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Is there a way to keep apps on computer but not on iPad?
Started by chookpea , Jan 03 2013 08:29 AM
8 replies to this topic
Posted 03 January 2013 - 08:29 AM
DS has too many games on the iPad. I'd like to keep them all on my computer and have one or two on rotation on the iPad.
I've deleted most of them off the iPad, but when I open up iTunes on my computer, but I don't see option to select which ones I want to sync to the iPad, like I can with songs. Is it possible?
Posted 03 January 2013 - 08:35 AM
There is an option to manually sinc everything, I believe it is on the front page when you open iTunes. I do this so that nothing sincs unless I go in and manually tick the box and then update.
I don't have my device here so I can't open iTunes to check, but it is definately able to be done
Posted 03 January 2013 - 08:36 AM
We have the option ticked to manually sync as well so we choose what goes on what device.
Posted 03 January 2013 - 08:51 AM
I am not sure why you would need to do that if you can't use them on pc of anyway. If you click on the app store icon on the iPad and click on purchased you can easily add things back to your iPad that have been deleted.
Posted 03 January 2013 - 08:58 AM
Ah...didn't think to look in the purchased page. Thought I had to keep a copy of the app on my computer and sync it over to the iPad when I wanted to use it. Thanks.
Posted 03 January 2013 - 08:59 AM
QUOTE (Helen Magnus @ 03/01/2013, 08:51 AM) <{POST_SNAPBACK}>
I am not sure why you would need to do that if you can't use them on pc of anyway. If you click on the app store icon on the iPad and click on purchased you can easily add things back to your iPad that have been deleted.
This is the way I'd do it - if you have already purchased it you can just add them back whenever you like. I'm not sure if you need the password to do this though so depending on your child's age they might be able to do it on their own!
Posted 03 January 2013 - 09:38 AM
In iTunes, when you click on the device, there is a tab called Apps, and here you can sync only what is ticked. Otherwise you can do it manually by dragging to the device, but if you then go to sync it, you want to make sure you've ticked the right apps. Either way, pick the method you're going to continue to use as it's a pain to swap between manual and syncing.
Posted 03 January 2013 - 09:44 AM
Once you've bought them they are yours as others have said you can download them again from the Purchased section.
But have you thought of grouping your apps into folders?
Posted 03 January 2013 - 09:51 AM
I was also going to suggest folders on the ipad.
Cooper has a schools app folder and a games folder. It makes it clearer of what can be used where and when.
I also just delete them for more space and pop them back on if needed.
Cheers bron
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Rated 4 out of 5 by 1092 reviewers.
Rated 5 out of 5 by mauigirl Awesome view! I only stayed one night in this beautiful hotel and everything was perfect. The staff at the front desk was very nice and professional and gave me all the information I needed. May 28, 2013
Rated 5 out of 5 by Jordan Everything was Excellent This was such an amazing trip and the Sheraton Waikiki was the true reason. From valet when we arrived late at night to the front desk when we checked out early in the morning, EVERYONE was so nice and accommodating. The rooms were spacious and clean, housekeeping attentive and boasted a beautiful view. The food by the pool was some of the best we've ever had outside of a four star restaurant. We will be returning in the future! May 28, 2013
Rated 4 out of 5 by WJCHANG FOOD OF THE LOUNGE the breakfast of the Lounge need more kinds... May 26, 2013
Rated 5 out of 5 by Jen73 get ready to relax and enjoy the views The Sheraton Waikiki is our favorite place to vacation as it always means that we will enjoy a fantastic vacation. We take several nice vacations yearly, but our annual trip to the Sheraton Waikiki is the one that we look forward to the most for relaxation. We always know what to expect..... it is so nice to see the many familiar faces year after year. The joy of watching the waves and the sea turtles, right in front of the resort is fabulous. Thank you. May 26, 2013
Rated 2 out of 5 by DG0071 DG0071 Location excellent, Ocean view was great, Unfortunately was given a room with 2 double beds when should have been given 1 queen, made my romantic stay a bit uncomfortable, generally felt that if I wasn't part of a tour group I didn't matter to them, definitely come back to Hawaii but not stay here again. May 26, 2013
Rated 5 out of 5 by Andrea001 Awesome hotel! Loved our stay here! Resort amenities and pool were fantastic. Staff is super friendly and helpful...everyone was constantly greeting us. Room seemed a little bare...minimal modern-ish furniture and our view was terrible (we saw the rooftop pool and parking garage of the hotel next door). This was my only complaint given that we are SPG gold members I expected a better room since other SPG hotels always gave us a decent view. On a positive note, the beds were awesome and very comfortable, my kids especially loved them. We had a mini fridge in the room which was fantastic to have. Rooms were superbly cleaned. We've seen other hotels and we are so glad we chose this one! High end shopping all around as well as restaurants and the International Market place (pearls and Hawaiian souveners). Resort fees and parking was actually lower the other hotels. Thank you for an great anniversary experience! May 25, 2013
Rated 4 out of 5 by Nevertoreturn Wonderful Beach View Great position on point and has therefore best views and most sun. We has amazing views from 25th floor of Waikiki. Rooms and common areas are a bit tired and need refurbishment but it did not detract from the experience. The hotel is also very centrally located. I would definitely stay there again May 22, 2013
Rated 2 out of 5 by NickM Not the best :( Spent Nearly $2000 For 3 nights, Friday, Saturday and Sunday Expecting alot from my money and all i got that was worth it was the View from my hotel room balcony. The view was amazing but the hotel room was very out dated. I would have been better and more happier staying a $50 a night back packers. I had lamps that didn't work and a piece of glass in my carpet that wasn't cleaned from the last guests( room 2058). There was no service at all any place in the hotel for me. No staff checking up on me to see if i was happy Or needed anything !!!!The only time i got service was when i hired a cabana on Sunday and the waitress dropped a tray of drinks on me. Defiantly not happy with my 3 days... When i checked out the lady at the counter didn't ask how my stay was. she just walked away ! The only person that was decent and helpful for me was the lady that helped me find my shuttle bus back to the air port. Very pore effort! i don't think ill ever return or stay in another Sheraton hotel ever again :( I'am a chef in a big hotel in Australia and ill never recomened This hotel to my staff or friends Sorry Nick M May 22, 2013
Rated 2 out of 5 by Joshy un satisfactory. I would not reccomend We are Gold members of starwood. We asked for an upgrade which we are entitled to. Did not get upgraded to club level. Our room had very basic beds not the excellent Sheraton beds we have slept on before. We did not even have a chair in our room let alone a table. I wiil never stay here again or reccomend. This should be a 1 star hotel. May 21, 2013
Rated 5 out of 5 by Candy15 Perfect location on Waikiki The hotel's location on Waikiki Beach makes it a wonderful choice if you want to be right in the action! May 21, 2013
Rated 5 out of 5 by Holly84 Great central Waikiki beachfront Hotel This hotel is exceptional, it right on Waikiki Beach, in a great central location and offers fantastic service! I will be recommending to all my family and friends! May 21, 2013
