Tiotropium bromide (INN) (originally marketed as Spriva) is a long-acting, 24-hour, anticholinergic bronchodilator used in the management of chronic obstructive pulmonary disease (COPD).

Tiotroprium was discovered in 1991 and came to market in 2004.

Medical uses

Tiotropium is used for maintenance treatment of chronic obstructive pulmonary disease (COPD) which includes chronic bronchitis and emphysema. It is not however used for acute exacerbations.

Adverse effects

Adverse effects are mainly related to its antimuscarinic effects. Common adverse drug reactions (≥1% of patients) associated with tiotropium therapy include: dry mouth and/or throat irritation. Rarely (<0.1% of patients) treatment is associated with:urinary retention, constipation, acute angle closure glaucoma, palpitations (notably supraventricular tachycardia and atrial fibrillation) and/or allergy (rash, angioedema, anaphylaxis).

Tiotropium and another member of its class ipratropium were linked to increased risk of heart attacks, stroke and cardiovascular death. The FDA requested further trials; these are now complete, and adequately resolve the previous safety concerns.

Tiotropium mist inhaler (Respimat) has been found to be associated with an increase of all cause mortality in people with COPD.

Dosage

The standard dose of tiotropium is 18 mcg which is administered by a HandiHaler inhalation device.

Mechanism of action

Tiotropium is a muscarinic receptor antagonist, often referred to as an antimuscarinic or anticholinergic agent. Although it does not display selectivity for specific muscarinic receptors, when topically applied it acts mainly on M₃ muscarinic receptors located on smooth muscle cells and submucosal glands. This leads to a reduction in smooth muscle contraction and mucus secretion and thus produces a bronchodilatory effect.

Mode of delivery

The patient removes one tiotropium capsule from the blister pack, places it into the piercing chamber of the inhalation device and closes the mouthpiece.

The capsule is manually pierced, and the medication is inhaled through the mouthpiece. It is recommended that inhalations be repeated 2 to 3 times to ensure all medication is drawn from the capsule. When properly done, the capsule will make a distinctive flutter or rattle, audible to the patient.

Once the powder capsules are removed from the blister pack, it should be taken immediately via the inhalation device. If a capsule is exposed to the air, it will rapidly degrade to the point the dose will become ineffective. Any previously exposed capsules should be discarded.

The capsules cannot be taken orally - they will not be effective as respiratory medication if absorbed through the gastrointestinal tract and may have side effects if absorbed via this route.

References

External links

• Official SPIRIVA Site
• Thomson CenterWatch

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In the history of video games, the seventh generation includes consoles released since late 2005 by Nintendo, Microsoft, and Sony Computer Entertainment. The eighth generation began in November 2012. For home consoles, the seventh generation began on November 22, 2005 with the release of Microsoft's Xbox 360 and continued with the release of Sony Computer Entertainment's PlayStation 3 on November 17, 2006, and Nintendo's Wii on November 19, 2006. Each new console introduced a new type of breakthrough in technology. The Xbox 360 offered games rendered natively at high-definition video (HD) resolutions, the PlayStation 3 offered HD movie playback via a bui lt-in 3D Blu-ray Disc player, and the Wii focused on integrating controllers with movement sensors as well as joysticks. Some of the Wii controllers could be moved about to control in-game actions, which enabled players to simulate real-world actions during gameplay (e.g., in the Wii sports tennis game, the user swings the controller to hit the on-screen image of a tennis ball). Video game consoles had become an important part of the global IT infrastructure. It is estimated that video game consoles represented 25% of the world's general-purpose computational power in the year 2007.

