included in each series. Gnarly plays a major roll in most of these. He makes a great star, if troublesome at times. His antics always amuse, as do his ’serious side’ when there is trouble. Then we see his training as a law enforcement dog come into play. He is very good at what he does.
Mike Alger is the narrator who will keep you amused and tense as appropriate. His voice becomes the character’s voices. You will get attached.
It’s a fast listen, yet oh-so entertaining. Don’t miss this one! We received a copy of this audiobook as part of IRead Book Tours virtual tour for Spring Thaw. Can't wait for more.
Quick hits of humor, mystery, & a touch of romance
Audio book review. At under two hours listening time, Spring Thaw and Other Mystery Short Stories gives listeners a very satisfying, quick-fix of what author Lauren Carr does so well. Within just a few minutes of starting Spring Thaw, the first story, Carr fully defines a not-so-holy bishop (he’s a jerk), sets the tone for the scene (contentious), and brutally kills-off a character (BAM)! To say I was sucked-in to Spring Thaw is an understatement. Whether they’ve met main character Chris Matheson and crew before or not, readers won’t be able to resist this fully developed mystery packed into a novella.
“Chris cast a glance at the coffee pot; it was only one third full. The way his day was going, it was two thirds empty.”
Back to main character Chris Matheson and crew… Carr’s writing makes you feel like you are at the kitchen table with Chris and Doris, his FABULOUS mother, and part of this family and life. They are my people! If you haven’t read ICE, the first book in the Chris Matheson Cold Case Mysteries, you need to get busy! Spring Thaw, like Ice, is smart, infused with subtle humor, and keeps leading and misleading you along until the big reveal to neatly tie-up the loose ends.
In addition to the two books thus far in the Chris Matheson series, the only other of Carr’s series I have read is Murder by Perfection, one of the Thorny Rose Mystery books. So, Spring Thaw is a great sampler of what readers can expect in the Mac Faraday and Lovers in Crime series. There are a few common denominators in all the short stories (these people are rich, for one), but the real scene-stealer in these is Gnarly the dog. Actually, Gnarly is pretty much the main character in three/four of the seven short stories! His stories are fun little capers full of irony and yes, even a Scooby-Doo line (“I would have gotten away with it if…”) and ending or two. This light-hearted comedy is perfect.
The two Lovers in Crime short stories are surprisingly intricate and complete mysteries for such brief stories. Again, Carr’s writing skills shine as she masterfully and efficiently writes the twists and turns and surprises. Each of the stories involves a wide cast of characters (tip: trust no one), and I was completely caught off guard with the ending of “Beauty to Die For.” WHOA. This and “Countdown to Murder” shows the sparks and connections between MCs, Joshua and Cameron, and make me want to go back to the beginning to see how they met in the first place.
Several of the story lines take place in in Pennsylvania and in/around Pittsburgh, which adds a layer of fun and interest for me since I lived there for seven years. The descriptions of landscape and places is richly written, and even those who aren’t familiar with that part of the world will enjoy it. It’s been more than a few years since I lived there, so it’s possible these things have changed, but my ear did catch some misfit information: one, (sadly) I never once came across a person in Pennsylvania who offered sweet tea, and two, (sadly) Hershey Park (well, the rides anyhow) aren’t open in April. Who knows? Maybe since the ‘80s, circumstances have evolved, but consider this a PSI to avoid a potential Griswold kind of experience.
ABOUT THE AUDIO BOOK: There are some jaunty music snippets that introduce the book and provide segues between the stories, which give the audio a real production feel. Also, there’s a little echo sound-effect to indicate we’re hearing a character’s internal monologue/thoughts – super helpful. Mike Alger is back as narrator, and though his pace is a little slow for me (I swear he could be the Smuckers commercial guy), I left it alone and listened at regular speed. He voices the numerous characters well (Doris is best) and his accents really complement the personalities. There are a few technical issues – places where voices overlap and sound blips that draw the ear. It is a little hard to separate the characters from story to story when listening to the audio book – for example, Mac and Catherine from story two sound like Chris and Doris from story one. The stories are so good that I listened straight through, so from this perspective, it might be better to take a breather between and not listen back-to-back. Overall, it’s a recording well-done.
I highly recommend this set of short stories, which are perfect listening for quick hits of humor and mystery -- with a dash of romance. And with that gorgeous winter-y cover, go ahead and add a print copy to your library to show your shelf some love. I am looking forward to immersing myself into my next adventure from Lauren Carr, and fortunately there are a lot to choose from … decisions, decisions.
Thank you to iRead Book Tours and the author for providing me an audio download in exchange for my honest opinion – the only kind I give.

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Patent US20040157926 - Pharmaceutical compositions for the treatment of movement disorders - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign inPatentsThe invention provides a pharmaceutical composition, medical food, dietary supplement or micronutrient for the treatment of a movement disorder comprising an NMDAR agonist or partial agonist as active ingredient therein in combination with a pharmaceutically acceptable carrier....http://www.google.com/patents/US20040157926?utm_source=gb-gplus-sharePatent US20040157926 - Pharmaceutical compositions for the treatment of movement disordersAdvanced Patent SearchTry the new Google Patents, with machine-classified Google Scholar results, and Japanese and South Korean patents.Publication numberUS20040157926 A1Publication typeApplicationApplication numberUS 10/744,452Publication dateAug 12, 2004Filing dateDec 23, 2003Priority dateFeb 6, 2003Also published asCA2454337A1, CA2454337C, DE60330542D1, EP1444979A1, EP1444979B1, US8629105, US9029410, US9271966, US20140121254, US20140187597Publication number10744452, 744452, US 2004/0157926 A1, US 2004/157926 A1, US 20040157926 A1, US 20040157926A1, US 2004157926 A1, US 2004157926A1, US-A1-20040157926, US-A1-2004157926, US2004/0157926A1, US2004/157926A1, US20040157926 A1, US20040157926A1, US2004157926 A1, US2004157926A1InventorsUriel Heresco-Levy, Daniel JavittOriginal AssigneeUriel Heresco-Levy, Javitt Daniel C.Export CitationBiBTeX, EndNote, RefManPatent Citations (13), Non-Patent Citations (2), Referenced by (34), Classifications (10), Legal Events (1) External Links: USPTO, USPTO Assignment, EspacenetPharmaceutical compositions for the treatment of movement disorders