Rated 4 out of 5 by Paul45 Special Mention I'd like to commend Jennifer in Guest Services for her exceptional effort in difficult circumstances to rearrange rooms to enable us to be located near to our grandchildren during the AIMS Convention earlier this month. Her diligence and helpfulness was much appreciated. May 20, 2013
Rated 5 out of 5 by Jermar Elevators I have stayed in probably stayed in 750 to 2000 hotels and never have I seen elevators not ring to noticing you when it's stops on your floor after pressing button. This has 10 elevators. You push down button and 1 stops but dosn't ring. If your not looking all around you miss it May 20, 2013
Rated 2 out of 5 by JayJay Disapointing stay. Too noisy room and small capacity. - I've complained about nextdoor and bar noise even after midnight. No good room /c poor view No kind staff. May 20, 2013
Rated 2 out of 5 by RufusInHI Hit or Miss; More Miss than Hit. OVERALL IMPRESSION: Nothing terribly wrong with this place except for the inconsistent Front Desk and the poor Club Lounge unhospitible service. Having stayed at this properties several times the SPG check in line is hot or cold when it comes to delivering genuine Hawaiian hospitality. SPG RECOGNITION: Is more miss then hit. The typical excuse is the hotel is sold out of premium rooms and suites, yet a call to SPG reservation or check online shows that the hotels has high category rooms and suites are still available. After complaining to Management; it is amazing for the Hotel to eventually find a suite that was just returned to inventory by the maintenance department. How many of us Seasoned Platinum SPG Members have heard this same excuse time and time again. THE ROOM: Non-suite rooms are small; typical for Waikiki. If you are very fortunate to get a suite upgrades, the suites are very spacious. Rooms are clean and recently renovated and nicely furnished with Hawaiian theme. LOCATION: You can't beat it! It is definitely central Waikiki off the main street (Kalakaua Ave); so traffic noise is not an issue. EXCEEDED EXPECTATIONS: Hotel has two swimming pools. The adult only infinity pool (Ewa side) is a nice respite from the loud and crowded main resort pool on the Diamond Head side of the hotel. DID NOT MEET EXPECTATIONS: Club Lounge while has a spectacular view of Waikiki Beach and Diamond head, the staff is unfriendly and the evening food selection is very stodgy. Lounge Agents are more concerned about whether you are eligible to enter the lounge/ NOTE: access to the lounge requires your room preprogrammed electronic key to unlock the club lounge door which has to be programmed by the Front Desk. Yet you still have to provide your name and room number to the club agent which is validated prior to club entry. I invited two business colleagues to the lounge and was embarrassed and chastised by the Club lounge agent and reprimanded me in front of my guests that the Club lounge was only for Hotel guests. The Club lounge access restricted to only Hotel Guests not allowing the Hotel Guests to bring their guest/friends/family/business colleagues makes no sense especially when alcoholic beverages are not free and provided at an absorbent cost. The is no Aloha in the pretentious Club Lounge. Complaints to Hotel Management went unheeded and meet with curt excuses to defend the club policies. May 18, 2013
Rated 1 out of 5 by larry0358 HORRIBLE EXPERIENCE! Horrible experience, would not recommend to anyone. There was NO ONE there at the front of the hotel when we unloaded our car for check in, it took 30 minutes in line to check in in the early afternoon, they gave us TWO DOUBLE beds when our reservation was for one KING and did not TELL US until after we took all our OWN luggage (6 items) upstairs to our room. Then, we had to take our OWN LUGGAGE back downstairs and wait in the check-in line, which took another 30 minutes, and get in line again to get the room we wanted. The manager did not seem to believe anything I told him that just happened to us, so I had to SHOW him my one KING bed reservation on my phone. The service provided overall was really bad. I would not come here ever EVER EVER again. May 16, 2013
Rated 5 out of 5 by suesue22 Best Pool on the beach. The Sheraton Waikiki seems to be the best place to stay whether you want night life or relaxation. The infinity pool is the best pool on the beach. The staff is always right there with whatever you need but they don't hang on you waiting for your requests. If you want to go down to the beach and get in the ocean it's right there. The room was clean and the staff was attentive to your needs. May 15, 2013
Rated 4 out of 5 by Jilly47 Good location for Waikiki activities For such a large hotel everything seems to work remarkably smoothly. Breakfast buffet seating very adequate inside and outside on lanai. Check in/out handled very efficiently. Poolside/beach personnel efficient and helpful. May 14, 2013
Rated 4 out of 5 by jack26 Better than expected but resort charge I was there with my fiance last week and I used my points for a stay but I found out that there were $31 resort fee that I had to pay which was disappointing because I was not notified when making reservation. Pool was good but the bar was little overpriced. Late check out was good but I had to change room in the morning. May 14, 2013
Rated 3 out of 5 by Mini30 The staff make it This hotel needs to be seriously updated. The rooms are old and tired...like something out of the 70s. The pool isnt big enough, and its not a pleasant experience to spend an afternoon there. On the other hand the staff were amazing, especially Alex who does the graveyard shift. he went out of his way to make us feel welcome. Some other good points are the Edge bar...the food is good here and cocktails are yummy. The location of the hotel is perfect too. I would only stay here again if they did a complete renovations. May 13, 2013
Rated 5 out of 5 by Edwin Mahalo Sheraton Team A wonderful location, run by a fantastic GM and capable staff. Everyone was so wonderful. I would have to say that the housekeeping staff was always smiling, saying good morning and so well motivated. The crew at the Pool - Bruno and Nate! The whole staff at the Peet's Coffee (Guy with the Mohawk and pregnant girl) Rum Fire - Aaron, great service and attention to detail. May 12, 2013
Rated 5 out of 5 by KJlized KJlized Location is great for family trip. It is close to beach, main street and Duty free shops. Two pools are clean and great to relax in. Kids love the slide. Ocenview Room is excellent and the staff are really friendly. May 8, 2013
Rated 5 out of 5 by Becky AMAZING CUSTOMER SERVICE Everyone was very friendly...everywhere we went. May 8, 2013
Rated 4 out of 5 by Bobcat12 Nice and convienent property Hotel was in popular area close to shopping, restaurants, and entertainment. Facility was clean and offered many extras. Property is worth return stay in the future. May 8, 2013
Rated 4 out of 5 by Smokey52 Beautiful Hotel but needs nice restaurant It was a beautiful hotel. Our room, balcony and view was very nice. The lobby and shops were nice. However, a nice restaurant for fine dining is needed. Also, the Kai Market needs to be open for lunch as well. The Rum Fire restaurant didn't have much of a menu, very limited. Get rid of those orange floating bean bags in the infinity pool. They are useless and everyone I saw had trouble getting on them. May 8, 2013
Rated 5 out of 5 by JULIE GOOD THE ONLY PROBLEM THAT I HAVE WITH THE COMPANY I BOOKED WITH I WAS NOT AWARE THAT I DID NOT EARN STARWOOD POINTS BECAUSE I BOOKED WITH A THIRD PARTY. THIS SHOULD BE MADE KNOWN TO CUSTOMERS I BOOKED A TOTAL OF 12 NIGHTS ALL AT SHERATONS AND ALSO I JOINED MY FRIENDS AS WELL ONLY TO FIND OUT WE ARE NOT ENTITLED TO ANY POINTS May 8, 2013
