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Information about Sandalwood Hotel & Retreat Hotel
Sandalwood Hotel & Retreat is located in Dona Paula, just 100 metres from Vainguinim Beach. It offers 4 dining options, spa facility, free Wi-Fi and an outdoor swimming pool. The hotel is 30 km from Dabolim Airport and 21 km from Karmali Railway Station. Panjim Shopping Area is 7 km from the hotel while Chance's Casino is just next door. Rooms at Sandalwood come with private balconies and air-conditioning. 24-hour room service, flat-screen TVs and a personal safe are provided. Free morning newspapers are available upon request. Guests can exercise at the well-equipped fitness centre or find entertainment at the games room. Sandalwood Retreat also provides car rentals and a tour desk. Sea Pearl Restaurant serves local, Asian and international dishes. Tea and snacks can be enjoyed at the poolside Upper Coast Café. Drinks and cocktails are available at Caitan 'n' Joe Bar and Salud Latino Bar.
Please note the below: Booking for minimum 3 rooms and above together on the same name would be considered as a group. Cancellation / Amendment Policy – Group Booking 45 days and above : No charge 30 – 45 days : 01 night retention Below 30 days : Entire charge Please note that the property will charge the credit card with a pre-authorization amount of INR 10. This amount will be adjusted against the final bill. Please note that the swimming pool would be closed for maintenance from 27th May 2018 until further notice. For guest convenience, an alternate arrangement is organized at adjoining property.
Services of Sandalwood Hotel & Retreat Hotel
- Air conditioning
- On-site parking
- Ironing service
- Airport shuttle (additional charge)
- Dry cleaning
- Parking
- Restaurant
- Family rooms
- WiFi
- Fitness centre
- Car hire
- Airport shuttle
- Trouser press
- Express check-in/check-out
- Table tennis
- Bar
- VIP room facilities
- Shoeshine
- Non-smoking rooms
- Special diet menus (on request)
- Entertainment staff
- 24-hour front desk
- WiFi available in all areas
- Tour desk
- Spa and wellness centre
- Laundry
- Free parking
- Internet services
- Free WiFi
- Meeting/banquet facilities
- Newspapers
- Outdoor pool (all year)
- Shuttle service (additional charge)
- Room service
- Games room
- Currency exchange
- Fax/photocopying
- Private parking
Vainguinim Beach, Dona Paula
Similar hotels to Sandalwood Hotel & Retreat Hotel
The Crown Goa offers 4-star accommodation with breathtaking views of Mandovi River, 6-minute walk from Casino Royale Goa. It features an outdoor pool, a day spa and 2 restaurants. The spacious rooms include free internet. The Crown Goa Hotel is located in Panaji, the capital of Goa. The beautiful Miramar and Caranzalem beaches are just a 10-minute taxi ride away. It is 5 km from the Salim Ali Bird Sanctuary and 15 km from the 17th-century Fort Aguada. Guests can relax in air-conditioned comfort and enjoy views of the garden, city or river. All rooms include a flat-screen TV with cable channels and a refrigerator with minibar. Entertainment options at The Crown include children's park along with indoor games. Sightseeing can be arranged at the tour desk. The poolside Hanging Garden Restaurant serves barbeque and Indian dishes with river views. Harbour Cafe offers international cuisine. Room service and a breakfast buffet are available.
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This women's specific design is optimised to keep up with whatever you put it through and is perfect for fast road races, long days in the saddle and tough uphill climbs. With a carbon frameset and exceptional components, it is ready to race.
|Number of gears:
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|Model Year:
|Liz C, 24T HM Unidirectional Carbon
|Fork Material:
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The Liz features an all-carbon frame with unique diamond-shaped, aerodynamically optimised tubing to provide comfort, speed and low weight to conquer any challenge on race day. Plus, it's equipped with a Shimano 105 groupset, which ensures reliable and efficient performance, so you spend more time in the saddle and less in the workshop. Additionally, with its fast-spinning Forza RC31 wheels and Vittoria Zaffiro wire tyres, this bike provides exceptional grip and rolling efficiency that's necessary to achieve victory when it comes to race day.
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Longitudinal Study of Patients With Opioid-Induced Constipation
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
|ClinicalTrials.gov Identifier: NCT01928953
Recruitment Status : Completed
First Posted : August 27, 2013
Last Update Posted : July 8, 2015
- Study Details
- Tabular View
- No Results Posted
- Disclaimer
- How to Read a Study Record
This prospective hybrid longitudinal study was conducted in the United States (US), Canada, the United Kingdom (UK), and Germany. To obtain the most complete and comprehensive understanding of the burden of opioid-induced constipation (OIC) in these countries, this study used a combination of web-based, longitudinal patient survey, retrospective data abstraction from medical records, and a prospective physician survey.
The primary objective of this study was to estimate the rate of inadequate response to laxatives (LIR), which was defined as having sufficient laxative use (at least one laxative use ≥ four times per reference period), and inadequate response (defined as fewer than three bowel movements (BMs) OR at least one of the following symptoms on the Patient Assessment of Constipation Symptoms (PAC-SYM) measure scored as moderate, severe or very severe: BMs too hard, straining to have a BM, feeling like you didn't "finish" a BM, and feeling like you had to pass a BM but could not), in a cohort of non-cancer pain and cancer pain (separately) participants with OIC, by country and overall.
The secondary study objectives are as follows:
- To estimate the rate of LIR for two subgroups: 1xLIR and 2xLIR. 1xLIR was defined as use of at least one laxative agent ≥ 4 times in the reference period while 2xLIR was defined as the use of at least two laxative agents, each used ≥ 4 times in the reference period;
- To describe the baseline demographic and clinical characteristics, including prior health status, comorbidities, constipation-related GI symptoms, and concomitant medications of patients with OIC;
- To describe drug utilization and self-management of OIC;
- To describe the pre-index and post-index healthcare resource utilization and estimate costs associated with the diagnosis, treatment, and general management of OIC (including laxative use) and events attributed to OIC, including both direct and indirect costs;
- To describe patient-reported impact of OIC on health-related quality of life, productivity, and pain management;
- To describe patient-reported treatment satisfaction with laxative use; and
- To describe physician-reported awareness of OIC and symptoms and understanding of patient-reported impact of OIC.