[0001] The present invention relates to pharmaceutical compositions for the treatment of movement disorders. More particularly, the present invention relates to the use of N-methyl-D-aspartate type glutamate receptor (NMDAR) agonists (NMDAR agonists, also known as NMDA agonists) and partial agonists for the treatment of movement disorders such as Parkinsons disease. [0002] NMDAR are a type of receptor for the excitatory neurotransmitter glutamate. MDAR contain additional modulatory sites, including the following: glycine binding site, polyamine binding site, redox site, Zinc (Zn) site, phosphorylation sites, post-synaptic membrane docking sites and protein-protein interaction sites (e.g., Lynch and Guttman, 2001). The glycine binding site is sensitive to monocarboxyllic amino acids including the endogenous amino acids glycineD-serine and D-alanine. Glycine is synthesized via serine or threonine by serine hydroxymethyltransferase. Synaptic glycine concentrations are regulated by type 1 (GLYT1) and type 2 (GLYT2) glycine transporters, as well as by other amino acid transporters belonging to Systems A, L, ASC, and N (Sershen et al., 1979). GLYT1 transport inhibitors, such as N[3-(4′-fluorophenyl )-3-(4′-phenylphenoxy)propyl]sarcosine (NFPS), potentiate NMDAR activity in vivo, (Bergeron et al., 1989; Klitenick et al., 2001) suggesting a critical role for glycine transporters in NMDAR regulation. Methylated glycine derivates (e.g., methylglycine, sarcosine) may serve as non-specific glycine transport inhibitors D-serine and D-alanine are metabolized by D-amino acid oxidase (DAAO), which is localized particularly in hindbrain. Further, DAAO is regulated by a novel protein termed G72, which may affect metabolic activity of the DAAO enzyme (Chumakov et al., 2002). Glycine, D-serine and D-alanine levels in brain may be modulated by administering exogenous compound (i.e., glycine, D-serine or D-alanine), or naturally occurring precursors to these compounds including but not limited to L-serine, L-phosphoserine, D-phosphoserine and threonine, or by modulation of the synthetic enzymes serine hydroxymethyltransferase or serine racemase. D-Serine or D-alanine levels may also be increased by modulation inhibiting D-serine or D-alanine breakdown, for example, by antagonizing DAAO activity either directly or indirectly (e.g., via modulatory proteins). [0003] Parkinsons disease is neurological disorder characterized by movement disturbances related to extrapyramidal system dysfunction. Key symptoms of Parkinsons disease include tremor, rigidity, dystonia, bradykinesia and akinesia. The primary current treatments for Parkinsons disease include anticholinergics, L-dopa and MAO inhibitors. Dyskinesia is a long-term consequence of antiParkinsonian treatment. Parkinsons disease may occur under several conditions, including 1) idiopathically, 2) as a result of exposure to environmental toxins, particularly those affecting the dopamine system (e.g., 6-OH dopamine, MPTP) or 3) during treatment with antidopaminergic agents, particularly in connection with schizophrenia. Parkinsonian side effects are particularly common during treatment using typical antipsychotic agents such as, but not limited to, haloperidol, flupenazine or chlorpromazine. More recently developed atypical antipsychotics such as olanzapine, risperidone, quetiapine, ziprasidone and aripiprazole are associated with decreased rates of Parkinsonian symptoms. Significant Parkinsonian symptoms also occur spontaneously in up to 20% of individuals with schizophrenia. In general, agents effective in treatment of drug-induced Parkinsonian symptoms, such as anticholinergics and amantadine, are also effective in treatment of idiopathic Parkinsons disease. Symptoms of Parkinsons disease may be evaluated using the Simpson Angus Scale (SAS, Simpson & Angus, 1970) or similar instrument. [0004] Dyskinesias are abnormal movements characterized by having a snakelike or writhing character. Dyskinesias may occur as a consequence of neurological disease such as Huntington's chorea, as a result of damage to specific brain regions such as corpus striatum or subthalamic nucleus, or as a consequence of medical conditions (e.g., Syndenham's chorea), but may also occur as a consequence of long-term exposure to antipsychotic medication. Tardive dyskinesia (TD) is a form of dyskinesia that results from long-term exposure to antipsychotics such as chlorpromazine or haloperidol. TD occurs less frequently following treatment with newer antipsychotics, and symptoms of TD can be suppressed by clozapine. Symptoms of TD are evaluated using instruments such as the Abnormal Involuntary Movement Scale (AIMS, Guy, 1976). [0005] Tics are sudden, rapid, recurrent, nonrhythmic stereotyped movements or vocalizations. Examples of tic disorders include Tourette's disorder, Chronic Motor or Vocal Tic Disorder, Transient Tic Disorder and Tic Disoder Not Otherwise Specified. Tourette's disorder is inherited in an autosomal dominant fashion, which penetrance of approximately 70% in females and 99% in males (DSM-IV, 1994, p. 100). Obsessive compulsive disorder is a disorder characterized by recurrent obsessions or compulsions, leading often to repetitive motor behaviors (e.g., hand washing, ordering, checking) or mental acts (e.g., praying, counting, repeating words silently) (DSM-IV, 1994, p. 418). Obsessive-compulsive disorder is common in patients with Tourette's disorder. Conversely, 20-30% of individuals with Obsessive-Compulsive disorder have reported current or past tics. Etiology of tic disorders and obsessive compulsive disorder are unknown, but may involve autoimmune factors (Hallet et al., 2000), serotonergic dysfunction (e.g., Dursun et al., 1996), or gene expression abnormalities (Greer et al., 2002). Nevertheless, NMDAR may play a critical role in regulation of circuits involved in movement disorders, as NMDAR antagonists worsen symptoms in animal models of the disorder (McGrath et al., 2000). [0006] Although the primary pathology in Parkinsons disease is a loss of dopaminergic neurons in the substantia nigra and ventral tegmental areas, expression of symptoms is the result of interactions between multiple populations of dopaminergic, glutamatergic and GABAergic neurons within the extrapyramidal system. Many neurons involved in the pathophysiology of Parkinsons disease express additional transmitters, including enkephalin (ENK), substance P (SP), somatostatin (SOM), opioids, adenosine, and acetylcholine (ACh). Key structures that may be involved in Parkinsons disease include the nigrostiatal, mesolimbic and mesocortical dopaminegic systems, the basal ganglia including corpus striatum, caudate, putamen and globus pallidus, the subthalamic nuclei, cerebral cortex, cerebellum and portions of thalamus. [0007] NMDAR play a key role in the regulation of movement and striatal function. NMDARs are found on multiple classes of neuron within striatum including projection neurons and internuerons. NMDARs are composed of multiple subunits including an NR1 subunit which is present in virtually all functional NMDARs, and NR2 subunits that are present in variable proporations. Four NR2 subunits (NR2A-D) have been described. NR2A expression is high in GABAergic neurons that express the marker GAD67, intermediate over SP neurons, low in ENK neurons, not found in cholinergic and SOM neurons. In contrast, NR2B expression is intense in all populations of neurons, while expression of NR2C,D is weak (Kuppenbender et al., 2000). The existence of multiple subforms of NMDAR in striatum is supported by the observation that NMDARs controlling GABA and DA release are less sensitive to NMDA than receptors controlling spermidine or ACh release (Nankai et al., 1995). [0008] Current theories of Parkinsons disease postulate an important role of NMDAR in the networks subserving development of Parkinsonian symptoms. However, based upon the clinical observation that amantadine, a widely used anti-Parkinsonian agent, has NMDAR antagonist (as opposed to agonist) properties, it has been suggested that NMDAR antagonists may be beneficial in treating movement disorders. Other findings, such as the ability of glycine antagonists to increase locomotion in monoamine-depleted mice (Slusher et al., 1994) have also been used to teach use of NMDAR antagonists in the treatment oParkinsons disease. Thus e.g. the literature is replete with