Rated 3 out of 5 by Pickle Great location. Service needs improvement Pros: Great location. Easy access to beach/pool and convenient. Everyone in Hawaii is friendly Cons: Our phone and room internet wasn't working. We went to front desk and they said they would send an engineer to look at the issues and fix them. Went back to room that night and issues still not fixed and voicemail light was on. Obviously, we couldn't check vmail cause the phone doesn't work! Vmail prob from housekeeping. Left it alone. Maybe needed another day to fix it. Nothing happened. Eventually, we had to get the internet fixed ourselves. During the last night, we had to complain about the phone again because apparently, my sister left me an urgent voicemail days ago. During the stay we also couldn't ask for morning calls cause the phone doesn't work. I also got misinformed about some information. Fitness Center not up to par. Food ok. I would stay here again but service needs improvement. May 3, 2013
Rated 3 out of 5 by KirbyWe Disappointed in Waikiki Whe the hotel location was very good, that is about all I can say. The platinum suite upgrade was nothing more than what appeared to be a regular room on a higher floor. On my day departure, I had to ask 3 different staff members if there was someone manning the SPG preferred desk. Twice the person I asked disappered and never came back. It wasn't until the thrid time and 15 mnutes later that I told a front desk employee hat I could not wait any longer and that the hotel could bill me for any expenses. She then went to the back office and within about 5 minutes a staff member came out to help me. In the mean time I realized I would have been almost just as well off and probably much less frustrated if I had ust waited in line with everyone else trying to check in to the hotel but I was under the impression that the SPG preferred desk would/should be manned at all times. If not then I would expect that an employee working the front desk would recognize a preferred customer and come to the SPG desk to assist that customer. If not then why bother havnig an SPG preferrd status at all. All in all I have been very satisified with SPG. However, due to the front desk staff I will never stay at the Sheraton Waikiki again. May 3, 2013
Rated 5 out of 5 by KaySL True Resort Living Great location and amenities. Kai Market was a great breakfast buffet option. Dole whips around every corner. Convenient shops for needs and gifts. Resort fee a little high, but take advantage of all that it offers. Lei making class was fun. Khakari Spa - excellent. Gorgeous infinity pool. Extremely close to everything in Waikiki. Only down-side - sheets had stains or odor on fresh change. May 3, 2013
Rated 1 out of 5 by Reese Sheraton Waikiki Unsatisfactory! I had to contact the front desk manager about the room cleanliness and that my rooms toilet ran all night... May 2, 2013


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Astray Motel & Backpackers
Astray Motel & Backpackers
Hotel Guest Rating: 8.1/10
1202 Pukuatua Street
Rotorua 3010
Hotel Freebies Available*
• Free Internet Available show dates
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Astray Motel & Backpackers
Offering free Wi-Fi and free on-site parking, Astray Motel & Backpackers is located in central Rotorua. Guest facilities include a shared kitchen and a common room with a large flat-screen satellite TV.The airport shuttle bus stops right outside of Astray Motel. Kuirau Park, with many of the geothermal activities for which Rotorua is famous, is 500 metres away.The hostel offers rooms with either private or shared bathroom facilities. All bed linen is provided. Guests have access to laundry facilities and a tour desk.Astray Motel & Backpackers is located 1 km from Rotorua's lakefront. Wi-Fi internet access is available. ...read more
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- Internet services
- Free parking
Astray Motel & Backpackers Amenities
- Facilities for disabled guests
- Family rooms
- Free parking
- Free WiFi
- Heating
- Internet services
- Laundry
- Non-smoking rooms
- On-site parking
- Private parking
- Tour desk
- WiFi
- WiFi available in all areas
Hotel Information
Please note that you cannot check in outside reception opening hours.
- Blarney's Rock (0.1mi)
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Sarah Millican - Outsider
17/11/15 - 28/05/16
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Michael's big break came at the Royal Variety Performance in 2006.His debut DVD, Live and Laughing, was the fastest selling of all time, only to be eclipsed by his second, Hello Wembley, that sold over 1.4 million copies and was the 2009 Christmas number one.He now hosts his own BAFTA nominated BBC 1 series, Michael Mcintyre's Comedy Roadshow, and ...
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I Love to Wear Pantyhose
Personal Stories, Advice, and Support 1,556 People
My affinity for pantyhose grew (as a young boy),whilst on a flight down South as I caught a glimpse of a young lady standing in the isle adjusting her hose, as most of the other passengers slept. As I matured, the occasional pantyhose experience with girlfriends caused my affinity to somewhat increase. Fast forward to my...
greenhornet77 31-35, M 2 Responses 7 May 21
Pantyhose LoverI love my pantyhose so much! I have worn thigh highs and stockings with garter belts over the years because everyone says they are sexier, more classic or have "easier access". Pantyhose always got a bum rap as far as I'm concerned, they can be very sexy and...
MonicaCD 51-55, T 8 Responses 11 Dec 26, 2008
If there is one advantage to the coldwhether wearing pantyhose is a must! It seems like it has been very cold, especially wear I am living. Rather than turn the heater up I just throw another pair of pantyhose on. So wearing two pair sometimes three not only keeps me warm but is three times the sexy feeling. Plus...
jilliank 51-55, M 3 Responses 9 Dec 5, 2014
I have been wearing pantyhosesince the age of. 13 found them exciting,soft and sexy, and very comfortable to wear.meet a girl at 14 , she always wore navy blue pantyhose.she asked me to feel them ,was so excited, I almost lost it there. She asked me if I would like to wear some said yes had a wonderful time...
lvrofhose 56-60, M 2 Responses 10 Dec 3, 2014
An Amazing Blessing...How can a garment that is so light and nearly see through make a person feel so amazing and so alive? I can't describe how good wearing a good pair of well fitting pantyhose makes me feel. It makes me feel complete and calm. I love the color it adds to my legs, and how it...
PHSensei 36-40, M 4 Responses 9 Nov 12, 2010
Touching your feet and legswhile wearing pantyhose is the best
justin12397 16-17, M 2 Responses 3 Oct 18, 2014
Hi,, I am a pantyhose wearing bikerand It is bike rally time again, I am going to wear my pantyhose from now till Sunday, I am going to sleep in them and can't weight, During the night I am going to walk around the campsite, wearing pantyhose, crocks and a t-shirt and nothing else. The feeling of walking around...
hosebiker 51-55, M 2 Responses 5 Nov 14, 2014
I'd like to change my channel URL,but YouTube says I need at least 500 subscribers! Please subscribe to my YouTube Channel: https://www.youtube.com/channel/UCY_0vXB7oKVWNekeHD5cIXA
LegStyles 26-30, M 1 Jan 14
I just ordered can not waitfor it to come.
wtbwoman 41-45, T 2 Responses 2 Jan 11
My Pantyhose History Pt3I was only back home from my grans for a week,when i had to go camping with St.Johns Ambulance down at Bexhill on sea,me and my friends had a grand old time doing various activities,but unknown to me the best bit of the week was to come. On the Friday the...
sheerdesire 51-55, T 5 Responses 9 Aug 24, 2011
JennyTom 36-40, F 8 Responses 14 Apr 18
When i was younger, around 15,i didnt wanna hide it as much anymore, i wanted to have someone to talk to about it and not be judged for it. I remember i told my mom about it very shyly and the first thing she asked waa if i liked boys and i said no, i dont like guys, im straight, j just like the feeling of...