|Condition or disease
|Patients With Opioid Induced Constipation
|Study Type :
|Actual Enrollment :
|520 participants
|Observational Model:
|Time Perspective:
|Official Title:
|Longitudinal Study of Patients With Opioid-Induced Constipation
|Study Start Date :
|October 2012
|Actual Primary Completion Date :
|December 2014
|Actual Study Completion Date :
|December 2014
- Rate of LIR among the OIC population [ Time Frame: 6 months ]
- Rate of inadequate response to first and second-line laxative treatment for OIC (1x LIR and 2x LIR). [ Time Frame: 6 months ]
- Baseline demographic and clinical characteristics of patients with OIC (prior health status, comorbidities, GI symptoms, and concomitant medications). [ Time Frame: 12months retrospectively ]
- Drug utilization and self-management of OIC at baseline and changes from baseline over the 24-week follow-up period. [ Time Frame: 6 months ]
- Healthcare resource utilization profiles pre- and post-baseline [ Time Frame: 6 months ]
- Cost of illness related to the diagnosis, treatment, and general management of OIC (including laxative use) and events attributed to OIC, including both direct and indirect costs. [ Time Frame: 6 months ]
- Baseline constipation-associated GI symptoms and changes from baseline over the 24-week follow-up period (PAC-SYM and additional symptom questions). [ Time Frame: 6 months ]
- Baseline health-related quality of life (PAC-QOL and EQ-5D) and changes from baseline over the 24-week follow-up period (PAC-QOL). [ Time Frame: 6 months ]
- Loss of productivity (WPAI-SHP score) at baseline and changes from baseline over the 24-week follow-up period. [ Time Frame: 6 months ]
- Persistence on opioid therapy at baseline and changes from baseline over the 24-week follow-up period [ Time Frame: 6 months ]
- Treatment satisfaction with laxative use at baseline and changes from baseline over the 24-week follow-up period, for all patients taking laxatives. [ Time Frame: 6 months ]
- Physician-reported awareness of OIC and symptoms, and understanding of patient reported impact of OIC at baseline. [ Time Frame: 6 months ]
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
|Ages Eligible for Study:
|18 Years to 85 Years (Adult, Older Adult)
|Sexes Eligible for Study:
|Accepts Healthy Volunteers:
|Sampling Method:
|Probability Sample
Inclusion Criteria:
Patient is receiving a minimum total daily dose of 30 mg of oral morphine, or equianalgesic amount[s] of 1 or more other opioid therapies, for a minimum of 4 weeks for chronic pain or cancer relate pain Presence of OIC in the past 2 weeks
- (for cancer patients only) Patient has a current diagnosis of cancer that is not currently in remission and has cancer-related pain Internet access and is able and willing to complete a longitudinal web-based survey
- Patient is able to understand and comply with the requirements of the study, as judged by the investigator (includes ability to read and write and to use
Exclusion Criteria:
Patient is unable or refuses to provide informed consent;
- Patient does not have access to a computer with internet connectivity, or is unable to use a computer to complete the web-based survey; Based on clinical judgment, patient has a history of chronic constipation (i.e. clinical diagnosis, note in the medical record, or patient history);
- Patient has a history of (or current) colon cancer (primary or metastatic) (i.e., clinical diagnosis Patient has received an investigational medication to treat constipation or participated in any study involving investigational compound naloxegol within ≤90 days prior to the baseline visit
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01928953
Show 30 Study Locations
|Study Director:
|Mark Sostek, M.D.
|Study Director:
|Cathy Datto, M.D., M.S.
|Principal Investigator:
|Robert J LoCasale, Phd, MS
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
|Responsible Party:
|ClinicalTrials.gov Identifier:
|NCT01928953 History of Changes
|Other Study ID Numbers:
|First Posted:
|August 27, 2013 Key Record Dates
|Last Update Posted:
|July 8, 2015
|Last Verified:
|July 2015
Keywords provided by AstraZeneca:
opioid induced constipation in patients without cancer and with cancer
Additional relevant MeSH terms:
Signs and Symptoms, Digestive
Signs and Symptoms
Analgesics, Opioid
Central Nervous System Depressants
Physiological Effects of Drugs
Sensory System Agents
Peripheral Nervous System Agents


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text:
Exceptionally brutal video shows a struggling man with peeled face and no hands being brutally beheaded with flimsy blades. The floor is covered with blood from his face having been peeled off and his hands cut off, but the victim is clearly still alive, experiencing the indescribable agony with consciousness. After the beheading attempt with … Continue reading "Struggling Man with Peeled Face and Hands Cut Off Is Brutally Beheaded with Flimsy Blade"
Tag: Beheaded
Decapitated Head Kicked by Two Inmates, Prison Yard Sports in Guayaquil, Ecuador
Outside a prison in Guayaquil, Ecuador, two inmates pass the time with a severed head. Props to Best Gore member @ccccccjjj2 for the video: Fill browser window Zero-Decibels ®
Human Head Relaxing on Granite Sidewalk, Policeman Uses Cellphone Standing Nearby
man 1: look, there is a human head. man 2: what are you surprised about? … we are in Brazil. man1: true, this happens every day. a posile title can be: "a normal day in the streets of Brazil" Props to Best Gore member @nomar for post and the video: Fill browser window Zero-Decibels ®
Moderate Terrorists Behead Syrian Arab Soldier
Syrian "moderate terrorists" behead a Syrian Arab army soldier, date and location unknown, presumably North West Hama where battle between Syrian troops and head choppers enrages. Alot of Allahu Akbar, too much to bear! Props to Best Gore member @a-sick-mind for the video: Fill browser window Zero-Decibels ®
Inmates Have Fun in Brazilian Prison
Two videos here. They both appear to be taken of a single incident. Not sure though. In Brazil, in what looks like prison of some sort, criminals have their fun with miserable convicts. Props to Best Gore member @honkeykong for the video: Fill browser window Zero-Decibels ®
Assassins of Achilles Use Hacksaw to Behead and Dismember Hombre in Centro, Solidaridad, Mexico
In Centro, Solidaridad, Mexico, the 12th of April, an hombre is killed to prove a point. What point, you say? Well, do not threaten lively hood for People of Achilles! Any threat will be liquidated to achieve compliant utopia. Considered an enemy not comrade, you must DIE! Remember folks, a solid foundation is needed to … Continue reading "Assassins of Achilles Use Hacksaw to Behead and Dismember Hombre in Centro, Solidaridad, Mexico"
Venezuelan Ventriloquists
In Venezuela at night time, freshly after beheading two, the killers have fun with the heads. You gotta bloody laugh at this. The two dummies provide more in death than life. UPDATE This is Venezuela and the decapitated heads are President Juan Guaidó supporters. With any luck more videos like this will surface. Props to … Continue reading "Venezuelan Ventriloquists"
Turkish Soldiers Behead Slain PKK Fighters
Not much backinfo except what's in the title – Turkish soldiers filmed themselves beheading corpses of slain PKK fighters. PKK is the acronym for the Kurdistan Workers Party. The Turks consider the PKK fighters terrorists, but for the Kurds they are the freedom fighters. Props to Best Gore member @dopegank for the video:
Ritualistic Beheading of 9 Year Old Child
I got this video with a claim that it shows a 9 year old child bride being beheaded in front of large crowd because she refused to have sex with \her adult husband. That doesn't add up at all. If you can be a slave owner of a child, you can force her to have … Continue reading "Ritualistic Beheading of 9 Year Old Child"
Bleed Out IV: Aloha Snackbar Edition
Following in the footsteps of our dearly beloved Southland flat globe contestants, snackbarists play the game and castoff blood spatter all the way from the Center East directly into your viewing eyes. A handcuffed and blindfolded man is eager to oblige to his brethrens requests for the opportunity to appear on Bleed Out – Still … Continue reading "Bleed Out IV: Aloha Snackbar Edition"


text:
Library Assistant – Reader Services
- Location
- London (Greater)
- Salary
- £26,533 to £29,622 pa inclusive of London allowance
- Posted
- 31 May 2019
- Closing date
- 16 Jun 2019
- Industry
- Arts & heritage, Arts education & training, Librarian & archivist, Further education, Higher education, Non-academic
- Job level
- Experienced (non manager)
- Hours
- Full time
- Contract
- Contract
- Listing type
- Job vacancy
This is a fixed term appointment to August 2020
The post is full-time for 35 hours per week. Some evening (5-7pm, Monday-Friday) and weekend (11am – 6pm) may be required.
