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Lokelani 'Ohana creates socially therapeutic programs within our community with elements of native Hawaiian culture and tradition for adults with developmental disabilities. One of the programs we run is in biodynamic gardening. Our farm is located on old Hawaiian land on the North shore of Maui, Hawaii.
The land presents a combination of established and newer fruit trees with terraces of taro, potatoes and many varieties of vegetables and herbs. We presently sell our produce to the local health food stores. The farm also grows cotton and other products for a second program we offer the community in Saori Weaving.
We work with people from Mediaid Waiver Programs and enjoy working with wwoofers for the last three years from around the world. We are a vibrant sustainable ohana where adults with developmental disabilities live, learn, and work together with reverence for spirit, creativity and nature supporting each other's potential and sharing a life of purpose.
We are advertising for a biodynamically trained farmer to move to our small community and join us in expanding our farm and service.
We sell produce to the health food stores on a week;y basis. Some people buy from us wholesale and resale the produce at the local farmers market.
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International Edition
5@5 is a daily, food-related list from chefs, writers, political pundits, musicians, actors, and all manner of opinionated people from around the globe.
Tom Pizzica may have not won season six of The Next Food Network Star – but don't go throwing a pity party. He received a pretty sweet consolation prize out of the ordeal - namely his own show.
When Outrageous Food premieres on the Food Network tomorrow night (10 p.m. ET), it's sure to deliver all sorts of unhinged, gravity-defying, exorbitant eats.
But first, a few ground rules on outrageousness from Mr. Pizzica:
In order for something to be considered outrageous, it doesn't necessarily need to be the biggest, spiciest or the priciest. Sometimes we have memories about a particular story of culinary mayhem,or the first time you eat something that becomes a lifelong favorite, and I consider those to be outrageous as well. Here are five of those memories.
Five Outrageous Food Memories: Tom Pizzica
1. Feast in Houston, Texas: The brined and fried pig face "This is a dish that will be featured on Outrageous Food but I had to put it in here because the idea is completely outrageous. These two chaps from England take an entire pig face - I'm talking straight off the skull, crazy horror movie mask pig face - and roll the tongue up inside. They truss it and then cut off the snout (don't worry - they use that in another dish, nothing goes to waste).
The whole thing is brined for three days, then braised for a few hours. After it has cooled for 24 hours, they take thin slices of it and fry them on a flat-top griddle. When you eat it, the whole thing melts in your mouth and is unbelievably delicious. It's like the most outrageous bacon you've ever had. The recipe alone is outrageous, and for a pork lover like myself, I'm kind of jealous I never thought of it!"
2. My first Cadbury Easter egg "This is a story I remember from my childhood, and while I consider the concept of the Cadbury egg outrageous enough alone, it's how I went about obtaining one that could also be considered outrageous.
When I was about four years old, I saw a commercial for this brand new candy called a Cadbury Easter Egg, and absolutely had to have one! It was the coolest thing I'd ever seen. I mean it looks like an egg, complete with the whites and the yolk, but its chocolate and nougat!
I pleaded with my mother to buy me that egg to the point that I didn't go to sleep. I just sat up and complained and cried until my mother put on her quilted vest (they were cool back then), drove to the store and bought me one. I must have fallen asleep while she was gone because the next flashbulb memory I have is of my mother coming onto my room (in her sweet vest) with a look of complete anger/defeat and told me I couldn't eat it until the morning.
Well, I woke up at 6 a.m. to eat that sucker, and it was the most outrageous thing this 4-year-old had ever seen or put into his mouth! I couldn't understand how they made it look so much like an egg and taste so sweet and delicious! I was hooked and to this day, it is an Easter tradition for me."
3. Cooking wild geese for hunters in Maryland "When I was a chef at my family's hotel/restaurant on the eastern shore of the Chesapeake Bay in Maryland, I created a lot of wonderful dishes using wild game as the star. All were farm-raised and came in nice little packages from the meat purveyor.
On one particular November weekend, my kitchen became full of wild geese that had been freshly hunted and plucked. There was this group of hunters who got together every year to hunt geese and ducks and they always stayed in the hotel. On the way out, they asked me if I would cook their game if they got any. I agreed but had never in my life cooked a goose nor did I worry because it was very dreary outside and didn't think they would have any success. I was dead wrong.
These guys came back with bags and bags of geese that were still warm from being alive two hours ago! Yuck! So, not only did these guys expect dinner that night, but I had enough to feed them for two nights. I had no idea what I was going to prepare and I found the texture of the meat and the scrawny little bodies not appealing at all. I found myself doing everything to these geese! I confited, grilled, roasted, pan-seared, fried, brined, marinated, smoked - I mean everything I could think of. In the end the hunters were very pleased, or just very polite."
4. Outlaw Catering, Texas "This is another segment from "Outrageous Food." I had to include it because I truly consider this completely outrageous, hence the name of the show. Picture a city boy on a north Texas cattle ranch cooking out of a 160-year-old chuck wagon in handmade cast iron pans over an open flame for a bunch of real deal cowboys! Yeah, I felt about as out-of-place as, well, a city boy in the middle of a north Texas cattle ranch.
The characters I was with were outrageous enough, but just being out there, in the pouring rain, making great food the same way they did in the days of the Pony Express was awesome. The whole time I felt like a kid with his first Cadbury Easter egg!"
5. Crisping duck confit in hot oil for 500 people "I mean the title to this one should tell you how outrageous it really was. This, again, goes back to my Maryland days, but this time we find our hero in the first ever 'Taste of the Town' festival in a little town called Chestertown, Maryland - which is the town in which I had my hotel/restaurant.
I had to come out guns blazing because there was a competition that was crowning the best taste of the town. What do I do? I thought that making my crispy duck confit with shaved Brussels sprouts and grapefruit marmalade would definitely be a winner. I was right - however, I didn't know what crisping 500 confited duck legs would entail. I will never try it again. I had a turkey fryer blazing at 450 degrees, and I spent five hours that day dipping duck legs into it trying not to burn my skin off and trying to keep the soft duck legs from falling apart. I accomplished one of those feats.
I have the crown but still have scars. It was so much fun but a completely outrageous way to try to make your mark on a small town."
Fancy a pig face? Got a over-the-top grubbing memory? Share with us in the comments.
Is there someone you'd like to see in the hot seat? Let us know in the comments below and if we agree, we'll do our best to chase 'em down.
Memories associated with food are so prevalent in my family I compiled a cookbook that is as much memoir as recipe collection. Each recipe is accompanied by a story (many of them really outrageous) about the dish. I printed out several copies, placed each page in a sheet protector (to make spills easy to wipe off), "bound" it in 3-ring binders and entitled it "My Memories Are Made Like This".
The books were given to family members and friends as Christmas, wedding and "leaving home" presents and, although I'm sure some are never used, many recipients have told me how much they (and their friends) love to read the stories as well as use the recipes. Most of the comments I received were about the recipes and stories I HADN'T included, so the cookbook became a computer file that is constantly updated and made available through email. I recommend this as a fun and useful way to keep family stories alive for the next generation.
Glad to see Tom got his own show. I was crushed when he didn't win. LIke a previous poster said, I wouldn't watch Artie and her "party" if she were the only show on the FN.
I've eaten foods from many cultures as I grew up in the Foreign Service and then married into the military. Blood sausage, "mountain oysters", etc. I didn't think of most foods from these countries as outrageous because I was young and that's what you ate there. Looking back, probably the most "outrageous" thing I ever ate was pigeon, which in itself isn't outrageous, but the way it was obtained was. It was our first overseas tour, Rio de Janeiro in Brazil, 1966, and we lived on the ground floor of a 3-story apartment building. There was a small flock of pigeons roosting on the roof right over the door leading out to the patio, and you never knew if you were going to be bombed with pigeon poo or not whenever one of us walked outside. Finally, one of the neighbors offered to get rid of them for us (it was a very neighborly building with only 5 apartments and families living there – we all knew one another). He shot them all and then plucked them and cooked them for us. As a 7-year old, I remember it was utterly delicious, even though the little legs were like doll-size chicken legs.
Interesting article. I enjoy hearing/reading other people tell of their experiences with memorable food. Here's 2 of my memories: #1 – Muskrat. That's right, muskrat. My Dutch ex mother-in-law was an intimidating hulk of a woman who was quite possibly the worst cook ever to lift a frying pan. She lived in rural Indiana, and (having been raised in Holland during WW2 and experiencing near starvation at the hand of the Nazis) she took advantage of the considerable bounty right outside her back door – which included muskrat. I don't know how she managed to accidentally cook it to perfection, but it was the most amazing meat I have ever eaten. Period. #2 – Doves and Dumplings. My southern parents were both my culinary heroes. Dad? The man could not cook to save his life, but he knew good stuff when he ate it, for certain. He's the one who introduced me to sardines, as well as brains, testicles, wild greens, wild game, offal, and countless other delights. My mother was a fantastic cook, as was her mother, and so on. I'll never forget my dad and I bringing home a bunch of doves from our hunting trip, and my mother making chicken and dumplings – but using doves instead of chicken. Outrageously good. Instead of having one identifiable food memory – it simply started in my childhood and adolescence, and has lasted into adulthood. Thanks Mom, thanks Dad.
I love the caramel Cadbury eggs. Yummy.
I love Cadbury eggs
Don't know what that dish is – but it looks like some horrible appetizer from Ruby Tuesday – guacamole, sour cream, nachos, and velveeta. I have never seen the appeal to guacamole – it has zero taste. I'm from the south – and I know zero taste – just try grits – that will get you zero taste and flavor.
