My strong feeling is the usual method of white men ganging up against a poor oriental
As the local Christian fundamentalists who think world was created by their Judeo christian God want to stop scientific discovery and any advantages which accrue from that discovery specially when it comes from a n Eastern center .
We should all oppose this diabolical plot and expose it for what it is .
The allegations are ;aughable.
if South Koreans and other Asians have any memory of what History has taught US stop this plot now and Restore Him back to the head of the institute
S Korea cloning pioneer disgraced
Professor Hwang Woo-suk announces his resignation
Dr Hwang admitted he had misled the magazine Nature
A cloning pioneer regarded as a hero in his South Korean homeland has resigned and apologised for using human eggs from his own researchers.
Professor Hwang Woo-suk was chairman of the World Stem Cell Hub, which opened this month, based in Seoul.
"I am very sorry that I have to tell the public words that are too shameful and horrible," he announced publicly.
International medical standards warn against using eggs from researchers who may be vulnerable to pressure.
However, the health ministry in Seoul insists that he is not guilty of any moral or legal wrongdoing, as the eggs were given voluntarily, without the professor's knowledge, and before South Korea introduced a bioethics law in January.
QUICK GUIDE
Cloning
Dr Hwang, 52, gained worldwide fame after producing the world's first cloned human embryos and stem cells tailored to be used on individuals.
Human cloning science offers the possibility that stem cells harvested from cloned embryos could be used to treat diseases like Parkinson's, diabetes and heart disease.
Click here to see a graphic showing how human cloning works
Dr Hwang's breakthrough was seen as particularly important as the stem cells he created were a perfect match for the patient, which could mean treatments without the risk of the body rejecting them.
However, opponents argue that creating and experimenting with human embryos is unethical.
Paid for eggs
Earlier this month Gerald Schatten, a prominent American colleague of Dr Hwang, broke off their collaboration saying he was concerned by the way the group procured human eggs.
Being too focused on scientific development, I may not have seen all the ethical issues related to my research
Professor Hwang Woo-suk
Interview: Hwang Woo-suk
Send us your comments
When the medical journal Nature pressed Dr Hwang in 2004 about the origin of the eggs, he denied they had been donated by his own researchers.
At a press conference on Thursday he admitted he had not told the truth.
Dr Hwang said when two women on his team offered their own eggs he turned them down.
Later, the women donated their eggs under false names, without his permission.
When asked about this he investigated, and was told about the provenance of the eggs, but lied to Nature because of a "strong request by the researchers to protect their privacy", he said.
South Korea's health ministry also admitted that other women were paid thousands of dollars for their eggs, though this took place without Dr Hwang's knowledge and before a new law outlawed trading in human eggs.
Egg shortage
The professor said he was resigning from all public posts, including his chairmanship of the World Stem Cell Hub, which is designed to produce stem cell lines for disease research worldwide.
"It is my way of seeking repentance," he said.
Professor Hwang Woo-suk and cloned puppy Snuppy
Dr Hwang led the project that led to the creation of cloned dog Snuppy
He added he would continue his research at Seoul National University.
"I again sincerely apologise for having stirred concern at home and abroad," he said.
"Being too focused on scientific development, I may not have seen all the ethical issues related to my research.
"We needed a lot of ova [eggs] for the research but there were not enough ova around," Dr Hwang said, explaining why standards may have slipped.
The research conducted by his team requires large numbers of human eggs, which are difficult to obtain.
'Stain'
The revelations have shaken fellow scientists.
"We are saddened by the confusion that has arisen in Korea and the distress that has been caused to those concerned," said British professors Ian Wilmut and Christopher Shaw.
There are no international laws governing the use of cells and embryos, but scientists said a tough regulatory climate - like that in force in the UK - could prevent such abuses or misunderstandings.
"The excellent research carried out by Hwang and his team must continue, but in a way that considers the ethics in an appropriate way," said Prof Robin Lovell-Badge of the UK's National Institute for Medical Research.
Thursday, November 24, 2005
Friday, November 18, 2005
Not only do they cry of piracy I think the Intellectual in IPR needs to be removed
Crazy Patents! For the USPTO to issue a patent, the invention must be novel, non-obvious, and "useful." The standard for usefulness is certainly the weakest of the three -- any possible utility, no matter how small, will suffice. And, useful does not necessarily mean commercially viable. In other words, you can get a patent on some crazy things that will never make it to the shelves of your local store. For instance:
Patent Number Title Summary
6055910 Toy gas fired missile and launcher assembly
The title sounds simple enough, right? Well, you better read the abstract to find out where you put this rocket and where the gas comes from... No, seriously -- you better read it. Somebody paid to patent this??? Submitted by Samuel Pai.
6360693 Animal Toy
Thanks to Samuel Pai for this submission, which is nearly unbelievable. Claim 1 describes (in fancy language of course), a synthetic STICK. Yes, a stick. I'm not kidding. This patent was applied for in 1999. Do you think anyone had ever conceived of the idea of using a stick (albeit a plastic one) as an animal toy prior to 1999? Check out the front page image -- a picture is worth a thousands words, or in this case, a stick.
6883462 Doggie Poop Freeze Wand
Is this disgustingly useless, or a great idea? I'm leaning towards the former. It is a device that can freeze or enzymatically break down dog poop. You still have to dispose of it, right? And I haven't heard of a big problem with non-biodegradable poop filling up landfills. Submitted by Jared McDonald.
5904268 Mug incorporating a simulated artificial horizon
Granted, this isn't very useful, but let me tell you what really worries me about it: I know what I would do with it. I'd sit the cup on my dashboard and use it to see how many G's I could pull while driving. The lure of always going for a new "personal best" would surely be hazardous to one's health. Thanks to Oliver Kroth for submitting this one!
5443036 Method of exercising a cat
In 1993 the USPTO issued this patent for using a laser pointer to exercise a cat (yes, by moving the laser pointer beam around and having the cat chase it). Come on now... Not only is this crazy to patent, but this idea had surely been thought of long before this patent came about. In fact, a bit of research turned up the book "One Hundred and Eighty-Seven Ways to Amuse a Bored Cat" (Ballantine Books; May, 1982) that describes the exact same idea, but using a flashlight. Sorry guys -- the use of a laser pointer for the same thing is obvious.
Update: Michael Burns pointed out something truly amazing about this patent. Not only should this patent probalby never have been issued, but it appears that the USPTO has issued what is essentially the same patent many times! See:
6505576 Pet Toy
6557495 Laser Pet Toy
6651591 Automatic laser pet toy and exerciser
6701872 Method and apparatus for automatically exercising a curious animal
6837185 Religious Meditation Apparatus
A bird feeder shaped like a church, so that you can watch the birds as you pray.
6826983 Light Bulb Changer
How many machines does it take to change a light bulb? Come on now, who is going to buy a machine, that looks like it weighs 100 pounds and costs plenty, to change light bulbs. How would one even get this contraption up to a light bulb?
6752088 Eating counter apparatus for mobile vending vehicle
This guy must have been sitting around with a hotdog cart, a park bench, and a welding torch, and decided he needed to patent something using only these three things.
6745394 Ballistic resistant body covering
From the picture, one would guess that this is a super hero costume which purports to protect the wearer from bullets. All I can do here is to pray for the test engineers. Good luck pals.
6739074 Tamper Resistant Institutional Shoe And Method
A shoe with a transparent sole to prevent concealing contraband. Don't laugh just yet -- these might be required on planes soon!
6725510 Inclining coffin
I'm not sure why anyone wants a dead person sitting upright, but even the person who patented this says it is spooky.
6718554 Hands free towel carrying system
A towel with a neck loop. Seriously -- that's all it is. And it took until 2004 to patent such a thing. I wonder what other amazing inventions remain to be discovered???
6711769 Pillow with retractable umbrella
A pillow, with a built-in umbrella to protect the user from the sun. Somehow the idea of having a tanned body and a ghostly white head doesn't appeal to me, but whatever floats your boat.
6659880 Chin Putter
The funny thing about this is that I think the authors take it seriously it does not seem to be a novelty item.
6650315 Mouse device with a built-in printer
The title is pretty self-explanatory. Yes, it takes very small paper. Maybe it could serve as a label maker -- that's about all I can think of.
6637447 Beerbrella
Keeps the sun off your beer (no, I am not kidding). One would think that those little insulating sleeves would be much more effective, but perhaps they were worried about their beer getting sunburned.
6557994 Stud Spectacles
Eyeglasses that don't need a frame because they attach to body piercings on the face. Yeah
6368227 Method of swinging on a swing
So these fools think that in all the years of swinging no one has ever before thought to pull on the opposite chains and swing form side to side? Well, I guess they got the PTO to issue the patent, so I'm not sure who the fool really is... But, even so, what do these guys expect to do with this anyway? Are they going to go around and collect royalties from kids on the playground?
6293874 User-operated amusement apparatus for kicking the user's buttocks
I'm not sure if this is a comedy prop or what. I do know one thing however: someone has a lot of time on their hands.
6125480 Vehicle mounted toilet seat
Being a bit of a outdoorsman I would like to give the creator of the Vehicle mounted toilet seat a bit of advice, people who go into the woods don't mind going to the bathroom in the woods. This guy just took a toilet seat, which has been around for a while, and strapped it on the back of a car.
6035447 Halloween Mask with Flash Device
This guy took a Halloween mask, strapped a light on it and called it a new invention. I know that Halloween is a relatively new holiday compared to some of the others, but I do recall seeing glowing masks well before this patent existed. In fact, I had a Jason mask that glowed when you pushed a button. I bet I know the next patent this guy submitted. He took a tree and stuck some lights and decorations on them and called it a "Christmas Tree." Pure genius.
5971829 Motorized ice cream cone
I am usually a proponent of anything that allows me to do less work, but everyone knows that the best part of eating an ice cream cone is eating the cone and ice cream at the end!
5970981 Mouthguard made at least partially from an edible candy
A mouth guard made from gummy candy... Maybe this guy is a dentist who wants to promote tooth decay to help his business.
5901666 Pet display clothing
A wearable Habitrail! This is a system of tubes that you can wear around, while your hamster crawls around in them. I have yet to see anyone wearing this, so I am guessing that it wasn't a smashing success at the pet stores (or clothing stores?).
5878931 Halloween Backpack
A backpack that dispenses candy! I'm sure this will be a hot seller at Walmart.
5787895 Kissing Shield
"The present invention proposes a method and device in which a flexible membrane is used as a kissing shield to lessen one's chances of becoming infected by disease from casual contact." Yeah, and it's very romantic too. These must be hot items on the bar scene. Seriously though, Frank McKeil (RPA) informed us that he had a chance to talk with the inventor of this patent and she mentioned that there actually is a very practical use: Burn vicitms that are susceptible to infection use them to allows safer kisses from loved-ones!
5678617 Method and apparatus for making a drink hop along a bar or counter
This is essentially the same as the fountains that Disney has at Epcot -- controlled streams of water designed to look like that are "jumping" (in this case, into a beer glass). But hey, this probalby IS amusing when you are drunk!