Founded in 1896 the London School of Economics and Political Science (LSE) is one of the foremost social science universities in the world. The Library of LSE provides one of the best social science collections in any university – supporting the research and teaching of LSE, as well as opening its doors to the wider world.
The Library Assistant vacancy is based in the Reader Services team to support the Reader Services Manager in the delivery of front facing services.
Candidates should have previous experience of working in a busy frontline service in the education or retail sectors, together with excellent interpersonal skills, the ability to consistently deliver an effective and high standard of customer service to a diverse range of users, and have strong team working skills.
Some evening (Monday to Friday, 5-7pm) and weekend working (11am to 6pm) may be required.
We offer an occupational pension scheme, generous annual leave and excellent training and development opportunities.
For further information about the post, please see the how to apply document, job description and the person specification.
Applications should be by CV and a covering letter of no more than two sides of A4. If you have any technical queries with applying on the online system, please use the "contact us" links at the bottom of the LSE Jobs page.
The closing date for receipt of applications is 16 June 2019 (23.59 UK time). Regrettably, we are unable to accept any late applications.
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- Further education Experienced (non manager) jobs in City of Westminster
- Arts education & training Experienced (non manager) jobs in City of Westminster
- Librarian & archivist Experienced (non manager) jobs in City of Westminster


text: SpamBayes stopped filtering in Outlook. The toolbar was still there, but the "Delete As Spam" never did anything, and the "SpamBayes" dropdown menu never reacted. I could disable and enable the toolbar on the menu, but couldn't do anything with it. I ran the the Add/Delete programs and deleted SpamBayes, then reinstalled. There was no difference - it still didn't respond. The toolbar always remained an option on Outlook, even after Deleting (perhaps that's a separate issue.) I'd be interested to know how to get it working again. If it requires cleaning out a few files, I'm willing to go through that. Many thanks! Ken Duisenberg duisenberg at rcsis.com Windows XP, Outlook 2003 -------------- next part -------------- An HTML attachment was scrubbed... URL: http://mail.python.org/pipermail/spambayes/attachments/20040922/fa07b834/attachment.htm


text:
Usg Army Corp of Engrs
2000 Fort Point Rd Galveston, Texas 77550(409) 766-3059
Print | Save | Directions
AboutUsg Army Corp of Engrs is located at the address 2000 Fort Point Rd in Galveston, Texas 77550. They can be contacted via phone at (409) 766-3059 for pricing, hours and directions.
For maps and directions to Usg Army Corp of Engrs view the map to the right. For reviews of Usg Army Corp of Engrs see below.
Phone: (409) 766-3059
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4223 Pirates Bch Galveston, Texas 77554
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Discussion List
So Wave have announced they're pretty much back stepping from UK & EU customers - all bank links to be terminated from September for users with UK/EU based banks, and a clear decision too to abandon all hope of MTD for Income Tax compliance (potentially to come into effect in April 2021). Where does it leave you, the UK user then? Well, th…MerlinAccounts_UK 33 views 0 comments 0 points Started by MerlinAccounts_UK June 18, 2019 2:27PM Accounting
Hi I have a 2 part question, 1. Since Wave accounting does not close accounts, and use accounts like income summary, how do we properly update Owners Equity? Without making the December Profit and Loss account wrong, which happens if you use closing accounts? 2. A separate issue, how do we categorizes Interest Expense? Since it is not an operat…ddme 23 views 3 comments 0 points Most recent by Kimpton June 11, 2019 7:22PMAccounting
Hello,I am a professional full time accountant that does bookkeeping/consulting on the side. I work remotely, but am based in sunny Sarasota FL. You will have my personal phone number to call or text with questions. This is done on the side so I charge much lower than a CPA or full time bookkeeper. I am also available during the evenings and wee…troympapa 111 views 8 comments 2 points Most recent by HuskyLogic June 9, 2019 7:07PMPro Network Listings
I need to submit my business return to CRA and because my first year was very simple (zero revenue, very few expenses), I don't want to use my accountant for this (I have another business that is much more complicated and he and my bookkeeper use Quickbooks to manage bookkeeping and accounting for that). From what I can tell, Wave doesn't have …Mikebrcic 49 views 5 comments 0 points Most recent by greenwave June 8, 2019 3:16PMAccounting
Getting Error trying to save add end of month balance totals in Wave, driving me mad.. any ideas please? EDIT: I can only update certain months, others throw the errorsnappyfish 5 views 1 comment 0 points Most recent by JamieD June 5, 2019 3:49PMTechnical Support
Hi guys! Does anyone know an Estonian accountant using WaveApp? Thanks for the recommendations.SaraG 10 views 0 comments 0 points Started by SaraG June 5, 2019 10:56AM Accounting
Hi there! I have operated a very small business since 2015 and I have never kept track of things like: inventory, assets, liabilities. My transactions have been extremely minimal, though I do have inventory and I have filed taxes and kept bad records. I want to start a fresh set of books from 2018 onwards, but I am lost as to how I account for…KathleenEmilyAnne 15 views 1 comment 0 points Most recent by Mikeg June 3, 2019 1:09PMAccounting
Hi all. I am a new consultant that just incorporated and I recently started a contract with a client. I am new to being a business owner and know nothing about accounting. I'd like to list off what I'm going to be doing and I hope someone can tell me if Wave can take care of these items. 1) I know that Wave can connect to my Business Bank Acc…BrianH 17 views 3 comments 0 points Most recent by alexlewiszarkos May 31, 2019 4:04PMWave Discussion
Small business based in London looking for accounting services familiar with Wave. Would like help with HMRC filings, VAT (if applicable), and PAYE (for 1 employee).ryan_uk 13 views 0 comments 0 points Started by ryan_uk May 15, 2019 12:26PM Pro Network Listings
The transaction are appearing after the invoices are paid. However for the past 5 days they are still in transit and are not being sent into my bank account. The bank connection has no errors and I have updated it multiple times over the past few days. Could you help in resolving this issue. Thank you.Nathan101 16 views 1 comment 0 points Most recent by Zoe_caff May 13, 2019 6:38PMBank Connections
so I don't normally use account reconciliation, should I? I run a small self employed business with somewhere between 50 and 100 transactions occur in wave. I have looked back through reconciliation and first month that doesn't match is November 2017 Difference is £52.85 Looks like an invoice was recorded as paid in Wave transactions 25/1…snappyfish 21 views 4 comments 0 points Most recent by Samd May 3, 2019 8:18PMAccounting
Non-recoverable Sales Tax (PST) is acting like a recoverable sales tax, but only for Asset PurchasesHi there, I live in BC where we have both two sales taxes: GST (recoverable) and PST (non-recoverable). When I record an EXPENSE using Wave (see my Shopify transaction), you can see only GST is marked as recoverable, even though I accounted for both taxes in my entry. For expenses, my sales taxes are behaving as expected. However, whe…youngstreet 39 views 4 comments 0 points Most recent by youngstreet April 23, 2019 2:55AMAccounting