He's right, Cadbury eggs are my favorite candies for their magical quality. Only the ones that look like whites and yolks inside though, the others are nice, but ordinary. Unlike Pizzaca, I didn't discover them till I was like 21, a boyfriend brought me some and it remains the fondest memory I have of that relationship. In other food outrageousness though, I like trying new things. So once at my deli, I picked up a little salad, I think it was some kind of Greek thing, or Italian antipasto. It's a shame I can't recall, exactly what it was because I have never been so – uh – gassy, in my LIFE. I'm not prone to this problem, even with foods famous for it, but it was awful, I offended myself, it wasn't even real flatulence, it was like this horrible, intense kind of sweet smell that OOZED from my pores. Thank god I ate it on a Friday night so I could barricade myself indoors all day Saturday. Not very appetizing I know, but it WAS outrageous. I haven't touched a deli salad since. :-O
Wild goose = yuck?? That's absurd. I marinade wild goose breasts in sesame, orange, and ginger then grill them to medium rare on the grill on kabobs. It would probably help if he identified which type of geese they were. Were they Canadas or Snow Geese? Snow Geese are disgusting, I'll concur with that.
It's tough to beat eating leaning, fresh meat free from antibiotics, added hormones, etc.
JEM! Truly outrageous. Truly, truly, truly outrageous!
I'm soooo glad they gave Tom his own show. He deserved to win NFNS. My bf and I have both agreed, we have NO desire to watch Artie and her 'party'.
@rebel thank you so well said!
500 Duck confit at 450 degrees, all in 5 hours?! hehehe... Google duck confit, the whole point of the dish is to slow cook the duck in it's own fat, at a low temperature, around 200-250F. What he was making was just deep fried duck....
fried chicken feet and fried sea anemone at a stall in Pusan Korea. Many an OB before and with. Mmmmm
the cadbury easter egg...yes! I hope your kids put you through the same torment, pain an eventual surrender as you put your mom! ( and they will love you for it, haha:)
1. Eating my first Big Mac and getting it everywhere and loving every second of it.
2. Mushroom soup in Paris. I've never eaten Campbell's since. It was beautiful and mushroomy and delicious.
3. My grandmother's baking powder biscuits straight out of the oven with butter dripping down and homemade jam. I can still smell them.
I know what you mean about the Big Mac, I'll never forget my first one.
My first Big Mac made me sick. How about the first REAL burger you had?
I love your baking powder biscuits memory!
My great-grandmother used to make biscuits from scratch- literally took handfuls of flour, poured in milk haphazardly- I would watch awestruck at someone cooking without a recipe or measuring cups (or Bisquick, hi mom!) Every time they came out perfectly. I was too young to have thought to have taken notes, even if I had, they could never be as good as hers were.
Tom is entertaining and for me, eating pig face would be outrageous. Some of us out here have not had some of the dishes he is making. I wanted him to win the FN challenge and I'm very pleased he got his own show. I hope his unique approach to his show grows just as it did for Guy and other very talented people they feature. Not all folks are going to be stars and thankfully the FN knows when to pull the plug on a show. The FN has a nice variety and they have changed the way many people entertain with food. It's a great network. You rock Tom and your fiance is a doll too!
The most outrageous thing I've experienced is an all you can eat cheese cart with 15-20 different types of Roquefort cheese. I was in a small town right outside of Roquefort and the cheese was the 5th course of a 6 course meal.
Dear Tom, I love you.
The original Cadbury Creme Egg is heavenly! I get excited every year before Easter when they are put out for sale. <3 I remember discovering CCE vending machines in the London Underground. I lost a quid in one of those machines and I was crushed.
Love, Trish
Seriously? They have this guy on here? Someone who couldn't even win that joke of a show Next foodnetwork star...FN has gotten so bad it's un-watcable. They caught lightening in a bottle with Guy and they keep rolling out these nobody's who's shows get cancelled within 2 weeks. PBS has the only good cooking shows.
OMG ... CADBURY EGGS are amazing! I buy at least a dozen (or more) at easter and savor them all year long ... one a month, that's about all i can handle but seriously those things are outrageous!
Some of you are so angry and bitter, take some anti-depressants or get therapy
A lot of people seem bitter over what other people eat. Get over it people.
And lol @ "pig face is not outrageous" Well excuse me if I'm not yet a citizen of the world and have yet to experience many cultures (though I would like to someday..), but to me and my culture, that's fairly outrageous. Sounds tasty though!
Well said, Matt!
Of course you can't forget the macaroni noodles and the peas!!!
Chestertown, MD? My son went to school at WaC for two years. Sorry to have missed your restaurant...would have enjoyed the variety... and can't imagine what you did with geese...always a puzzle.
Pig's face sounds outstanding.
I don't see any of these stories as "outrageous" food memories. Even the pig face dish is not unusual. Animal tissue is animal tissue, and I say that as a vegetarian. Doesn't matter where it comes from. And although the duck confit dish sounds wonderful (I used to love to eat duck), I'm pretty sure deep frying the legs is not how you crisp them up (not the way I did it, anyway). Cooking for cowboys? II's called camping - no big deal. Mom giving into a tantrum? It's called spoiling. Cooking shot geese? If that upsets you, maybe you should question whether you should cook that any of that meat that comes in "nice little packages from the meat purveyor." Outrageous is...your Aunt Mona's chicken marshmallow tuna surprise.
"Cooking for cowboys? II's called camping – no big deal."
Really? Camping is when you cook for a handful of people at the most. Chuck Wagon cooking is when you cook a full four course meal outdoors for a full crew of hungry cowboys, sometimes for several dozen very hungry men. There's a world of difference between the two.
Pig face really isn't anything extreme or revolutionary. It might be "weird" to somebody who has a really mundane palate, but swine products made from head are nothing new.
Exactly. You only have to check the closest neighbors south (Mexico) and enjoy their "tacos de cabeza". Awesome stuff and just the intro. to how most cultures use the "whole hog".
Outrageous seems to be his favorite word because he uses it to describe a lot of different things.
He's no Adam Richman.
Cadbury Easter eggs were created by the devil, easily the worst candy ever made with Peeps one step behind.
If you say Peeps are a step behind in evilness, is that because Peeps have no fat, unlike the chocolatey goodness of the Cadbury Creme Egg? I think that Peeps can be just as bad as they are addictive – I always say "Just one row, just one row" but I usually kid myself and eat way too many of those deceptively delicious sugared marshmallows in a sitting. Pure sugary Peep goodness – ah, my fave. But Cadbury chocolate tastes like Easter to me, it's THE chocolate for Easter bunnies. Mmmmm.
Potato chip tuna casserole who my sister got from her mother-in-law in Kansas. Large can light tuna, bag potato chips, cream of mushroom soup mixed with milk. Layer everything in a dutch oven casserole dish and bake in the oven about 40 min. My son used to beg me for this one.
Oh my goodness! I remember eating casseroles like that back in the 1970's! Cream of Mushroom Soup...the universal binder.
Of course you can't forget the macaroni noodles and the peas!
This is not news.
you come to CNN for news? try NPR
LOL NPR is not news either. It's depression in a can. :-)
What's ironic is that I used to be a staff member at an NPR radio affiliate.
Agree this is not new. Its just another show showing food that will make you fat fat fat. Gotta love TV these days
LUV YOU, Tom, and can't wait to see you succeed in your new show. My family thought you were great on the NFNS show. And btw...also agree about the Cadbury egg. I remember the first year it came out and I have been eating them ever year since.
I LOVE those Cadbury Eggs and that cute bunny from the commercial!
One of the best things I ever ate was a steak with calvados (apple brandy) sauce at The Precinct in Cincinnati. I still remember it decades later.
I also have many memories of eating the world's best pizza at Pepe's in New Haven CT. One time, one pizza that was about to be served to us had a soda spilled on it, so they made it again. The 2nd pizza had a bubble in the crust and exploded in the oven. Finally, we ate the 3rd pizza about 1.5 hours later, and it was gratis.
Everything's bigger (and better) in Texas. ;P
Especially the women and their muffin tops...:)
They should have given Brad Sorenson his own show...
I'd hit that...
This is becoming a tradition on 5@5. =)
I keep waiting for a story on Kelly Choi (Top Chef Masters) droooooool!!!!!!!!!!!!!!!!!!
OMG–are you the real deal Guy Fieri? Love, love, love your show. Seriously are you the real Guy?
It all sounds good. However, the guacamole and sour cream in the pic = BARF. Odd how I'll eat Menudo, chicken hearts and gizzards while sour cream and guacamole make me gag.
Sour cream I LOVE. Guac I don't. We agree half and half. I also love half&half. And white russians.
The dish in the photo looks like a pile of plate scrapings. In other words....garbage. It makes me cringe to look at it.
In our family, 6 out of 8 of us are allergic to dairy and eggs. So I discovered sourdough!! Sourdough starter is a wonderful egg replacer. I'm always experimenting with sourdough and adding it to anything...pecan pie, cakes, squash casseroles, etc. It's outragious...but delicious. Btw ~ I think the nachos in the picture look delicious!
Anyone who doesn't like guacamole (pronounced "WOCKA", not "GWOCKA") hasn't had good and simple guacamole. I love sour cream, but can see how that can be off-putting to some of you sissy girls.
Check yer shivvies fer skid marks, you jock closet case.
Chicken hearts make an amazing addition to tacos, soups, stir fries, etc. They're my favourite part of the bird.
You always seem to manage to get this pitch in for these cookbooks, don't you?? Don't you think people realize by now that you're selling these here just as blatantly as if you were standing on the street corner with a stack of books, yelling "Cookbook for sale!!"??
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From Barnes & Noble
This July 1st marks the 150th anniversary of the first day of the Battle of Gettysburg, the beginning of the three-day confrontation that decisively turned the tide in the War Between the States. In this important new narrative, revered Civil War historian Allen Guelzo (Lincoln's Emancipation Proclamation; Abraham Lincoln) delves beneath the grand sweep of strategic decisions to grasp the stories of real people in the experience of war. Gettysburg: The Last Invasion reveals how the realities of nineteenth century warfare impacted the lives of those hurled suddenly into it. A spring release certain to be prominently reviewed.