Phlover544 18-21, M 1 Response 5 May 7
My Pantyhose History Pt2So by now i was now 11 years old,and getting very good about hiding and wearing pantyhose,my sisters did'nt really wear any,as they were younger than me,so i had to make do with my mums,which as you know were a bit on the large side,but i did'nt really care. Summer came...
sheerdesire 51-55, T 1 Response 7 Aug 23, 2011
How I Started Loving PantyhoseI first wore pantyhose at 5. Although is years before i really started LOVING pantyhose, but my story of pantyhose do starts here... when i was 5, at elementary school, our class has to play a show in the graduation ceremony. some of the boys are playing a character that need to...
england4ever 22-25 5 Responses 6 Jan 11, 2012
I had this crazy dream last nightthat I was having a Super Bowl party at my house and I was wearing just a Hooter's Girl uniform. My friends were there and family were mingling and eating hot wings...that I apparently just served them. I was unaware of my attire at first then upon realizing became a little...
Brianhi26 51-55, M 6 Responses 9 Feb 25
I love wearing black pantyhose under my jeanswhen I go out, I adore the feeling on sheer tights on my newly shaven legs
Emmajane1956 56-60, M 8 Responses 9 Oct 9, 2014
Just got home from work.Looking forward to a weekend wearing pantyhose. Lovely
Emmajane1956 56-60, M 7 Responses 10 Oct 24, 2014
Wearing Pantyhose TonightTonight I'm going to go grab me my favorite pair of white pantyhose, :) pantyhose are the best thing to ever come into my life! I love the colors the feel everything about them!! If anyone else feels this way heart my experience :* <3
ZeldaGuardian95 18-21, T 3 Responses 7 Oct 12, 2013
JennyTom 36-40, F 4 Responses 5 May 1
HairyPanties 18-21, M 6 Responses 3 Sep 28, 2014
justin12397 16-17, M 1 Response 3 Oct 18, 2014
Tlo1969 41-45, M 5 Responses 8 Apr 5
kendoomondoo 66-70, M 1 Jan 9
Just some comments. I have been wearingpantyhose for a long time. It seems that it goes in cycles from wearing everyday to most days. Lately I have been dressed completely under my pants and button down shirt. I find the days I don't wear them I definitely feel like I am missing something. Yesterday I noticed that...
jilliank 51-55, M 8 Responses 17 Mar 25
A Day Without Wearing Hose Is A Wasted DayDoes anyone else feel that way? I love wearing hose everyday. If not pantyhose, then thigh high stockings or knee highs. Some form of sheer nylons. A pedicure and keeping my legs shaved, and wearing hose is like air and water for me ;-)
hunterloveshose 41-45, M 13 Responses 8 Jul 2, 2011
The first time i tried on pantyhose i wasprobably 10 or 11, i dont know what made me so interested in them, i just was. The very first memory i have of seeing them was when my mom used to dump all the laundry on my bed (everyones laundry) and i used to help her fold clothes. Well this one time i was looking through...
Phlover544 18-21, M 3 May 7
Part (2)... So after having broken up with myx girlfriend who introduced me to the art of pantyhose, I once again went on a drought. Fast forward several years when I put myself on a dating site, and wherein I met a young lady who in casual conversation, via email asked, "what kind of fun things are you into"? So I...
greenhornet77 31-35, M 1 Response 8 May 24
First Pantyhose ArousalHi everyone! When I was 5 years old, my mom used to wash her pantyhose in the shower and let them dry nearby. One day when i was taking a shower i decided to put the pantyhose on and the feeling of wet nylon on my skin got me aroused for the first time. Since that moment there...
mediaswolford 26-30, M 14 Responses 10 Jan 31, 2009
I'll Never StopMy addiction to wearing pantyhose and tights truly is an addiction. I will take any opportunity I can get to slip into a pair of silky, shiny hose. The way they make me feel is indescribable. It's like being embraced, caressed, massaged, and aroused all at once...
silkyhoseman 31-35, M 4 Responses 8 Mar 10, 2012
I had another great day at Disney,wearing openly of course. And...."I MET JASMINE!!!" Shes so pretty!
Dockilo 41-45, M 4 Sep 19, 2014
I fell in love with hose backas a kid sneaking clothes from my mother and sister. Then it was hose with garters. Pantyhose came along about the time I hit puberty and by the time I was dating it was rare to find a girl in gartered hose - which was a real turn on for me. No every crotch I ever got to even...
cdsubalice 56-60, M 7 Responses 21 Mar 26
Just because its Christmas Eve I thought what agreat time to dress up. I decided to dress all the way starting with a nice bath and soft bath oils freshly shaven legs and a glass of early morning wine. Full makeup and a brand new pair of Leggs taupe pantyhose. They are extra soft and feel so good on an oiled and shaved...
jilliank 51-55, M 7 Responses 12 Dec 24, 2014
This is what I love to wear during my earlymorning walks,, pantyhose, and a jacket or t-shirt,, nothing else...
hosebiker 51-55, M 0 Jun 20
CrotchlessMy favorite pantyhose are crotchless. Drives my man nuts knowing how accessible my treasures are when we're in public.
Ann242 46-50, F 9 Responses 9 Feb 19, 2012
My mother encouraged my crossdressing at anearly age 11 she was happy to let me wear my older sisters panties and bras. I'm sure this is why I have always been a sissy.
My Pantyhose Experience I am a 47 year oldseparated woman and I have enjoyed wearing pantyhose from my early teens. I just can't understand why other woman hate them so much. I am a pale skinned red head who neither wants to or can get a tan. Pantyhose have given me the confidence that my legs always look nice in them...
Lilly500 46-50 12 Responses 19 2 days ago
So wearing pantyhose is still very enjoyableafter several years of daily wear. I wear support hose (leggs everyday support) everyday, year round. I love the all day massage with each leg movement. I like to be a little more relaxed at home though. I do not care for light weight hose such as all sheer or just every day...
BenHosedGuy 51-55, M 1 Response 10 Apr 5
I love to wear pantiesand pantyhose to work
Skirtman101 31-35, M 8 Responses 11 Oct 23, 2014
I love Easter and all the other holidaysthat require a girl to dress up and be so feminine and it really makes me feel that I'm being normal and accepted k love the looks at my legs when I'm in public very rare do I do this but today I got a complement from a really cute guy and he thanked me for doing what his...
samara11besc 51-55 2 Responses 8 Apr 5
Why is it ok for women to wear men's clothesand not get remarked at or made fun of, but it is not ok for men to wear women's clothes, men should be able to wear whatever we want, if men wore pantyhose or skirts or dresses out in public we would be called perverts or have people staring at us thinking we were weird, but it...
wtbwoman 41-45, T 10 Responses 20 May 8
I Love Most Of 'em!Over the years I've collected quite an assortment of pantyhose. Most of them are L'eggs Sheer Energy, some No Nonsense, a few Silkies, and lately some George. Of course my favorites are still L'eggs Sheer Energy. Anyway, after realizing at the beginning of the year just how...