Hola si ocupas ayuda con tu contabilidad y a revisar tu empresa estoy para ayudarte. Vivo en Honduras y he trabajado con contabilidades de Honduras, Guatemala, Panama, Colombia, El Salvador y Mexico. escribeme a [email protected] SaludosJacinto_Cho 7 views 0 comments 0 points Started by Jacinto_Cho April 21, 2019 10:15AM Find a Wave Pro
Jacinto Cho Honduras, Centro America Hola, trabaje en auditoria en Deloitte una de las 4 grandes firmas del mundo. Luego trabaje en Tesoreria en Louis Dreyfus Company, unas de las 4 grandes empresas de Commodities del Mundo. Ahora trabajo en Grupo Cadelga como analista financiero. Tambien tengo mi propia empresa que se llama Desarrollo Emprended…Jacinto_Cho 12 views 0 comments 0 points Started by Jacinto_Cho April 21, 2019 10:02AM Pro Network Listings
Need help on creating Share Capital Account , common shares and class preferred shared accountMMaynard 69 views 1 comment 0 points Most recent by Samd April 12, 2019 5:43PMAccounting
Is there a way to attach a photo to the invoice? I have an art gallery and would like to attach in the description a picture of each artwork. Thank youAzel 17 views 3 comments 1 point Most recent by RobC April 11, 2019 2:54PMSales & Invoicing
Hi, How should the following two transactions in an S Corp's Wave account be categorized and/or handled? Transaction #1: A $50 personal expense is mistakingly made with the business debit card Transaction #2: In an effort to correct transaction #1, a $50 deposit is made to the business checking account from the owner's personal bank accou…HOSPM 17 views 5 comments 0 points Most recent by Mikeg April 10, 2019 12:58AMAccounting
I'm an international user (there's no option to link my bank account to Wave), with not much accounting experience. I'm trying to find out how to enter my credit card information in Wave Accounting. I created an account for my Cash Back Credit Card under "Liabilities and Credit Cards". What I'd like to know is what is the best approach to…Acumen3 25 views 5 comments 0 points Most recent by Mikeg April 8, 2019 5:56PMAccounting
6 April 2019 kicks off the new tax year (2019-20), but this is also when the 2019 tax returns (covering the 2018-19 tax year) can start to be filed. . Returns done on paper MUST be filed by 31 October whilst returns filed online have until 31 January 2020 to be filed. Your self assessment tax payments are due in January and July each (save for …MerlinAccounts_UK 55 views 1 comment 0 points Most recent by MerlinAccounts_UK April 8, 2019 11:45AMFind a Wave Pro
New tax year has started so we're now open for new client's, and where better to start than by inviting our UK Wave user community to get in touch. We're experienced not only with Wave but with several other accounting solutions, not to mention 3 decades of practical experience in the accounting world. . Size doesn't matter - its true! We are h…MerlinAccounts_UK 24 views 0 comments 0 points Started by MerlinAccounts_UK April 8, 2019 11:36AM Pro Network Listings
Good day Wave community, probably an entry level question, here is the scenario: My business model currently includes an Online Event Registration provider that captures attendee information, availability etc, and which uses Stripe as a payment gateway My Event Registration provider currently allows me to capture each Client registration in …Fpal 16 views 1 comment 0 points Most recent by Samd April 4, 2019 5:35PMHelp Center Discussion
How should I handle cash back rewards from the credit card I use for my business? The cash back reward gets automatically applied to my balance, reducing what I owe. I don't want to chart it as Income. Should I create a new chart of account in the Assets or Equity section specifically for the cash back reward? Any other suggestions?BernieB 102 views 5 comments 0 points Most recent by Carole April 4, 2019 2:47PMAccounting
Hi all, I have been recording my expenses in wave apps using cash on hand before I made any deposits into a bank account. So, I have been running a negative balance for a few months. I have recently made a deposit into a bank account and would like to withdraw money from the business account back to my personal account covering the expenses I h…billtlee 22 views 3 comments 0 points Most recent by Mikeg April 4, 2019 11:24AMAccounting
Hi everyone, I'm a new Australian-based small business owner and I'm struggling with a problem with Wave. Everything has been working well, however I have noticed that my 'All Accounts' balance is inaccurate because it contains duplicate transactions. For example, my 'Payments by Wave' page will show "Invoice payment for Invoice 5" and then my b…brightstar123 29 views 3 comments 0 points Most recent by mcullison April 3, 2019 3:38PMAccounting
Hi am a new wave user looking to file my business taxes for the year and I looking for an accountant or booker keeper who is using wave. You can reach me on [email protected]JustinIyizoba 12 views 0 comments 0 points Started by JustinIyizoba March 29, 2019 4:21PM Pro Network
Hi! We are hoping to receive some much-needed assistance from a Wave Pro/Wave Experienced Accountant in Australia. We are a small Not-For-Profit animal rescue and education organisation and have recently been victims of an accountancy scam. We are hoping for a Wave Pro accountant to perhaps donate a little bit of time helping us fix our system …ATS 27 views 1 comment 0 points Most recent by ClaireWryghtAccounts March 26, 2019 7:34AMFind a Wave Pro
I was just wondering where I would put a bank loan in the accounts? And for the monthly repayments too, where should I put that? The same thing for a grant given by the government. Thanks in advance!Kadthulas2004 30 views 5 comments 0 points Most recent by MerlinAccounts_UK March 25, 2019 1:04PMAccounting
Hello all, I was wondering what the process would be if I'd like to setup my ETF investment accounts on my wave bookeeping accounts. Basically amounts are debited via my checking account and then ported over to an investment account. Since this isn't really a withdrawal and more of a deposit into another account, how should i go about allocatin…Violanation 21 views 3 comments 0 points Most recent by JamieD March 20, 2019 9:52PMHelp Center Discussion
Hi, I'm just wondering how to enter a Start up Government Grant into my wave accounts, which Category. Is it a "Capital Interest" or anything else? I also need to know where and how to enter Personal Investment into my wave account? Which category does it go in?Kadthulas2004 25 views 1 comment 0 points Most recent by Samd March 19, 2019 7:21PMAccounting
Hi Guys, Wondering how we can integrate or merge invoice payments which we submitted as Cash on Hand to reflect E-Transfer payments which we received directly to our bank. The payments are showing as duplicates for our Sales and causing a conflict with our imported bank data. We don't want to delete the invoice or e-transfer payment and not …sixlabel 22 views 1 comment 0 points Most recent by Samd March 18, 2019 3:01PMSales & Invoicing


text:
Girls ghostbuster costume
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text:
Sophie Turner's Secret Circus Skills | The Graham Norton Show | BBC America
- Publicado em 24 Mai 2019
- In this BBC America exclusive clip, Sophie Turner is a champion sleeper and she's also a little bendy.
New episodes of #GrahamNortonBBCA premiere Fridays at 11pm on BBC America.
Subscribe now: bit.ly/1aP6Fo9
Twitter: twitter.com/bbcamerica
Facebook: facebook.com/bbcamerica
Tumblr: bbcamerica.tumblr.com
Instagram: instagram.com/bbcamerica
Snapchat: snapchat.com/add/bbcamerica_tv
Visit our official website to watch full episodes and more: www.bbcamerica.com/
- Entretenimento
Comentários • 874
- Gucci Cone 3 dias atrás
I too like trying different positions
- Shashwat Srivastava 3 dias atrás
its actually good to see the way 3 of them treat her, like a kid in the family
- A_ Lundgaard 4 dias atrás
ooooh she tries so hard but ultimately is neither charming nor interesting. Thankfully Dark Phoenix should be the last we see of her.