5593398 Protective underwear with malodorous flatus filter
An air freshener system for your drawers. Right. I can understand how an untimely fart in a professional or romantic situation could be embarrassing, but I think its time to practice what we big-boys call self-control. If this isn't an option perhaps it's time to see a doctor.
5491007 Carvable Artificial Pumpkin and Method
Who ever said creativity is dead in America? No one who knows the patenter of the Carvable Artificial Pumpkin. This guy took a hollow Styrofoam ball (that may or may not be painted orange) and called it a new invention. Somehow this reminds me of that Saturday Night Live skit with Dan Akroyd playing the crazy defective toy maker. I can just see this product coming with a big butcher's knife for the carving and maybe a bag of glass and nails for this kids to play with.
5265827 Paddle Wheel Plane
Does this thing really fly??? I'd be amazed.
5175571 Subliminal Glasses
Glasses that project subliminal images? They claim to ge a possible aid for everything from quitting smoking, stopping drug and alcohol abuse, and learning. Yeah, because the submliminal tapes that are available work so well
4858627 Smokers Hat
A hat with an air intake, which filters and then expels the air. Looks pretty much like wearing the exhaust hood for a stove on your head.
4553748 Electrostatically Enhanced Game
Unless you take some pleasure out of being shocked or shocking someone else, the Electrostatically Enhanced Game is not for you. I personally could find some joy in shocking my buddy while beating him at Madden, but unfortunately I don't think this is an original invention. I seem to recall a James Bond flick that had a video game like that, and that's kind of sad ripping off Bond.
4524471 Power Operated Separable Beds and Support Therefore
Again we see that American ingenuity is still running strong.? Really all this guy did was get two beds and put them on a track that lets you move them.? While I appreciate the touch of a button convenience, is it that hard to sleep next to someone?? Besides we all know that its not going to get you out of cuddling.
4455816 Tricycle Lawnmower
No, you aren't misreading anything. This really is a child's tricyle with a lawnmower attached. Real safe, eh?
4432545 Non-lethal cock fighting system
Cock fighting is illegal in the US (except for Louisiana and 1 other state as one of our readers has pointed out). So, these geniuses probably just drew attention to the fact that they are breaking the law. While this is a ridiculous patent, it did give me a idea for my next patent: A Kangaroo Kickboxing Kit.
4344424 Anti-Eating Mouth Cage
Just think Hannibal Lecter
4300473 Device For Moistening The Adhesive Coating On Postage Stamps and Envelopes
Describes a device containing an applicator to moisten stamps. Check out this quote: "The applicator may be in the form of a human tongue" Boy, that's novel.
4233942 Animal Ear Protection
A device for protecting the ears of animals, especially long-haired dogs, from becoming soiled by the animal's food while the animal is eating. Ok, your pet might look better without dirty hair, but it's going to look pretty dumb wearing this thing.
Crazy Patents! For the USPTO to issue a patent, the invention must be novel, non-obvious, and "useful." The standard for usefulness is certainly the weakest of the three -- any possible utility, no matter how small, will suffice. And, useful does not necessarily mean commercially viable. In other words, you can get a patent on some crazy things that will never make it to the shelves of your local store. For instance:
Patent Number Title Summary
6055910 Toy gas fired missile and launcher assembly
The title sounds simple enough, right? Well, you better read the abstract to find out where you put this rocket and where the gas comes from... No, seriously -- you better read it. Somebody paid to patent this??? Submitted by Samuel Pai.
6360693 Animal Toy
Thanks to Samuel Pai for this submission, which is nearly unbelievable. Claim 1 describes (in fancy language of course), a synthetic STICK. Yes, a stick. I'm not kidding. This patent was applied for in 1999. Do you think anyone had ever conceived of the idea of using a stick (albeit a plastic one) as an animal toy prior to 1999? Check out the front page image -- a picture is worth a thousands words, or in this case, a stick.
6883462 Doggie Poop Freeze Wand
Is this disgustingly useless, or a great idea? I'm leaning towards the former. It is a device that can freeze or enzymatically break down dog poop. You still have to dispose of it, right? And I haven't heard of a big problem with non-biodegradable poop filling up landfills. Submitted by Jared McDonald.
5904268 Mug incorporating a simulated artificial horizon
Granted, this isn't very useful, but let me tell you what really worries me about it: I know what I would do with it. I'd sit the cup on my dashboard and use it to see how many G's I could pull while driving. The lure of always going for a new "personal best" would surely be hazardous to one's health. Thanks to Oliver Kroth for submitting this one!
5443036 Method of exercising a cat
In 1993 the USPTO issued this patent for using a laser pointer to exercise a cat (yes, by moving the laser pointer beam around and having the cat chase it). Come on now... Not only is this crazy to patent, but this idea had surely been thought of long before this patent came about. In fact, a bit of research turned up the book "One Hundred and Eighty-Seven Ways to Amuse a Bored Cat" (Ballantine Books; May, 1982) that describes the exact same idea, but using a flashlight. Sorry guys -- the use of a laser pointer for the same thing is obvious.
Update: Michael Burns pointed out something truly amazing about this patent. Not only should this patent probalby never have been issued, but it appears that the USPTO has issued what is essentially the same patent many times! See:
6505576 Pet Toy
6557495 Laser Pet Toy
6651591 Automatic laser pet toy and exerciser
6701872 Method and apparatus for automatically exercising a curious animal
6837185 Religious Meditation Apparatus
A bird feeder shaped like a church, so that you can watch the birds as you pray.
6826983 Light Bulb Changer
How many machines does it take to change a light bulb? Come on now, who is going to buy a machine, that looks like it weighs 100 pounds and costs plenty, to change light bulbs. How would one even get this contraption up to a light bulb?
6752088 Eating counter apparatus for mobile vending vehicle
This guy must have been sitting around with a hotdog cart, a park bench, and a welding torch, and decided he needed to patent something using only these three things.
6745394 Ballistic resistant body covering
From the picture, one would guess that this is a super hero costume which purports to protect the wearer from bullets. All I can do here is to pray for the test engineers. Good luck pals.
6739074 Tamper Resistant Institutional Shoe And Method
A shoe with a transparent sole to prevent concealing contraband. Don't laugh just yet -- these might be required on planes soon!
6725510 Inclining coffin
I'm not sure why anyone wants a dead person sitting upright, but even the person who patented this says it is spooky.
6718554 Hands free towel carrying system
A towel with a neck loop. Seriously -- that's all it is. And it took until 2004 to patent such a thing. I wonder what other amazing inventions remain to be discovered???
6711769 Pillow with retractable umbrella
A pillow, with a built-in umbrella to protect the user from the sun. Somehow the idea of having a tanned body and a ghostly white head doesn't appeal to me, but whatever floats your boat.
6659880 Chin Putter
The funny thing about this is that I think the authors take it seriously it does not seem to be a novelty item.
6650315 Mouse device with a built-in printer
The title is pretty self-explanatory. Yes, it takes very small paper. Maybe it could serve as a label maker -- that's about all I can think of.
6637447 Beerbrella
Keeps the sun off your beer (no, I am not kidding). One would think that those little insulating sleeves would be much more effective, but perhaps they were worried about their beer getting sunburned.
6557994 Stud Spectacles
Eyeglasses that don't need a frame because they attach to body piercings on the face. Yeah
6368227 Method of swinging on a swing
So these fools think that in all the years of swinging no one has ever before thought to pull on the opposite chains and swing form side to side? Well, I guess they got the PTO to issue the patent, so I'm not sure who the fool really is... But, even so, what do these guys expect to do with this anyway? Are they going to go around and collect royalties from kids on the playground?
6293874 User-operated amusement apparatus for kicking the user's buttocks
I'm not sure if this is a comedy prop or what. I do know one thing however: someone has a lot of time on their hands.
6125480 Vehicle mounted toilet seat
Being a bit of a outdoorsman I would like to give the creator of the Vehicle mounted toilet seat a bit of advice, people who go into the woods don't mind going to the bathroom in the woods. This guy just took a toilet seat, which has been around for a while, and strapped it on the back of a car.
6035447 Halloween Mask with Flash Device
This guy took a Halloween mask, strapped a light on it and called it a new invention. I know that Halloween is a relatively new holiday compared to some of the others, but I do recall seeing glowing masks well before this patent existed. In fact, I had a Jason mask that glowed when you pushed a button. I bet I know the next patent this guy submitted. He took a tree and stuck some lights and decorations on them and called it a "Christmas Tree." Pure genius.
5971829 Motorized ice cream cone
I am usually a proponent of anything that allows me to do less work, but everyone knows that the best part of eating an ice cream cone is eating the cone and ice cream at the end!
5970981 Mouthguard made at least partially from an edible candy
A mouth guard made from gummy candy... Maybe this guy is a dentist who wants to promote tooth decay to help his business.
5901666 Pet display clothing
A wearable Habitrail! This is a system of tubes that you can wear around, while your hamster crawls around in them. I have yet to see anyone wearing this, so I am guessing that it wasn't a smashing success at the pet stores (or clothing stores?).
5878931 Halloween Backpack
A backpack that dispenses candy! I'm sure this will be a hot seller at Walmart.
5787895 Kissing Shield
"The present invention proposes a method and device in which a flexible membrane is used as a kissing shield to lessen one's chances of becoming infected by disease from casual contact." Yeah, and it's very romantic too. These must be hot items on the bar scene. Seriously though, Frank McKeil (RPA) informed us that he had a chance to talk with the inventor of this patent and she mentioned that there actually is a very practical use: Burn vicitms that are susceptible to infection use them to allows safer kisses from loved-ones!
5678617 Method and apparatus for making a drink hop along a bar or counter
This is essentially the same as the fountains that Disney has at Epcot -- controlled streams of water designed to look like that are "jumping" (in this case, into a beer glass). But hey, this probalby IS amusing when you are drunk!
5593398 Protective underwear with malodorous flatus filter
An air freshener system for your drawers. Right. I can understand how an untimely fart in a professional or romantic situation could be embarrassing, but I think its time to practice what we big-boys call self-control. If this isn't an option perhaps it's time to see a doctor.
5491007 Carvable Artificial Pumpkin and Method
Who ever said creativity is dead in America? No one who knows the patenter of the Carvable Artificial Pumpkin. This guy took a hollow Styrofoam ball (that may or may not be painted orange) and called it a new invention. Somehow this reminds me of that Saturday Night Live skit with Dan Akroyd playing the crazy defective toy maker. I can just see this product coming with a big butcher's knife for the carving and maybe a bag of glass and nails for this kids to play with.
5265827 Paddle Wheel Plane
Does this thing really fly??? I'd be amazed.