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Chief Phil Lane of the Yankton Dakota and Chickasaw First Nations... News Photo 161925054Activity,Barack Obama,California,Call,Chickasaw,Chief,City Of Los Angeles,Climate,Crisis,Demonstration,Environment,Environmental Issues,First Nations,Forward on Climate,Global Warming,Motion,One Person,People,Phil Lane,Political Rally,Politics,Sierra Club,Steps,Strategy,Strength,Taking,Talking,Town Hall,US President,USA,Vertical,Yankton DakotaPhotographer David McNewCollection: Getty Images News 2013 David McNewLOS ANGELES, CA - FEBRUARY 17: Chief Phil Lane of the Yankton Dakota and Chickasaw First Nations speaks on the steps of City Hall during the 'Forward on Climate' rally to call on President Obama to take strong action on the climate crisis on February 17, 2013 in Los Angeles, California. Organizers say the rally, which is led by Tar Sands Action Southern California and Sierra Club, is composed of a coalition of over 90 groups and coincides with similar rallies in Washington D.C. and other U.S. cities. (Photo by David McNew/Getty Images)


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Elisabeth Hasselbeck Marked for Death!
Who could possibly hate Elisabeth Hasselbeck? Plenty of people, according to her cohort Whoopi Goldberg.
The New York Post quotes the Dreaded One as saying that staunch Republican Hasselbeck receives more death threats than anyone else within the talk-show coven.
Which is saying something, given the level of contentiousness on The View lately.
But the Sister Act comedienne shouldn't be considered a suspect in the Hasselbeck threats.
"Truth is, we could not have a dialogue without Elizabeth," Goldberg asserts. "It's not that we have to agree, the important thing is that we have the conversation."
A "conversation"? Is that what they're calling The View's daily screech-fest?
Thanks for the clarification, Whoopi; maybe the WWE should change the name of its weekly televised matches to Friday Night Tea Party.


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Janis, Jeffrey E. M.D.; Hatef, Daniel A. M.D.; Reece, Edward M. M.D., M.S.; McCluskey, Paul D. M.D.; Schaub, Timothy A. M.D.; Guyuron, Bahman M.D.
Background: Surgical release of the greater occipital nerve has been demonstrated to be clinically effective in eliminating or reducing chronic migraine symptoms. However, migraine symptoms in some patients continue after this procedure. It was theorized that a different relationship between the greater occipital nerve and occipital artery may exist in these patients that may be contributing to these outcomes. A cadaveric investigation was performed in an effort to further delineate the occipital artery-greater occipital nerve relationship.
Methods: Fifty sides of 25 fresh cadaveric posterior necks and scalps were dissected. The greater occipital nerve was identified within the subcutaneous tissue and its relationship with the occipital artery was delineated. A topographic map of the intersection of the two structures was created.
Results: The greater occipital nerve and occipital artery have an intimate relationship, and crossed each other in 27 hemiheads (54.0 percent). The relationship between these structures when they crossed varied from a single intersection to a helical intertwining.
Conclusions: The greater occipital nerve and occipital artery have an anatomical intersection 54 percent of the time. There are two morphologic types of relationships between the structures: a single intersection point and a helical intertwining. Vascular pulsation may cause irritation of the nerve and is a possible explanation for migraine headaches that have the occipital region as a trigger point. Future imaging studies and clinical investigation is necessary to further examine the link between anatomy and clinical presentation.
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The Clinical Masters of PRS – Breast eBooks 4 Essential eBooks for Plastic Surgeons


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DAVID FRYE, the father of the Fryes, came to this town from Worcester County, Mass., and settled in the west part of the town, near the Mountain.
Biographical Sketch of David Frye
MLA Source Citation:
Partridge, Dennis N. Croydon New Hampshire Genealogy. AccessGenealogy.com. Web. 25 January 2015. http://www.accessgenealogy.com/new-hampshire/biographical-sketch-of-david-frye.htm - Last updated on Aug 27th, 2012Categories: New Hampshire
Topics: Biography
Locations: Croydon New Hampshire, Sullivan County NH
Surnames: Fryer
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US 6482800 B1 Abstract The present invention provides methods and kits for increasing blood flow to isehemic tissue, comprising the administration of an effective amount of angiotensinogen, angiotensin I (AI), AI analogues, AI fragments and analogues thereof, angiotensin II (AII), AII analogues, AII fragments or analogues thereof or AII AT2 type 2 receptor agonists.
Claims(12) 1. A method for increasing blood flow to ischemic cardiac tissue comprising the administration of an amount effective for increasing blood flow to ischemic cardiac tissue of at least one active agent comprising a sequence of at least five contiguous amino acids of groups R1-R8 in the sequence of general formula I
R1 is selected from the group consisting of H, Asp, Glu, Asn, Acpc (1-aminocyclopentane carboxylic acid), Ala, Me2Gly, Pro, Bet, Glu(NH2), Gly, Asp(NH2) and Suc;
R2 is selected from the group consisting of Arg, Lys, Ala, Om, Ser(Ac), Sar, D-Arg and D-Lys;
R3 is selected from the group consisting of Val, Ala, Leu, norLeu, Ile, Gly, Pro, Aib, Acpc and Tyr;
R4 is selected from the group consisting of Tyr, Tyr(PO3)2, Thr, Ala, Ser, homoSer and azaTyr;
R5 is selected from the group consisting of Ile, Ala, Leu, norLeu, Val and Gly;
R6 is selected from the group consisting of His, Arg and 6-NH2-Phe;
R7 is selected from the group consisting of Pro and Ala; and
R8 is selected from the group consisting of Phe, Phe(Br), Ile and Tyr, or is absent; excluding sequences including R4 as a terminal Tyr group;
and wherein the active agent is not AII.
2. The method of
3. The method of
4. A method for increasing blood flow to ischemic cardiac tissue comprising the administration of an amount effective for increasing blood flow to ischemic cardiac tissue of at least one active agent consisting of a sequence of at least three contiguous amino acids of groups R1-R8 in the sequence of general formula I
R1 is selected from the group consisting of H, Asp, Glu, Asn, Acpc (1-aminocyclopentane carboxylic acid), Ala, Me2Gly, Pro, Bet, Glu(NH2), Gly, Asp(NH2) and Suc;
R2 is selected from the group consisting of Arg, Lys, Ala, Om, Ser(Ac), Sar, D-Arg and D-Lys;
R3 is selected from the group consisting of Val, Ala, Leu, norLeu, Ile, Gly, Pro, Aib, Acpc and Tyr;
R4 is selected from the group consisting of Tyr, Tyr(PO3)2, Thr, Ala, Ser, homoSer and azaTyr;
R5 is selected from the group consisting of Ile, Ala, Leu, norLeu, Val and Gly;
R6 is selected from the group consisting of His, Arg and 6-NH2-Phe;
R7 is selected from the group consisting of Pro and Ala; and
R8 is selected from the group consisting of Phe, Phe(Br), Ile and Tyr, or is absent;
excluding sequences including R4 as a terminal Tyr group;
and wherein the active agent is not AII.
5. The method of
6. The method of
7. The method of
8. The method of
9. The method of
10. The method of
11. The method of
12. The method of
Description This application is a continuation of U.S. patent application Ser. No. 09/373,962 filed Aug. 13, 1999, now U.S. Pat. No. 6,177,407, which claims priority from U.S. patent application Ser. Nos. 60/096,414 filed Aug. 13, 1998 and 60/101,024 filed Sep. 18, 1998. Collateral circulation to tissues can be stimulated in two independent ways: 1) the formation of new blood vessels through angiogenesis and 2) the enhancement in function of preexisting blood vessels (Fernandez et al., J Lab. Clin. Med. 105:141-145 (1985)). Angiogenesis is the process by which new blood vessels are formed from existing capillaries. (U.S. Pat. No. 5,318,957, incorporated by reference herein in its entirety.) Angiogenesis plays an important role in such widely divergent biological conditions as embryonic development, tumor growth, wound healing, and chronic inflammatory disease. (Folkman et al., Science 235:442-447 (1987)) Capillaries are composed almost entirely of endothelial cells. Angiogenesis comprises a cascade of events, including protease secretion by endothelial cells, degradation of the basement membrane, migration through the surrounding matrix, proliferation, alignment, differentiation into tube-like structures, and synthesis of a new basement membrane. (U.S. Pat. No. 5,318,957) Several angiogenic agents with different properties and mechanisms of action are well known in the art, including acidic and basic fibroblast growth factor, transforming growth factor alpha and beta, tumor necrosis factor, platelet-derived growth factor, vascular endothelial growth factor, angiogenin, and haptoglobin. (U.S. Pat. No. 5,318,957) However, the therapeutic applicability of some of these compounds is limited by their potent pleiotropic effects on various cell types. Thus, there remains a need in the art for angiogenic agents with more general applicability. Very few therapies have been demonstrated to increase collateral circulation by S enhancing the function of existing blood vessels. In an isolated case, U.S. Pat. No. 4,296,100 discloses animal experiments wherein bovine fibroblast growth factor (FGF) was injected into the heart to distribute the desired amount of FGF over the area of the heart to be treated. This treatment was given as close to the time the heart attack as possible in order to control damage, possibly by improving collateral circulation, although the exact mechanism is unknown. The experiments showed that a one time treatment could reduce infarct size (area that will scar or remain permanently damaged) in the test animal to one quarter the size of the control (non-treated) hearts. Histological studies did not show a significant increase in capillary areas in the hearts as a result of such treatment with FGF. Congestive heart failure is the leading cause of cardiovascular mortality (Tyagi, J. Cell Biochem. 65:388-394. (1997), and is caused by cardiac remodeling that leads to an enlargement of the heart following a myocardial infarction (Pfeffer, Am. J.Cardiol. 