57Peggy 56-60, M 4 Responses 8 Apr 18, 2012
Hi. Good for you and I know the feeling.Sheer to waist pantyhose and heels are gorgeous. Annie
annieinhose 46-50, T 1 Response 8 Jul 16, 2014
Related Experiences
Just been to the supermarket in my pullup , I was wearing shorts , they fell down - everyone saw me wearing my pullup ! I felt so naughty
biguy2015 22-25, M 0 20 hrs ago
Women's clothes are so irresistible! So many different types of dresses, shirts, skirts SO MANY OPTIONS! I love the variety. I can't stop buying them, even though I don't always...
00nothankyou2010 22-25, T 4 Responses 19 1 day ago
I just wear silk underwear now...my wife calls them J's knickers to guests after she has washed them!
JoSometimes 61-65, M 5 2 days ago
I wear dirty ones after my female coworker wears them the day before I rub my hot dog on them and I wet them
bandit5320 31-35, M 0 2 days ago


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PHOTOS: Opening Ceremonies of the Gay Games
Cleveland knows how to throw a party.
Cleveland knows how to throw a party.
Celebrities combined their star power for a good cause that prepares and trains young adults on how to become LGBT allies.
Three men are being considered to take baseball's top job, and one of them is a strong LGBT ally.
An executive for the Baltimore Ravens invokes the tired 'hate the sin, love the sinner' philosophy, but is that truly Christlike?
President Obama welcomes foreign LGBT athletes to the United States for Gay Games 9 in Cleveland, Ohio.
What If star Daniel Radcliffe is a big football fan, and he's amazed that openly gay player Michael Sam was the 249th pick in the NFL draft.
Michael Sam made a tackle put the pressure on Saints' third-string quarterback Ryan Griffin in his first NFL game.
As the Gay Games kick off in the Cleveland area this weekend, a church signs onto the event as a sponsor.
Anti-gay White Sox fans react predictably to the announcement of an LGBT Pride Night in support of the community.
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- Frits R. Rosendaal
- Department of Clinical Epidemiology and Department of Thrombosis and Haemostasis, Leiden University Medical Center, Leiden, The Netherlands
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The author reports no competing interests in relation to statins. The author is named on several patents for prothrombotic gene variants (such as Factor V Leiden) but does not benefit personally from royalties on these.
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Wrote the first draft of the manuscript: FRR. ICMJE criteria for authorship read and met: FRR. Agree with manuscript results and conclusions: FRR.


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Hypnotherapy for relationships also works to rid the patient of the fears and phobias that may be sabotaging their relationships. For example if a person suffered from a lot of rejection in the past then this is something that could be addressed during hypnotherapy. The hypnotherapist would work to make the past fears go away and replace the fears with positive, hopeful thinking about the future.
Everyone has a "time line" in his or her head. It is how and where you store all of the memories of your past on an unconscious level. The time line is also how the grain knows how to differentiate the difference between a memory from the past and the potential events that could take place in the future. It is important to realize that behavioural types of modifications do not take place consciously but instead they take place at an unconscious level that is not detected by the conscious mind.
Hypnotherapy will also help you alter the way you think about food and will help bring about more respect and love for yourself. Relaxation is another positive attribute of hypnotherapy. As a patient of hypnotherapy, you will develop a more positive and relaxed outlook on food, dieting, nutrition and how you feel about yourself in general.
For More information http://www.myhypnotherapist.com.au


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Poor bets placed on Apple taking dual tablet route in SeptemberAnalysts and industry-watchers alike are constantly scraping the barrel for details on Apple's forthcoming tablet-based device but are consistently missing the mark, AppleInsider has been told.
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More specifically, Doherty said one resembles a large-sized iPod with a 6-inch screen, while the second sports an even larger display. He added that Apple could launch both devices as early as September, a decision which he said rests in the hands of chief executive Steve Jobs.
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Simulation of multiple ion channel block provides improved early prediction of compounds' clinical torsadogenic risk
Aims The level of inhibition of the human Ether-à-go-go-related gene (hERG) channel is one of the earliest preclinical markers used to predict the risk of a compound causing Torsade-de-Pointes (TdP) arrhythmias. While avoiding the use of drugs with maximum therapeutic concentrations within 30-fold of their hERG inhibitory concentration 50% (IC50) values has been suggested, there are drugs that are exceptions to this rule: hERG inhibitors that do not cause TdP, and drugs that can cause TdP but are not strong hERG inhibitors. In this study, we investigate whether a simulated evaluation of multi-channel effects could be used to improve this early prediction of TdP risk.
Methods and results We collected multiple ion channel data (hERG, Na, l-type Ca) on 31 drugs associated with varied risks of TdP. To integrate the information on multi-channel block, we have performed simulations with a variety of mathematical models of cardiac cells (for rabbit, dog, and human ventricular myocyte models). Drug action is modelled using IC50 values, and therapeutic drug concentrations to calculate the proportion of blocked channels and the channel conductances are modified accordingly. Various pacing protocols are simulated, and classification analysis is performed to evaluate the predictive power of the models for TdP risk. We find that simulation of action potential duration prolongation, at therapeutic concentrations, provides improved prediction of the TdP risk associated with a compound, above that provided by existing markers.
Conclusion The suggested calculations improve the reliability of early cardiac safety assessments, beyond those based solely on a hERG block effect.
- Computer modelling
- Drug development
- Pharmacology
- Risk prediction
- Torsade-de-pointes
1. Introduction
Many drug compounds have a tendency to associate with, and to block, cardiac ion channels; this can lead to abnormal propagation of electrical action potentials (APs) through the heart tissue. This action is 'designed in' to anti-arrhythmic drugs, but is often an unwanted side effect of non-cardiac drugs. In the complex geometry of the heart, this change in electrical propagation can cause degeneration of the normal heart rhythm into life-threatening Torsade-de-Pointes (TdP) arrhythmia.
TdP can arise months into treatment,1 and only in a very small subset of the patients receiving a drug2 (individuals are predisposed to TdP dependent on a large number of factors, such as: the presence of congenital long QT syndromes, heart failure, bradycardia, electrolyte imbalance, gender, hepatic or renal impairment, impaired metabolism, and co-administration of certain drugs3). It is therefore difficult to predict preclinically, or assess during clinical trials on healthy individuals, which drugs will have the potential to cause TdP and which are safe. As such, a number of drugs have been withdrawn from the market due to an unacceptable TdP risk (for example, astemizole, cisapride, terfenadine, and thioridazine were withdrawn between 1997 and 2002).4–7
The rapid delayed rectifying potassium channel [IKr, with a human isoform known as Ether-à-go-go-related gene (hERG)] is both important in controlling repolarization of the ventricular myocyte AP, and particularly susceptible to block by many different compounds. IKr blockade leads to a lengthening of the AP duration (APD) and has long been associated with an increased TdP risk.8
Apart from the predisposing factors, we might suppose that the level of TdP risk conferred by a particular drug will depend upon the affinity of the drug compound for different ion channels, and its concentration. The affinity of a compound for a channel is quantified using its inhibitory concentration 50% (IC50) value: the concentration of the drug that will cause the current flowing through an ion channel to be reduced by 50%. The concentration of a compound to which cardiac ion channels are exposed is assumed to be the effective free therapeutic plasma concentration (EFTPC); that is, the concentration of unbound/free compound in the blood plasma when the drug is given at its therapeutic dose.