references such as U.S. Pat. No. 6,284,774 which teach the use of NMDA receptor antagonists for the treatment of Parkinsons disease. [0009] In contradistinction to the teachings of the prior art it has now been surprisingly found that NMDA receptor agonists, particularly those that target the NMDAR-associated glycine binding site are effective for the treatment of movement disorders such as Parkinsons disease. [0010] NMDAR agonists described in the present application, including glycine and D-serine, are naturally occurring compounds that may be marketed as pharmaceuticals, medical foods or dietary supplements. Previous applications (e.g., U.S. Pat. No. 6,228,875) have described and claimed use of NMDAR agonists only as pharmaceuticals. In contrast, the present application teaches use as medical foods or dietary supplements as well as pharmaceuticals. Thus according to the present invention there is now provided a pharmaceutical composition, medical food or dietary supplement for the treatment of a movement disorder comprising an NMDAR agonist or partial agonist as active ingredient therein in combination with a pharmaceutically acceptable carrier. [0011] The present invention also provides for the use of an NMDAR agonist or partial agonist in the manufacture of a pharmaceutical composition, medical food, or dietary supplement for the treatment of a movement disorder and especially for the treatment of antipsychotic-induced movement disorders and Parkinsons disease. [0012] Prior literature regarding use of NMDAR agonists (as opposed to antagonists) in treatment of Parkinsons disease is minimal. Casey and Shiigi (1999) showed that administration of ketamine induces bradykinesia, dystonia and salivation in neuroleptic sensitized monkeys (Shiigi and Casey, 1999), suggesting that NMDA dysfunction might contribute to symptoms. Schneider et al. (Brain Res 860:190-4, 1991) demonstrated that low dose (320 or 1000 mg/kg) D-cycloserine significantly improved variable delayed-response task (VDR) performance in MPTP-treated monkeys but did not show improvement in bradykinesia, tremor or other core Parkinsonian symptoms (Schneider et al., Brain Res 860:190-4, 1991). [0013] In U.S. Pat. No. 6,228,875 there is described and claimed methods and pharmaceutical compositions for treating neuropsychiatric disorders such as schizophrenia, Alzheimer's Disease, autism, depression, benign forgetfulness, childhood learning disorders, close head injury, and attention deficit disorder using at least one agonist of the glycine site of an NMDA receptor however said patent neither teaches nor suggests that such agonists are effective for the treatment of movement disorders such as Parkinsons disease. [0014] The present findings are also not anticipated by subsequent articles relating to the examples in Tsai and Coyle '875. As shown in Table 2 of Tsai et al., 1998, a paper relating to '875, patients participating in studies disclosed in '875 had minimal levels of pretreatment Parkinsonian symptoms as measured by the SAS (1.4±1.4 points) and dyskinetic symptoms as measured by the AIMS (0.3±0.7 points). Because of patients recruited for that study, therefore, Tsai and Coyle were unable to assess effects of NMDA agonists on movement disorders in general or on Parkinsonian and dyskinetic symptoms in particular. A subsequent study (Tsai et al., 1999) also did not find significant change in SAS or AIMS scores during treatment with D-serine combined with clozapine. In Tsai and Coyle '875, data are presented also with D-alanine and N-methylglycine. In these cases also, no significant changes in SAS or AIMS scores were observed, due in part to low baseline. levels. Therefore, neither Tsai and Coyle '875 nor related references teach use of NMDA agonists or partial agonists in treatment of movement disorders or movement-related side effects of antipsychotic medication. In a prior study of glycine (Heresco-Levy et al., 1999, Table 3), SAS scores declined from 1.3 to 0.6 points during glycine treatment vs. no change during placebo. AIMS scores declined from 1.9 to 1.4 during glycine but increased during placebo. Nevertheless, in that study, change scores for SAS and AIMS were not significant for glycine vs. placebo (p>0.02 for both). Thus, the present results are not anticipated by '875 or continuations thereof. [0015] In prior studies of schizophrenia, we and others have demonstrated improvement in negative symptoms during treatment with the NMDAR agonists glycine (Heresco-Levy et al., 1999a; Javitt et al., 2000; Heresco-Levy et al., submitted), D-serine (Tsai et al., 1999) and D-cycloserine (Heresco-Levy et al., 1998; Goff et al., 1999; Heresco-Levy et al., 1999b). Several negative symptoms, including motor retardation and affective blunting resemble symptoms of Parkinsons disease. Nevertheless, these studies did not show significant improvement of motor symptoms during treatment with NMDAR agonists or the partial agonist D-cycloserine, and did not teach use of NMDAR agonists in treatment of movement disorders. [0016] The mechanism by which NMDAR agonists or partial agonists ameliorate symptoms of movement disorder remain to be determined. One potential explanation, however, is that subpopulations of NMDAR may contribute differentially to both pathogenesis and therapeutics. Thus, in terms of pathogenesis, NR2B receptors in striatum have been specifically implicated (Nash & Brotchie, 2002). Further, agents that have shown greatest preliminary effectiveness in Parkinsons disease are all NR2B antagonists (Nikam & Meltzer, 2002). In monkeys, NR2A and NR2B selective antagonists were observed to have differential effects, with the NR2A antagonist MDL 100,453 worsening symptoms of dyskinesia (Woodward et al., 1999). NR2B receptors have numerically lower affinity for glycine than NR2A receptors, and so may be saturated under physiological conditions. Administration of NMDAR agonists such as glycine and D-serine and the NMDA partial agonist D-cycloserine may therefore selectively active NR2A receptors. Activation of NR2A vs. NR2B receptors by NMDAR agonists and partial agonists may, therefore, restore the balance between NR2A and NR2B containing receptors similarly and additively to the effects of NR2B antagonists. [0017] The finding that NMDAR agonists improve antipsychotic-induced movement disorders including Parkinsoriism and TD is not anticipated by prior literature. These findings moreover indicate that NMDAR agonists may be effective in treatment of other movement disorders, including Parkinsons disease, dyskinetic disorders, obsessive-compulsive disorder, tic disorders etc. [0018] While the invention will now be described in connection. with certain preferred embodiments in the following examples so that aspects thereof may be more fully understood and appreciated, it is not intended to limit the invention to these particular embodiments. On the contrary, it is intended to cover all alternatives, modifications and equivalents as may be included within the scope of the invention as defined by the appended claims. Thus, the following examples which include preferred embodiments will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purposes of illustrative discussion of preferred embodiments of the present invention only and are presented in the cause of providing what is believed to be the most useful and readily understood description of formulation procedures as well as of the principles and conceptual aspects of the invention.