68:17D-25D (1991)). There is a strong correlation between long term morbidity from congestive heart failure and the degree of post-infarct remodeling. As little as a 35% increase in the volume of the heart in the months following infarction leads to an increase in mortality by a factor of 3-4 (Hammermeister et al., Circulation 59:421-435 (1979)). Therefore, therapies that attenuate cardiac remodeling following myocardial infarction are needed to prevent the development of congestive heart disease. The loss of blood flow to the ischemic tissue is the primary factor in causing cardiac remodeling. Studies show that there is major cardiac remodeling following a myocardial infarction if the infarct-related artery is totally occluded (Kim and Braunwald, Circulation 88:2426-2436 (1993)). However, cardiac remodeling can be minimized if blood flow can be restored to the ischemic tissue. In addition, the earlier blood flow is restored the more cardiac remodelling can be attenuated (Hochman et al., Circulation 75:299-306 (1987); Bonaduce et al., J.Am. Coll. Cardiol 16:1561-1568 (1990)). Therefore, treatments aimed at quickly restoring blood flow following myocardial infarction can minimize cardiac remodeling and the development of congestive heart disease. Chemical therapies are currently one of the most useful treatments for restoring blood flow to ischemic tissue following myocardial infarction. Thrombolytic therapies are based on clearing the occluded coronary artery in order to restore blood flow (U.S. Pat. No. 5,589,173). In addition to clearing the occluded coronary artery, the presence of a collateral blood supply can minimize the effect of cardiac remodeling. Therefore, chemical therapies directed at stimulating collateral circulation could minimize cardiac remodeling following myocardial infarction. However, there are currently few materials available for stimulating collateral blood flow. Based on the above, there remains a need for the development of methods to increase blood flow to ischemic tissue in general, and a particular need for increasing blood flow to the heart following a myocardial infarction. The present invention provides improved methods and kits to increase blood flow to ischemic tissue comprising the administration of angiotensinogen, angiotensin I (AI), AI analogues, AI fragments and analogues thereof, angiotensin II (AI) analogues, AII fragments or analogues thereof or AII AT2 type 2 receptor agonists. FIG. 1 is a graph showing the effect of AII analogues on blood flow in conjunction with Apligraf treatment. FIG. 2 is a graph showing the effect of AII analogues on endothelial cell production in conjunction with Apligraf treatment. FIG. 3 is a graph showing the effect of AII analogues on blood flow after thermal injury. All references, patents and patent applications are hereby incorporated by reference in their entirety. As used herein, the term �ischemia� refers to any condition associated with an inadequate flow of oxygenated blood to a part of the body. Ischemia occurs any time that blood flow to a tissue is reduced below a critical level. This reduction in blood flow can result from the following non-limiting conditions: (i) the blockage of a vessel by an embolus (blood clot); (ii) the blockage of a vessel due to atherosclerosis; (iii) the breakage of a blood vessel (a bleeding stroke); (iv) the blockage of a blood vessel due to vasoconstriction such as occurs during vasospasms and possibly, during transient ischemic attacks (TIA) and following subarachnoid hemorrhage. Further conditions in which ischemia occurs, include (i) during myocardial infarction (when the heart stops, the flow of blood to organs is reduced and ischemia results); (ii) trauma; and (iii) during cardiac and neurosurgery (blood flow needs to be reduced or stopped to achieve the aims of surgery). As used herein, the term �ischemic tissue� refers to any tissue that is receiving an inadequate flow of oxygenated blood. As used herein, �increasing blood flow� refers to such increases mediated by either the formation of new blood vessels through angiogenesis or the enhancement in function of preexisting blood vessels. Within this application, unless otherwise stated, the techniques utilized may be found in any of several well-known references such as: Molecular Cloning: A Laboratory Manual (Sambrook, et al., 1989, Cold Spring Harbor Laboratory Press), Gene Expression Technology (Methods in Enzymology, Vol. 185, edited by D. Goeddel, 1991. Academic Press, San Diego, Calif.), �Guide to Protein Purification� in Methods in Enzymology (M. P. Deutshcer, ed., (1990) Academic Press, Inc.); PCR Protocols: A Guide to Methods and Applications (Innis, et al. 1990. Academic Press, San Diego, Calif.), Culture of Animal Cells: A Manual of Basic Technique, 2nd Ed. (R.I. Freshney. 1987. Liss, Inc. New York, N.Y.), Gene Transfer and Expression Protocols, pp. 109-128, ed. E. J. Murray, The Humana Press Inc., Clifton, N.J.), and the Ambion 1998 Catalog (Ambion, Austin, Tex). U.S. Pat. No. 5,015,629 to DiZerega (the entire disclosure of which is hereby incorporated by reference) describes a method for increasing the rate of healing of wound tissue, comprising the application to such tissue of angiotensin II (AII) in an amount which is sufficient for said increase. The application of AII to wound tissue significantly increases the rate of wound healing, leading to a more rapid re-epithelialization and tissue repair. The term AII refers to an octapeptide present in humans and other species having the sequence Asp-Arg-Val-Tyr-Ile-His-Pro-Phe [SEQ ID NO:1]. The biological formation of angiotensin is initiated by the action of renin on the plasma substrate angiotensinogen (Clouston et al., Genomics 2:240-248 (1988); Kageyama et al, Biochemistry 23:3603-3609; Ohkubo et al., Proc. Natl. Acad. Sci. 80:2196-2200 (1983); each reference hereby incorporated in its entirety). The substance so formed is a decapeptide called angiotensin I (AI) which is converted to AII by the angiotensin converting enzyme (ACE) which removes the C-terminal His-Leu residues from AI [SEQ ID NO: 37]. AII is a known pressor agent and is commercially available. Studies have shown that AII increases mitogenesis and chemotaxis in cultured cells that are involved in wound repair, and also increases their release of growth factors and extracellular to matrices (diZerega, U.S. Pat. No. 5,015,629; Dzau et. al., J Mol. Cell. Cardiol. 21:S7 (Supp III) 1989; Berk et. al., Hypertension 13:305-14 (1989); Kawahara, et al., BBRC 150:52-9 (1988); Naftilan, et al., J. Clin. Invest. 83:1419-23 (1989); Taubman et al., J. Biol. Chem. 264:526-530 (1989); Nakahara, et al., BBRC 184:811-8 (1992); Stouffer and Owens, Circ. Res. 70:820 (1992); Wolf, et al., Am. J. Pathol. 140:95-107 (1992); Bell and Madri, Am. J Pathol. 137:7-12 (1990). In addition, AII was shown to be angiogenic in rabbit corneal eye and chick chorioallantoic membrane models (Fernandez, et al., J. Lab. Clin. Med. 105:141 (1985); LeNoble, et al., Eur. J. Pharmacol. 195:305-6 (1991). Additionally, AII and angiotensin III analogs and fragments, and AII Type 2 receptor agonsists thereof have been shown to be effective in wound healing. (U.S. Pat. Nos. 5,629,292; 5,716,935; International Application Nos. WO 94/10502; WO 94/10503; WO 95/14764; WO 95/08565; WO 95/08337; WO 96/09747; WO 96/39164; WO 97/23461; WO 98/26437; all references hereby incorporated in their entirety.) Angiotensin II is also known as a potent stimulator of angiogenesis (Fernandez et al., J. Lab. Clin. Med. 105:141-145 (1985)), and has been shown to activate collateral circulation via preformed blood vessels in rat kidneys (Fernandez et al., Am. J. Physiol. 243:H869-H875 (1982)). The effect of AII on a given cell type has been hypothesized to be dependent, in part, upon the AII receptor subtypes the cell expresses (Shanugam et al., Am. J Physiol. 268:F922-F930 (1995); Helin et al., Annals of Medicine 29:23-29 (1997); Bedecs et al., Biochem J. 325:449-454 (1997)). These studies have shown that AII receptor subtype expression is a dynamic process that changes during development, at least in some cell types (Id.). AII activity is typically modulated by either or both the AT1 and AT2 AII receptors. However, AII has recently been shown to stimulate proliferation of primary human keratinocytes via a non-AT1, non-AT2 receptor. (Steckelings et al., Biochem. Biophys. Res. Commun. 229:329-333 (1996)). These results underscore the cell-type (ie: based on receptor expression) specific nature of AII activity. Other data suggests that the AII fragment AII(1-7) acts through a receptor(s) that is distinct from the AT1 and AT2 receptors which modulate AII activity. (Ferrario et al., J. Am. Soc. Nephrol. 9:1716-1722 (1998); Iyer et al., Hypertension 31:699-705 (1998); Freeman et al., Hypertension 28:104 (1996); Ambuhl et al., Brain Res. Bull. 35:289 (1994). Thus, AII(1-7) activity, on a particular cell type cannot be predicted based solely on the effect of AII on the same cell type. However, based on all of the above, it is unknown whether the use of angiotensinogen, angiotensin I (AI), AI analogues, AI fragments and analogues thereof, AII analogues, AII fragments or analogues thereof or AII AT2 type 2 receptor (AT2) agonists would be effective in stimulating blood flow to ischemic tissue. The identification of AII analogues and fragments that stimulate blood flow with fewer side effects than AII would be extremely beneficial. A peptide agonist selective for the AT2 receptor (AII has 100 times higher affinity for AT2 than ATI) has been identified. This peptide is p-aminophenylalanine 6-AII [�(p-NH2-Phe) 6-AII)�], Asp-Arg-Val-Tyr-Ile-Xaa-Pro-Phe [SEQ ID NO.36] wherein Xaa is p-NH2-Phe (Speth and Kim, BBRC 169:997-1006 (1990). This peptide gave binding characteristics comparable to AT2 antagonists in the experimental models tested (Catalioto, et al., Eur. J. Pharmacol. 256:93-97 (1994); Bryson, et al., Eur. J Pharmacol. 225:119-127 (1992). The effects of AII receptor and AII receptor antagonists have been examined in two experimental models of vascular injury and repair which suggest that both AII receptor subtypes (AT1 and AT2) play a role in wound healing (Janiak et al., Hypertension 20:737-45 (1992); Prescott, et al., Am. J. Pathol. 139:1291-1296 (1991); Kauffmnan, et al., Life Sci. 49:223-228 (1991); Viswanathan, et al., Peptides 13:783-786 (1992); Kimura, et al., BBRC 187:1083-1090 (1992). Many studies have focused upon AII(1-7) (AII residues 1-7) or other fragments of AII to evaluate their activity. AII(1-7) elicits some, but not the full range of effects elicited by AII. Pfeilschifter, et al., Eur. J Pharmacol. 225:57-62 (1992); Jaiswal,.et al., Hypertension 19(Supp. II):II-49-II-55 (1992); Edwards and Stack, J Pharmacol. Exper. Ther. 266:506-510 (1993); Jaiswal, et al., J. Pharmacol. Exper. Ther. 265:664-673 (1991); Jaiswal, et al., Hypertension 17:1115-1120 (1991); Portsi, et a., Br. J. Pharmacol. 111:652-654 (1994). As hereinafter defined, a preferred class of AT2 agonists for use in accordance with the present invention comprises angiotensinogen, angiotensin I (AI), AI analogues, AI fragments and analogues thereof, AII analogues, AII fragments or analogues thereof or AII AT2 type 2 receptor agonists having p-NH-Phe. in a position corresponding to a position 6 of AII. In addition to peptide agents, various nonpeptidic agents (e.g., peptidomimetics) having the requisite AT2 agonist activity are further contemplated for use in accordance with the present invention. The active AII analogues, fragments of AII and analogues thereof of particular interest in accordance with the present invention comprise a sequence consisting of at least three contiguous amino acids of groups R1-R8 in the sequence of general formula I