- Klayden004 4 dias atrás
Sophie just got even hotter!
- Tal Moore 7 dias atrás
An Englishwoman, an Irishman, a Scotsman and an American sit on a couch...
- Pei Liu 8 dias atrás
Lucky Joe
- Michael Adams 15 dias atrás
This lady will more than likely have a long and prosperous career ahead of her.
- J C 17 dias atrás
He might have hip dysplasia or EDS and poor thing doesn't even know it.
- Horus Lupercal 17 dias atrás
Sophie just became a billion times more attractive after that 😍😍😍
- Mr Mayhem 18 dias atrás
God I want to lick the soles of Sophie's feet so bad. I bet the taste heavenly.
- Dahlia is a flower 18 dias atrás
Well now we really know why they got married
- Brent P 18 dias atrás
I envy her husband.
- Syed Noore Rasul 19 dias atrás +1
Phoebe: I'm very bendy....
Sophie: hold my fake fringe
- Pablo Torres 19 dias atrás +1
I Love Her Even More!!! My Lady!! My Queen!!!
- A Guy Named Chad 22 dias atrás
Sophie looks like she just walked out of a 60's movie
- Arushi C. 22 dias atrás
I took a shot everytime there was an innuendo. Now it's just me and an empty bottle of vodka laughing at NVM nvm nevermboluol!!! 😂😂😂
- Violett Bellerose 22 dias atrás
Joe Jonas is a lucky man
- Sqweeky Badger 22 dias atrás
Wooooooooo meet you in the green room
- Odette Gonzalez 23 dias atrás
Sleeping, same for real. Fassie❤💞Sophie❤💞
- Zx 1oo 24 dias atrás
No Disney character is worth the murder of baby's.
- abdul wani 24 dias atrás
Michael Fassbender is the MAN
- Sh 24 dias atrás
Thank god someone else can do this
- Paloma R 25 dias atrás
she the best
- KayleeBrowncoat 25 dias atrás +4
Maisie Williams is a lucky girl 😜😂
- a girl has no name 25 dias atrás
I can do that too (leg behind your head thing!) xD I'm pretty flexible for someone who's not double-jointed and have always wished I were...although my hands seem to be since they bend inward in a way that until high school I thought was normal but freaked everyone out...
- -MISTKING- 25 dias atrás +1
- ArtemisScribe 25 dias atrás
And that's how you bag a Jonas brother!
- Farah Abbasi 23 dias atrás
Ugh i hate the jonas brothers.. and sophie can get anyone.. she's gorgeous, funny and really talented
- Gugu M 25 dias atrás +13
"Imagine what I can do when I'm warmed up"
Yaaaaas Sophie 😍😍😍💪
- Shijoe Joseph 26 dias atrás +3
James and Michael! Look at them redden up! 😂😋
- James Lee 26 dias atrás +2
She is so cool. I think the only one from GOT that will have a ongoing career.
- Verónica Mora Vega 26 dias atrás +1
I love how Jessica is so in whenever someone says they have a skill to demonstrate she's like: SHOW US
- Mind Job 26 dias atrás
She is a lucky man.
- GreenWitch Olsen 26 dias atrás +1
Big Sharon Tate's ways in that look
- AM Sarguru 26 dias atrás +7
Sophie: Imagine what I can do when I'm warmed up...
Joe Jonas: I've seen 😉
- Octopus Food 26 dias atrás
- So Jin Choi 26 dias atrás
Sheen has a new rival.
- ZIEEMAR 26 dias atrás
It seems like Jessica Chastain has been on every GN Show ive watched
- S McGrath 26 dias atrás
story with that fringe?
- akhil boddula 26 dias atrás
Ramsay Bolton : she is good ! she is very good!!
- Charles Bloomer 26 dias atrás
She can her leg behind my neck if she wants, or even both of them. 😁
- haderaeden 27 dias atrás
She reminds me of a younger mischa Barton with her "fake fringe" lol
- commandZee 27 dias atrás
Little fingers across the globe just stood at attention.
- Maryann Saldanha 27 dias atrás +2
I love her ❤❤❤❤❤❤❤❤❤❤❤❤❤❤❤❤❤❤❤❤❤❤❤❤
- Austin Elliott 27 dias atrás +1
We know why Joe married her now
- Sudhanshu Dixit 27 dias atrás +3
Lady stark stahp!
- Joyce Chahine - Pianist 27 dias atrás +4
I've been attracted to all four of these people at one stage or another (sorry Graham)
- truth cker 27 dias atrás
Watched Sophie act .... now I'm again thinking sexual
- Elder Cruz 27 dias atrás
- aaajjworm 27 dias atrás
Ramsey Bolton took full advantage of her "skills". Giggidy
- StuTheBru me 27 dias atrás
blonde and black eyes look weird to me
- Angie Cristina 27 dias atrás
Of course she's the queen of the north!
- jeffescantube 27 dias atrás +1
joe jonas be like... thats wifey for you guys
- SOTIA POI 27 dias atrás +1
😳 she's beautiful ❤
- ScottishStark240 27 dias atrás
Well both the Stark sisters have been on The Graham Norton show now!
- ScottishStark240 27 dias atrás +1
Well...I tried to copy Sophie.....aaaand nearly ended up with a broken leg. Ah well xD
- Bdhacker101 27 dias atrás
Sophie is looking too much like Kate Hudson here
- Ivette Parra 27 dias atrás +1
Ahh, long May she reign!! 😂
- Star Catch Films 27 dias atrás
Michaels grin 😋
He's a horny little rascal haaaa
- Gracie C. 27 dias atrás
That's hypermoblity. 😶
- Aamir Tanoli 27 dias atrás +1
Great at "sleeping" anytime anywhere,
Imagine what can i do when i am "warmed-up"
- Dante Gallo 27 dias atrás +15
Her mother and father were in the audience which is why she tried to gloss over the 'warming up' comment 😂😂😂
- Rae'Quan Morgan 27 dias atrás +1
I have the same face as michael fassbender 😂😂👀
- Seanachie's Court 27 dias atrás
How is she still singlee???
- Wladyslaw Aaron 27 dias atrás
If I smoke As much as she does I would sleep anywhere As well ^^
- The Stegman 27 dias atrás
Is there anything she can't do???
- Jennifer Walne 27 dias atrás +13
"My fake fringe nearly fell off there" -Sophie Turner, 2019
- Jenna Halvorson 27 dias atrás
I love her, but those bangs are not flattering.
- Robs 27 dias atrás +5
She's so REAL, I can't.
- tyrone loki 27 dias atrás +1
And this is one of the thousand reasons why joe jonas married her
- Ed W 27 dias atrás
I certainly hope she has other skills... Because acting isn't one of them...
- 吳若華 28 dias atrás
I can do that too. Useless tricks . Long legs have nothing to do with it.