5175571 Subliminal Glasses
Glasses that project subliminal images? They claim to ge a possible aid for everything from quitting smoking, stopping drug and alcohol abuse, and learning. Yeah, because the submliminal tapes that are available work so well
4858627 Smokers Hat
A hat with an air intake, which filters and then expels the air. Looks pretty much like wearing the exhaust hood for a stove on your head.
4553748 Electrostatically Enhanced Game
Unless you take some pleasure out of being shocked or shocking someone else, the Electrostatically Enhanced Game is not for you. I personally could find some joy in shocking my buddy while beating him at Madden, but unfortunately I don't think this is an original invention. I seem to recall a James Bond flick that had a video game like that, and that's kind of sad ripping off Bond.
4524471 Power Operated Separable Beds and Support Therefore
Again we see that American ingenuity is still running strong.? Really all this guy did was get two beds and put them on a track that lets you move them.? While I appreciate the touch of a button convenience, is it that hard to sleep next to someone?? Besides we all know that its not going to get you out of cuddling.
4455816 Tricycle Lawnmower
No, you aren't misreading anything. This really is a child's tricyle with a lawnmower attached. Real safe, eh?
4432545 Non-lethal cock fighting system
Cock fighting is illegal in the US (except for Louisiana and 1 other state as one of our readers has pointed out). So, these geniuses probably just drew attention to the fact that they are breaking the law. While this is a ridiculous patent, it did give me a idea for my next patent: A Kangaroo Kickboxing Kit.
4344424 Anti-Eating Mouth Cage
Just think Hannibal Lecter
4300473 Device For Moistening The Adhesive Coating On Postage Stamps and Envelopes
Describes a device containing an applicator to moisten stamps. Check out this quote: "The applicator may be in the form of a human tongue" Boy, that's novel.
4233942 Animal Ear Protection
A device for protecting the ears of animals, especially long-haired dogs, from becoming soiled by the animal's food while the animal is eating. Ok, your pet might look better without dirty hair, but it's going to look pretty dumb wearing this thing.
Thursday, November 17, 2005
not only does the US patent office grant antigravity but some silly ones like the following
United States Patent Application 20050239024
Kind Code A1
Kemp, Ian David ; et al. October 27, 2005
--------------------------------------------------------------------------------
Toilet training aides and kits
Abstract
Toilet training aides, toilet training kits and related bathroom training aides and kits are disclosed. Toilet training aides may take the form of a multiple page booklet such a passport like booklet. The pages of the booklet may have a series of iconic images each depicting a toilet activity to a pre-literate or semi-literate child. Associated with each iconic image is a progress indicating area in which success indicating means may be placed for successful completion of the represented activity. Kits can include personal hygiene products ergonomically adapted to be used by a child. The aides and kits disclosed motivate and instruct a toddler or young child on all aspects of toilet training in both a comprehensive and focused manner.
--------------------------------------------------------------------------------
Inventors: Kemp, Ian David; (Gosforth, GB) ; McCabe, Michael Gerard; (Consett Co., GB) ; Naess, Jon Aleksander; (Lancy, CH)
Correspondence Name and Address: THE PROCTER & GAMBLE COMPANY
INTELLECTUAL PROPERTY DIVISION
WINTON HILL TECHNICAL CENTER - BOX 161
6110 CENTER HILL AVENUE
CINCINNATI
OH
45224
US
Assignee Name and Adress: The Procter & Gamble Company
Serial No.: 879337
Series Code: 10
Filed: June 29, 2004
U.S. Current Class: 434/236
U.S. Class at Publication: 434/236
Intern'l Class:
Kind Code A1
Kemp, Ian David ; et al. October 27, 2005
--------------------------------------------------------------------------------
Toilet training aides and kits
Abstract
Toilet training aides, toilet training kits and related bathroom training aides and kits are disclosed. Toilet training aides may take the form of a multiple page booklet such a passport like booklet. The pages of the booklet may have a series of iconic images each depicting a toilet activity to a pre-literate or semi-literate child. Associated with each iconic image is a progress indicating area in which success indicating means may be placed for successful completion of the represented activity. Kits can include personal hygiene products ergonomically adapted to be used by a child. The aides and kits disclosed motivate and instruct a toddler or young child on all aspects of toilet training in both a comprehensive and focused manner.
--------------------------------------------------------------------------------
Inventors: Kemp, Ian David; (Gosforth, GB) ; McCabe, Michael Gerard; (Consett Co., GB) ; Naess, Jon Aleksander; (Lancy, CH)
Correspondence Name and Address: THE PROCTER & GAMBLE COMPANY
INTELLECTUAL PROPERTY DIVISION
WINTON HILL TECHNICAL CENTER - BOX 161
6110 CENTER HILL AVENUE
CINCINNATI
OH
45224
US
Assignee Name and Adress: The Procter & Gamble Company
Serial No.: 879337
Series Code: 10
Filed: June 29, 2004
U.S. Current Class: 434/236
U.S. Class at Publication: 434/236
Intern'l Class:
Saturday, November 05, 2005
carrot and the donkey
India which is widely regarded as having a surplus of doctors and a major supplier of doctors and nurses to various rich foreign countries has vacancy rates in health services ranging from 30% to 90 % depending on which areas are surveyed.
In a country suffering from over population and unemployment this fact is unexplainable to me.
Provision of free health services is political and emotional one.
Politicians dare not suggest to the public that government can not provide adequate health services with out some payment from the public.
Just like free power free health is a carrot at the end of the stick
The stick is very long and the donkey will never get the carrot.
Till we realise this and bring changes in the way public health services are rendered in india we can not eradicte major haelth problems of the public and progress economically.
In a country suffering from over population and unemployment this fact is unexplainable to me.
Provision of free health services is political and emotional one.
Politicians dare not suggest to the public that government can not provide adequate health services with out some payment from the public.
Just like free power free health is a carrot at the end of the stick
The stick is very long and the donkey will never get the carrot.
Till we realise this and bring changes in the way public health services are rendered in india we can not eradicte major haelth problems of the public and progress economically.
Friday, September 30, 2005
Natural killer cells_islet cell transplants
there are 2 big problems in islet cell transplants for curing (see the word CURE)diabetes .
1) lack of sufficent donor islet cells .
2)destruction of transplanted cells.
may be we are finding ways and means of combating the second problem
It is a proud moment for us to see an Indian (NAGENDRA SINGE) working with the japanese in USA
The natural killer T-cell ligand -galactosylceramideprevents autoimmune diabetes in non-obese diabetic mice
SEOKMANN HONG1, MICHAEL T. WILSON1, ISAO SERIZAWA2, LAN WU3, NAGENDRA SINGH1,
OLGA V. NAIDENKO4, TORU MIURA2, TOMOKU HABA2, DAVID C. SCHERER1, JIE WEI1,
MITCHELL KRONENBERG4, YASUHIKO KOEZUKA2 & LUC VAN KAER1
1Howard Hughes Medical Institute, Department of Microbiology and Immunology,
Vanderbilt University School of Medicine, Nashville, Tennessee, USA
2Pharmaceutical Research Laboratory, Kirin Brewery Co, Ltd., Gunma, Japan
3Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
4La Jolla Institute for Allergy and Immunology, San Diego, California, USA
S.H., M.T.W. and I.S. contributed equally to this study.
Correspondence should be addressed to L.V.K.; e-mail: vankael@ctrvax.vanderbilt.edu
base on this .
the same chemical is found to help protect transplanted islet cells .
Discovery Could Boost Type 1 Diabetes Care
Researchers spot key player in success of transplanted insulin-producing cells
TUESDAY, Sept. 27 (HealthDay News) -- The survival of transplanted insulin-producing cells is improved when activation of "natural killer T" immune cells is blocked, Japanese researchers report.
They believe the finding could help boost the effectiveness of islet cell transplants for the treatment of insulin-dependent type 1 diabetes. This form of the disease (affecting about 5 percent of diabetics) is caused by the destruction of insulin-producing cells in the pancreas by the body's own immune T-cells.
Transplantation of these "islet cells" requires patientto continue lifelong immunosuppression therapy.Even with immunosuppression treatment, up to half the transplanted islet cells are quickly destroyed by the patient's own T-cells, however.
In their research with mice, the Japanese team showed that natural killer T (NTK) cells instigate this rapid destruction of transplanted islet cells. When the NKT cells become activated -- most likely in response to the stress of the transplant procedure -- they produce an inflammatory molecule called interferon (IFN)-gamma.
It's this molecule that helps activate immune T-cells to destroy islet cells, the researchers report in the Oct. 3 issue of the Journal of Experimental Medicine.
Transplanted islet cells survived in mice that lacked NKT cells or were unable to produce IFN-gamma, the researchers found. They also found that multiple doses of the drug alpha-galactosylceramide caused NKT cells to produce less IFN-gamma. Decreased production of IFN-gamma greatly improved the survival of transplanted islet cells, the study found.
According to the Japanese team, multiple doses of the drug -- currently in human clinical trials -- may help prevent the early loss of transplanted islet cells in humans.
In an extension of the same anology
this same chemical may prove to be useful in preventing rejection of other transplanted organs .
1) lack of sufficent donor islet cells .
2)destruction of transplanted cells.
may be we are finding ways and means of combating the second problem
It is a proud moment for us to see an Indian (NAGENDRA SINGE) working with the japanese in USA
The natural killer T-cell ligand -galactosylceramideprevents autoimmune diabetes in non-obese diabetic mice
SEOKMANN HONG1, MICHAEL T. WILSON1, ISAO SERIZAWA2, LAN WU3, NAGENDRA SINGH1,
OLGA V. NAIDENKO4, TORU MIURA2, TOMOKU HABA2, DAVID C. SCHERER1, JIE WEI1,
MITCHELL KRONENBERG4, YASUHIKO KOEZUKA2 & LUC VAN KAER1
1Howard Hughes Medical Institute, Department of Microbiology and Immunology,
Vanderbilt University School of Medicine, Nashville, Tennessee, USA
2Pharmaceutical Research Laboratory, Kirin Brewery Co, Ltd., Gunma, Japan
3Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
4La Jolla Institute for Allergy and Immunology, San Diego, California, USA
S.H., M.T.W. and I.S. contributed equally to this study.
Correspondence should be addressed to L.V.K.; e-mail: vankael@ctrvax.vanderbilt.edu
base on this .
the same chemical is found to help protect transplanted islet cells .
Discovery Could Boost Type 1 Diabetes Care
Researchers spot key player in success of transplanted insulin-producing cells
TUESDAY, Sept. 27 (HealthDay News) -- The survival of transplanted insulin-producing cells is improved when activation of "natural killer T" immune cells is blocked, Japanese researchers report.
They believe the finding could help boost the effectiveness of islet cell transplants for the treatment of insulin-dependent type 1 diabetes. This form of the disease (affecting about 5 percent of diabetics) is caused by the destruction of insulin-producing cells in the pancreas by the body's own immune T-cells.
Transplantation of these "islet cells" requires patientto continue lifelong immunosuppression therapy.Even with immunosuppression treatment, up to half the transplanted islet cells are quickly destroyed by the patient's own T-cells, however.