Joining Nintendo in the motion market, Sony Computer Entertainment released the PlayStation Move in September 2010. The PlayStation Move features motion sensing gaming, similar to that of the Wii. Microsoft joined the scene in November 2010, with its Kinect (previously announced under the working title "Project Natal" in June 2009). Unlike the other two systems (PlayStation 3 and Wii), Kinect does not use controllers of any sort and makes the users the "controller." Having sold 8 million units in its first 60 days on the market, Kinect has claimed the Guinness World Record of being the "fastest selling consumer electronics device". While the Xbox 360 offers wired as well as wireless controllers as a standalone product, all PlayStation 3 controllers can be used in wired and wireless configurations. Starting with handheld consoles, the seventh generation began on November 21, 2004 with the North American introduction of the Nintendo DS as a "third pillar", alongside Nintendo's exist ing Game Boy Advance and GameCube consoles.

The Nintendo DS (NDS) features a touch screen and built-in microphone, and supports wireless IEEE 802.11 (Wi-Fi) standards. Additionally, the revised version of the NDS, the Nintendo DSi, features two built in cameras, the ability to download games from the DSi store, and a web browser. The PlayStation Portable (PSP) released later the same year on December 12, 2004, followed a different pattern. It became the first handheld video game console to use an optical disc format, Universal Media Disc (UMD), as its primary storage media. Sony also gave the PSP robust multi-media capability, connectivity with the PlayStation 3, PlayStation 2 (only on some games), other PSPs, as well as Internet connectivity. The Nintendo DS likewise had connectivity to the internet through the Nintendo Wi-Fi Connection and Nintendo DS Browser, as well as wireless connectivity to other DS systems and Wii consoles. Despite high sales numbers for both consoles, PlayStation Portable sales have consistently la gged behind those of the Nintendo DS; nevertheless, the PlayStation Portable has the distinction of being the best-selling non-Nintendo handheld gaming system. Sony announced in 2014 that they had discontinued the production of the PlayStation Portable worldwide, this follows Nintendo's announcement in 2014 that it had discontinued its original line of the Nintendo DS family devices to move onto the Nintendo 3DS line. Microsoft also announced in 2016, that they would discontinue the Xbox 360 at the end of April that year.

A crowdfunded console, the Ouya, received $8.5 million in pre-orders, launching in 2013. Post-launch sales were poor, and the device was a commercial failure. The business was wound down due to financial problems and sold to Razer Inc.. Razer discontinued the Ouya in July 2015.

The microconsoles like Nvidia Shield Console, MOJO, Razer Switchblade, GamePop, GameStick, Ouya, and even more powerful PC-based Steam Machine consoles are attempting to compete in the game console market; but even though some of these are theoretically powerful on paper, they are however seldom referred to as "seventh generation" consoles.

Home consoles

Wii

Nintendo entered this generation with a new approach embodied by its Wii. The company planned to attract current hardcore and casual gamers, non-gamers, and lapsed gamers by focusing on new gameplay experiences and new forms of interaction with games rather than cutting edge graphics and expensive technology. This approach was previously implemented in the portable market with the Nintendo DS. Nintendo expressed hope that the new control schemes it had implemented would render conventionally controlled consoles obsolete, leading to Nintendo capturing a large portion of the existing market as well.This strategy paid off, with demand for the Wii outstripping supply throughout 2007. Since Nintendo profited on each console right from the start unlike its competitors, it achieved very positive returns. With only a few exceptions, monthly worldwide sales for the Wii were higher than those of the Xbox 360 and PlayStation 3, eroding Microsoft's early lead and widening the gap between its market share and Sony's. On September 12, 2007, it was reported by the British newspaper Financial Times that the Wii's sales surpassed those of the Xbox 360, which had been released one year previously, and became the market leader in worldwide home console sales for the generation.

As in previous generations, Nintendo provided strong support for its new console with popular first-party franchises like Mario, The Legend of Zelda, Metroid, and Pokémon, among others. To appeal to casual and non-gamers, Nintendo developed a group of core Wii games, consisting of Wii Sports, Wii Play, Wii Fit, and Wii Music, where players make use of the motion-sensing abilities of the console and its peripherals to simulate real world activities. With the exception of Wii Music, the games and their sequels have all been highly successful.