EXAMPLE 1 Beneficial Effects of High Dose Glycine (60 g/d) on EPS and TD in Schizophrenia [0019] Methods: [0020] The study was approved by the appropriate institutional review boards. Seventeen stable inpatients meeting DSM-IV criteria for schizophrenia and free of other axis I diagnoses or significant medical illness were. enrolled in the study. Diagnosis was established on the basis of semistructured psychiatric interviews, review of all available medical records, and confirmation by two board-certified psychiatrists. Patients fulfilled criteria for treatment resistance used in previous trials of glycine and had been receiving stable doses of olanzapine or risperidone for at least 3 months before study entry. Medication doses remained fixed throughout the study. [0021] After complete description of the study, written informed consent was obtained from all participating patients. The double-blind, placebo-controlled, crossover study consisted of two random-order 6-week treatment arms (glycine 0.8 g/kg/day, or placebo), separated by a 2-week adjuvant treatment washout. Patients were assessed biweekly with the Positive and Negative Syndrome Scale (PANSS), Brief Psychiatric Rating Scale (BPRS), Simpson-Angus Rating Scale (SAS), and Abnormal Involuntary Movement Scale (AIMS) performed by one trained research psychiatrist, as previously described (3). CBC and SMA-20 measures were assessed biweekly throughout the study. Trough glycine and serine serum levels were assessed at baseline and at the end of the two treatment phases. Data were analyzed by repeated measures ANOVA with within group factor of study phase (glycine/placebo) and time within study phase (pre/post), and between group factor of treatment order. [0022] Results [0023] Three patients were withdrawn from the study during glycine administration due to non-compliance and mild upper gastrointestinal tract discomfort that ceased following discontinuation of glycine treatment (2 patients). Three of the 14 patients who completed the study were women and 11 were men. Their mean age was 46.5 years (SD=9.6), the mean duration of their illness was 25.8 years (SD=11.0) and the mean duration of their current hospitalization was 3.0 years (SD=3.7). Ten patients were receiving olanzapine (mean daily dose: 14.3 mg (SD=3.1); four patients were receiving risperidone (mean daily dose: 6.2 mg (SD=3.1). Seven patients were randomized to receive placebo during the first treatment phase, eight received glycine. Repeated measures multivariate analyses of variance were performed with within-subject factors of treatment phase (placebo versus glycine) and time within phase (baseline versus week 6) and a between-subjects factor of treatment order. [0024] Analyses demonstrated highly significant, large effect size reductions in PANSS negative and cognitive symptoms and for BPRS total scores (Table 1), indicating significant therapeutic efficacy of glycine. Smaller but still significant improvements were observed for positive symptoms. Treatment effects for negative symptoms remained highly significant (F=22.2, df=1,8, p<0.002) even following covariation for changes in all other PANSS symptom factors. [0025] Significant moderate-effect-size treatment effects were noted for both SAS and AIMS scores that decreased following glycine treatment (Table 1). SAS scores decreased by 1.3 points (18%) during glycine treatment vs. a 0.5 point increase during placebo treatment, the result being statistically significant (p<0.05). AIMS scores decreased by 1.0 point (32.2.%) during glycine treatment vs. an 0.3 point increase during placebo treatment, the results being statistically significant (p<0.02). This represents the first study to show changes in SAS or AIMS score during treatment with NMDAR agonists. TABLE 1 Mean (sd) PANSS, BPRS, SAS and AIMS Scores of 14 Inpatients with Treatment-Resistant Schizophrenia During the Addition of Glycine, 0.8 g/kg/day, and Placebo to Olanzapine and Risperidone Treatment1 % Change Adjuvant Score at Score at ANOVA during Effect Treatment Baseline Week 6 (F, p) glycine2 size (d) PANSS Negative Glycine 24.6 (4.4) 20.4 (3.9) 72.1, 23.3 (8.4) 2.1 Symptoms Placebo 22.0 (3.9) 23.3 (4.0) 0.006 CI: 18-28% Positive Glycine 15.4 (2.2) 14.0 (1.5) 7.3, 11.4 (11.7) 0.7 Symptoms Placebo 14.3 (1.1) 14.7 (1.9) 0.02 CI: 5-18% , Cognitive Glycine 19.1 (2.8) 17.9 (3.1) 11.0, 9.2 (6.8) 0.9 Symptoms Placebo 18.0 (3.4) 18.6 (2.4) 0.006 CI: 5-132% Excitement Glycine 13.2 (2.1) 12.0 (1.5) 13.3, 10.6 (20.9) 0.6 Placebo 12.3 (1.6) 12.9 (2.1) 0.003 CI: −2-23 Depression Glycine 14.4 (3.0) 13.4 (2.1) 7.2, 7.4 (17.1) 0.7 Placebo 13.3 (2.3) 14.4 (3.0) 0.02 CI: −2-17 BPRS Total Glycine 42.6 (6.0) 36.6 (4.8) 35.0, 13.7 (7.5) 1.6 Placebo 37.9 (4.6) 40.4 (6.4) 0.0001 CI: 9-18 SAS Glycine 5.3 (3.3) 4.0 (3.0) 4.7, 17.9 (40.1) 0.6 Placebo 4.4 (2.7) 4.9 (3.3) 0.05 CI: −5-41 AIMS Glycine 3.6 (2.0) 2.6 (7.1) 7.5, 32.2 (30.4) 0.6 Placebo 2.9 (1.6) 3.2 (2.4) 0.02 CI: 15-50 EXAMPLE 2 Beneficial Effects of High Dose D-serine (0.03 g/d) on EPS and TD in Schizophrenia [0026] Methods: Methods for this study are the same as in example 1, except that D-serine (0.3 g/d=approx. 2.1 g/day) was used for treatment. As previously, outcome was assessd using the PANSS, SAS and AIMS. In addition, the Schedule for Assessement of Negative Symptoms (SANS) was used to provide further assessment of negative symptoms. This represents an interim analysis of an ongoing study. Data were analyzed by between-treatment t-test of change scores during D-serine or placebo treatment. Data are analyzed only from subjects (n=23) who completed both study phases. [0027] Results: As with glycine, D-serine led to highly significant improvements in negative, positive and cognitive symptoms. of schizophrenia, similar to reported previously by Tsai et al. (1998). As rated by the SAS, a highly significant 42% decline in Parkinsonian symptoms was observed during D-serine, but not placebo, treatment, leading to a highly significant between group response difference (see Table 2). As rated by the AIMS, a highly significant 50% decline in dyskinetic symptoms was observed during D-serine, but not placebo, treatment, leading to a highly significant between group response difference (see Table 2). These findings are similar to those observed previously with glycine, as detailed in example 1. TABLE 2 Mean (sd) Positive and Negative Syndrome (PANSS), Simpson Angus (SAS) and Abnormal Involuntary Movement (AIMS) scale scores during D-serine (n = 23) and placebo (n = 22) treatment (crossover design) Treatment Treatment week Δ Between-group Assignment 0 6 symptoms difference (t, p) PANSS Positive D-serine 14.2 ± 2.3 13.0 ± 2.3 −1.2 ± 1.1 t = 2.90, Symptoms Placebo 13.7 ± 2.4 13.5 ± 2.3 −0.3 ± 1.2 p = .006 Negative D-serine 23.9 ± 4.0 21.0 ± 3.5 −2.9 ± 1.9 t = 4.53, symptoms Placebo 22.8 ± 3.5 22.5 ± 3.0 −0.3 ± 1.8 p < .00001 Cognitive D-serine 18.5 ± 2.2 17.1 ± 2.7 −1.4 ± 1.3 t = 5.90 symptoms Placebo 18.0 ± 2.5 18.4 ± 2.1 0.4 ± 1.1 p < 0.0001 Depression D-serine 15.3 ± 2.6 13.8 ± 2.2 −1.5 ± 1.8 t = 4.85, Placebo 14.5 ± 2.6 15.1 ± 2.4 0.6 ± 1.5 p < .00001 Excitement D-serine 11.6 ± 1.5 10.9 ± 1.4 −0.7 ± 1.2 t = 1.21, Placebo 11.1 ± 1.6 11.0 ± 1.5 −0.1 ± 1.2 p = .2 SANS Total D-serine 60.0 ± 9.3 51.9 ± 8.0 −9.0 ± 54.3 t = 7.15 (with globals) Placebo 56.1 ± 10.1 56.9 ± 9.4 0.9 ± 5.3 p < .00001 SAS D-serine 4.2 ± 1.4 2.4 ± 0.8 −1.8 + 1.3 t = 5.66, Placebo 3.7 ± 1.6 4.0 ± 1.3 0.2 ± 1.1 p < 00001 AIMS D-serine 3.0 ± 0.8 1.6 ± 1.2 −1.4 ± 1.1 t = 5.51 Placebo 2.5 ± 1.2 2.7 ± 0.9 0.2 ± 0.9 p < .00001 EXAMPLE 3 Beneficial Effects of the Partial Agonist D-cycloserine [0028] Methods: Methods for this study are the same as in example 1, except that D-cycloserine (50 mg/d) was used for treatment. As previously, outcome was assessd using the PANSS, SAS and AIMS. In addition, the Schedule for Assessement of Negative Symptoms (SANS) was used to provide further assessment of negative symptoms. Data are pooled from two previously published studies (Heresco-Levy et al., 1998, 2002). Because analyses were confirmatory, one-tailed statistics were used throughout. [0029] Results: Significant improvements in positive and negative symptoms and general psychopathology were observed, as previously described. D-cycloserine treatment was associated with a significant reduction in dyskinetic symptoms (t=2.21, p<0.025, one tailed) and a nearly significant improvement in Parkinsonian symptoms (t=1.77, p.