The earliest indicator used to assess torsadogenic risk in the pharmaceutical compound development process is usually based on the hERG IC50 value; compounds that block hERG too readily are discarded. Channel interactions are detected in multi-target toxicity screens, and hERG IC50 values are generally established from automated patch-clamp experiments on expression system cell lines.
However, there are many exceptions to this association between hERG block and TdP: both hERG inhibitors that do not cause TdP (e.g. verapamil and propafenone), and less commonly, drugs that cause TdP that are weak hERG inhibitors (e.g. tedisamil).9 These cases can arise when a drug blocks other ion channels: particularly susceptible are INa (fast sodium channel) and ICaL (the l-type calcium channel).10,11 Blockade of these channels will lead to a shortening of APD, countering some of the effects of a hERG block. It has been suggested previously that multi-channel effects must be considered when evaluating the TdP risk.11,12
Safety tests undertaken later in the drug development process attempt to address multi-channel effects, by taking into account the action of a compound on the tissue as a whole. These tests are usually based on the ECG: QTc interval prolongation from in vitro animal models (such as wedge preparations and Langendorff-perfused heart13), in vivo animal models, clinical trials, and eventually human thorough QT trials, specified by the ICH E14 document.14 There are concerns that thorough QT trials may be overly restrictive, as some drugs registered pre-ICH E14 prolong QT but are not associated with high rates of TdP.15 Concerns over cardiovascular side effects now account for an estimated 30% of potential compound discontinuations.16 It would be ideal to screen out troublesome compounds at the earliest possible opportunity—saving money, time, and lives.
In 2003, in an effort to provide such a screening process, Redfern et al.17 evaluated the clinical TdP risk of many drugs, proposed that a measure of [hERG IC50]/[EFTPCmax] be used as a TdP risk indicator, and that a value of 30 or over is a provisional safety margin. This was suggested as an improvement over simply [hERG IC50]; in the following we shall quantify the improvement in predictive power that this achieved. De Bruin et al.18 confirmed that the marker proposed by Redfern et al. was an indicator of risk, by showing a statistically significant correlation between [hERG IC50]/[EFTPCmax] and the number of abnormal cardiac events occurring per patient.
We aim to quantify how much information the earliest stage of safety screening can give on clinical TdP risk. By performing experiments, and by mining the literature, we gather IC50 values for two other channels in addition to hERG, namely INa and ICaL, for a total of 31 drugs. We use mathematical cardiac electrophysiology models of ventricular cells to incorporate the information on the degree of drug block for each channel, and then predict the changes in cell behaviour that would result under different protocols. We then correlate these model predictions with the clinical risk of TdP as indicated by the Redfern et al.17 risk classification, quantifying their predictive power and identifying risk indicators.
2. Methods
In this section, we detail the following steps: classification of drugs into TdP risk categories; measurement of IC50 values; simulation of possible risk indicators; and prediction of risk categories according to the indicators.
2.1 Clinical risk classification
We have taken the TdP risk classification system proposed by Redfern et al.17 defining the following categories in terms of clinical human TdP risk:
Class Ia and III anti-arrhythmics; generally associated with a large, but acceptable, risk of TdP.
Drugs that have been withdrawn from the market (by at least one major regulatory authority) due to unacceptable TdP risk.
Drugs with a measurable incidence of TdP, or for which numerous case reports exist.
Drugs for which there have been isolated case reports of TdP.
Drugs for which there have been no published reports of TdP.
We refer to these categories as the 'risk categories'. Lawrence et al.13 updated the list, adding further drugs and reclassifying others. Further modifications have been made: thioridazine has been moved from risk category 3 to 2, as it was withdrawn from general use in 2005, due to association with excessive QT prolongation and cases of TdP.19 Quetiapine has been reclassified from category 5 to 4, as it has recently been associated with isolated TdP case reports.20 Risk categories for all the drugs in this study can be seen in Table 1.
|Generic drug name
|TdP risk
|Na IC50 (nM)
|CaL IC50 (nM)
|hERG IC50 (nM)
|EFTPCmax (nM)
|71 00035
|20 00040
|11 60041
|30 00048
|22 60049
|14 700a
|45053, 54
|17 30055
|41 000a
|228 000a
|300 00056, 57
|60 00057
|39 400a
|43 00061
|100 00062
|50 000b63
|37 00044
|275 00067
|36 00044
|10 00017
|49 000a
|103 000a
|100 00017
|18 000a
|16 900a
|10 400a
|16 600a
|15 600a
|102 000a
|73 000a
|20 00078
|41 500a
aMeasured as part of this work as described in Section 2.2 and Supplementary material online, S1.
Reference 63 states a value of '≫10 000' and so 50 000 was taken.
2.2 IC50 and EFTPC values
Redfern et al.17 performed a thorough literature search for hERG IC50 values and EFTPC data for over 90 drugs; these form the basis of our data set. To investigate multi-channel effects, we performed experiments on 15 compounds to measure INa and ICaL IC50 values directly. Concentration–response curves for IKr were measured in HEK-293 cells stably transfected with hERG cDNA (for amiodarone and prenylamine; IC50 values in the literature were highly variable and absent, respectively); for INa in HEK-293 cells stably transfected with hNaV1.5 cDNA; and for ICaL in isolated ventricular myocytes from guinea pig, killed by cervical dislocation following stunning; using a conventional whole-cell patch-clamp technique.21 Full details of our experimental protocols can be found in Supplementary material online, S1. The investigation conforms with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85–23, revised 1996). All animals were treated in accordance with UK Home Office regulations [Animals (Scientific Procedures) Act 1986: London: Her Majesty's Stationery Office 1986], and the work was approved by GlaxoSmithKline internal ethical review.
To expand our drug data set to include at least four drugs from each category, we utilized the Aureus Pharma database (http://www.aureus-pharma.com/Pages/Products/Aurquest.php) and a manual literature search to find INa and ICaL IC50 values for 16 further compounds. Where more than one IC50 value was available in the literature, we have followed Redfern et al. in utilizing the lower value in our analysis. We were therefore able to establish IKr, INa, and ICaL IC50 values and EFTPC data for 31 compounds; a full list is presented in Table 1.
The three IC50 values and maximum EFTPC values for these drugs are plotted against the risk categories in Figure 1. The lack of association displayed in Figure 1 suggests that these 'raw' IC50 values will have little predictive power for the risk category, a concept we quantify in section 2.4.