- moochim edits 28 dias atrás +1
her makeup makes her too so much older
- roter13 28 dias atrás +1
Joe Jonas. I bow down to you
- Azin Kaveh 28 dias atrás +2
She's a worldly treasure and we must protect her
- SushiRoll Speaks 28 dias atrás
"If you can't do it we'll edit it out" bless Graham!
- Cadi Levox 28 dias atrás
Why does "a little bendy" sound like a euphemism?
- Lou 28 dias atrás +1
That hair is gorgeous on her!
- isabellamaria914 28 dias atrás +1
I'm so happy she acknowledged the fake fringe... it was bothering the crap out of me!!
- Dora Balog 28 dias atrás +4
she really seems like she figured out who she is, I admire that
- Setziprikly 28 dias atrás
Little finger likes this
- JB W 28 dias atrás +1
Lucky Joe.
- Eli 28 dias atrás +1
McAvoy Is so hot!!!
- Lucas Gray 28 dias atrás
I wish I was as good at sleeping as Sophie is
- The One 28 dias atrás
Now shoot a ping pong ball out of your cooch.
- Richard Ransom 28 dias atrás +2
Joe Jonas is ALL UP IN THERE 😂
- L Meto 28 dias atrás
That bang doesn't fit her at all. She looks old !
- ronisworld2 28 dias atrás
i would Loooooovvveeee to warm her up!!!
- man of the woods 28 dias atrás
Shes just 24, no wonder her limbs still work
- 니콜 입니다 28 dias atrás
I love her personality
- T R 28 dias atrás
Those bangs. Yikes
- monkey Zella 28 dias atrás +1
1:32 .... wait ... WHAT???? 😂😂😂😂
- Jess Barnes 28 dias atrás +1
joe is one lucky fella
- Sis I Si 28 dias atrás
Impressive....not losing the fringe...
- Adrian Brookes 28 dias atrás
Usefull talent for her next film (s) 😉..... cause she can't act
- Nell Mordecai 28 dias atrás
Quiero marry
- NAT 28 dias atrás
lmao nevermind
- OMG Network 28 dias atrás +1
Up top, Joe!✋
- jonathan carson 28 dias atrás +1
Lmao. She does it then looks like.. "yeah, imma boss"


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Master of Fine Art, Nature & Landscape Photography
THE YOGA CHALLENGE WITH MY BOYFRIEND!! || Georgia Productions
The Onion's Tips For Healthy Eating
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Democrats Call on Ralph Northam to Resign After Racist Photo Surfaces: A Closer Look


text: tag:blogger.com,1999:blog-2516684467932407107.post5520563603690535012..comments2019-06-15T08:30:49.559-07:00Comments on The Freckled Fieldnotes: Summer Picnic PartySianhttp://firstname.lastname@example.com:blogger.com,1999:blog-2516684467932407107.post-44909061518949807882016-08-10T04:05:32.584-07:002016-08-10T04:05:32.584-07:00Thank you Rowan! Aah, of course I just couldn'...Thank you Rowan! Aah, of course I just couldn't resist posting lots and lots of pictures :D you really should have yourself a picnic- it was such a fun and relaxing way of getting everyone together for a meal! Thanks for reading lovely! xxx Sianhttps://email@example.com:blogger.com,1999:blog-2516684467932407107.post-38838859660007547552016-08-10T04:01:59.057-07:002016-08-10T04:01:59.057-07:00Thank you for such a lovely comment! We actually d...Thank you for such a lovely comment! We actually didn't get a lot of bugs (which was a blessing because, as we live in the county, I was a bit worried!) so I think the citronella candles did their job very well :) We were only really pestered by the odd escapee chicken! Thanks for reading :D xxxSianhttps://firstname.lastname@example.com:blogger.com,1999:blog-2516684467932407107.post-4699113542012209672016-08-08T12:25:19.146-07:002016-08-08T12:25:19.146-07:00What a lovely spread! When you posted pictures of ...What a lovely spread! When you posted pictures of the cupcakes on Instagram I was hoping you would write a blog post! This makes me want to have a picnic with all my friends :)<br />xo, Rowan | rowanmorrissy.comRowan Morrissyhttps://email@example.com:blogger.com,1999:blog-2516684467932407107.post-4821600373884064162016-08-07T05:24:15.406-07:002016-08-07T05:24:15.406-07:00What a cute idea! I'd love to have a picnic, b...What a cute idea! I'd love to have a picnic, but the mosquitos here in southern Germany are horrible. Did you have many bugs at your picnic? I've never been to England so I'm curious about your summers. (I'm American for reference.)firstname.lastname@example.com


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|Home > Movies > Science Fiction > The Darkest Minds
The Darkest Minds
Torrent Description
A sudden disease kills over 98% of the children throughout the world, leaving the survivors with unusual abilities. As a result, the governments of the world place the survivors in a "rehabilitation camp", where they attempt to cure the children of their disease, distinguishing them into classes based on their abilities.
Ruby Daly celebrates her tenth birthday with her family, where her father gives her a keychain. Seeing her parents' concern about the disease, Ruby goes to comfort her parents in the night, touching their hands, and inadvertently erasing all their memories with Ruby. In the morning, her mother locks Ruby in the garage; having no recollection of her, she sends Ruby to an internment camp, where Ruby is determined to be an Orange, the most dangerous class where they have the abilities to control other people's minds and memories. Ruby uses her abilities to convince her supervisor that she is a Green, the least dangerous one with extremely high intelligence.
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Used Buick Encore FWD 4dr Essence STOCK NO. 181738
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Condition: Used
Mileage: 33,985
Exterior Color: Summit White
Interior Color: Brandy
Interior Material: Leather
Doors: 4
Model #: 4JV76
Engine: 4cyl, 1.4L, 138.0hp
Transmission: Transmission, 6-speed Automatic, Electronically-co
Drive Train: Front Wheel Drive, Drivetrain, front-wheel drive (
Notes on This Vehicle:
Used Buick Encore, options include: an Onboard Hands-Free Communications System, a Sunroof, Blind Spot Monitoring, Multi-zone Climate Control, Automatic Climate Control, Cross Traffic Alerts, Fog Lights, Keyless Entry, Power Windows, Satellite Radio, a Turbocharged Engine, Leather Seat Trim, Remote Engine Start, a Heated Passenger Seat, a Back-Up Camera, Push Button Start, Heated Mirrors, Keyless Start, Steering Wheel Audio Controls, Heated Seats, Side Mirror Turn Signals, Heated Steering Wheel, Aluminum Wheels, WiFi Hotspot Capable, Electronic Stability Control, a Cargo Shade, Power Mirrors, Power Locks, a Power Drivers Seat, an Adjustable Lumbar Seat(s), a Electronic Messaging Assistance, Daytime Running Lights, Traction Control, Integrated Turn Signal Mirrors, an Auxiliary Audio Input, Memory Seats, Steering Wheel Controls, a Leather Wrapped Steering Wheel, an Anti Theft System, Front Wheel Drive, a Compass, Bluetooth Connection, Privacy Glass, Rear Side Curtain Airbags, Cruise Control, Knee AirBag, an AM/FM Stereo, Bucket Seats, a Tire Pressure Monitoring System, an Adjustable Steering Wheel, a Power Passenger Seat, Anti-Lock Brakes, a Gasoline Engine, a Driver Illuminated Vanity Mirror, a Sunroof Sunshield, a Pass-Through Rear Seat, an Auto Transmission with Manual Mode, a Bench Seat (Split), Tinted Glass, a Fourth Passenger Door, a Rear Head Air Bag, a Garage Door Opener, a Drivers Air Bag, Disc Brakes, Air Conditioning, an MP3 Compatible Radio, a Rear Body Air Bag, a Passenger Illuminated Visor Mirror, Child Proof Locks, an Auto Dimming R/V Mirror, a Passenger Air Bag Sensor, Adjustable Head Rests, a Front Side Air Bags, a Front Head Air Bag, Intermittent Wipers, a Trip Odometer, a Center Arm Rest, a Rear Window Defroster, a Tilt Steering Wheel, Vanity Mirrors, a Spare Tire (Small Size), a Digital Clock, a Passenger Air Bag, and Power Steering.