in which R1 and R2 together form a group of formula
wherein X is H or a one to three peptide group, or is absent, RA is suitably selected from H, Asp, Glu, Asn, Acpc (1-aminocyclopentane carboxylic acid), Ala, Me2Gly, Pro, Bet, Glu(NH2), Gly, Asp(NH2) and Suc, R is suitably selected from Arg, Lys, Ala, Om, Citron, Ser(Ac), Sar, D-Arg and D-Lys; R3 is selected from the group consisting of Val, Ala, Leu, norLeu, Ile, Gly, Pro, Aib, Acpc and Tyr; R4 is selected from the group consisting of Tyr, Tyr(PO3)2, Thr, Ala, Ser, homoSer and azaTyr; R5 is selected from the group consisting of Ile, Ala, Leu, norLeu, Val and Gly; R6 is His, Arg or 6-NH2-Phe; R7 is Pro or Ala; and R8 is selected from the group consisting of Phe, Phe(Br), Ile and Tyr, excluding sequences including R4 as a terminal Tyr group, or is absent, wherein the active agent is not AII. Compounds falling within the category of AT2 agonists useful in the practice of the invention include the AII analogues set forth above subject to the restriction that R6 is p-NH2-Phe. Particularly preferred combinations for RA and RB are Asp-Arg, Asp-Lys, Glu-Arg and Glu-Lys. Particularly preferred embodiments of this class include the following: AIII or AII(2-8), Arg-Val-Tyr-Ile-His-Pro-Phe [SEQ ID NO:2]; AII(3-8), also known as desl-AIII or AIV, Val-Tyr-Ile-His-Pro-Phe [SEQ ID NO:3]; AII(1-7), Asp-Arg-Val-Tyr-Ile-His-Pro [SEQ ID NO:4]; AII(2-7). Arg-Val-Tyr-Ile-His-Pro [SEQ ID NO:5]; AII(3-7), Val-Tyr-Ile-His-Pro [SEQ ID NO:6]; AII(5-8), Ile-His-Pro-Phe [SEQ ID NO:7]; AII(1-6), Asp-Arg-Val-Tyr-Ile-His [SEQ ID NO:8]; AII(1-5), Asp-Arg-Val-Tyr-Ile [SEQ ID NO:9]; AII(1-4), Asp-Arg-Val-Tyr [SEQ ID NO:10]; and AII(1-3), Asp-Arg-Val [SEQ ID NO:11]. Other preferred embodiments include: Arg-norLeu-Tyr-Ile-His-Pro-Phe [SEQ ID NO: 12] and Arg-Val-Tyr-norLeu-His-Pro-Phe [SEQ ID NO:13]. Still another preferred embodiment encompassed within the scope of the invention is a peptide having the sequence Asp-Arg-Pro-Tyr-Ile-His-Pro-Phe [SEQ ID NO:31]. AII(6-8), His-Pro-Phe [SEQ ID NO:14] and AII(4-8), Tyr-Ile-His-Pro-Phe [SEQ ID NO:15] were also tested and found not to be effective. In a particularly preferred embodiment, the active compounds of the present invention are selected from those comprising the following general formula:
wherein R1 is Asp or is absent; R2 is selected from the group consisting of Val, Ala, Ile, Pro, Lys, Norleu, and Leu; R3 is selected from the group consisting of Ala, Tyr, and Tyr(PO3)2; and R4 is selected from the group consisting of Val, Ala, Ile, Norleu, and Leu; R5 is Phe, Ile, or is absent; wherein the compound is not AII. In a most particularly preferred embodiment, the active compound is selected from the group consisting of SEQ ID NO:4, SEQ ID NO:19, SEQ ID NO:24, SEQ ID NO:26, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, and SEQ ID NO:42. Another class of compounds of particular interest in accordance with the present invention are those of the general formula II
in which R2 is selected from the group consisting of H, Arg, Lys, Ala, Orn, Citron, Ser(Ac), Sar, D-Arg and D-Lys; R3 is selected from the group consisting of Val, Ala, Leu, norLeu, Ile, Gly, Pro, Aib, Acpc and Tyr; R4 is selected from the group consisting of Tyr, Tyr(PO3)2, Thr, Ser, homoSer, Ala, and azaTyr; R5 is selected from the group consisting of Ile, Ala, Leu, norLeu, Val and Gly; R6 is His, Arg or 6-NH2-Phe; R7 is Pro or Ala; and R8 is selected from the group consisting of Phe, Phe(Br), Ile and Tyr. A particularly preferred subclass of the compounds of general formula II has the formula
wherein R2, R3 and R5 are as previously defined. Particularly preferred is angiotensin III of the formula Arg-Val-Tyr-Ile-His-Pro-Phe [SEQ ID NO:2]. Other preferred compounds include peptides having the structures Arg,-Val-Tyr-Gly-His-Pro-Phe [SEQ ID NO:17] and Arg-Val-Tyr-Ala-His-Pro-Phe [SEQ ID NO:18]. The fragment AII(4-8) was ineffective in repeated tests; this is believed to be due to the exposed tyrosine on the N-terminus. In the above formulas, the standard three-letter abbreviations for amino acid residues are employed. In the absence of an indication to the contrary, the L-form of the amino acid is intended. Other residues are abbreviated as follows:
It has been suggested that AII and its analogues adopt either a gamma or a beta turn (Regoli, et al., Pharmacological Reviews 26:69 (1974). In general, it is believed that neutral side chains in position R3, R5 and R7 may be involved in maintaining the appropriate distance between active groups in positions R4, R6 and R8 primarily responsible for binding to receptors and/or intrinsic activity. Hydrophobic side chains in positions R3, R5 and R8 may also play an important role in the whole conformation of the peptide and/or contribute to the formation of a hypothetical hydrophobic pocket. Appropriate side chains on the amino acid in position R2 may contribute to affinity of the compounds for target receptors and/or play an important role in the conformation of the peptide. For this reason, Arg and Lys are particularly preferred as R2. For purposes of the present invention, it is believed that R3 may be involved in the formation of linear or nonlinear hydrogen bonds with R5 (in the gamma turn model) or R6 (in the beta turn model). R3 would also participate in the first turn in a beta antiparallel structure (which has also been proposed as a possible structure). In contrast to other positions in general formula I, it appears that beta and gamma branching are equally effective in this position. Moreover, a single hydrogen bond may be sufficient to maintain a relatively stable conformation. Accordingly, R3 may suitably be selected from Val, Ala, Leu, norLeu, Ile, Gly, Pro, Aib, Acpc and Tyr. R3 may also suitably be Lys. With respect to R4, conformational analyses have suggested that the side chain in this position (as well as in R3 and R5) contribute to a hydrophobic cluster believed to be essential for occupation and stimulation of receptors. Thus, R4 is preferably selected from Tyr, Thr, Tyr (PO3)2, homoSer, Ser and azaTyr. In this position, Tyr is particularly preferred as it may form a hydrogen bond with the receptor site capable of accepting a hydrogen from the phenolic hydroxyl (Regoli, et al. (1974), supra). R4 may also suitably be Ala. In position R5, an amino acid with a β aliphatic or alicyclic chain is particularly desirable. Therefore, while Gly is suitable in position R5, it is preferred that the amino acid in this position be selected from Ile, Ala, Leu, norLeu, Gly and Val. In the angiotensinogen, AI, AI analogues, AI fragments and analogues thereof, AII analogues, fragments and analogues of fragments of particular interest in accordance with the present invention, R6 is His, Arg or 6-NH2-Phe. The unique properties of the imidazole ring of histidine (e.g., ionization at physiological pH, ability to act as proton donor or acceptor, aromatic character) are believed to contribute to its particular utility as R6. For example, conformational models suggest that His may participate in hydrogen bond formation (in the beta model) or in the second turn of the antiparallel structure by influencing the orientation of R7. Similarly, it is presently considered that R7 should be Pro in order to provide the most desirable orientation of R8. In position R8, both a hydrophobic ring and an anionic carboxyl terminal appear to be particularly useful in binding of the analogues of interest to receptors; therefore, Tyr and especially Phe are preferred for purposes of the present invention. R8 may also suitably be Ile. Analogues of particular interest include the following:
The polypeptides of the instant invention may be synthesized by any conventional method, including, but not limited to, those set forth in J. M. Stewart and J. D. Young, Solid Phase Peptide Synthesis, 2nd ed., Pierce Chemical Co., Rockford, Ill. (1984) and J. Meienhofer, Hormonal Proteins and Peptides, Vol. 2, Academic Press, New York, (1973) for solid phase synthesis and E. Schroder and K. Lubke, The Peptides, Vol. 1, Academic Press, New York, (1965) for solution synthesis. The disclosures of the foregoing treatises are incorporated by reference herein. In general, these methods involve the sequential addition of protected amino acids to a growing peptide chain (U.S. Pat. No. 5,693,616, herein incorporated by reference in its entirety). Normally, either the amino or carboxyl group of the first amino acid and any reactive side chain group are protected. This protected amino acid is then either attached to an inert solid support, or utilized in solution, and the next amino acid in the sequence, also suitably protected, is added under conditions amenable to formation of the amide linkage. After all the desired amino acids have been linked in the proper sequence, protecting groups and any solid support are removed to afford the crude polypeptide. The polypeptide is desalted and purified, preferably chromatographically, to yield the final product. Preferably, peptides are synthesized according to standard solid-phase methodologies, such as may be performed on an Applied Biosystems Model 430A peptide synthesizer (Applied Biosystems, Foster City, Calif.), according to manufacturer's instructions. Other methods of synthesizing peptides or peptidomimetics, either by solid phase methodologies or in liquid phase, are well known to those skilled in the art. In one aspect, the present invention provides methods and kits to increase blood flow to ischemic tissue, comprising the administration of angiotensinogen, angiotensin I (AI), AI analogues, AI fragments and analogues thereof, angiotensin II (AII) analogues, AII fragments or analogues thereof or AII AT2 type 2 receptor