Publishers such as Ubisoft, Electronic Arts, Capcom, and Majesco continued to release exclusive titles for the console, but the Wii's strongest titles remained within its first-party line-up. Analysts speculated that this would change in time as the Wii's growing popularity persuaded third-party publishers to focus on it; however, some third party developers expressed frustration at low software sales. Goichi Suda, developer of No More Heroes for the Wii, noted that "only Nintendo titles are doing well. This isn't just because of the current situation in Japan, as this is happening outside Japan. I am very surprised about the reality about Wii, because before I was making this game, I wasn't expecting that Wii would be a console targeted only for non-gamers. I expected more games for hardcore gamers. The reality is different to what I expected." Conversely, the PAL publisher of No More Heroes Rising Star Games were greatly impressed with the game's sales. Goichi Suda later retracted his comment, saying his "point was that No More Heroes, unlike a lot of Nintendo Wii titles currently available is the kind of product that will attract a different kind of consumer to the hardware, i.e. gamers who are looking for a different genre to the products that have been successful on this platform thus far."

In early 2008, the NPD Group revealed sales data showing that, while the Wii's life-to-date attach rate was low, in December 2007, it reached 8.11â€"higher than the attach rates for the Xbox 360 and PlayStation 3 in that month. The Wii's low overall attach rate could be explained by reference to its rapidly increasing installed base, as financial analysts have pointed to the Xbox 360's high attach rates as indicative of an unhealthy lack of installed base growth, and warned that what actually benefits third-party developers is "quicker adoption of hardware and a rapidly growing installed base on which to sell progressively more game units," which tends to lower the attach rate of a product.

On September 23, 2009, Nintendo announced its first price drops for the console. In the United States, the price was reduced by fifty dollars, resulting in a new Manufacturer's Suggested Retail Price (MSRP) of $199.99, effective September 27, 2009. For Japan, the price dropped from ¥25,000 to ¥20,000, effective October 1, 2009. In Europe (with the exception of the United Kingdom), the price of a Wii console dropped from €249 to €199. On May 3, 2010, Nintendo announced that Wii consoles sold in the Americas now would include Wii Sports Resort and Wii MotionPlus, effective May 9, 2010. Since May 15, 2011, the Wii Console is US$149.99 and comes bundled with Mario Kart Wii.

Xbox 360

Microsoft Xbox 360 gained an early lead in terms of market share, largely due to its established Xbox Live online gaming system, and its early launch date, which was one year before its rivals. Sales in North America and Europe have continued to be strong, even after the release of the Wii and PlayStation 3. Like its predecessor, the Xbox 360 received a muted reception in Japan, attributed to the lack of content aimed at Japanese gamers.

This early launch did come with some trouble, as technical problems appeared in a portion of Xbox 360 units sold. The most well-known problem is the "red ring of death" and Error E74, which received (and still receives) a great deal of attention due to some users having to replace their consoles multiple times. Microsoft attempted to address this by offering a three-year warranty on all affected consoles and repairing them free of charge. It also retroactively reimbursed owners of affected systems who paid for repairs. According to The Mercury News, new models of the console featuring 65-nanometer technology will address this and other issues; the new technology is expected to reduce heat production, which will lower the risk of overheating and system failures; although, this has never been officially confirmed by Microsoft.

As they share many cross-platform games and compete for the same audience as their predecessors, frequent comparisons are made between the Xbox 360 and PlayStation 3. The PS3 uses the Blu-ray format, while the Xbox 360 uses a standard DVD9. The Xbox 360 is less expensive to produce, and analysts expect that a mid-revision will allow Microsoft to break-even on manufacturing costs, while industry consensus is that the Xbox 360's conventional architecture is easier to develop for.

At the end of first half of 2007, the console stabilized at 11.6 million units shipped as sales dropped 60% while its rival, Wii, gained momentum and Sony announced a competitive price drop on the PlayStation 3. Microsoft's strategy to boost sales with the release of the highly anticipated Halo 3 in September 2007 paid off, outselling the Wii that month in North America. Microsoft's Entertainment and Devices Division experienced a huge increase in revenue, largely driven by the release of Halo 3, and posted a quarterly profit for the first time in two years.