2.3 Simulations
In addition to using the 'raw' IC50 and EFTPC values to associate a drug with a risk category, we hypothesize that some function of these values may provide a stronger association. We turn to mathematical cardiac electrophysiology models of ventricular myocytes; these models integrate information about individual channel currents to describe their collective behaviour, and AP formation. We use these models to predict changes to whole-cell behaviour under drug action, using the IC50 values and concentration data as model inputs, dictating the degree of drug-induced channel block. The aim is to find model outputs that correlate with the risk categories more strongly than the markers shown in Figure 1, and so provide in silico TdP risk indicators.
Mathematical cardiac electrophysiology models are systems of (typically) tens of highly non-linear ordinary differential equations (ODEs), governing the evolution of model variables through time. These variables represent ion channel gates/states, ion concentrations, and other quantities such as membrane voltage. We have taken five of the recent ventricular myocyte models for rabbit,22,23 dog,24 and human.25,26 Each of these models has an ODE for the evolution of membrane voltage (V) through time (t), which takes the form where Cm is the membrane capacitance, Ij represent the currents due to each species of ion channel 'j', and Istim is the stimulus current applied to pace the cell. Channel currents take the form Here, gj is the maximal conductance of channel 'j', O is its open probability, and Eion is the reversal potential for the species of ion which flows through channel j.
There are a number of ways to modify such models to incorporate the effects of channel block by drug compounds. One of the simplest is a 'conductance-block' formulation; gj is reduced by a factor which is a function of the IC50 value of a drug for this channel, and the concentration of the drug [which we denote by [D]]. In general, for the conductance of a channel of type j we have Here, gcontrol,j is the drug-free maximal conductance of the j channel. For all drugs and channels in this study, we have assumed that the Hill coefficient n = 1 (or equivalently, one molecule of drug is assumed to be sufficient to block one ion channel—typical values of n for hERG block are around 0.7–1.111). Where a drug effect on a channel has been tested and no block was observed, the original conductance gcontrol was used. We have applied this model for drug block to IKr, INa, and ICaL.
In general, drug effects at steady-state concentration can be well represented by a conductance-block model.27 This assumption seems to hold even if the drug exhibits state- or voltage-dependent binding (since, at physiological cardiac pacing rates, the timescale over which binding and unbinding occur is much longer than the timescale over which voltage changes or channel–state transitions occur). One case in which a conductance block may not be an accurate model is that of an allosteric drug block, in which a compound affects the ability of a channel to transition between open, closed, or inactivated states. Since the precise mechanism of channel block is usually not known or measured at the early stages of compound development, we have modelled drug action using the conductance-block formulation.
We performed steady 1 Hz pacing, S1–S2, and dynamic restitution protocols on the models, recording quantities such as APD50, APD90, triangulation, and maximum restitution slopes. Full details of the simulation protocols and the 15-recorded quantities can be found in Supplementary material online, S2. The protocols were performed for each model at four concentrations: low EFTPC and high EFTPC values are the lowest and highest EFTPCmax values, respectively, as reported in the literature, medium EFTPC was taken to be the mean of these, and the overdose to be 10 × high EFTPCmax.
An example of the AP that the steady pacing protocol generates can be seen in Figure 2 for the Grandi et al.26 model. We see the effect of adding verapamil at low, medium, and high EFTPC; both for a case where we consider only a hERG block, and for the multi-channel case. The importance of multi-channel effects becomes clear: in the case of a solely hERG block, the APD is prolonged, in the case of hERG, Na, and CaL blocks, the effect is the opposite, with a marked reduction in APD.
2.3.1 A note on implementation
XML format representations of the models22–26 were taken from the CellML repository.28 PyCML29 was used to translate the CellML format into C++ code. CVODE30 was then used to integrate the ODEs in a custom-made program based on the open-source Chaste library.31 For the interested reader, our full code is available to download from http://www.comlab.ox.ac.uk/chaste.
2.4 Classification
For a previously unseen compound, we wish to take the continuous measures produced by the simulation protocols above, and then categorize the compound into a discrete risk category, based upon the measure's value and our prior knowledge of this measure for other compounds. This type of problem is ubiquitous in statistics, and is known as a 'classification problem'.
We have used one of the simpler classification methods, known as linear discriminant analysis (LDA), to place our compounds into the risk categories. LDA uses maximum likelihood estimates to calculate the probability of each point in variable space being a member of each category. To classify an unseen observation, we simply assign it to the category with the highest probability at that point. Supplementary material online, S3 provides further details of this method.
The risk of adverse cardiac events associated with drugs in risk categories 1 and 2 is similar.18 Since our aim is to predict the clinical risk category associated with an early compound, we would not know whether the compound is being developed as an anti-arrhythmic or not. Since categories 1 and 2 exhibit indistinguishable TdP risks, we combine them for the LDA and subsequent classification, labelling all these drugs as 'category 2' to avoid the confusion that would arise in re-indexing the rest of the risk categories.
To quantify the predictive power of the LDA, we perform 'leave-one-out' validation. One drug is removed from our data set, leaving 30 out of the 31 drugs remaining to form the training data set. An LDA is performed on the training data set, then the 'left-out' drug is categorized accordingly. We assign an error score as follows which will be a positive integer; 0 if the predicted category is the same as the actual category, 1 if the predicted category is ±1 away from the actual category, etc. We then repeat the analysis leaving out each of the drugs in turn. It should be noted that this analysis immediately provides a tool that can predict the torsadogenic risk of an unseen drug, according to the risk categories it has 'learnt' from a database of, in this case, 30 other drugs.
3. Results
In Figure 3A, we plot [hERG IC50]/[EFTPCmax] against the risk categories for the drugs in this study, for the spread of EFTPCmax values in the literature. The relationship appears to be of a similar quality to that shown for [hERG IC50] in Figure 1. The difficulty in associating a drug with a risk category is evident, as drugs across all five risk categories exhibit overlapping values.
Simulation of the markers discussed in Section 2.3 was undertaken for each of the models, with a hERG-only or multi-channel block, at low, medium, high, and overdose EFTPCs. This resulted in 350 simulated markers for both multi-channel and hERG-only cases.
The LDA described above was then performed for the raw IC50 values, previously suggested risk indicators, and the simulated markers, a total of 761 possible markers. As a result of the 'leave-one-out' trial, we identified the most predictive single marker as the maximum APD90 at low/medium/high EFTPC under steady 1 Hz pacing as simulated by the Grandi et al. model; we present this in Figure 3B.
By comparing Figure 3A and B, it is evident that this simulated marker provides an improved association relative to that of the existing safety measure. In Figure 3B, there is one drug worthy of particular note: thioridazine (category 2) appears to have both prolongation and shortening, dependent on the EFTPC value. This situation arises because the low EFTPC is higher than the hERG IC50 and therefore significant prolongation occurs below (and at low) EFTPC values; as the EFTPC increases, other channels also become significantly blocked and shorten the AP.