agonists (hereinafter referred to as the �active agents�). According to the invention, an area of ischemic tissue is treated in vivo to maintain viability of that area for a sustained period of time to salvage the area. An effective dose of the active agents is applied to the ischemic tissue, preferably after ischemia, although it can also be applied when there is an indication of impending ischemia. The ischemic tissue is suitably any tissue that can benefit by an increased blood flow to the tissue to reverse or prevent the adverse effects of ischemia on the tissue. In preferred embodiments, the tissue is selected from skin and heart. In a further preferred embodiment, the active agents can be used to stimulate blood flow to tissue grafts, whether artificial or transplanted. The active agents may be administered by any suitable route, including orally, parentally, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjuvants, and vehicles. The term parenteral as used herein includes, subcutaneous, intravenous, intraarterial, intramuscular, intrasternal, intracardiac, intratendinous, intraspinal, intracranial, intrathoracic, infusion techniques or intraperitoneally. Furthermore, angiotensino can be administered by gene therapy techniques. The active agents of the invention may be made up in a solid form (including granules, powders or suppositories) or in a liquid form (e.g. solutions, suspensions, or emulsions). The compounds of the invention may be applied in a variety of solutions. Suitable solutions for use in accordance with the invention are sterile, dissolve sufficient amounts of the peptide, and are not harmful for the proposed application. In this regard, the compounds of the present invention are very stable but are hydrolyzed by strong acids and bases. The compounds of the present invention are soluble in organic solvents and in aqueous solutions at pH 5-8. The active agents may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers etc. The active agents of the invention can be used alone or in a combination of active agents, or may be used in combination with other agents that increase blood flow to ischemic tissue, either via production of new blood vessels (including, but not limited to AII, acidic and basic fibroblast growth factor, transforming growth factor alpha and beta, tumor necrosis factor, platelet-derived growth factor, vascular eudothelial growth factor,angiogenin, and haptoglobin), or by stimulating blood flow to ischemic tissue through pre-existing blood vessels, including but not limited to fibroblast growth factor. For administration, the active agents are ordinarily combined with one or more adjuvants appropriate for the indicated route of administration. The compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, stearic acid, talc, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulphuric acids, acacia, gelatin, sodium alginate, polyvinylpyrrolidine, and/or polyvinyl alcohol, and tableted or encapsulated for conventional administration. Alternatively, the compounds of this invention may be dissolved in saline, water, polyethylene glycol, propylene glycol, carboxymethyl cellulose colloidal solutions, ethanol, corn oil, peanut oil, cottonseed oil, sesame oil, tragacanth gum, and/or various buffers. Other adjuvants and modes of administration are well known in the pharmaceutical art. The carrier or diluent may include time delay material, such as glyceryl monostearate or glyceryl distearate alone or with a wax, or other materials well known in the art. Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin (e.g., liniments, lotions, ointments, creams, or pastes) and drops suitable for administration to the eye, ear, or nose. The dosage regimen for increasing blood flow to ischemic tissue with the active agents of the invention is based on a variety of factors, including the type of injury, the age, weight, sex, medical condition of the individual, the severity of the condition, the route of administration, and the particular compound employed. Thus, the dosage regimen may vary widely, but can be determined routinely by a physician using standard methods. Dosage levels of the order of between 0.1 ng/kg and 10 mg/kg body weight active agent per body weight are useful for all methods of use disclosed herein. The treatment regime will also vary depending on the condition of the subject, based on a variety of factors, including the type of injury, the age, weight, sex, medical condition of the individual, the severity of the condition, the route of administration, and the particular compound employed. For example, an active agents is administered to a patient as soon as possible after myocardial infarction for up to 30 days. The therapy is administered for 1 to 6 times per day at dosages as described above. In a preferred embodiment, the active agent is administered subcutaneously. A suitable subcutaneous dose of active ingredient of active agent is preferably between about 0.1 ng/kg and about 10 mg/kg administered twice daily for a time sufficient to increase blood flow to ischemic tissue. In a more preferred embodiment, the concentration of active agent is between about 100 ng/kg body weight and about 10.0 mg/kg body weight. In a most preferred embodiment, the concentration of active agent is between about 10 μg/kg body weight and about 10.0 mg/kg body weight. This dosage regimen maximizes the therapeutic benefits of the subject invention while minimizing the amount of antagonist needed. Such an application minimizes costs as well as possible deleterious side effects. For subcutaneous administration, the active ingredient may comprise from 0.0001% to 10% w/w, e.g., from 1% to 2% by weight of the formulation, although it may comprise as much as 10% w/w, but preferably not more than 5% w/w, and more preferably from 0.1% to 1% of the formulation. In a preferred embodiment, a catheter is placed into the coronary artery of a subject between about immediately after to about 24 hours after myocardial infarction and injecting an effective amount of the active agent into the heart of the subject. The concentration of active agent injected is between about 100 ng/kg body weight and about 10.0 mg/kg body weight, as described above. The injection can be repeated as needed to stimulate increased blood flow in the existing collateral circulation. Injections can also be by other routes, including but not limited to by catheter such via arterial angiography, intracoronary injection, or in a cardioplegic solution by the aortic route. Increased collateral blood flow is determined by standard procedures. For example, collateral flow can be quantified during Chromonar-induced maximum vasodilation and expressed as an ischemic/normal zone (IZ/NZ) ratio. (U.S. Pat. No. 5,244,460 incorporated by reference herein in its entirety) Alternatively, collateral blood flow can be quantitated using radioactive microspheres using a reference flow technique (Dole, et al, Am. J. Physiol., 1982; 243:H371-378). In another preferred embodiment of the present invention, the active agent is administered topically. Suitable topical doses and active ingredient concentration in the formulation are as described for subcutaneous administration. In a further preferred embodiment of all of the aspects of the invention, the active agent is selected from the group consisting of angiotensinogen, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO: 16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34; SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, and SEQ ID NO:42. In a further aspect, the present invention provides kits to increase blood flow to ischemic tissue, wherein the kits comprise an effective amount of active agent for increasing blood flow to ischemic tissue, and instructions for using the amount effective of active agent as a therapeutic. In a preferred embodiment, the kit further comprises a pharmaceutically acceptable carrier, such as those adjuvants described above. In another preferred embodiment, the kit further comprises a means for delivery of the active agent to a patient. Such devices include, but are not limited to syringes, matrical or micellar solutions, bandages, wound dressings, aerosol sprays, lipid foams, transdermal patches, topical administrative agents, polyethylene glycol polymers, carboxymethyl cellulose preparations, crystalloid preparations (e.g., saline, Ringer's lactate solution, phosphate-buffered saline, etc.), viscoelastics, polyethylene glycols, and polypropylene glycols. The means for delivery may either contain the effective amount of active agent, or may be separate from the compounds, which are then applied to the means for delivery at the time of use. The present invention may be better understood with reference to the accompanying examples that are intended for purposes of illustration only and should not be construed to limit the scope of the invention. Engraftment of Living of Living-Skin Equivalent Male Swiss nude mice (22-24 g) were anesthetized with an intramuscular injection of Ketaset/Rompun and a 1 cm�1 cm full thickness skin excision was made on their dorsal surface. Living skin equivalent (LSE) was placed in the defect and trimmed with microscissors so that no gap was observed between the edges of the mouse skin and the LSE. The mice were divided into 6 groups based upon the peptide tested: (0 [LRS-Dextrose], or 1.0 mg/ml AII or AII analogues, AII (1-7) [SEQ ID NO:4]; Ala4AIII [SEQ ID NO:18]; Pro3AII [SEQ ID NO:31]; and Ile8AII [SEQ ID NO: 42]; see Table 3) and the LSE was soaked for 15 minutes in lactated Ringers solution with 5% dextrose with or without peptides prior to placement. After the graft was placed, the dorsal surface of the mouse was covered by petrolatum-embedded gauze followed by two adhesive bandages. After recovery from anesthesia, the mice were returned to their individual cages and observed daily until euthanasia. The mice received intramuscular analgesia for the first three days after surgery. No mouse lost its bandages prior to necropsy or bandage removal on day 7. The mice were necropsied on day 7. At necropsy, the degree of graft take and the appearance of the grafted tissue was noted prior to placement of the biopsy in 10% buffered formalin in preparation for paraffin embedding and section for hematoxylin and eosin staining. The number of endothelial cells and vascular channels were assessed microscopically and the data are presented in FIGS. 1 and 2. These data demonstrate that AII and the AII analogue-treated LSE increased both angiogenesis (vascular channel formation) and endothelial cell production in graft tissue compared to untreated LSE.