In their research with mice, the Japanese team showed that natural killer T (NTK) cells instigate this rapid destruction of transplanted islet cells. When the NKT cells become activated -- most likely in response to the stress of the transplant procedure -- they produce an inflammatory molecule called interferon (IFN)-gamma.
It's this molecule that helps activate immune T-cells to destroy islet cells, the researchers report in the Oct. 3 issue of the Journal of Experimental Medicine.
Transplanted islet cells survived in mice that lacked NKT cells or were unable to produce IFN-gamma, the researchers found. They also found that multiple doses of the drug alpha-galactosylceramide caused NKT cells to produce less IFN-gamma. Decreased production of IFN-gamma greatly improved the survival of transplanted islet cells, the study found.
According to the Japanese team, multiple doses of the drug -- currently in human clinical trials -- may help prevent the early loss of transplanted islet cells in humans.
In an extension of the same anology
this same chemical may prove to be useful in preventing rejection of other transplanted organs .
getting serious about telugu Diabetes educational site
Ihave been collecting content for the last 1 year to stsart this web site but hasnt had enough spare time to up load articles
it will be set up at daibetiisu.com
unless we educate evry one about theses diseases and how to take care of them properly we are going to see a major portion of GDP of India being wasted on treating complications and in wasted man hours .
it will be set up at daibetiisu.com
unless we educate evry one about theses diseases and how to take care of them properly we are going to see a major portion of GDP of India being wasted on treating complications and in wasted man hours .
Wednesday, July 13, 2005
broadband?slowband?
if you thought you ordered DSL and think you will have service mayb in 24 or 48 hours with Verizon ,you wont hear anything from them for one week and after a week when you try to call the elusive customer service number,you will spend 2 hours before hearing it will be 1 week more before the service may start?
talk of customer disservice .
would verizon say this upfront NO!
wish I could find the fellow who wrote the advt and wring his neck .
talk of customer disservice .
would verizon say this upfront NO!
wish I could find the fellow who wrote the advt and wring his neck .
Tuesday, May 17, 2005
the "PROPHESY" of general Satish Nambiar
in 1999 general satish nambiar who was the first UN force commander wrote teh following
"The United Nations has been made totally redundant, ineffective, and
impotent. The Western world, led by the USA, will lay down the moral
values that the rest of the world must adhere to; it does not matter
that they themselves do not adhere to the same values when it does not
suit them. National sovereignty and territorial integrity have no
sanctity. And finally, secessionist movements, which often start wit
terrorist activity, will get greater encouragement. One can only hope
that good sense will prevail, hopefully sooner rather than later"
so which soverign nation is next on US list to be attacked ?
IRAN ?North Korea? SYRIA ?Uzbekistan ?
I think no one else was as prophetic as Gen Nambiar.
I dont know if he wrote any thing about the ongoing IRAQ DRAMA .
"The United Nations has been made totally redundant, ineffective, and
impotent. The Western world, led by the USA, will lay down the moral
values that the rest of the world must adhere to; it does not matter
that they themselves do not adhere to the same values when it does not
suit them. National sovereignty and territorial integrity have no
sanctity. And finally, secessionist movements, which often start wit
terrorist activity, will get greater encouragement. One can only hope
that good sense will prevail, hopefully sooner rather than later"
so which soverign nation is next on US list to be attacked ?
IRAN ?North Korea? SYRIA ?Uzbekistan ?
I think no one else was as prophetic as Gen Nambiar.
I dont know if he wrote any thing about the ongoing IRAQ DRAMA .
Thursday, April 28, 2005
superjumbo_BOEING IS GOING TO EAT ITS WORDS
read to day the following
Yesterday the world's largest passenger plane, the Airbus A380, made its first flight which lasted about 4 hours.
The A380 took off from and landed inToulouse, France with about 30,000 people watching.
Airbus rival, Boeing acknowledges the accomplishment Airbus has made, but doesn't see the A380 as very practical.
It is ''a very large airplane for a very small market,'' said Boeing spokesman Jim Condelles.
''First flights are always very interesting and exciting. It's an engineering accomplishment that Airbus should be very proud of,'' he added. ''We just don't see a market for 1,250 of these airplanes over the next 20 years.''
A Chicago Sun-Times article says, "Condelles was referring to Airbus' global market forecast for very large jets. Boeing sees demand for just 400 jets with 450 seats or more. If Airbus is right, it could enjoy a near-monopoly in that market while Boeing scrambles to produce a competitor."
The A380 will only fly into 25 airports at first, but that number will grow over the next 20 years.
Airbus has received orders for 154 of the planes so far. No American carriers have ordered any.
will it be another concorde airplane which was a technical marvel but acommercial disaster .
or will it be a fuel efficient machine and the only one to fly in the future with the way oil prices are soaring .
MY BET IS THIS TIME BOEING IS GOING TO EAT ITS WORDS>
Yesterday the world's largest passenger plane, the Airbus A380, made its first flight which lasted about 4 hours.
The A380 took off from and landed inToulouse, France with about 30,000 people watching.
Airbus rival, Boeing acknowledges the accomplishment Airbus has made, but doesn't see the A380 as very practical.
It is ''a very large airplane for a very small market,'' said Boeing spokesman Jim Condelles.
''First flights are always very interesting and exciting. It's an engineering accomplishment that Airbus should be very proud of,'' he added. ''We just don't see a market for 1,250 of these airplanes over the next 20 years.''
A Chicago Sun-Times article says, "Condelles was referring to Airbus' global market forecast for very large jets. Boeing sees demand for just 400 jets with 450 seats or more. If Airbus is right, it could enjoy a near-monopoly in that market while Boeing scrambles to produce a competitor."
The A380 will only fly into 25 airports at first, but that number will grow over the next 20 years.
Airbus has received orders for 154 of the planes so far. No American carriers have ordered any.
will it be another concorde airplane which was a technical marvel but acommercial disaster .
or will it be a fuel efficient machine and the only one to fly in the future with the way oil prices are soaring .
MY BET IS THIS TIME BOEING IS GOING TO EAT ITS WORDS>
Saturday, April 16, 2005
Deadly flu virus
Apr 16, 2005, 13:45
"The World Health Organization says two samples of a deadly flu virus shipped to Mexico and Lebanon remain unaccounted for.
The virus, known as H2N2 , a strain of "Asian Flu," responsible for up to 4 million deaths worldwide in 1957 was shipped to 18 nations in the form of test kits, numbering close to 5000.
WHO influenza expert, Klaus Stohr, said the specimens were never received in Lebanon and Mexico, despite being on the distribution list.
The test kits containing the virus, distributed by Ohio's Meridian Bioscience Inc., were designed to test the ability of labs to identify virus strains."
the question no one seems to be asking is how come such a deadly viral specimen were stored by
"meridian Bioscience "?
what other deadly viruses are stored by different bio companies all over the world and specially in USA ?
what about ebola does CDC have any guidelines rules and precautions for such viral research ?
"The World Health Organization says two samples of a deadly flu virus shipped to Mexico and Lebanon remain unaccounted for.
The virus, known as H2N2 , a strain of "Asian Flu," responsible for up to 4 million deaths worldwide in 1957 was shipped to 18 nations in the form of test kits, numbering close to 5000.
WHO influenza expert, Klaus Stohr, said the specimens were never received in Lebanon and Mexico, despite being on the distribution list.
The test kits containing the virus, distributed by Ohio's Meridian Bioscience Inc., were designed to test the ability of labs to identify virus strains."
the question no one seems to be asking is how come such a deadly viral specimen were stored by
"meridian Bioscience "?
what other deadly viruses are stored by different bio companies all over the world and specially in USA ?
what about ebola does CDC have any guidelines rules and precautions for such viral research ?
Wednesday, April 13, 2005
oxytocin and orgasm _yawning
Oxytocin receptor antagonists prevent apomorphine induced yawning .(orgasm )this suggests that dopamine (d3) receptor agonists induce yawning (erection/orgasm )by activating oxytocinergic neurons .
anxiety, drug abuse, sexual dysfunctions, eating disorders, or autism. treatment of theses disorders may be improved by elucidating all the neuropeptide actions of oxytocin .
the normal milk lettig reflex which is essentially breast/nipple stimulation causing oxytocin release and contraction of smooth muscle may be a reflex acting in female orgasm .
is this one of the rerasons for orgasms in breast stimulated women ?
anxiety, drug abuse, sexual dysfunctions, eating disorders, or autism. treatment of theses disorders may be improved by elucidating all the neuropeptide actions of oxytocin .
the normal milk lettig reflex which is essentially breast/nipple stimulation causing oxytocin release and contraction of smooth muscle may be a reflex acting in female orgasm .
is this one of the rerasons for orgasms in breast stimulated women ?
efficacies of centrally active drugs in erectile dysfunction
Apomorphine for erectile dysfunction
"Clinical bottom line
There is one randomised trial of sublingual apomorphine for the treatment of erectile dysfunction. Doses of 2-6 mg provided erections good enough for sexual intercourse in about 50% of men treated with apomorphine, compared with 32% with placebo. Six men would need to be treated with sublingual apomorphine for one to have successful erections who would not have had with placebo."
no wonder uprima is not another viagra !
any way my interest in apomorphine is froma different point of view .
apomorphine can produce yawning and penile erections even when amphetamine raised dopamine levels .
D3 reports are postulated to mediate the yawning response by extension
I hypothesise that orgasm is mediated by D3 receptors too.
"Clinical bottom line
There is one randomised trial of sublingual apomorphine for the treatment of erectile dysfunction. Doses of 2-6 mg provided erections good enough for sexual intercourse in about 50% of men treated with apomorphine, compared with 32% with placebo. Six men would need to be treated with sublingual apomorphine for one to have successful erections who would not have had with placebo."
no wonder uprima is not another viagra !
any way my interest in apomorphine is froma different point of view .
apomorphine can produce yawning and penile erections even when amphetamine raised dopamine levels .
D3 reports are postulated to mediate the yawning response by extension
I hypothesise that orgasm is mediated by D3 receptors too.
dreams some interesting facts
Congenitally blind have auditory dreams.
Acquired blind gradually lose their ability to dream visually.
Nightmares occur during REM sleep and during SWS with different characteristics:
SWS terrors are responsive to drugs that reduce SWS.
SWS terrors decrease with SWS decrease with age.
REM nightmares have storylines, SWS ones have image and poorer recall.
Acquired blind gradually lose their ability to dream visually.
Nightmares occur during REM sleep and during SWS with different characteristics:
SWS terrors are responsive to drugs that reduce SWS.
SWS terrors decrease with SWS decrease with age.
REM nightmares have storylines, SWS ones have image and poorer recall.