This 2017 Buick Encore FWD 4dr Essence, Stock number 181738 has a Summit White exterior with 33,985 miles. Equipped with an impressive 4cyl, 1.4l, 138.0hp engine, an transmission, 6-speed automatic, electronically-co transmission and front wheel drive, drivetrain, front-wheel drive (, this Buick Encore is ready to conquer the roads!
This 2017 Buick Encore FWD 4dr Essence also comes equipped with: a Digital Clock, a Tilt Steering Wheel, a Trip Odometer, a Rear Window Defroster, a Spare Tire (Small Size), Vanity Mirrors, a Center Arm Rest, a Passenger Air Bag, and Power Steering. As well as: a Passenger Air Bag Sensor, an Auto Dimming R/V Mirror, a Front Head Air Bag, Child Proof Locks, Intermittent Wipers, Adjustable Head Rests, a Front Side Air Bags, and a Passenger Illuminated Visor Mirror
Contact us today to schedule a test drive of this 2017 Buick Encore FWD 4dr Essence! Or stop in at 920 N Michigan Ave Greensburg, IN to check it out in person!
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We attempt to update our website in a timely manner however Acra Automotive Group can not guarantee that the inventory shown will be available at the dealership. We cannot be responsible for typographical and other errors, including data transmissions or software errors that may appear on the site. If the posted price, incentive, offer or other service is incorrect due to typographical or other error we will only be responsible for honoring the correct price, incentive or offer. We make every effort to provide you the most accurate, up-to-the-minute information however when you are ready to purchase products or services, it is your responsibility to verify with us that all details listed are accurate. The list of standard equipment and accessories contained on this document reflect equipment which was standard at the time vehicle was manufactured. This vehicle may or may not contain some or most of the equipment and accessories listed as a result of the vehicle identification number equipment compilation provided by a third party source. This VIN equipment compilation is provided as a service by the dealer and a third party source and is in no way intended to serve as a warranty or list of actual equipment contained on the vehicle.


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Devon received her Doctor of Physical Therapy degree from the University of St. Augustine for Health Sciences in 2011 after earning her B.S. degree in Kinesiology from Louisiana State University in 2009. She earned her certification in manual therapy (MTC) from the University of St. Augustine in 2012 and is also certified in dry needling.
Devon LockfieldMay 20th, 2019
Ashlee YorkApril 4th, 2019
Ashlee York was born and raised here in Covington, LA. She received her undergraduate degree through Southeastern Louisiana University in 2011 and her Doctorate of Physical Therapy Degree from Louisiana State University Health Sciences Center in New Orleans in 2015. Since graduating, Ashlee has spent most of her career in the hospital-based setting. However, she
Luke KinnardJanuary 22nd, 2019
Luke Kinnard is a native of Houma, Louisiana. He attended The University of Louisiana-Lafayette, where he was a member of the football and track & field teams. For the Ragin' Cajuns, he was a two-time All-Conference and a Junior All-American in the javelin. He transferred to Louisiana State University and earned a Bachelor of Science


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Belgian Tripel9.5% ABV25 IBU
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Golden Monkey is both playfully delightful and profoundly satisfying. Exotic spices from the East round out this global journey to joy.
Belgian Dark Strong Ale10.5% ABV
Brouwerij Van SteenbergeErtvelde, Belgium
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Belgian Tripel10.0% ABV
Allagash Brewing CompanyPortland, ME
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~Retirement Celebration~
At the end of this week, Mary Louise will be retiring after 20 years of employment at Roanoke Farmers
and over 46 years in the Ag Industry!!
We hope you can join us in honoring Mary Louise for all her years of service, hard work, and dedication.
We will be celebrating all this week during office hours at the Benson office!!
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Wheat futures are firm to 5 cents higher in most contracts at midday. USDA crop condition ratings declined vs. last week for both winter wheat and
Lean Hog futures are up 85 cents to $2.275 so far on Turnaround Tuesday. The CME Lean Hog Index was down 49 cents from the previous day @ $78.65 on
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Live cattle futures are firm to 37.5 cents higher on Tuesday. Feeder cattle futures are steady to 55 cents lower. The CME feeder cattle index was
Cotton futures are up 6 to 33 points in most contracts on Tuesday. The Cotlook A index for June 24 was down 45 points from the previous day to 76.40
Soybean futures are down 4 to 5 1/2 cents in the front months on Tuesday. Soybean meal is down $1.10/ton, with soy oil 25 points lower. USDA
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|Systematic (IUPAC) name
|CAS number
|152459-95-5 220127-57-1 (mesilate)
|ATC code
|Chemical data
|Mol. mass
|493.603 g/mol
589.7 g/mol (mesilate)
|eMolecules & PubChem
|Pharmacokinetic data
|Protein binding
|Hepatic (mainly CYP3A4-mediated)
|Half life
|18 hours (imatinib)
40 hours (active metabolite)
|Fecal (68%) and renal (13%)
|Therapeutic considerations
|Licence data
|Pregnancy cat.
|Legal status
|POM (UK) ℞-only (US)
(what is this?) (verify)
Imatinib is a drug used to treat certain types of cancer. It is currently marketed by Novartis as Gleevec (USA) or Glivec (Europe/Australia/Latin America) as its mesylate salt, imatinib mesilate (INN) (formerly called CGP57148B or STI-571). It is used in treating chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GISTs) and other cancers.
It is the first member of a new class of agents that act by specifically inhibiting a certain enzyme that is characteristic of a particular cancer cell, rather than non-specifically inhibiting and killing all rapidly dividing cells.
In CML, the enzyme tyrosine kinase is stuck in the "on" position. Imatinib binds to the site of tyrosine kinase activity, and prevents its activity.
Imatinib was developed in the late 1990s by biochemist Nicholas Lydon, a former researcher for Novartis, oncologist Brian Druker of Oregon Health and Science University (OHSU), and Charles Sawyers of Memorial Sloan-Kettering Cancer Center,[1] who led the clinical trials confirming its efficacy in CML. Important contributions to its development were also made by Carlo Gambacorti-Passerini, a physician scientist at University of Milano Bicocca in Italy, and John Goldman, a hematologist at Hammersmith Hospital in London, UK.
Imatinib was developed by rational drug design. After the Philadelphia chromosome mutation and defective bcr-abl protein were discovered, the investigators screened chemical libraries to find a drug that would inhibit that protein. With high-throughput screening, they identified 2-phenylaminopyrimidine. This lead compound was then tested and modified by the introduction of methyl and benzamide groups to give it enhanced binding properties, resulting in imatinib.[2]
Gleevec received FDA approval in May 2001. On the same month it made the cover of TIME magazine as the "magic bullet" to cure cancer.