Partial Thickness Thermal Injury Model Animals Thirty-six male Hartley guinea pigs weighing approximately 500 grams were purchased from Charles Rivers Laboratory (Charles Rivers Mass.). The guinea pigs were housed in a 12:12 hour light:dark, cycle in the USC Vivaria. Food and water were available ad libitum. Surgical Procedures The guinea pigs were anesthetized by intramuscular injection of 14 mg/kg Rompun and 130 mg/kg Ketamine. Hair was then removed from the dorsal surface through shaving with animal clippers followed by treatment with a thioglycollate depilatory. After hair removal the area was scrubbed with betadine twice followed by 70% ethanol. Two burns were produced on each guinea pig with an 18 mm solid brass rod, which was warmed in a 75� C. water bath. One end of the brass rod was placed on the back of the guinea pig for 50 seconds. This procedure was repeated with different brass rods for each animal and each burn. Each burn was treated with 10% low-viscosity CMC with and without 1 mg/ml AII, AII analogue or fragment (0[LRS-Dextrose], or 1.0 mg/ml AII or AII analogues, AII (1-7) [SEQ ID NO:4]; Ala4AIII [SEQ ID NO:18]; Pro3AII [SEQ ID NO:31]; or IIe8AII [SEQ ID NO:42]) in 0.05 mol/L phosphate buffer, pH 7.3, and was individually dressed with a Hilltop Chamber and covered with Tegaderm. The bandages were checked and changed daily for the first 5 days and every other day until necropsy on day 7 after injury. The guinea pigs were given 20 μg/kg bupronex (buprenorphine hydrochloride) intramuscularly for pain on the day of injury and the first 3 days after injury. Validation with India Ink Injection Initial studies were conducted in which the depth of the burn was evaluated with intraaortic injection of India Ink. One or 2 days after initiation of the thermal injury, the guinea pigs were anesthetized with intramuscular ketamine and rompun. The ascending thoracic aorta was cannulated, and 60 ml India Ink was injected through the cannula under 500 mm Hg. This pressure was used to ensure filling of all patent vessels. After the India Ink was injected the animals were sacrificed, and the injury sites were excised and-placed in 10% buffered formalin and prepared for histologic evaluation. The histologic sections from these preparations were examined to evaluate the depth of necrosis and capillary ischemia. Histologic Evaluation On day 7 after thermal injury, the guinea pigs were euthanized, the burned areas were excised en bloc and the tissues were placed in 10% buffered formaldehyde solution overnight. The tissues were embedded in paraffin, and 5 μm sections were prepared. The sections were processed for immunohistochemical analysis with a primary antibody to cyclin (MIB-1) (AMAC, Westbrook, Mass.) followed by recognition of the primary antibody with a DAKO kit (DAKO, Santa Barbara, Calif.) used as described below. The paraffin-embedded sections were baked in an oven overnight at 60� C. Deparaffinization was performed by four 5-minute incubations in �fresh� xylene followed by two 5-minute incubations with 100% ethanol, two 5-minute incubations with 95% ethanol, and one 5-minute incubation with H2O. Endogenous peroxidase activity was then quenched with 0.3% H2O2 in H2O. Antigen retrieval was performed following the protocol of Shi et al. with minor modifications. In brief, the slides were placed in plastic coplin jars in 5% urea in 0.1 mol/L Tris buffer (pH 9.0). The slides were then placed in a microwave oven and set at maximal power for 3 minutes. The antigen retrieval solution was replenished with distilled water when evaporation was excessive and were microwaved again for 5 minutes at 50% power. The slides were then allowed to cool for 10 minutes and were placed in phosphate-buffered saline solution (PBS) for 5 minutes. Immunohistochemical staining was performed with the avidin-blotin-peroxidase conjugate method with some modifications. The slides were placed in a PBS bath for 5 minutes and then laid in humidified incubation chambers. Blocking for nonspecific antibody binding was performed by incubating the sections in 5% horse serum in PBS. The solution was decanted and replaced with the solution of primary antibody. The primary antibody, MIB-1, was used at a dilution of 1:100 in PBS and was incubated for 60 minutes at room temperature. The slides were washed with PBS for 5 minutes and were then incubated with the secondary biotinylated horse-anti -mouse antibody. After a 5-minute wash in PBS the avidin-biotin complex was applied to slides at a dilution of 1:100 in PBS at room temperature and was incubated for 1 hour. After a final rinse in PBS, the sections were incubated in 0.06% 3,3′-diaminobenzidine in PBS with 0.03% hydrogen peroxide for 5 minutes. After a counterstain was performed in modified Harris' hematoxylin-eosin the sections were dehydrated and coverslipped with Permount. With an Olympus Vanox-S AH-2 dissecting microscope and a magnification power of 100�, each section of the biopsy specimen was separated into either areas on the bum edge or the actual burn areas. The area of the burn was excised and serially cut into three to five sections 4 to 5 mm in thickness. The entire area of the burn and edge of the burn was embedded and examined histologically. In each section four to six consecutive medium-power fields (mpf, 100�) were evaluated. The cells that stained with the MIB-1 antibody were a distinct brown color. All stained cells located within the hair follicles of the biopsy sections were counted. To count the MIB-1 stained cells each section on the slide was separated into individual medium power fields (mpf). Each field was then determined to be either a section on the edge of the burn or a part of the burn area itself. An edge was indicated by a positive stain showing brown epithelial cells along the edge of the section. A burn area was indicated by an absence of brown staining cells along the edge. The brown cells located within each hair follicle were counted one at a time under mpf magnification. To move to the next mpf a landmark was established, and the slide was then moved to the next adjacent field. All animals survived the bum procedures and did not demonstrate evidence of significant discomfort throughout the study interval. The depth of the bums was determined to be deep partial-thickness to full-thickness by (1) analysis of vessel patency with intraaortic injection of India Ink and (2) the appearance of the cells in the hair follicles by microscopic analysis of hematoxylin-eosin-stained sections. This analysis revealed most of the preexisting blood vessels and cells were destroyed in the burn site, although the injuries did not extend through the panniculus carnosus. FIG. 3 demonstrates the effect of AII and the same AII analogues used in Example 1 on angiogenesis after thermal injury. These data demonstrate that treatment of the bum areas with the AII and AII analogues produces an increased blood flow response compared to control, with the AII analogues showing an increased blood flow response compared to AII. Effect of Angiotensin Peptides on the Formation of Collateral Circulation in Ischemic Myocardial Tissue Rabbits underwent a surgical procedure under intramuscular anesthesia (Ketamine and Rompum) after shaving with animal clippers and preparation with betadine and isopropyl alcohol. A midline sternotomy was performed. After exposure of the pericardial sac, a three centimeter incision was made into the pericardium. After visualization of the epicardial surface, two coronary arteries, the left circumflex and the left anterior descending arteries, were exposed and ligated by 4-0 Vicryl suture. Vehicle (10% Hydron, 60% ethanol and 1% polyethylene glycol), with or without peptide (1 mg/ml, 0.05 ml) was injected in the cardiac muscle distal to the site of coronary occlusion. The sternum was then closed with 2-0 Silk. The muscle and skin were then closed with 3-0 Dexon II suture. Starting at 7 days after surgery, the animals were euthanized and necropsies performed. The number of blood vessels present in the infarct site was assessed grossly and by microscopic evaluation. The presence of a blood vessel was defined as a channel lined with endothelial cells that contained red blood cells (indicating that the vessels had a blood source). All peptides (AII, AII(1-7), 1GD, 2GD, 5GD and 9GD: see table 4) tested increase vascularization of the infarct site. The increases ranged from approximately 4 fold to approximately 14 fold increase in the formation of collateral circulation after ligation of the artery. The data collected from microscopic examination of multiple tissue sections are in Table 4.
The methods and kits of the present invention, by increasing blood flow to ischemic tissue, significantly enhance the utility of presently available treatments for ischemia, and particularly benefit treatments for skin and heart ischemia, and significantly benefit tissue grafting by increasing blood flow to tissue grafts. It is to be understood that the invention is not to be limited to the exact details of operation, or to the exact compounds, compositions, methods, procedures or embodiments shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the full scope of the appended claims. Patent Citations
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315 posts found | |
Novice Member
Joined: 7/27/11 I swear by my pretty floral bonnet, I will end you. |
Originally posted by Parasitenoir Because I dont find this scenario fun at all: I'm attacking a mob or two or three and Im down to half health and I get ganked in the back. I return to area and fight the dope that killed me. He dies. I try to continue with what I was doing. But he comes back and kills me. I go back and kill him. We do this back and forth for awhile. Eventually he calls in a friend or two. And now Im being camped. So I call out some friends and we all start fighting. We kill some of them, they kill some of us and this goes on back and forth for about an hour or two. Not counting the original hour or half an hour I fought the original ganker. During this time no one accomplished anything. The entire endevour was the most pointless, futile thing in existence. There was no real victory in any of it, as in anyone I killed just reappears so we can harrass each other only minutes later and do the whole stinking thing all over again. FUN! No...no its not. I guess some people find that kind of crap fun but past the first fight I'm already bored to death. At least in structured PVP deaths will matter at times, and there's a point. There's a way to win. That's a game. That's a purpose. So I highly enjoy that stuff as opposed to open world PVP which is always one of the most pointless and time wasting experiences I've ever had in gaming. |
Originally posted by Corehaven Taking so much mobs that your health went low is a risktaking you take. If you aren't willing to deal with the possible negative outcome of risky behaviour: don't engage in it. As for the constant back-and-forth killing you describe: several properly designed Open PvP games solved that by either making deaths meaningful or some form of flagging system that makes the situation unfavorable for the initial aggressor. |
There are no raids in GW2, this seems to be all they have as endgame. I asked before if there are any videos to show how good this sort of endgame is as posters were raving about it. Not seen any links so far...