=04, one tailed) (Table 3). TABLE 3 Mean (sd) Positive and Negative Syndrome (PANSS), Simpson Angus (SAS) and Abnormal Involuntary Movement (AIMS) scale scores during D-cycloserine (n = 26) and placebo (n = 28) treatment (crossover design) Between- group Treatment Week Within Treatment Ä difference Assignment Phase symptoms (t, p) PANSS 0 6 Positive D-cycloserine 26.7 ± 4.5 24.6 ± 4.1 −2.1 ± 2.6 t = 3.01, symptoms p < .003 Placebo 25.8 ± 3.7 26 ± 4.2 0.1 ± 2.8 Negative D-cycloserine 34.6 ± 6.2 31.4 ± 6.5 −3.2 ± 2.5 t = 2.93, symptoms p < .003 Placebo 33.9 ± 6.9 32.6 ± 6.4 −1.2 ± 2.4 General D-cycloserine 58.7 ± 8.4 53.8 ± 8.2 −4.9 ± 6.2 t = 2.70, Psycho- p < .005 pathaol- ogy Placebo 57.5 ± 8.2 57.1 ± 9.5 −0.4 ± 6.2 Total D-cycloserine 120 ± 16.7 109.7 ± 15.8 −10.2 ± 8.9 t = 3.60, Symptoms p < .001 Placebo 117.2 ± 16.2 115.6 ± 17.4 −1.6 ± 8.8 SAS D-cycloserine 4.3 ± 2.4 3.6 ± 2.1 −0.7 ± 1.7 t = 1.77 Placebo 3.6 ± 2.1 3.8 ± 2.2 0.2 ± 1.9 p < .05 AIMS D-cycloserine 4.7 ± 3.1 3.9 ± 3 −0.8 ± 1.3 t = 2.21 Placebo 3.9 ± 2.7 3.9 ± 2.6 0 ± 1.2 p < .03 EXAMPLE 4 Effect of Glycine on Vacuous Chewing Motions in Rodents [0030] Vacuous chewing movements (VCM) are a rodent model of TD (Andreassen et al., 1996). In this model, animals are treated chronically with antipsychotics and their vacuous chewing motions are assessed by observation. This model has been shown to be sensitive to differential effects of typical and atypical antipsychotics and potential anti-dyskinetic agents. This example describes effects of the NMDAR agonist glycine on haloperidol-induced VCM. [0031] Methods and Materials [0032] Subjects [0033] Sprague-Dewley rats (Harlan Laboratories, Jerusalem, Israel) weighing 150 to 170 g. were used. The rats were housed in polycarbonate cages (4 in each cage), maintained under a 12 hour-12 hour dark-light (04.00-16.00 hours) cycle, and were allowed water ad libitum. In order to limit neuroleptic-induced weight gain, the food was restricted to 15 g. pellets per animal per day, as used by Andreassen et al (1996). Rats were weighed biweekly throughout the study. Room temperature was maintained at 22±2° C. All procedures were conducted in accordance with local and international laws for the care and use of laboratory animals. [0034] Protocol and Drugs [0035] For two weeks prior to the first drug injection, animals were handled daily and habituated to the animal colony and the procedures related to drug administration and video recording situation. Subsequently (week 0), rats underwent a behavior video recording session following which they were randomized to a haloperidol treatment and a control group. The rats in the treatment group received an intramuscular injection in the thigh muscles with haloperidol decanoate (Pericate, Unipharm Ltd., Tel Aviv, Israel), 100 mg/ml in sesame oil, at a dose of 0.35 mg/kg. The control rats were similarly injected with an equal volume of phosphate buffered saline (PBS). Twenty-three G hypodermic needles were used for all injections. Subsequently, the haloperidol decanoate and saline injections were repeated every four weeks, for 20 weeks. Additional behavior video recording sessions were performed at weeks 12, 20 and 24 (i.e., 4 weeks after the last (fifth) injection). During the injection procedures, rats were handheld with minimal restraint. [0036] On the basis of the results of the behavior assessment performed 24 weeks after the first haloperidol injection (i.e., baseline day), the haloperidol-treated rats were assigned to 10 subject-each treatment groups having an equal mean frequency of observed VCM episodes. One week later (i.e., test day), the groups reported on here were randomized to receive one intraperitoneal injection with either 0.5 ml PBS (vehicle) or 1.6 g/kg glycine in 0.5 ml PBS. Rats underwent a video recorded behavior assessment session 30-150 minutes following the injection. Two weeks after the test day (i.e., post-test day), the video recorded behavior assessment session was repeated in order to investigate longer-term effects of the experimental treatments. [0037] Behavioral Observations and Statistics [0038] Before experiments were started, the rats were handled and habituated to the behavior observation situation. During videotaping, the rats were kept in a clear perspex cage (13×20.5×13.5 cm), equipped with mirrors allowing videotaping of the rat from all sides simultaneously. The behavior of the animals was videotaped for 5 minutes after a 1 minute adaptation period in the cage. [0039] A trained observer, unaware of the treatment received by the rats, scored the behavior while watching the videotapes. A VCM episode was defined as a bout of vertical deflections of the lower jaw, which could be accompanied by contractions of the jaw musculature. Statistical analyses were performed using the STATISTICA software package (StatSoft Inc., USA). Student's t-test was used to assess the effects of chronic haloperidol treatment compared to placebo. Analysis of variance (ANOVA) with one between group factor (experimental drug treatment) and one repeated measures factor (baseline day vs. test day vs. post-treatment day) was performed to assess the effects of glycine. The statistical significance of interaction of the between group factor and the repeated measures factor is determined in the STATISTICA software package using the Rao R statistic and the F distribution. Post hoc Newman-Keuls tests were used for comparisons between treatments. [0040] RESULTS [0041] Effects of chronic haloperidol treatment on motor activity Rats that had received haloperidol for 24 weeks displayed an approximately 4-fold significantly higher number of VCM episodes than rats that had received placebo (t=3.29, df=47, p<0.001) indicating that chronic haloperidol administration induced spontaneous VCM. Furthermore, the number of rearing episodes was significantly lower in the haloperidol-treated group (t=5.2, df=47, p<0.0001). Moreover, mobility in general was significantly reduced in the haloperidol-treated rats. During a 5 minute observation interval, the mean time spend in immobility by the haloperidol-treated rats was 103.2±7.8 seconds, in contrast to 53.0±12.7 seconds spent in immobility by the rats that had received placebo (t=2.9, df=45, p<0.005). Overall, the number of grooming episodes did not differ between haloperidol-treated rats and controls (t=1.4, df=47, p<0.17). [0042] VCM measures were compared on test day between animals receiving vehicle injections and those receiving glycine. One way ANOVA with repeated measures revealed significant interaction of drug and observation day on VCM frequency with Rao R (6,64)=3.44, p<0.005). Post hoc comparisons of VCM frequency at baseline and following GLY administration at the test day further revealed that the administration of GLY resulted in a significant 82% reduction in the number of VCM episodes (p<0.001). Moreover, post hoc comparison of VCM frequencies in the placebo and glycine groups at test day indicated a significantly lower VCM frequency following glycine acute administration (p<0.01). The number of VCM in the glycine-treated groups at baseline and post-test day did not differ significantly (p<0.07), indicating that 2 weeks post-acute GLY administration, VCM levels returned to their previous, pre-experimental treatment levels. These findings, overall, support the clinical observation of decreased VCM following NMDAR agonist treatment. [0043] The examples above demonstrate effectiveness