Dreams, yawning and orgasm
One of the most intence pleasurable sensations a man (or woman )can experience is the orgasm.
so much so in a science fiction classic the ability to record and replay emotions becomes common place an old engineer records an orgasm from a young couple then he starts using and reusing the tape to get the sensation over and over again so much so that he becomes like one of those rats with an electrode implanted in their pleasure center who keep on self stimulating ignoring all other activity .
he is so much in to this that he is committed by his wife to a mental asylum.
which neural stimulus produces this sensation (short of mastrubation which almost every boy and man knows )?
this is a question to be answered in detail .
there was a glimmer when it was reported patients who were taking the drug "clomiopramine " developed an orgasm when they yawned.
the paraventricular nucleus of hypothalamus is the trigger of yawning when stimulated by electrical impulses and chemicals such as histamine ( histamine the neglected neurotransmitter at a differenttime ).
so is the orgasmic center near the paraventricular nucleus of hypothalamus .
is there a way to produce orgasm on demand ?
is there a fatigue and nonreactive period for orgasm
why do mebn get orgasms more easily but are single but in women they are multiple ?
is this an inherent capbility or a learned reaction ?
I am r4ading up on all available material and may be soon will be able to report more stuff till then happy J*&king ;-)
so much so in a science fiction classic the ability to record and replay emotions becomes common place an old engineer records an orgasm from a young couple then he starts using and reusing the tape to get the sensation over and over again so much so that he becomes like one of those rats with an electrode implanted in their pleasure center who keep on self stimulating ignoring all other activity .
he is so much in to this that he is committed by his wife to a mental asylum.
which neural stimulus produces this sensation (short of mastrubation which almost every boy and man knows )?
this is a question to be answered in detail .
there was a glimmer when it was reported patients who were taking the drug "clomiopramine " developed an orgasm when they yawned.
the paraventricular nucleus of hypothalamus is the trigger of yawning when stimulated by electrical impulses and chemicals such as histamine ( histamine the neglected neurotransmitter at a differenttime ).
so is the orgasmic center near the paraventricular nucleus of hypothalamus .
is there a way to produce orgasm on demand ?
is there a fatigue and nonreactive period for orgasm
why do mebn get orgasms more easily but are single but in women they are multiple ?
is this an inherent capbility or a learned reaction ?
I am r4ading up on all available material and may be soon will be able to report more stuff till then happy J*&king ;-)
Friday, February 25, 2005
malaria eradication
a BT gene introduced in to synecocystis and synecococus bacteria and introduced in to all water where mosquito larvae grow theses will kill all larvae no mosquitoes no malaria .no westnile no dengue etc .
BIOTECHNOLOGY
i have been looking up biotechnology articles on BIOmass utilization and bio remediation .
it is interesting that an INDIAN (american) recieved the first US patent for a newly manufactured bacterium for crude oil spill remediation
and the recent a 2 year old news of death of the lawyer who argued for chakraborty
August 14, 2003
Edward McKie
Edward F. McKie Jr., a Washington lawyer who successfully argued to the U.S. Supreme Court that microorganisms were patentable, died on July 31 of congestive heart failure. He was 78.
McKie graduated from Rensselaer Polytechnic Institute and received his law degree from Georgetown University. In 1960, McKie co-founded the Washington D.C. law firm Irons, Birch, Swindler & McKie, the predecessor firm to Banner & Witcoff. He was a member of the Advisory Committee to the U.S. Patent and Trademark Office and on the International Industrial Property Panel for the U.S. Department of State. He also testified before various Congressional committees on patent matters.
McKie was best known for representing Ananda Chakrabarty, a scientist who sought to patent a genetically engineered bacterium capable of breaking down crude oil. Chakrabarty's application was denied by the Patent Office because regulations said living things could not be patented. After 10 years of litigation, McKie argued the Diamond v. Chakrabarty case before the U.S. Supreme Court. In a 5-4 decision, the Court ruled that a live, artificially engineered microorganism could be patented.
McKie also spent 38 years teaching intellectual property law at Georgetown University. He received a Silver Vicennial Medal in 2002 for his loyal and distinguished service at the school.
Posted on August 14, 2003 01:11 AM
it is interesting that an INDIAN (american) recieved the first US patent for a newly manufactured bacterium for crude oil spill remediation
and the recent a 2 year old news of death of the lawyer who argued for chakraborty
August 14, 2003
Edward McKie
Edward F. McKie Jr., a Washington lawyer who successfully argued to the U.S. Supreme Court that microorganisms were patentable, died on July 31 of congestive heart failure. He was 78.
McKie graduated from Rensselaer Polytechnic Institute and received his law degree from Georgetown University. In 1960, McKie co-founded the Washington D.C. law firm Irons, Birch, Swindler & McKie, the predecessor firm to Banner & Witcoff. He was a member of the Advisory Committee to the U.S. Patent and Trademark Office and on the International Industrial Property Panel for the U.S. Department of State. He also testified before various Congressional committees on patent matters.
McKie was best known for representing Ananda Chakrabarty, a scientist who sought to patent a genetically engineered bacterium capable of breaking down crude oil. Chakrabarty's application was denied by the Patent Office because regulations said living things could not be patented. After 10 years of litigation, McKie argued the Diamond v. Chakrabarty case before the U.S. Supreme Court. In a 5-4 decision, the Court ruled that a live, artificially engineered microorganism could be patented.
McKie also spent 38 years teaching intellectual property law at Georgetown University. He received a Silver Vicennial Medal in 2002 for his loyal and distinguished service at the school.
Posted on August 14, 2003 01:11 AM
Friday, February 18, 2005
toxin from cynobacteria
Anatoxin
also known as Very Fast Death Factor
By Neil Edwards
The Chemical Laboratories
School of Chemistry, Physics
& Environmental Science
University of Sussex at Brighton
Chime enhanced version VRML version Chemsymphony version
Introduction
Anatoxin is a potent alkaloid toxin derived from a species of cyanobacteria called Anabaena flos-aquae. The first published report of the potentially lethal effects of microorganisms known as blue-green algae appeared in Nature in 1878. George Francis described an algal bloom that had formed in the estuary of the Murray River, in Australia, as "a thick scum like green oil paint, some two to six inches thick." The water at this point of the river was rendered toxic to wildlife, with animals drinking it becoming rapidly ill and dying terrible deaths. The effect of microalgal toxins, both in marine and freshwater environments, has increased in severity in recent years, and poisoning episodes are becoming more common and more widespread. For example, in the midwestern United States, the consumption of contaminated water has resulted in the deaths of ducks and geese by the thousands.
Concern for wildlife and also issues related to public health led to much investigation into the causes of these mass animal mortalities, and in the 1950s and 1960s Paul Gorham and his co-workers at the National Research Council in Ottawa established cultures for Anabaena flos-aquae, which allowed them to isolate the poisonous compounds which it produces. Anatoxin is perhaps one of the most toxic of the cyanobacterial toxins in this group, since the effects of ingestion can be lethal within 4 minutes, depending on the quantity consumed. This led to the compound being dubbed "Very Fast Death Factor." The chemical structure is shown (right) and is an interesting bicyclic alkaloid, and it was hoped that knowledge of this structure would enable scientists to discover the mode of action of the toxin.
Anatoxin is a severe neurotoxin, and as such affects the functioning of the nervous system, often causing death due to paralysis of the respiratory muscles. It is known that it acts as a mimic of the neurotransmitter, acetylcholine and irreversibly binds the nicotinic acetylcholine receptor (NAChR). Normal neuromuscular action involves the release of acetylcholine, which binds its receptor, leading to the opening of a related sodium channel. The resulting movement of sodium ions produces the action potential causing the muscles to contract. At this point, an enzyme called acetylcholinesterase then cleaves the neurotransmitter, allowing the sodium channel to return eventually to its resting state, and hence the muscle can relax. Anatoxin also binds the NAChR to produce an action potential, but cannot be cleaved by the enzyme. The sodium channel is essentially locked open, and the muscles become over-stimulated and become fatigued and then paralysed. When respiratory muscles become affected, convulsions occur due to a lack of oxygen supply to the brain. Suffocation is the final result a few minutes after ingestion of the toxin.
Anatoxin & its Scientific & Medical Applications
Despite its poisonous nature, however, anatoxin and many related man-made analogues have found widespread use in medicine and for pharmacological applications. Since it binds the nicotinic acetylcholine receptor irreversibly, it is an excellent means of studying this receptor, and also the mechanisms of neuromuscular action. Modified analogues are being used in order to further elucidate the receptor sub-types, and this research may lead to the development of new drugs which have none of the toxicity associated with anatoxin itself, but which act merely as acetylcholine replacement candidates. For example, the neurodegenerative disorder, Alzheimer's disease is associated with an inability of neurons to produce acetylcholine. Using the neurotransmitter itself as a therapy would not work since it is not long-lived enough. A more stable (and non-toxic!) agonist similar to anatoxin may work very well indeed.
Chemical Synthesis
There have been many total syntheses of anatoxin in both racemic and in optically pure form. The syntheses can be grouped into six general categories.
1. Ring-Expansion of Tropanes
Edwards and his co-workers utilised a photochemical ring-expansion method to access the anatoxin skeleton. The full report of this work can be found in the primary literature (Can. J. Chem. 1977, 55, 1372).
2. Cyclisation of Cyclooctenes
A very commonly employed method for creating the anatoxin skeleton is by a transannular cyclisation of a suitably substituted cyclooctene. This approach was taken by the Wiseman group (J. Org. Chem. 1986, 51, 2485).
A similar protocol was developed by Danheiser and co-workers (J. Am. Chem. Soc. 1985, 107, 8066). The cyclooctene was synthesised by ring-expansion of a cyclopropyl cycloheptanamine.
3. Cyclisation of Iminium Salts
Rapoport's synthesis of anatoxin relied on the formation of a reactive iminium ion, which was generated by a Lewis acid-induced decarboxylation. Intramolecular trapping produced the anatoxin skeleton (J. Am. Chem. Soc. 1976, 98, 7448). In fact, Rapoport has synthesised a whole range of related analogues using this type of chemistry in order to probe the requirements of the nicotinic acetylcholine receptor.
The Speckamp group (Tetrahedron Lett. 1986, 27, 4799) and the Somfai group (Tetrahedron Lett. 1992, 33, 3791) have both used similar strategies for their research on the total synthesis of anatoxin.
4. Cycloaddition of Nitrones
A very elegant approach to anatoxin developed by Tufariello used a nitrone cycloaddition to produce the core structure. Reduction of the N-O bond and subsequent elaboration allowed the total synthesis to be completed.
This is the only example of a nitrone cycloaddition approach to anatoxin in the literature to date (J. Am. Chem. Soc. 1984, 106, 7979).
Cyclisation of Allenes
A new synthetic strategy for the synthesis of an early intermediate in the Gallagher route to anatoxin employed the cyclisation of allenes using silver tetrafluoroborate (J. Chem. Soc,. Perkin Trans. 1 1991, 145).
This early intermediate was then further elaborated, culminating the total synthesis of anatoxin.