The Xbox 360's advantage over its competitors owes itself to the release of high-profile games, such as additions to the Halo franchise. The 2007 Game Critics Awards honored the platform with 38 nominations and 12 wins â€" more than any other platform. By March 2008, the Xbox 360 had reached a software attach rate of 7.5 games per console in the US; the rate was 7.0 in Europe, while its competitors were 3.8 (PS3) and 3.5 (Wii), according to Microsoft. At the 2008 Game Developers Conference, Microsoft announced that it expected over 1,000 games available for Xbox 360 by the end of the year. The Xbox 360 has managed to gain a simultaneous release of titles that were initially planned to be PS3 exclusives, including Devil May Cry, Ace Combat, Virtua Fighter, Grand Theft Auto IV, Final Fantasy XIII, Tekken 6, Metal Gear Rising: Revengeance, and L.A. Noire.

In August 2007, the first price drop was announced for all Stock Keeping Units (SKU's) of the Xbox 360. The Core system's price was reduced in the United States by $20, the Premium by $50, and the Elite model by $30. Also, the HDMI port, previously exclusive to the Elite system, was added to new models of the Premium and Arcade systems; the Core system was discontinued.

At E3 2010, Microsoft revealed a new US$299.99 Xbox 360 SKU known officially as the Xbox 360 S and referred to as the "Slim" by various media outlets. It replaced the Elite and comes with an integrated 802.11n WLAN adapter, integrated TOSLINK port, 5 USB ports and a 250 GB HDD. It also does not require an additional power supply to make use of Microsoft Kinect motion control accessory. A US$199.99 version was released on August 3, 2010 in the US which replaced the Arcade model. It has 4 GB and a 250 GB model of internal memory, it has a matte or glossy finish and it comes with a headset. At E3 2013 Microsoft revealed the Xbox 360 E, the final iteration of the Xbox 360 series, to be succeeded by Xbox One. The Xbox 360 E was originally priced at US$199.99 for a 4GB model, and US$299.99 for the 250GB model. The 360 E featured a new square design with a simplified exterior akin to the Xbox One.

PlayStation 3

Sony Computer Entertainment PlayStation 3 was released on November 11, 2006 in Japan and November 17, 2006 in the US and Canada. The system's reliance on new technologies such as the Cell microprocessor and Blu-ray format caused difficulties in manufacturing, especially the Blu-ray diode, leading to shortages at launch and the delay of the PAL region launches; however, by early December 2006, Sony announced that all production issues had been resolved. Market analysts and Sony executives noted that the success of the PlayStation 3 and the Blu-ray format were dependent on each other; Rich Marty, VP of New Business Development at Sony Pictures Home Entertainment stated that the "PS3 is critical to the success of Blu-ray," while Phil Harrison stated that the PlayStation 3's success would be ensured because "the growth of the Blu-ray Disc movie market ... is a positive factor which will play more into the consumer psyche ... as more consumer electronics firms launch standalone disc pl ayers, as more Blu-ray Disc movies become available, and as more shelf space is dedicated to the category at retail."

Sony would provide support for its console with new titles from acclaimed first-party franchises such as Gran Turismo, Team Ico, and God of War, and secured a number of highly anticipated third-party exclusive titles, including Metal Gear Solid 4: Guns of the Patriots, Yakuza 3 and Valkyria Chronicles. Titles that were originally exclusive or recognized with the platform, such as Devil May Cry, Ace Combat, Virtua Fighter, and Monster Hunter, have been released on other platforms. The previous Grand Theft Auto titles were originally timed exclusives on the PlayStation 2, before making their release on other platforms, such as the Xbox, months later; however, Grand Theft Auto IV, the latest installment, was released simultaneously on the Xbox 360 and PlayStation 3. Announced exclusives titles for the PlayStation 3 such as Assassin's Creed; Bladestorm: The Hundred Years' War, and Fata l Inertia were released on Xbox 360 as well, with the latter making its release on Xbox 360 before the PlayStation 3 version.