of two full NMDAR agonists, as well as a partial NMDAR agonist in treatment of antipsychotic-induced movement disorder, including Parkinsonian and dyskinetic symptoms. Other methods for augmenting NMDA transmission via the glycine binding site have been proposed including use of glycine transport inhibitors (aka transport antagonists, uptake inhibitors, uptake antagonists), acting at the GLYT1, GLYT2, System A, System ASC or other glycine transport sites, and modulators of D-serine metabolism including inhibitor of b-serine transport and of D-amino acid oxidase. Agents may be screened for effectiveness in stimulating NMDA transmission in vitro using assays, for example, measuring modulation of NMDAR-mediatedactivity in hippocampal slices (Bergeron et al., 1998) or of NMDAR-stimulated dopamine release in isolated mouse striatum (Javitt et al., 2000). Agents may be screened in vivo using assays, for example, measuring amphetamine induced dopamine release or NMDAR-mediated electrophysiological activity (Klitenick et al., 2001). Agents will be effective in ameliorating movement disorders at doses sufficient to potentiate NMDAR-mediated neurotransmission in vivo. [0044] In addition to the embodiments listed above, prodrugs may also be administered. Prodrugs are defined as agents that are not themselves agonists of the NMDAR, but which enter the brain and are converted or metabolized there into effective agonists. An example of a glycine prodrug is milacemide (Doheny et al., 1996). Simple precursors can be made by esterification, alkylation or other linkage (Kao et al., 2000; Schwartz et al., 1991; Toth et al., 1986), most effectively to hydrophobic groups that increase lipophilicity and diffusion into CNS (e.g., Cooper et al., 1987). In a preferred embodiment of the invention, NMDAR agonists, including but not limited to glycine, D-serine, or D-alanine, are conjugated to molecules that are actively transported into the CNS, leading to increased central penetration (e.g., Battaglia et al., 2000; Fernandez et al., 2000; Bonina et al., 1999; Halmos et al., 1997; de Boer et al., 2002; Kido e tal., 2001, Fisher et al., 2002, Rouselle et al., 2002). Precursors to glycine, D-serine or D-alanine, including threonine, L-phosphoserine and D-phosphoserine, may also be incorporated into prodrugs. [0045] The pharmaceutical compositions can be administered to the patient by any, or a combination, of several routes, such as oral, intravenous, trans-mucosal (e.g., nasal, vaginal, etc.), pulmonary, transdermal, ocular, buccal, sublingual, intraperitoneal, intrathecal, intramuscular, or long term depot preparation. Solid compositions for oral administration can contain suitable carriers or excipients, such as corn starch, gelatin, lactose, acacia, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, calcium carbonate, sodium chloride, lipids, alginic acid, or ingredients for controlled slow release. Disintegrators that can be used include, without limitation, micro-crystalline cellulose, corn starch, sodium starch glycolate and alginic acid. Tablet binders that may be used include, without limitation, acacia, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone (Povidone), hydroxypropyl methylcellulose, sucrose, starch, and ethylcellulose. [0046] Liquid compositions for oral administration prepared in water or other aqueous vehicles can include solutions, emulsions, syrups, and elixirs containing, together with the active compound(s), wetting agents, sweeteners, coloring agents, and flavoring agents. Various liquid and powder compositions can be prepared by conventional methods for inhalation into the lungs of the patient to be treated. [0047] Injectable compositions may contain various carriers such as vegetable oils, dimethylacetamide, dimethylformamide, ethyl lactate, ethyl carbonate, isopropyl myristate, ethanol, polyols (glycerol, propylene glycol, liquid polyethylene glycol, and the like). For intravenous injections, the compounds may be administered by the drip method, whereby a pharmaceutical composition containing the active compound(s) and a physiologically acceptable excipient is infused. Physiologically acceptable excipients may include, for example, 5% dextrose, 0.9% saline, Ringer's solution or other suitable excipients. For intramuscular preparations, a sterile composition of a suitable soluble salt form of the compound can be dissolved and administered in a pharmaceutical excipient such as Water-for-Injection, 0.9% saline, or 5% glucose solution, or depot forms of the compounds (e.g., decanoate, palmitate, undecylenic, enanthate) can be dissolved in sesame oil. Alternatively, the pharmaceutical composition can be formulated as a chewing gum, lollipop, or the like. [0048] It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. References [0049] Battaglia G, La Russa M, Bruno V, Arenare L, Ippolito R. Copani A, Bonina F, Nicoletti F. Systemically administered D-glucose conjugates of 7-chlorokynurenic acid are centrally available and exert anticonvulsant activity in rodents. Brain Res 2000;860(1-2):149-56. [0050] Bergeron R, Meyer T M, Coyle J T, Greene R W: Modulation of N-methyl-D-aspartate receptor function by glycine transport. Proc Natl Acad Sci USA 1998; 95(26): 15730-4 [0051] Blanchet P J, Konitsiotis S, Whittemore E R, Zhou Z L, Woodward R M, Chase T N: Differing effects of N-methyl-D-aspreceptor subtype selective antagonists on dyskinesias in levodopa-treated 1-methyl-4-phenyl-tetrahydropyridine monkeys. J Pharmacol Exp Ther 1999; 290(3):1034-40 [0052] Bonina F P, Arenare L, Palagiano F, Saija A, Nava F, Trombetta D, de Caprariis P. Synthesis, stability, and pharmacological evaluation of nipecotic acid prodrugs. J Pharm Sci 1999;88(5):561-7. [0053] Chumakov I, Blumenfeld M, Guerassimenko O, Cavarec L, Palicio M, Abderrahim H, Bougueleret L, et al. Genetic and physiological data implicating the new human gene G72 and the gene for D-amino acid oxidase in schizophrenia. Proc Natl Acad Sci USA 2002;99(21):13675-80. [0054] Cooper D R, Marrel C, van de Waterbeemd H, Testa B, Jenner P, Marsden C D. L-dopa esters as potential prodrugs: effect on brain concentration of dopamine metabolites in reserpinized mice. J Pharm Pharmacol 1987;39(10):809-18. [0055] De Boer A G, Van Der Sandt I C, Gaillard P J. The Role of Drug Transporters at the Blood-Brain Barrier. Annu Rev Pharmacol Toxicol 2002. [0056] Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV). American Psychiatric Press, Washington, D.C. 1994. [0057] Doheny M H, Nagaki S, Patsalos P N. A microdialysis study of glycinamide, glycine and other amino acid neurotransmitters in rat frontal cortex and hippocampus after the administration of milacemide, a glycine pro-drug. Naunyn Schmiedebergs Arch Pharmacol 1996;354(2):157-63. [0058] Dursun S M, Handley S L. Similarities in the pharmacology of spontaneous and DOI-induced head-shakes suggest 5HT2A receptors are active under physiological conditions. Psychopharmacology (Berl) 1996;128(2):198-205. [0059] Fernandez C, Nieto O, Rivas E, Montenegro G, Fontenla J A, Fernandez-Mayoralas A. Synthesis and biological studies of glycosyl dopamine derivatives as potential antiparkinsonian agents. Carbohydr Res 2000;327(4):353-65. [0060] Goff D C, Tsai G, Levitt J, Amico E, Manoach D, Schoenfeld D A, Hayden D L, McCarley R, Coyle J T: A placebo-controlled trial of D-cycloserine added to conventional neuroleptics in patients with schizophrenia. Arch Gen Psychiatry 1999; 56(1):21-7. [0061] Greer J M, Capecchi M R. Hoxb8 is required for normal grooming behavior in mice. Neuron 2002;33(1):23-34. [0062] Guy W, ed. ECDEU Assessment Manual for Psychopharmacology. Washington D.C.: US Department of Health, Education and Welfare; 1976. [0063] Hallett J J, Harling-Berg C J, Knopf P M, Stopa E G, Kiessling L S. Anti-striatal antibodies in Tourette syndrome cause neuronal dysfunction. J Neuroimmunol 2000;111(1-2):195-202. [0064] Halmos T, Santarromana M, Antonakis K, Scherman D. Synthesis of O-methylsulfonyl derivatives of D-glucose as potential alkylating agents for targeted drug delivery to the brain. Evaluation of their interaction with the human erythrocyte GLUT1 hexose transporter. Carbohydr Res 1997;299(1-2):15-21. [0065] Heresco-Levy U, Ermilov M, Shimoni J, Shapira B, Silipo G, Javitt D C: Placebo-controlled trial of D-cycloserine added to conventional neuroleptics, olanzapine, or risperidone in schizophrenia. Am J Psychiatry 2002; 159(3):480-2 [0066] Heresco-Levy U, Javitt D C, Ermilov M, Mordel C, Silipo G, Lichtenstein M: Efficacy of high-dose glycine in the treatment of enduring negative symptoms of schizophrenia. Arch Gen Psychiatry 1999; 56(1):29-36 [0067] Heresco-Levy U, Javitt D C, Ermilov M, Silipo G, Shimoni J: Double-blind, placebo-controlled, crossover trial of D-cycloserine adjuvant therapy for treatment-resistant schizophrenia. Int. J. Neuropsychopharmacol. 