6. Tandem Reactions
A very impressive synthesis of anatoxin was provided by the Parsons group (J. Chem. Soc., Chem. Commun. 1995, 1461) who utilised a tandem sequence of reactions in one pot, to add a nucleophile to a beta-lactam. Ring-opening of this beta lactam gave a new nitrogen nucleophile, which was able to undergo a transannular cyclisation via epoxide opening.
The total synthesis was completed using methodology developed in the Rapoport group.
also known as Very Fast Death Factor
By Neil Edwards
The Chemical Laboratories
School of Chemistry, Physics
& Environmental Science
University of Sussex at Brighton
Chime enhanced version VRML version Chemsymphony version
Introduction
Anatoxin is a potent alkaloid toxin derived from a species of cyanobacteria called Anabaena flos-aquae. The first published report of the potentially lethal effects of microorganisms known as blue-green algae appeared in Nature in 1878. George Francis described an algal bloom that had formed in the estuary of the Murray River, in Australia, as "a thick scum like green oil paint, some two to six inches thick." The water at this point of the river was rendered toxic to wildlife, with animals drinking it becoming rapidly ill and dying terrible deaths. The effect of microalgal toxins, both in marine and freshwater environments, has increased in severity in recent years, and poisoning episodes are becoming more common and more widespread. For example, in the midwestern United States, the consumption of contaminated water has resulted in the deaths of ducks and geese by the thousands.
Concern for wildlife and also issues related to public health led to much investigation into the causes of these mass animal mortalities, and in the 1950s and 1960s Paul Gorham and his co-workers at the National Research Council in Ottawa established cultures for Anabaena flos-aquae, which allowed them to isolate the poisonous compounds which it produces. Anatoxin is perhaps one of the most toxic of the cyanobacterial toxins in this group, since the effects of ingestion can be lethal within 4 minutes, depending on the quantity consumed. This led to the compound being dubbed "Very Fast Death Factor." The chemical structure is shown (right) and is an interesting bicyclic alkaloid, and it was hoped that knowledge of this structure would enable scientists to discover the mode of action of the toxin.
Anatoxin is a severe neurotoxin, and as such affects the functioning of the nervous system, often causing death due to paralysis of the respiratory muscles. It is known that it acts as a mimic of the neurotransmitter, acetylcholine and irreversibly binds the nicotinic acetylcholine receptor (NAChR). Normal neuromuscular action involves the release of acetylcholine, which binds its receptor, leading to the opening of a related sodium channel. The resulting movement of sodium ions produces the action potential causing the muscles to contract. At this point, an enzyme called acetylcholinesterase then cleaves the neurotransmitter, allowing the sodium channel to return eventually to its resting state, and hence the muscle can relax. Anatoxin also binds the NAChR to produce an action potential, but cannot be cleaved by the enzyme. The sodium channel is essentially locked open, and the muscles become over-stimulated and become fatigued and then paralysed. When respiratory muscles become affected, convulsions occur due to a lack of oxygen supply to the brain. Suffocation is the final result a few minutes after ingestion of the toxin.
Anatoxin & its Scientific & Medical Applications
Despite its poisonous nature, however, anatoxin and many related man-made analogues have found widespread use in medicine and for pharmacological applications. Since it binds the nicotinic acetylcholine receptor irreversibly, it is an excellent means of studying this receptor, and also the mechanisms of neuromuscular action. Modified analogues are being used in order to further elucidate the receptor sub-types, and this research may lead to the development of new drugs which have none of the toxicity associated with anatoxin itself, but which act merely as acetylcholine replacement candidates. For example, the neurodegenerative disorder, Alzheimer's disease is associated with an inability of neurons to produce acetylcholine. Using the neurotransmitter itself as a therapy would not work since it is not long-lived enough. A more stable (and non-toxic!) agonist similar to anatoxin may work very well indeed.
Chemical Synthesis
There have been many total syntheses of anatoxin in both racemic and in optically pure form. The syntheses can be grouped into six general categories.
1. Ring-Expansion of Tropanes
Edwards and his co-workers utilised a photochemical ring-expansion method to access the anatoxin skeleton. The full report of this work can be found in the primary literature (Can. J. Chem. 1977, 55, 1372).
2. Cyclisation of Cyclooctenes
A very commonly employed method for creating the anatoxin skeleton is by a transannular cyclisation of a suitably substituted cyclooctene. This approach was taken by the Wiseman group (J. Org. Chem. 1986, 51, 2485).
A similar protocol was developed by Danheiser and co-workers (J. Am. Chem. Soc. 1985, 107, 8066). The cyclooctene was synthesised by ring-expansion of a cyclopropyl cycloheptanamine.
3. Cyclisation of Iminium Salts
Rapoport's synthesis of anatoxin relied on the formation of a reactive iminium ion, which was generated by a Lewis acid-induced decarboxylation. Intramolecular trapping produced the anatoxin skeleton (J. Am. Chem. Soc. 1976, 98, 7448). In fact, Rapoport has synthesised a whole range of related analogues using this type of chemistry in order to probe the requirements of the nicotinic acetylcholine receptor.
The Speckamp group (Tetrahedron Lett. 1986, 27, 4799) and the Somfai group (Tetrahedron Lett. 1992, 33, 3791) have both used similar strategies for their research on the total synthesis of anatoxin.
4. Cycloaddition of Nitrones
A very elegant approach to anatoxin developed by Tufariello used a nitrone cycloaddition to produce the core structure. Reduction of the N-O bond and subsequent elaboration allowed the total synthesis to be completed.
This is the only example of a nitrone cycloaddition approach to anatoxin in the literature to date (J. Am. Chem. Soc. 1984, 106, 7979).
Cyclisation of Allenes
A new synthetic strategy for the synthesis of an early intermediate in the Gallagher route to anatoxin employed the cyclisation of allenes using silver tetrafluoroborate (J. Chem. Soc,. Perkin Trans. 1 1991, 145).
This early intermediate was then further elaborated, culminating the total synthesis of anatoxin.
6. Tandem Reactions
A very impressive synthesis of anatoxin was provided by the Parsons group (J. Chem. Soc., Chem. Commun. 1995, 1461) who utilised a tandem sequence of reactions in one pot, to add a nucleophile to a beta-lactam. Ring-opening of this beta lactam gave a new nitrogen nucleophile, which was able to undergo a transannular cyclisation via epoxide opening.
The total synthesis was completed using methodology developed in the Rapoport group.
HAZARD CODES
some thing I learnt today
B
C
E
F+
F
Xn
Xi
N
O
R
T
T+
Biohazard
Corrosive
Explosive
Extremely Flammable
Highly Flammable
Harmful
Irritant
Dangerous for the enviroment
Oxidizing
Radioactive
Toxic
Very Toxic
B
C
E
F+
F
Xn
Xi
N
O
R
T
T+
Biohazard
Corrosive
Explosive
Extremely Flammable
Highly Flammable
Harmful
Irritant
Dangerous for the enviroment
Oxidizing
Radioactive
Toxic
Very Toxic
NEW PAIN Killers from plants /snails and frogs
as a physician who has to face patients with ch pain and some malingerers addicted to pain medications I am always interested in finding out new developments .
I recently read about ZICONITIDE a conotoxin from a snail ,this is approved for infusion in to the spinal column for ch pain relief .
very few studies about 2000 patients allover the world have had the treatment in experiments so far .
another aspect is the socalled Nicotinic receptors in the brain some of theses are responsible for cognition ( remember alzheimers) and analgesia ( does somoking reduce pain ?
the article excerpt follows an alkaloid from a frog (may be from frog food !)
interesting reading
Epibatidine
--------------------------------------------------------------------------------
published on the net by
Matthew J. Dowd, Graduate Student
Department of Medicinal Chemistry
Virginia Commonwealth University
Richmond, VA 23298-0540 USA
Click here for the CHIME-enhanced version of this article. Also, click on any structure to view a 3-D version of the molecule.
Within the rainforest of Ecuador resides a small, colorful, seemingly harmless amphibian called Epipedobates tricolor (Figure 1). This frog first introduced itself to the scientific world in 1974. It was then that Dr. John Daly of the National Institutes of Health isolated from the frog a compound initially called alkaloid 208/210 (its MW from mass spectrometry) [1]. Daly demonstrated that this new alkaloid was a potent analgesic (as measured in the Straub-tail response when injected into mice). Even after subsequent trips to South America, too little of the compound was isolated to make a structural determination.[2,3] Because of this lack of compound, for both scientific and political reasons, the remaining sample, about 750 micrograms, was kept in storage for several years. During the early 1990's, when NMR instruments and methods became more sensitive and sophisticated, Daly's group was able to determine the structure of alkaloid 208/210, which was renamed epibatidine (1)(1R, 2R, 4S exo-2-(6-chloro-3-pyridyl)-7-azabicyclo[2.2.1]heptane).
As stated above, epibatidine was shown to be a potent analgetic (about 200 times more potent than morphine). The truly exciting discovery was that epibatidine's mechanism of action appeared to be non-opioid. Many potent pain relieving drugs are opiates, morphine (2) being a very familiar example. Morhpine is an effective and potent analgesic; however, the potential for addiction and the development of morphine tolerance are major drawbacks to its use. Several major pharmaceutical companies have focused their efforts on discovering better analgesics. When Daly showed that epibatidine's effect was not blocked by naloxone, an opioid antagonist, this revelation produced much enthusiasm in the hope for a better drug.
If epibatidine did not exert its analgesic effect through opioid receptors, how then did it produce the pain relief? Shortly after the publication of the structure of epibatidine, several research groups, including Daly's, determined the answer by examining epibatidine's interaction with nicotinic acetylcholine receptors (AChRs), a type of ligand-gated ion channel whose endogenous ligand is acetylcholine (3) [4-6]. S-(-)-Nicotine (4) also activates these receptors - hence their name. Not only did epibatidine bind to and activate these receptors, it did so at extremely low concentrations (Ki=0.043-0.055 nM or about 55 pM). The finding that the analgesic effects of epibatidine are blocked by mecamylamine (a noncompetitive nicotinic antagonist), along with previous research illustrating potentially beneficial effects of nicotine [7,8], sparked a resurgence in the medicinal chemistry of nicotine and nicotinic analogues.
Medicinal chemists have attempted to define the structural and chemical features that are important for epibatidine's high affinity. With many biologically active compounds, the chirality, or absolute spatial configuration of the molecule, often influences its activity. For example, S-(-)-nicotine (Ki = 1-2 nM), the naturally occurring stereoisomer, has about 20-fold higher affinity than its enantiomer, R-(+)-nicotine (4) (Ki = 25 nM). 1R, 2R, 4S-(-)-Epibatidine is the natural stereoisomer excreted by the frog. Its enantiomer has been synthesized, tested for receptor affinity, and shown to have the same affinity as the natural isomer. A molecular modeling study by Dukat et al. rationalized the nonstereospecificity of epibatidine [5]. The enantiomers of nicotine appear to occupy different volumes in spaces, whereas the enantiomers of epibatidine occupy the same molecular volume.