The Katamari series, which has long been PlayStation 2 exclusives, found one of the more recent installments, Beautiful Katamari, exclusive to Xbox 360. These releases fueled rumors and fear that Final Fantasy XIII and Tekken 6, two highly anticipated exclusive PlayStation 3 games at the time, would also be available for Xbox 360, the PlayStation 3's primary competitor and at E3 2008, it was announced that Final Fantasy XIII would be simultaneously released on the Xbox 360 in Europe and North America; later on October 8, 2008, it was announced that Tekken 6 would also be releasing on the Xbox 360. After the multiplatform releases of these games, the fifth installment of the Metal Gear series, Metal Gear Solid: Rising, has also been announced for the Xbox 360; L.A. Noire, which was announced as an exclusive since the beginning of its development, has also been released for the Xbox 360; Dark Souls, the spiritual successor to Demon's Souls, has also been released on Xbox 360; the Persona series, which has a long history of being PlayStation exclusive, found the seventh generation installment, Persona 4 Arena multiplatform; however, Metal Gear Solid 4, Yakuza 3, Tekken 5: Dark Resurrection ONLINE, and Disgaea 3: Absence of Justice still remain PlayStation 3 exclusives. Sony has blamed lower-than-expected sales, loss of exclusive titles in the PlayStation 3 software library, its higher price, and stock shortages.

In July 2007, Sony announced a drop in the price of the console by $100. This measure only applied to the 60 GB models and was exclusive to the United States and Canada, where those models are no longer in production. On October 18, 2007, Sony announced a US$100 price drop for the 80 GB model and a new US$399 40 GB model to launch on November 2, 2007 with reduced features such as the removal of backward compatibility with PS2 games. Within weeks, Sony announced that sales of the 40 GB and 80 GB models by major retailers had increased 192%. In November 2008, Sony launched a $499 160 GB model, and on August 18, 2009, Sony announced the PS3 Slim. The PS3 slim sold 1 million in under a month. It was then announced that a 250GB slim model was to be released. It was released on September 1 (or 3 depending on country) and costs $299, £249 and €299. In Australia the console will cost A$499, which is A$200 less than the standard PS3. In September 2009, a $299 120 GB Slim Model was rel eased. A $349 250 GB Model was later released later in 2009. In August 2010, the 160 GB Slim Model was released for $299. The same price for a 120 GB PS3 slim Model. In Japan, the 160GB slim model is also available in white. On September 17, 2010, Sony released the 320 GB Slim Model, but it only sold with the PlayStation Move for US$399.99.

In September 2012, Sony announced a new slimmer PS3 redesign (CECH-4000), commonly referred to as the "Super Slim" PS3. It was released in late 2012 it became available with either a 250 GB or 500 GB hard drive. The "Super Slim" model is currently the only model in production.

Comparison

^a Game packages not listed. Bundles, special editions and limited editions may include additional or exchanged items.
^b There is a verity of other input devices available for all three consoles, including rhythm game controllers, microphones and third-part gamepads/controllers.
^c All consoles are capable of producing 3D images using anaglyph or frame-compatible systems (side-by-side/SbS, top and bottom/TaB), as these do not require any special output hardware. As such, these display modes are dependent on the software being displayed rather than the console.
^d Facebook and Twitter apps for Xbox 360 were retired in October 2012.

Sales standings

Worldwide figures are based on data from the manufacturers. The Canada and the United States figures are based on data from the NPD Group, the Japan figures are based on data from Famitsu/Enterbrain, and the United Kingdom figures are based on data from GfK Chart-Track.