1998; 1(2):131-136 [0068] Javitt D C, Sershen H, Hashim A, Lajtha A: Inhibition of striatal dopamine release by glycine and glycyldodecylamide. Brain Res Bull 2000; 52(3):213-6 [0069] Javitt D C, Silipo G, Cienfuegos A, Shelley A M, Bark N, Park M, Lindenmayer J P, Suckow R, Zukin S R: Adjunctive high-dose glycine in the treatment of schizophrenia. Int J Neuropsychopharmacol 2001; 4(4):385-91 [0070] Kido Y, Tamai I, Ohnari A, Sai Y, Kagami T, Nezu J, Nikaido H, Hashimoto N, Asano M, Tsuji A. Functional relevance of carnitine transporter OCTN2 to brain distribution of L-carnitine and acetyl-L-carnitine across the blood-brain barrier. J Neurochem 2001;79(5):959-69. [0071] Klitenick M A, Atkinson B N, Baker D A, Bakker M, Bell S C, Borghys H, Caron M G, Ceuster M, De Coster R, DeVivo M, DelVecchio R A, Draper S, Egle I, Frey J, Calnetdinov R R, Hopper A T, Javitt D C, et al.: Development and characterization of GlyT1-selective glycine reuptake inhibitors, in American College of Neuropsychopharmacology 40th Annual Meeting. Kona, Hi., 2001. [0072] McGrath M J, Campbell K M, Parks C R, Burton F H. Glutamatergic drugs exacerbate symptomatic behavior in a transgenic model of comorbid Tourette's syndrome and obsessive-compulsive disorder. Brain Res 2000;877(1):23-30. [0073] Nash J E, Brotchie J M: Characterisation of striatal NMDARs involved in the generation of parkinsonian symptoms: intrastriatal microinjection studies in the 6-OHDA-lesioned rat. Mov Disord 2002; 17(3):455-66 [0074] Nikam S S, Meltzer L T: NR2B selective NMDAR antagonists. Curr Pharm Des 2002; 8(10):845-55 [0075] Rousselle C, Clair P, Temsamani J, Scherrmann J M. Improved brain delivery of benzylpenicillin with a peptide-vector-mediated strategy. J Drug Target 2002; 10(4):309-15. [0076] Schwartz B L, Hashtroudi S, Herting R L, Handerson H, Deutsch S I. Glycine prodrug facilitates memory retrieval in humans. Neurology 1991;41:1341-1343. [0077] Sershen H, Lajtha A. Inhibition pattern by analogs indicates the presence of ten or more transport systems for amino acids in brain cells. J Neurochem 1979;32:719-726. [0078] Simpson G M, Angus J W S. A rating scale for extrapyramidal side effects. Acta Psych Scand Suppl. 1970; 212:11-19. [0079] Toth E, Weiss B, Banay-Schwartz M, Lajtha A. Effect of glycine derivatives on behavioral changes induced by 3-mercaptopropionic acid or phencyclidine in mice. Res. Comm. Psychol. Psychiat. Behav. 1986;11:1-9. [0080] Tsai G, Yang P, Chung L C, Lange N, Coyle J T: D-serine added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry 1998; 44(11):1081-9 Patent CitationsCited PatentFiling datePublication dateApplicantTitleUS3795738 *Dec 26, 1972Mar 5, 1974Abbott LabUse of l-propyl l-leucyl glycine amide to treat parkinson's diseaseUS3851055 *Mar 1, 1973Nov 26, 1974Abbott LabMethod of treating tardive dyskinesia using l-prolyl l-leucyl glycine amideUS4966915 *Sep 16, 1988Oct 30, 1990Banyu Pharmaceutical Co., Ltd.L-dopa derivatives or their acid addition salts, process for producing same and their useUS5668117 *Jun 29, 1993Sep 16, 1997Shapiro; Howard K.Methods of treating neurological diseases and etiologically related symptomology using carbonyl trapping agents in combination with previously known medicamentsUS5837730 *Dec 6, 1996Nov 17, 1998Javitt; Daniel C.Treatment of negative and cognitive symptoms of schizophrenia with glycine uptake antagonistsUS6083941 *Jan 23, 1998Jul 4, 2000Trustees Of Boston UniversityInhibition of NMDA receptor activity by pregnenolone sulfate derivativesUS6228875 *Apr 14, 1999May 8, 2001The General Hospital CorporationMethods for treating neuropsychiatric disordersUS6310085 *Apr 2, 1999Oct 30, 2001Clarencew Pty Ltd.Method for the treatment of neurological or neuropsychiatric disordersUS6361957 *Aug 3, 1999Mar 26, 2002Glytech, Inc.Assay for D-serine transport antagonist and use for treating psychosisUS6506780 *Jul 2, 2001Jan 14, 2003Pfizer Inc.Benzophenones and sulfones as inhibitors of glycine uptakeUS6514973 *Oct 13, 1999Feb 4, 2003Merck Patent Geseilschaft Mit Beschrankter HaftungCompositions for the treatment and prevention of neurological and pathopsychological diseasesUS6551993 *Aug 15, 2000Apr 22, 2003Thomas Jefferson UniversityPartial agonists at the glycine modulatory site of the NMDA receptor for treating cognitive dysfunctionUS7160913 *Sep 11, 2003Jan 9, 2007Thomas Jefferson UniversityMethods and kit for treating Parkinson's disease* Cited by examinerNon-Patent CitationsReference1 *Moris Phy Ther (2000); 80:578-5972 *Webminister II New Riverside University Dictionary (1994) 3pages* Cited by examinerReferenced byCiting PatentFiling datePublication dateApplicantTitleUS7390496 *Apr 25, 2003Jun 24, 2008Allergan, Inc.Therapeutic treatments for repetitive hand washingUS7393537 *Apr 25, 2003Jul 1, 2008Allergan, Inc.Botulinum toxin for treatment of obsessive compulsive finger biting disorderUS7396535Apr 25, 2003Jul 8, 2008Ackerman Alan HTherapy for obsessive compulsive head bangingUS7731977Jan 25, 2008Jun 8, 2010Allergan, Inc.Use of a botulinum neurotoxin to alleviate various disordersUS8057808Apr 21, 2010Nov 15, 2011Allergen, Inc.Use of a botulinum neurotoxin to alleviate various disordersUS8377452Oct 4, 2011Feb 19, 2013Allergan, Inc.Use of a botulinum neurotoxin to alleviate various disordersUS8604080 *Feb 4, 2008Dec 10, 2013W. Louis ClevelandHigh dose glycine as a treatment for obsessive-compulsive disorder and obsessive compulsive spectrum disordersUS8609112Feb 1, 2013Dec 17, 2013Allergan, Inc.Botulinum toxin treatments of depressionUS8609113Feb 1, 2013Dec 17, 2013Allergan, Inc.Botulinum toxin treatments of depressionUS8617572Mar 22, 2011Dec 31, 2013Allergan, Inc.Botulinum toxin treatments of depressionUS9051592Mar 12, 2013Jun 9, 2015Garnet Biotherapeutics, Inc.Methods of ganglioside productionUS9238061Nov 21, 2013Jan 19, 2016Allergan, Inc.Botulinum toxin treatment of anxiety and bipolar disordersUS9394558Feb 28, 2012Jul 19, 2016Lz Therapeutics, Inc.Methods for extraction and purification of gangliosidesUS9415030May 6, 2013Aug 16, 2016W. Louis ClevelandHigh-dose glycine as a treatment for obsessive-compulsive disorder and obsessive-compulsive spectrum disordersUS9504665Sep 10, 2013Nov 29, 2016W. Louis ClevelandHigh-dose glycine as a treatment for obsessive-compulsive disorder and obsessive-compulsive spectrum disordersUS9556467Jan 18, 2013Jan 31, 2017Garnet Bio Therapeutics, Inc.Methods of ganglioside productionUS20040213811 *Apr 25, 2003Oct 28, 2004Allergan, Inc.Use of a botulinum neurotoxin to alleviate various disordersUS20040213813 *Apr 25, 2003Oct 28, 2004Allergan, Inc.Therapy for obsessive compulsive head bangingUS20040213814 *Apr 25, 2003Oct 28, 2004Allergan, Inc.Therapeutic treatments for repetitive hand