Originally posted by TwoThreeFour or you can engage in it in a game without OWPvP. I don't see a reason why i should be dealing with griefers when i am facing a pve challenge. |
Originally posted by IG-88 That's exactly it. I don't PvP. Ever. Under any circumstances. I don't care if other people want to beat each other over the head but I find no enjoyment in it whatsoever. In OWPvP though, I can't opt out. I can't tell the PvPers to take a flying leap. I'm a target. I refuse to be a target. Played: UO, EQ, WoW, DDO, SWG, AO, CoH, EvE, TR, AoC, GW, GA, Aion, Allods, lots more |
Originally posted by ZBergz I dislike all implementation of all PvP so you're wrong. Played: UO, EQ, WoW, DDO, SWG, AO, CoH, EvE, TR, AoC, GW, GA, Aion, Allods, lots more |
Most of the MMO gamers from WOW gen are cowards and have no idea what real PVP is, that is the honest truth. They have que times, wtf is que times doing in a MMO game, or a timer on PVP. Man DAOC is a older game but the PVP is ran 24/7 and it is also put into levels so no one gets ganked by higher levels.
Originally posted by Scot GW (1) was principally a PvP game... as evidenced by changes to classes that usually hurt the PvE side of all classes. Anet many times showed through actions that PvP was their master plan for GW. It is not surprising to me that a game that is a sequal to GW in many ways, is at least in some ways a PvP game. Now as to the OP's question... why do people hate OWPvP? I have no idea. Sounds great fun to me... sounds like DAoC. If so then I would surely enjoy it. I don't PvP anymore (too old really), but sounds like GW2 PvP might be like DAoC a little... But I'm not everyone. Everyone is different. We all like a few things differently than others. Some Players love PvP. Some Hate it. Some could take it or leave it, they don't care. Normality. |
That actually sounds like a lot more fun than questing to me. The problem is that most of the time, the person killing you is much higher level. If you were actually able to go back and kill your assassin, then that seems like fair fun, especially if you were bother able to get some other people in on it. Most of my experiences are just getting ganked by someone which I didn't stand a chance with, then I would just have to walk back to my body. And I think that's the problem with open world PvP in theme parks, it's just not really built into the gameplay, but it just feels kind of tacked on. If the game was constructed around it, and there was value to world PvP (and possibly ganking), then it would be much more fun. |
I used to love open PVP back when I had just graduated from college and had plenty of time to play. I roled open PVP in SWTOR and hated it for three reasons: 1. Faction imbalance - on most servers empire outnumbered republic at least 3-1. Even if a few noble level 50 heroes briefly rallied to defend the lowbies from evil ganking sith, within about 15 minutes the entire zone would be overrun by Imperials. This was also a huge problem for me in Warhammer too. 2. I'm casualcore - I'm play about 15-20 hours/week, enough to stay current in structured PVP but not really enough to take on a total PVP badass mano y mano. I'm also a slower leveler and thus will be subjected to several months of griefng from those who hit max level in the first week. 3. Cheap tactics by gankers - From my experience, OWPVP gankers seem to all follow the same tactics. They play the stealth class, always hit lowbies or wait until somebody is half-dead from fighting mobs before attacking. Then they melt away at the sign of any real challenge. |
Because people in games that have OWPvP for the most part act like douche bags, which is not a fun environment to most people. I get enough of that daily in real life, the last thing I want is to deal with it during my recreational time. Einherjar_LC says: WTB the true successor to UO or Asheron's Call pst! |
Originally posted by BattleFelon While SWTOR had open PvP you are missing the main reason it sucked. There was no objective. No gain. No reward. No penalties. It was just ass-hats running around killing for only the single reason of griefing. I personally didn't have any issues in that game with griefers (I usually killed them in their attempts), but, it was none the less boring. This generation of MMO players hasn't had the opportunity to play a proper open world pvp game. Its all just tacked on. There was a time where you didn't need a second set of gear for PvP either. Its all stupid now! But, thats just my opinion. |
I don't like OWPVP because there is rarely any pvp happening. It's usually just ganking or zerging. What's the point if it's me vs an entire group of people just one-shotting me? What's the point if it's a higher level player getting kicks by killing me repeatedly? For every one decent encounter, you experience dozens of pointless ones. I'd much rather queue up for a consensual pvp battleground. Ironically, I get to have way more 1v1 or 1v2 encounters in a battleground that I ever have in OWPVP. Not to mention group battles. |
Originally posted by madazz @madazz ... your reasons why SWTOR PvP sucked .... no objective, no gain, no reward... Yes these are valid reasons. So too are BattleFelons reasons for not liking SWTOR PvP. I have seen similar situations in other MMOs that the two of you discuss and it always sucked, for both your reasons. That's part of the problem with SWTOR PvP, there are so many problem areas it's hard for any Dev to know what to fix first to be honest. SWTOR reeks like a Thanksgiving Turkey that got pulled out of the Oven two hours early and allowed to sit out on the counter. Undercooked, and not taken care of properly. |
All the problems with PvP mentioned over the last few posts are genuine but they can be solved. You can have a good objective for PvP. You can level up players when they go into a PvP zone. You can make it a group effort, which makes it harder for gankers to find a lone victim. We saw leveling up in PvP missions in SWTOR, they could have done that for those who entered the open PvP zone too. Realm objectives in DAOC show how you set up a good objective. All thse things have been done, but concentrating on graphics or in SWTOR's case cutscenes and voice overs, is the prime thrust of todays MMO's. Graphics before gameplay rules the roost. |
It's because of the lowlife griefers.
Originally posted by Scot Best way to solve PVP problems ... put PVP in an instanced arena/battleground. Only those who want it will engage in it. Problem solved. |
Originally posted by Parasitenoir Umm...maybe because I don't want to be "ganked" while I am questing? I play a game for my enjoyment. Not to provide you with a means to make yourself feel better about whatever it is you're lacking in the real world. That's what moms are for. If you don't have one, get a dog or something. Just leave me the f**k alone. |
If they made it so you could not attack someone who is more than 5 levels below you than it would be fair, otherwise it is a gankfest
SWG had great PVP. Open world Rebel VS Imperial, space where Neutrals could pick which faction to fight along side with, and a great PVP Bounty Hunter system. The first year or so was great, once buffs became the deciding factor it lost a lot of it's luster. EQ had really good open world PVP on each of it's three servers. Most people played on the PVE servers but if you were on one of the Zek servers, the game had an entirely new dimension. The point is you can have open world PVP and have a great system, but you cannot have it in a quest-hub, themepark type of game. The best you can do is put it where the PVEers are not, like LOTRO's Ettenmoors which is suprisingly good. |


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Kids' Make and Take Crafts (ages 5 and up) (Main)
Submitted by site_admin on Wed, 11/26/2014 - 1:29pmPuzzle Day - Be a Piece of Fun!
Children ages 5 & up are invited to stop by anytime between 3:30 and 5:00 PM to make fun seasonal crafts to take home. There will be four projects to choose from. All supplies will be provided. Children must be accompanied by an adult.
This program will take place in the Lenski Program Room of the Main Library, 201 S. Fountain Ave., Springfield, OH. Please call us at (937) 328-6905 for more information.
Afterschool Movie - "Deck the Halls" (PG) - (Houston)
Submitted by site_admin on Mon, 11/24/2014 - 12:02pmTwo neighbors in a small New England town go to war when one of them decides to decorate his house with so many Christmas lights that they are visible from space. The neighborhood is turned upside down as the families try to discover the true meaning of Christmas. For families.
Refreshments will be served. This program will take place at the Houston Branch, 5 W. Jamestown Street, S. Charleston, OH. Please call (937) 462-8047 for more information.
National Picture Book Month Giveaway! (Main - Lenski)
Submitted by site_admin on Mon, 10/27/2014 - 3:07pmWin a copy of the book The Day the Crayons Quit!
Each day in November that you check out a picture book in the Lenski Children's Center you can enter to win!
Entries must be legible and a current phone number must be given.
One entry per day regardless of number of picture books checked out.
Clark County Public Library employee's and their immediate family are not eligible to win.


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Bills WR Johnson plays Jaguars with heavy heart
JACKSONVILLE, Fla. (AP)
Buffalo Bills receiver Stevie Johnson could have flown home - and no one would have blamed him.
Johnson's mother died unexpectedly Saturday at her Northern California home. Rhonda Lewis was 48.
Johnson and the Bills had already arrived in Jacksonville when he heard the devastating news. He sat down with coach Doug Marrone, who gave him the option of leaving or staying for Sunday's game against the Jaguars.
Johnson decided to stay with his teammates, and he opted not to tell any of them.
''Whatever I can do to help out the team,'' Johnson told a small group of reporters in the hallway after the game. ''I think I should give it my all no matter what. It was tough, but we got the win and I'm happy about that and I'm sure she's happy about that.''
Johnson finished with one catch for 4 yards in Buffalo's 27-20 victory.
But he garnered praise from Marrone and his teammate for how he handled a difficult situation.
''It says a lot about Stevie that he decided to play,'' rookie quarterback EJ Manuel said. ''We all look up to Stevie, especially us rookies on offense. He makes a lot of huge plays for us. He's a difference-maker on offense. It was a matter of him not wanting to be a distraction to the team or for anybody to feel bad for him. He just wanted us to go out there and get a win.''
The Bills (5-9) scored twice in the final 2:14 in the first half to open up a 20-10 lead. And they answered on both sides of the ball when Jacksonville had chances down the stretch.
''It's a tough situation,'' Marrone said. ''It's a very personal issue. We discussed it. It was in his corner to say what he would like to do and then I have to make a decision whether I'm comfortable with that and he's able to perform, which I thought he did.''
Johnson leads the Bills with 52 receptions for 597 yards and three touchdowns. With two games remaining, it's unlikely he will reach 1,000 yards receiving for the fourth consecutive year.
But that meant little Sunday - at least after teammates learned what he was going through.
''It was something he kind of kept to himself,'' running back Fred Jackson said. ''He didn't want to bother us. We appreciate him. We appreciate him coming out here and fighting with us and doing everything he could.''
AP NFL website: www.pro32.ap.org
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