Another early insight into the binding of epibatidine resulted from a comparison of the structures of nicotine and epibatidine. Both contain a six-membered pyridine ring; both contain a basic nitrogen linked to the pyridine ring by one or two carbons; both basic nitrogens are part of a five-membered ring (in epibatidine, the five membered ring is part of the azabicycloheptane structure). In fact, Dukat et al. showed that energy-minimized molecular models of the compounds could be overlayed such that major structural features are in similar positions in space (Figure 2) [5]. This modeling experiment was the first to show in a three dimensional fashion that epibatidine and nicotine may interact with similar receptor features.
Fig 2. Superposition of nicotine (cyan) and epibatidine (red). Nitrogens are blue; chlorine is green.
When studying biologically active compounds, one goal of medicinal chemists is to define a pharmacophore - the optimal three dimensional arrangement of chemical and structural molecular features required by a certain receptor. In the past, several research groups have proposed pharmacophores for the nicotinic receptor. Beers and Reich [9], Barlow and Johnson [10], and Sheridan and coworkers [11] have suggested nicotine pharmacophores. With some simplification, the models all contain a hyrogen bond acceptor atom (e.g., pyridine N or carbonyl O) and a center of positive charge (e.g., protonated basic nitrogen), separated by a distance of approximately 4.8 A. This distance is often referred to as the "internitrogen distance" because most, although not all, nicotinic analogues contain a pyridine nitrogen and a more basic nitrogen. With the emergence of epibatidine as a high affinity nicotinic agonist, Glennon and his group reevaluated the nicotinic pharmacophore and produced a model which indicated an optimal internitrogen distance of 5.1-5.5 A [12]. In 1996, a research group at Abbott Laboratories pubished work in which they synthesized a series of pyridyl ether compounds which are nicotinic agonists, some as potent as epibatidine. Molecular modeling studies incorporating these new agents suggested that a internitrogen distance closer to 6.1 A may be optimal for interaction at the nicotinic receptor [13]. There is still much work to be done before a precise nicotine pharmacophore can be agreed upon by the medicinal chemists.
With such a brief overview, it is impossible to review or mention all the research and scientists that have contributed to our understanding of epibatidine. Also, many of the complexities of the chemistry and biology have been omitted for brevity's sake. One area of complexity concerns receptor subtypes and populations. The nicotinic acetylcholine receptor, as stated above, is a ligand-gated ion channel, composed of five individual subunits: (alpha), (beta), (gamma), (delta), and (epsilon). There are, however, several different subtypes of receptor, each with a different composition of subunits, and different pharmacological properties. To date, nine alpha subunits (1 - 9) and four beta (1 - 4) subunits have been discovered. The muscle type nAChR, the most studied ligand-gated ion channel, is composed of (1)2 1 . Neuronal nAChRs are composed of various combinations of and subunits. The binding affinity and the pharmacological effects of a particular ligand are dependent upon the subunit composition of the nAChR. In a recent report from Dr. Luetje's lab, the affinity of epibatidine for several different subtypes of the nAChR was reported [14]. The results are shown in Table 1. As can be observed, there is a somewhat significant change in affinity when the subunits are changed (e.g., 30-fold difference in affinity when 3 2 is changed to 3 4). For more details, please refer to any of the excellent reviews of epibatidine[15-17], nicotinic ligands [18-20], and nicotinic receptors [7,8,21,22].
Table 1. Epibatidine Affinity at Neuronal nAChR subtypes.
Receptor Affinity (pM)
2 2
10.3 3 2
13.6 4 2
30.0
2 4
86.8 3 4
303 4 4
84.7
Synthetic organic chemists have also shown intense interest in epibatidine. Epibatidine's azabicycloheptane system is not common in natural products. E.J. Corey [23], T.Y. Chen [24], Broka [25], and Clayton and Regan [26] were the among the first to report total syntheses of epibatidine. Many other synthetic routes were later reported (See references 27-29 for reviews). More recently, Aoyagi reported a total sythesis in which the key reaction was an asymmetric Diels-Alder reaction with a chiral N-acylnitroso compound as the dieneophile [30]. Also, Sirisoma and Johnson described their synthetic route, which utilized an -iodocycloalkenone in a modified Stille reaction [31]. Because of the rather simple but intriguing structure of epibatine, chemists are certain to devise additional avenues to its synthesis.
So what does the future hold for epibatidine? The chance of epibatidine ever being used as a medicinal agent is quite low because of its high toxicity. However, new analogues of epibatidine have been and are still being synthesized. One interesting analogue is epiboxidine (6), a hybrid between epibatidine and ABT-418 (5) [32]. ABT-418, an isosteric analogue of nicotine, has analgesic and cognitive-enhancing properties in certain test systems. ABT-418 was designed by replacing the pyridine ring of nicotine with a methylisoxazole ring. Daly used this same isosteric replacement in epibatidine, replacing the chloropyridine ring with the methylisoxazole ring, producing epiboxidine. Although not as potent as epibatidine, epiboxidine (Ki = 0.6 nM) has higher affinity to the nAChR than nicotine (Ki = 1.01 nM) and ABT-418 (Ki = 10 nM). In addition, epiboxidine is 20-fold less toxic than epibatidine.
Several analogues of epibatidine, in which the azabicycloheptane ring has been altered, have been synthesized and tested. These include homoepibatidine (7), bis-homoepibatidine (8), and the azabicyclooctane analogue 9 [33-36]. Interestingly, compound 7 was shown to have analgesic potency comparable to that of epibatidine [34]. The diazabicyclic pyrazine DBO-83 (10) is another high affinity (Ki = 4 nM) nicotinic ligand that has some structural similarity to epibatidine [37, 38]. The idea for this compound originated partly from research aimed at discovering analgesics that were selective for the mu-opioid receptor.
Another puzzle to solve is the source of epibatidine. Researchers first thought that the frog produced the compound biochemically. However, when Daly raised some E. tricolor frogs in captivity, he could not isolate or detect any epibatidine[2,3]. The common presumption is that the frog obtains epibatidine, or some biological precursor, from a dietary source. Insects are one suspected source. On the other hand, because of the structural similarity of epibatidine and nicotine, a plant-derived alkaloid, a floral source may be a possibility. Whichever the answer, identifying the producer of this potent nicotinic agonist may provide an abundant source of epibatidine.
I recently read about ZICONITIDE a conotoxin from a snail ,this is approved for infusion in to the spinal column for ch pain relief .
very few studies about 2000 patients allover the world have had the treatment in experiments so far .
another aspect is the socalled Nicotinic receptors in the brain some of theses are responsible for cognition ( remember alzheimers) and analgesia ( does somoking reduce pain ?
the article excerpt follows an alkaloid from a frog (may be from frog food !)
interesting reading
Epibatidine
--------------------------------------------------------------------------------
published on the net by
Matthew J. Dowd, Graduate Student
Department of Medicinal Chemistry
Virginia Commonwealth University
Richmond, VA 23298-0540 USA
Click here for the CHIME-enhanced version of this article. Also, click on any structure to view a 3-D version of the molecule.
Within the rainforest of Ecuador resides a small, colorful, seemingly harmless amphibian called Epipedobates tricolor (Figure 1). This frog first introduced itself to the scientific world in 1974. It was then that Dr. John Daly of the National Institutes of Health isolated from the frog a compound initially called alkaloid 208/210 (its MW from mass spectrometry) [1]. Daly demonstrated that this new alkaloid was a potent analgesic (as measured in the Straub-tail response when injected into mice). Even after subsequent trips to South America, too little of the compound was isolated to make a structural determination.[2,3] Because of this lack of compound, for both scientific and political reasons, the remaining sample, about 750 micrograms, was kept in storage for several years. During the early 1990's, when NMR instruments and methods became more sensitive and sophisticated, Daly's group was able to determine the structure of alkaloid 208/210, which was renamed epibatidine (1)(1R, 2R, 4S exo-2-(6-chloro-3-pyridyl)-7-azabicyclo[2.2.1]heptane).
As stated above, epibatidine was shown to be a potent analgetic (about 200 times more potent than morphine). The truly exciting discovery was that epibatidine's mechanism of action appeared to be non-opioid. Many potent pain relieving drugs are opiates, morphine (2) being a very familiar example. Morhpine is an effective and potent analgesic; however, the potential for addiction and the development of morphine tolerance are major drawbacks to its use. Several major pharmaceutical companies have focused their efforts on discovering better analgesics. When Daly showed that epibatidine's effect was not blocked by naloxone, an opioid antagonist, this revelation produced much enthusiasm in the hope for a better drug.
If epibatidine did not exert its analgesic effect through opioid receptors, how then did it produce the pain relief? Shortly after the publication of the structure of epibatidine, several research groups, including Daly's, determined the answer by examining epibatidine's interaction with nicotinic acetylcholine receptors (AChRs), a type of ligand-gated ion channel whose endogenous ligand is acetylcholine (3) [4-6]. S-(-)-Nicotine (4) also activates these receptors - hence their name. Not only did epibatidine bind to and activate these receptors, it did so at extremely low concentrations (Ki=0.043-0.055 nM or about 55 pM). The finding that the analgesic effects of epibatidine are blocked by mecamylamine (a noncompetitive nicotinic antagonist), along with previous research illustrating potentially beneficial effects of nicotine [7,8], sparked a resurgence in the medicinal chemistry of nicotine and nicotinic analogues.
Medicinal chemists have attempted to define the structural and chemical features that are important for epibatidine's high affinity. With many biologically active compounds, the chirality, or absolute spatial configuration of the molecule, often influences its activity. For example, S-(-)-nicotine (Ki = 1-2 nM), the naturally occurring stereoisomer, has about 20-fold higher affinity than its enantiomer, R-(+)-nicotine (4) (Ki = 25 nM). 1R, 2R, 4S-(-)-Epibatidine is the natural stereoisomer excreted by the frog. Its enantiomer has been synthesized, tested for receptor affinity, and shown to have the same affinity as the natural isomer. A molecular modeling study by Dukat et al. rationalized the nonstereospecificity of epibatidine [5]. The enantiomers of nicotine appear to occupy different volumes in spaces, whereas the enantiomers of epibatidine occupy the same molecular volume.
Another early insight into the binding of epibatidine resulted from a comparison of the structures of nicotine and epibatidine. Both contain a six-membered pyridine ring; both contain a basic nitrogen linked to the pyridine ring by one or two carbons; both basic nitrogens are part of a five-membered ring (in epibatidine, the five membered ring is part of the azabicycloheptane structure). In fact, Dukat et al. showed that energy-minimized molecular models of the compounds could be overlayed such that major structural features are in similar positions in space (Figure 2) [5]. This modeling experiment was the first to show in a three dimensional fashion that epibatidine and nicotine may interact with similar receptor features.
Fig 2. Superposition of nicotine (cyan) and epibatidine (red). Nitrogens are blue; chlorine is green.