We now consider the errors associated with categorization based upon the different measures. Figure 4A provides a reference by displaying the mean errors when allocation of each drug into a risk category is performed at random (106 times). Figure 4B displays the error if classification is performed with an LDA based on log10([hERG IC50]); the mean error is 1.129. The metric of log10([hERG IC50]/[High EFTPC]) results in the errors in classification shown in Figure 4C; the mean error is reduced to 0.968 as there is a reduction in the number of completely wrongly characterized drugs (category 2 as 5 or vice versa), relative to Figure 4B. This finding confirms that the Redfern et al. safety factor was an improvement over the hERG IC50.
Errors for the most predictive marker found in this study are shown in Figure 4D, the mean error is reduced to 0.323, and no drugs are characterized to the wrong end of the risk scale. In fact, no drugs in categories 4 or 5 ('safe') are categorized as 2 or 3 ('dangerous'); we have no 'false positives'; see Supplementary material online, S5 for full results. Only one drug in category 2 or 3 is categorized as 4 or 5; this 'false negative' is amiodarone, categorized with an error of 2. Amiodarone is in classification risk category 2 (risk categories 1 and 2 being combined for classification as discussed earlier), but is classified as 4. In Figure 3B, it is the drug in risk category 1 which is very close to the control (100% line).
In a compound development setting, the results shown in Figure 3B and Figure 4D suggest a strategy: a compound in which the simulated APD90 at any realistic EFTPC is markedly prolonged will have a strong TdP risk and should not be progressed to the market (unless the clinical benefit outweighs the safety risk, e.g. it is intended to be used as an anti-arrhythmic or an anti-cancer drug). Similarly, compounds whose simulated APD90 is shortened will have a low risk of TdP and ought to be progressed. Compounds whose APD90 is affected to a small extent fall into two types: those for whom the channel IC50 values are all much higher than their EFTPC and little block occurs, we would suggest these should be rapidly progressed; and those for whom channel block effects are important and to some extent may be 'cancelling each other out', these compounds should be referred for further cardiac safety testing.
The mean and standard deviation of the errors in categorization for all markers are shown in Figure 5. The markers to the bottom left of the solid lines are more predictive than random allocation, and markers to the bottom left of the dashed lines are more predictive than the Redfern et al. measure. We have estimated that the chance of predicting these drug risk categories with this degree of accuracy by guessing at random is <1 in a million (see Supplementary material online, Figure S2). We also confirmed that the choice of predictive marker retained some independence from the drug data set by performing cross-validation on stratified subsets of the drugs; for details of these results, please refer to Supplementary material online, S3.2. The 30 most predictive markers (shown in bold on Figure 5) are all simulated markers for multi-channel effects and are listed in full in Supplementary material online, S4. None of the hERG-only block simulated markers achieved such a level of predictive power, and the majority of the most predictive markers are the result of protocols encapsulating prolongation of APD.
4. Discussion
We have developed a simulation tool that predicts a clinical torsadogenic risk category associated with a compound, based on the earliest preclinical data on its role in multiple-ion-channel blockade. Simulated markers based on EFTPC and the hERG, sodium, and l-type calcium channel IC50 values provide an improved prediction of a compound's torsadogenic risk, beyond that provided by the ratio of [hERG IC50]/[EFTPCmax].
By including these multi-channel effects, severe mis-classifications of other metrics can be correctly predicted: verapamil and propafenone, both potent hERG blockers, have their TdP risks predicted accurately. Our work confirms that consideration of hERG block is necessary, but not sufficient, to predict torsadogenic risk.11,12
Amiodarone was the only drug we could not characterize to within one risk category. There are many possible reasons for this, as it has intricate effects, being involved in membrane trafficking interference, chronic changes to ion channel expression, late sodium block, and has metabolites that are also active hERG inhibitors. Where compounds affect currents other than IKr, INa, or ICaL (e.g. ranolazine which also targets the late sodium channel), one would expect to be less able to predict their risks correctly.
The mathematical models of ventricular myocytes we have used are evidently capturing something of the channel interactions that are at work in determining cell behaviour. These cell models have now been developed for 50 years,32 and as the models advance, we hope this will refine the predictions provided by the techniques we have proposed. Of our many simulated markers, it is those related to an increase in APD which correlate best with the TdP risk; this is in keeping with current thinking which links QT prolongation to TdP initiation.
We did not find strong predictive power from the in silico markers associated with steep restitution curves or APD triangulation (as suggested by the TRIaD screen33), although this may be due to the mathematical models replicating this behaviour less accurately than the simpler changes to APD. However, it is important to note that no assumptions about the accuracy of the models' APD predictions, or the mechanisms leading to TdP, are needed to show the predictive power of this method.
Our study has limitations; to maximize the number of drugs, our IC50 data were taken from a multitude of different sources, and as such contain the associated variations inherent in such a data set. There are insufficient numbers of drugs to evaluate the impact of manual vs. high-throughput automated patch clamp; to ascertain this the whole study should be repeated based solely on high-throughput data. We included 31 drugs, for which we could ascertain the effects on the three channels, EFTPC, and the clinical TdP risk; as the data set expands, we expect to provide improved predictions. The mathematical model is not a perfect predictor: the model of a drug block is very simplistic and could be improved by measurement of dose–response curve hill coefficients. Kinetics of channel block have been ignored (voltage-/state-dependence, and allosteric effects); however, it would be difficult to include these effects: early safety testing does not measure such intricate details of compound–channel interactions as standard, and each compound would need associated channel block models developing for each ion channel. Interestingly, and perhaps surprisingly, despite these limitations, we have shown a marked improvement in the early prediction of torsadogenic risk.
In further work, we hope to address some of the limitations, adding more drugs to the data set, which is used as the basis of predictions. Further currents such as late sodium and IKs are known to be targets of many drugs, and inclusion of these into the study may also yield improved results. Inclusion of longer-term drug-induced changes to membrane protein trafficking and expression into the model may also improve predictions. As the mechanisms behind the initiation of Torsade-de-Pointes are elucidated, there is hope that simulation of these mechanisms directly will provide improved prediction of risk.
This type of simulated test has the potential to complement and extend existing safety tests; facilitating earlier detection of torsadogenic compounds, and preventing potentially safe compounds being discarded unnecessarily. Moreover, as the database of drugs expands, and confidence grows in the accuracy of model predictions, simulations may have the potential to replace some safety tests and thereby have a beneficial impact on replacement and reduction of animal models, cost, and time.
Supplementary material
Supplementary material is available at Cardiovascular Research online.
This work was supported by the European Commission as part of the Prediction of Drug Impact in Cardiac Toxicity (PreDiCT) Framework 7 grant (DG-INFSO 224381 to G.R.M., A.S., M.F., D.J.G., and D.N.). Funding to pay the Open Access publication charge was provided by the preDiCT project (European Commission DG-INFSO grant 224381).
Our thanks to Simon Preston and Kevin Burrage for discussions on statistical techniques, and to Peter Kohl for his comments on the work.
Conflicts of interest: Y.C., B.M.H., and N.C.M. are employees of GlaxoSmithKline PLC. M.F. is now employed at Novartis Pharma AG, but contributed to this work independently.
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