Druker, Lydon and Sawyers received the Lasker-DeBakey Clinical Medical Research Award in 2009 for "converting a fatal cancer into a manageable chronic condition".[1]
Imatinib is used in chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GISTs) and a number of other malignancies. One study demonstrated that Imatinib mesylate was effective in patients with systemic mastocytosis, including those who had the D816V mutation in c-Kit.[3] Experience has shown, however, that imatinib is much less effective in patients with this mutation, and patients with the mutation comprise nearly 90% of cases of mastocytosis. Early clinical trials also show its potential for treatment of hypereosinophilic syndrome and dermatofibrosarcoma protuberans.
Imatinib may also have a role in the treatment of pulmonary hypertension. It has been shown to reduce both the smooth muscle hypertrophy and hyperplasia of the pulmonary vasculature in a variety of disease processes, including portopulmonary hypertesion. [4]
In laboratory settings, imatinib is being used as an experimental agent to suppress platelet-derived growth factor (PDGF) by inhibiting its receptor (PDGF-Rβ). One of its effects is delaying atherosclerosis in mice without[5] or with diabetes.[6]
Recent mouse animal studies at Emory University in Atlanta have suggested that imatinib and related drugs may be useful in treating smallpox, should an outbreak ever occur.[7]
In the United States, the Food and Drug Administration has approved imatinib as first-line treatment for CML.[8] Imatinib has passed through Phase III trials for CML, and has been shown to be more effective than the previous standard treatment of α-interferon and cytarabine. Although the long-term side effects of imatinib have not yet been ascertained, research suggests that it is generally very well tolerated. Broadly, side effects such as edema, nausea, rash and musculoskeletal pain are common but mild.
Severe congestive cardiac failure is an uncommon but recognized side effect of imatinib and mice treated with large doses of imatinib show toxic damage to their myocardium.[9]
Imatinib is rapidly absorbed when given by mouth, and is highly bioavailable: 98% of an oral dose reaches the bloodstream. Metabolism of imatinib occurs in the liver and is mediated by several isozymes of the cytochrome P450 system, including CYP3A4 and, to a lesser extent, CYP1A2, CYP2D6, CYP2C9, and CYP2C19. The main metabolite, N-demethylated piperazine derivative, is also active. The major route of elimination is in the bile and feces; only a small portion of the drug is excreted in the urine. Most of imatinib is eliminated as metabolites, only 25% is eliminated unchanged. The half-lives of imatinib and its main metabolite are 18 and 40 hours, respectively.
Imatinib is a 2-phenylaminopyrimidine derivative that functions as a specific inhibitor of a number of tyrosine kinase enzymes. It occupies the TK active site, leading to a decrease in activity.
There are a large number of TK enzymes in the body, including the insulin receptor. Imatinib is specific for the TK domain in abl (the Abelson proto-oncogene), c-kit and PDGF-R (platelet-derived growth factor receptor).
In chronic myelogenous leukemia, the Philadelphia chromosome leads to a fusion protein of abl with bcr (breakpoint cluster region), termed bcr-abl. As this is now a continuously active tyrosine kinase, imatinib is used to decrease bcr-abl activity.
The active sites of tyrosine kinases each have a binding site for ATP. The enzymatic activity catalyzed by a tyrosine kinase is the transfer of the terminal phosphate from ATP to tyrosine residues on its substrates, a process known as protein tyrosine phosphorylation. Imatinib works by binding close to the ATP binding site of bcr-abl, locking it in a closed or self-inhibited conformation, and therefore inhibiting the enzyme activity of the protein semi-competitively.[10] This fact explains why many BCR-ABL mutations can cause resistance to imatinib by shifting its equilibrium toward the open or active conformation.[11]
Imatinib is quite selective for bcr-abl – it does also inhibit other targets mentioned above (c-kit and PDGF-R), but no other known tyrosine kinases. Imatinib also inhibits the abl protein of non-cancer cells but cells normally have additional redundant tyrosine kinases which allow them to continue to function even if abl tyrosine kinase is inhibited. Some tumor cells, however, have a dependence on bcr-abl.[8] Inhibition of the bcr-abl tyrosine kinase also stimulates its entry in to the nucleus, where it is unable to perform any of its normal anti-apoptopic functions.[12]
Gleevec is often cited as an example of pharmaceutical industry innovation that justifies the high cost of drugs. Marcia Angell and Arnold S. Relman argue that Gleevec is actually an example of the contribution of taxpayer-supported research and of industry inaction. Dr. Druker tested several, and imatinib was the most potent, and unusually, had almost no effect on normal cells. Novartis had "little corporate enthusiasm," they write, but Druker persisted.[13]
Further insight into the economics of the drug can be obtained by examining the cost to patients. The drug plan comparator at medicare.gov permits one to show the Medicare costs associated with specific drugs under various Medicare Part D plans. Examination of several such plans using 2010 data shows that the monthly cost for a 400 milligram dose while in the "donut hole," i.e. "after your total drug costs reach the initial coverage limit but before your total out of pocket expense equals $4,550.00," is approximately $3700 to $3900, corresponding to an annual cost of $44,400 to $46,800. Since the patient pays 100% of drug costs while in the "donut hole," this figure would be a reasonable lower bound for the cost of the drug in the United States.
Another source for drug cost information is pharmacychecker.com. Their figures (retrieved in June 2009) show that a single Gleevec 400mg pill costs between $110 and $130. That would correspond to about $44,000 per year at 400 mg/day. However, many patients take 600 mg/day or 800 mg/day, as ongoing research supports the finding that higher doses of the drug are more effective (see, for example, http://www.ncbi.nlm.nih.gov/pubmed/19720924.)
People who take 600 mg/day often take 6, 100 mg tablets. Costs for the 100 mg tablet are significantly different from the costs for the 400 mg tablet given above. When Gleevec was approved by the Patented Medicine Prices Review Board of Canada in 2002, the PMPRB published cost information for the 100 mg tablet in Canada, Italy, Sweden, Switzerland, the United Kingdom, and the United States (see http://www.pmprb-cepmb.gc.ca/english/View.asp?x=529&mp=572, retrieved 2/23/2010.) The lowest price per single 100 mg tablet was in Italy, at CN$20.0620. The highest price was in Sweden at CN$29.6054. The median price was in the UK at CN$26.1962. The United States price was second highest price listed at CN$27.1313. All of these prices were stated in Canadian dollars as of November 2002.
In 2007, imatinib became a test case through which Novartis challenged India's patent laws. A win for Novartis would make it harder for Indian companies to produce generic versions of drugs still manufactured under patent elsewhere in the world. Médecins Sans Frontières argues that a change in law would make it impossible for Indian companies to produce cheap generic antiretrovirals (anti-HIV medication), thus making it impossible for Third World countries to buy these essential medicines.[14] On 6 August 2007 the Madras High Court, dismissed the writ petition filed by Novartis, challenging the constitutionality of Section 3(d) of Indian Patent Act and deferred to the World Trade Organization (WTO) forum to resolve the TRIPS compliance question.