When studying biologically active compounds, one goal of medicinal chemists is to define a pharmacophore - the optimal three dimensional arrangement of chemical and structural molecular features required by a certain receptor. In the past, several research groups have proposed pharmacophores for the nicotinic receptor. Beers and Reich [9], Barlow and Johnson [10], and Sheridan and coworkers [11] have suggested nicotine pharmacophores. With some simplification, the models all contain a hyrogen bond acceptor atom (e.g., pyridine N or carbonyl O) and a center of positive charge (e.g., protonated basic nitrogen), separated by a distance of approximately 4.8 A. This distance is often referred to as the "internitrogen distance" because most, although not all, nicotinic analogues contain a pyridine nitrogen and a more basic nitrogen. With the emergence of epibatidine as a high affinity nicotinic agonist, Glennon and his group reevaluated the nicotinic pharmacophore and produced a model which indicated an optimal internitrogen distance of 5.1-5.5 A [12]. In 1996, a research group at Abbott Laboratories pubished work in which they synthesized a series of pyridyl ether compounds which are nicotinic agonists, some as potent as epibatidine. Molecular modeling studies incorporating these new agents suggested that a internitrogen distance closer to 6.1 A may be optimal for interaction at the nicotinic receptor [13]. There is still much work to be done before a precise nicotine pharmacophore can be agreed upon by the medicinal chemists.
With such a brief overview, it is impossible to review or mention all the research and scientists that have contributed to our understanding of epibatidine. Also, many of the complexities of the chemistry and biology have been omitted for brevity's sake. One area of complexity concerns receptor subtypes and populations. The nicotinic acetylcholine receptor, as stated above, is a ligand-gated ion channel, composed of five individual subunits: (alpha), (beta), (gamma), (delta), and (epsilon). There are, however, several different subtypes of receptor, each with a different composition of subunits, and different pharmacological properties. To date, nine alpha subunits (1 - 9) and four beta (1 - 4) subunits have been discovered. The muscle type nAChR, the most studied ligand-gated ion channel, is composed of (1)2 1 . Neuronal nAChRs are composed of various combinations of and subunits. The binding affinity and the pharmacological effects of a particular ligand are dependent upon the subunit composition of the nAChR. In a recent report from Dr. Luetje's lab, the affinity of epibatidine for several different subtypes of the nAChR was reported [14]. The results are shown in Table 1. As can be observed, there is a somewhat significant change in affinity when the subunits are changed (e.g., 30-fold difference in affinity when 3 2 is changed to 3 4). For more details, please refer to any of the excellent reviews of epibatidine[15-17], nicotinic ligands [18-20], and nicotinic receptors [7,8,21,22].
Table 1. Epibatidine Affinity at Neuronal nAChR subtypes.
Receptor Affinity (pM)
2 2
10.3 3 2
13.6 4 2
30.0
2 4
86.8 3 4
303 4 4
84.7
Synthetic organic chemists have also shown intense interest in epibatidine. Epibatidine's azabicycloheptane system is not common in natural products. E.J. Corey [23], T.Y. Chen [24], Broka [25], and Clayton and Regan [26] were the among the first to report total syntheses of epibatidine. Many other synthetic routes were later reported (See references 27-29 for reviews). More recently, Aoyagi reported a total sythesis in which the key reaction was an asymmetric Diels-Alder reaction with a chiral N-acylnitroso compound as the dieneophile [30]. Also, Sirisoma and Johnson described their synthetic route, which utilized an -iodocycloalkenone in a modified Stille reaction [31]. Because of the rather simple but intriguing structure of epibatine, chemists are certain to devise additional avenues to its synthesis.
So what does the future hold for epibatidine? The chance of epibatidine ever being used as a medicinal agent is quite low because of its high toxicity. However, new analogues of epibatidine have been and are still being synthesized. One interesting analogue is epiboxidine (6), a hybrid between epibatidine and ABT-418 (5) [32]. ABT-418, an isosteric analogue of nicotine, has analgesic and cognitive-enhancing properties in certain test systems. ABT-418 was designed by replacing the pyridine ring of nicotine with a methylisoxazole ring. Daly used this same isosteric replacement in epibatidine, replacing the chloropyridine ring with the methylisoxazole ring, producing epiboxidine. Although not as potent as epibatidine, epiboxidine (Ki = 0.6 nM) has higher affinity to the nAChR than nicotine (Ki = 1.01 nM) and ABT-418 (Ki = 10 nM). In addition, epiboxidine is 20-fold less toxic than epibatidine.
Several analogues of epibatidine, in which the azabicycloheptane ring has been altered, have been synthesized and tested. These include homoepibatidine (7), bis-homoepibatidine (8), and the azabicyclooctane analogue 9 [33-36]. Interestingly, compound 7 was shown to have analgesic potency comparable to that of epibatidine [34]. The diazabicyclic pyrazine DBO-83 (10) is another high affinity (Ki = 4 nM) nicotinic ligand that has some structural similarity to epibatidine [37, 38]. The idea for this compound originated partly from research aimed at discovering analgesics that were selective for the mu-opioid receptor.
Another puzzle to solve is the source of epibatidine. Researchers first thought that the frog produced the compound biochemically. However, when Daly raised some E. tricolor frogs in captivity, he could not isolate or detect any epibatidine[2,3]. The common presumption is that the frog obtains epibatidine, or some biological precursor, from a dietary source. Insects are one suspected source. On the other hand, because of the structural similarity of epibatidine and nicotine, a plant-derived alkaloid, a floral source may be a possibility. Whichever the answer, identifying the producer of this potent nicotinic agonist may provide an abundant source of epibatidine.
Wednesday, January 26, 2005
injections in INDIA
my brother SUBURAMA sent me the following article .
as a medical student we were posted for a week in the injection room in niloufer hospital where there used to be almost an assembly line technique which if practised by me now in USA would put me on the death row in texas for sure .
we used to fill a 20 cc syringe with penicilline and administer to 40 patients with the same syringe with needle changes
no one knew whether theye needles were sterilised at all.
boiling them was the way and aseptic technique was some thing learnt only after joining my MS in AIIMS I feel.
63% of the injections not safe: Study
New Delhi, Jan. 24: A shocking 62.9 per cent of injections administered in India are unsafe and the risk of spreading blood-borne viruses due to unsafe injection equipment is 32 per cent, a new study has said. According to the findings of a nationwide study by the All In-dia Institute of Medical Sciences to assess injection practices, an Indian, on an average, received 2.9 to 5.8 injections a year, with every other prescription (48.1 per cent) consisting of an injection.
“Approximately three to six billion injections are administered in the country every year, of which 1.9 to 3.8 billion injections are unsafe,” said N K Arora, who was part of the India CLEN Programme Evaluation Network that did the survey. “Safety is the least in immunisation clinics,” Arora said in a paper published by him. As part of IPEN, the country was divided into 15 zones, and clusters were drawn from urban and rural areas separately.
According to the findings, there were no major differences in the number of injections betw-een urban and rural populations. Almost three-fourths of injections administered in the immunisation sector were unsafe, the study said, with the risk of spre-ad of blood-borne viruses due to unsafe equipment being 32 per cent. Overall, 74.5 per cent injections were administered with plastic syringes. Glass syringes were used unsafely in as much as 90 per cent cases. In a bid to bring about safe injection practices in India, IPEN will soon set up model injection corners in 24 medical colleges in the country, the report said.
Health and Family Welfare Minister Anbumani Ramadoss has announced that auto-destructible syringes will be introduced under a universal immunisation programme in a few months. According to estimates by the World Health Organisation, around 112 billion injections are administered worldwide each year, and at least 50 per cent of these are unsafe, especially in developing countries.
as a medical student we were posted for a week in the injection room in niloufer hospital where there used to be almost an assembly line technique which if practised by me now in USA would put me on the death row in texas for sure .
we used to fill a 20 cc syringe with penicilline and administer to 40 patients with the same syringe with needle changes
no one knew whether theye needles were sterilised at all.
boiling them was the way and aseptic technique was some thing learnt only after joining my MS in AIIMS I feel.
63% of the injections not safe: Study
New Delhi, Jan. 24: A shocking 62.9 per cent of injections administered in India are unsafe and the risk of spreading blood-borne viruses due to unsafe injection equipment is 32 per cent, a new study has said. According to the findings of a nationwide study by the All In-dia Institute of Medical Sciences to assess injection practices, an Indian, on an average, received 2.9 to 5.8 injections a year, with every other prescription (48.1 per cent) consisting of an injection.
“Approximately three to six billion injections are administered in the country every year, of which 1.9 to 3.8 billion injections are unsafe,” said N K Arora, who was part of the India CLEN Programme Evaluation Network that did the survey. “Safety is the least in immunisation clinics,” Arora said in a paper published by him. As part of IPEN, the country was divided into 15 zones, and clusters were drawn from urban and rural areas separately.
According to the findings, there were no major differences in the number of injections betw-een urban and rural populations. Almost three-fourths of injections administered in the immunisation sector were unsafe, the study said, with the risk of spre-ad of blood-borne viruses due to unsafe equipment being 32 per cent. Overall, 74.5 per cent injections were administered with plastic syringes. Glass syringes were used unsafely in as much as 90 per cent cases. In a bid to bring about safe injection practices in India, IPEN will soon set up model injection corners in 24 medical colleges in the country, the report said.
Health and Family Welfare Minister Anbumani Ramadoss has announced that auto-destructible syringes will be introduced under a universal immunisation programme in a few months. According to estimates by the World Health Organisation, around 112 billion injections are administered worldwide each year, and at least 50 per cent of these are unsafe, especially in developing countries.
www.ekjalak.com
I have taken the first steps to create the web page for diabetis education in regional languages I have registeres a domain name called ekjalak.com
this is hindi for a view /glance .
as the subject is so vast all we can do is to give the patients a glance at proper diabetes management .I hope I will be able to interest others to join me in this task.
this is hindi for a view /glance .
as the subject is so vast all we can do is to give the patients a glance at proper diabetes management .I hope I will be able to interest others to join me in this task.
kakatiya univarsity and plant culture
I recently come across some papers By Dr.Ciddi Veeresham,about medicinal plant callus cultures and extraction of chemical components in commercial quatities ,he has also written a book about plant biotechnology ,I wish I could interest him in trying to culture the IBOGA plant to obtain ibogaine
I personally feel ibogaine would have interesting CNS efffects not only in addition treatment but in PTSD also and there will be a need for good PTSD treatment if the present iraq conflict continues the sane way it is going on .
I personally feel ibogaine would have interesting CNS efffects not only in addition treatment but in PTSD also and there will be a need for good PTSD treatment if the present iraq conflict continues the sane way it is going on .
Sunday, January 02, 2005
real audio in a blog !
http://www.eparivartan.com/realaudio/divyaprema.ram
to check if my testing real audio works !
it is not working needs more fine tuning
to check if my testing real audio works !
it is not working needs more fine tuning
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