washingUS20060217321 *Mar 23, 2006Sep 28, 2006Taiyokagaku Co., Ltd.Compositions to improve tic disordersUS20090176715 *Jan 8, 2009Jul 9, 2009Amino Acids Solutions Inc.Pharmaceutical Compositions and Methods Utilizing a D-Amino AcidUS20100048653 *Jul 14, 2006Feb 25, 2010The University Of British ColumbiaNeuroprotective modulation of nmda receptor subtype activitiesUS20100113598 *Feb 4, 2008May 6, 2010The Trustees Of Columbia University In The City OfHigh dose glycine as a treatment for obsessive-compulsive disorder and obsessive compulsive spectrum disordersUS20100204127 *Apr 21, 2010Aug 12, 2010Allergan, Inc.Use of a botulinum neurotoxin to alleviate various disordersUS20110200639 *Mar 22, 2011Aug 18, 2011Allergan, Inc.Botulinum toxin treatments of DepressionWO2008100727A2 *Feb 4, 2008Aug 21, 2008The Trustees Of Columbia University In The City Of New YorkHigh-dose glycine as a treatment for obsessive-compulsive disorder and obsessive-compulsive spectrum disordersWO2008100727A3 *Feb 4, 2008Dec 30, 2009The Trustees Of Columbia University In The City Of New YorkHigh-dose glycine as a treatment for obsessive-compulsive disorder and obsessive-compulsive spectrum disordersWO2009018368A1 *Jul 30, 2008Feb 5, 2009Los Angeles Biomedical Research Institute At Harbor-Ucla Medical CenterCombination treatment of nmda (n-methyl-d-aspartate)-enhancer, glycine transporter inhibitor, d-amino acid oxidase inhibitor (daaoi) for neuropsychiatric disordersWO2010053976A2 *Nov 4, 2009May 14, 2010Mclean Hospital CorporationDrug-enhanced neurofeedbackWO2010053976A3 *Nov 4, 2009Jul 29, 2010Mclean Hospital CorporationDrug-enhanced neurofeedbackWO2011028794A2 *Sep 1, 2010Mar 10, 2011Lazarus Therapeutics, Inc.Treatment of huntington's disease with cycloserine and an nmda receptor antagonistWO2011028794A3 *Sep 1, 2010Jul 21, 2011Lazarus Therapeutics, Inc.Treatment of huntington's disease with cycloserine and an nmda receptor antagonistWO2014191992A1 *May 26, 2014Dec 4, 2014Sarah Herzog Memorial Hospital-Ezrath NashimAutoimmune-induced glutamatergic receptor dysfunction methods and treatmentsWO2015127558A1 *Feb 27, 2015Sep 3, 2015UNIVERSITé LAVALMethods and uses for inducing or facilitating micturition in a patient in need thereof* Cited by examinerClassifications U.S. Classification514/561International ClassificationA61P25/16, A61P25/14, A61K31/198, A61K31/42Cooperative ClassificationA61K45/06, A61K31/198, A61K31/42European ClassificationA61K31/198, A61K31/42Legal EventsDateCodeEventDescriptionDec 23, 2003ASAssignmentOwner name: SARAH HERZOG MEMORIAL HOSPITAL EZARTH NASHIM ASSOCFree format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:HERESCO-LEVY, URIEL;JAVITT, DANIEL C.;REEL/FRAME:014854/0344Effective date: 20031212RotateOriginal ImageGoogle Home - Sitemap - USPTO Bulk Downloads - Privacy Policy - Terms of Service - About Google Patents - Send FeedbackData provided by IFI CLAIMS Patent Services


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Nikon D800 + 24-70 OR D7100 + 18-300: Open Talk Forum: Digital Photography Review
Forum indexOpen TalkChange forum Nikon D800 + 24-70 OR D7100 + 18-300
Nikon D800 + 24-70 OR D7100 + 18-300 Apr 16, 2013
I am switching from a good canon gear 50D+17-55 2.8 and 70-300.
i wanted to make a progress but with 18-300 combo I feel I loose on IQ and sharpness but in D800 set I loose reach (and more money - but better invest in good quality for years right?).
What's your advise? Canon EOS 50D
Post (hide subjects)Posted byWhenNikon D800 + 24-70 OR D7100 + 18-300Newgreg606 Apr 16, 2013 ForumParentFirstPreviousNextNext unread
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Definitions by thomasmcd6
Energy Market For Smart People
Whats reallydriving electricityprice increases? 2.
How the National Electricity Market Works ill Electricity BGenerator Transmission Retailer ‘your bill’ and Distribution 3.
What really makesup an energy bill? 14% ill ill Electricity B The retailers 41% Electricity B $ charges Networks 34% Wholesale price of power 6% 5% the Other carbon green price schemes [1] Building and New maintaining infrastructure of network makes your bill higher[1] Forecast data from Australian Government, National Energy SavingsInitiative Discussion Paper pg 5, for 2012-2013 4.
Network expenditureis growing fastest 2010 2015 2030 [2] [3] $46 Billion $240 Billion[2] Ernst and Young (2011) Rationale and drivers for DSP in the electricity market – demand and supplyof electricity Prepared for the AEMC Power of Choice Review - giving consumers options in the way they use electricity[3] Australian Energy Markets Commissions, Fact Sheet 2: demand side participation and prices 5.
How networks are used 12 12 11 1 11 1109 2 3 Most of the 10 9 2 3 Peak time January Rare peak times8 7 5 4 time (day) 8 7 5 4 (evenings) (40 hours /year) hot or cold days 6 6 100% 6.
Network spending over five years (2010-2015) = $46 billion 21.4 Peak Demand 100% $ Billion Growth + 24.6 Total $ Billion annual demand =[2] Ernst and Young (2011) Rationale and drivers for DSP in the electricitymarket – demand and supply of electricity Prepared for the AEMC Power $ 46 Billionof Choice Review - giving consumers options in the way they use electricity 7.
The Solution ! 50% A set of Will That could [4] smart system unlock save billions changes benefits[4] Think Small 2012: The Australian Decentralised Energy Roadmap. Institute for Sustainable Futures, University of Technology Sydney. 8.
Where will the savings come from ? 22608 MW 19 % 46 Cogen-trigen Energy efficiency (10423MW) % (4216MW) Storage 2% (380MW) 4% Local renewables 25 % (875MW) Local bioenergy (1032MW) 5% Peak demand measures (5682MW)[4] Think Small 2012: The Australian Decentralised Energy Roadmap. Institute for Sustainable Futures, University of Technology Sydney. 9.
Why is it green? 73MT CO2 per year Could save 35% More energy Prevents local of Australia’s 2009 supplied by impacts of mining and electricity sector renewables building high-voltage emissions[4] transmission lines[4] Think Small: The Australian Descentalised Energy Roadmap, ISF. The International Energy Agency estimates up to 60% of global emissions reductions must come from efficiency. Recommended
Research for medieval
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Definitions thomasmcd6
Terms 140912042449-phpapp01

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Great scenery - Review of Lookout Tavern, Oak Bluffs, MA - TripAdvisor
Great scenery - Lookout Tavern
This is great for a good view into Oak Bluffs waterfront. The staff was pleasant. The atmosphere is good. The food is a bit better than average. I had sushi which was good. I went for the MV roll. This place is great in the summer. A good place to meet folks for drinks.
Ask RhodyPhotographer about Lookout Tavern
504 - 508 of 547 reviews
This place has a great view of the atlantic ocean. It is an open air establishment during the summer. I have never been during the winter. The chowder, sushi, and cherrystones are all very good. I've yet to get cheated on a drink there either.
Ask CJ-Mass about Lookout Tavern
I strongly recommend this restaurant facing the ocean.
We had the lobster roll and it was so big that we had to use our forks and
Ask loulou942 about Lookout Tavern
Crazy Busy...but worth the wait and crowds. Best and freshest sushi I have ever had! Been trying to figure out how to get to the island just to have the sushi again!
Ask samsmomm about Lookout Tavern
I've been here many times and have never been disappointed! The drink menu has many great options, my favorite being an Elvis and my favorite meal I got was their California turkey sandwich. It was amazing! The home made chips were delicious as well. Can't wait to go back!
Ask Caroline W about Lookout Tavern

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