Discontinuations and revisions

• The PlayStation 3 20 GB was discontinued in North America in April 2007 and effectively discontinued in Japan in early 2008.
• The PlayStation 3 60 GB was discontinued in NTSC territories by September 2007, and replaced with the 80 GB version.
• The PlayStation 3 60 GB was effectively discontinued for PAL territories in late 2007. When the remaining stock in stores was sold, the 40 GB version served as its replacement.
• Sony announced before the PS3 launch in Europe that the PlayStation 2's Emotion Engine CPU would be removed from it for cost savings, and all backwards compatibility would be software-based. This is also the same for the 80 GB model launched in the North American market in 2007.
• An HDMI out port was added to the Premium Xbox 360 in May 2007.
• The Xbox 360 Core system was discontinued and replaced by the "Arcade" version in October 2007.
• The price of the Xbox 360 Premium version was dropped to US$299 in North America on July 13, 2008. Supplies of the existing 20 GB model were exhausted by early August and it was replaced by an identical model with a 60 GB HDD at a MSRP of US$349.
• The PlayStation 3 40 GB was discontinued in all territories in early August 2008 and the new 80 GB version served as its replacement.
• The Xbox 360 Arcade 256 MB internal memory SKU was discontinued in all territories in early 2009 and a new 512 MB internal memory SKU still named the Xbox 360 Arcade was released.
• The PlayStation 3 Slim was introduced on August 18, 2009. At US$299, it is US$100 cheaper than the previous model; it is also approximately â…" lighter and more energy efficient. The two original PS3 Slim models, priced at US$299.99 and US$349.99 respectively, hold 120/250 GB. These were then superseded by 160 GB and 320 GB models, which are priced at US$249.99 and US$299.99 respectively.
• The black Wii console was released in Japan on August 1, 2009 and in Europe in November 2009.
• The Wii package for North America has been updated to include a copy of Wii Sports Resort as well as the required Wii MotionPlus accessory to play it, beginning May 9, 2010. The console is also available in black.
• A special edition red Wii console was released in honor of Super Mario Bros. 25th Anniversary.
• The Xbox 360 S was announced at E3 2010 by Microsoft. It is a smaller revision of the Xbox 360 hardware, which includes either a built-in 250 GB hard drive or 4 GB of Flash storage, 802.11n Wi-Fi, a TOSLINK connector, 5 USB ports and an AUX connector for the Kinect sensor device.
• The Wii Family Edition was released on October 23, 2011. It drops support for GameCube games and accessories, and is designed to sit horizontally.
• The Xbox 360 E was revealed and released at E3 2013 on June 10, 2013. It featured a new slimmer design, that was quieter than previous models.

Backward compatibility

Early models of the Wii are fully backwards compatible with GameCube software and most of its accessories; the Wii Family Edition and the Wii Mini iterations lack GameCube support. Early versions of the PlayStation 3 and all models of the Xbox 360 only offer partial support and use software emulation for backwards compatibility. Current versions of the PS3 do not offer PlayStation 2 compatibility, though PS1 compatibility is retained. Some models of the first generation of the PS3 offered full backwards compatibility for PS2 games. The Xbox 360's compatibility is increased through game-specific patches automatically downloaded from Xbox Live or downloaded and burned to a CD or DVD from the Xbox website and the PS3's compatibility is expanded with firmware updates.

All three consoles provide titles from older consoles for download; the Xbox 360 through the Xbox Originals service, the PlayStation 3 through the PlayStation Store, and the Wii through the Virtual Console. When purchased, the game is saved to console's internal memory or, optionally on the Wii, to an inserted SD/SDHC card. Initially the Xbox 360 also provided Xbox Live support for backwards compatible games, but the service has since been discontinued for original Xbox games. No more games will be added to the list of backwards compatible games for the Xbox 360. In response to the lack of backward compatibility for most PS3s, many popular games have been released for download as PlayStation 2 Classics and other popular series have been updated with gameplay/graphics as high-definition remasters for PlayStation consoles and have been released on Blu-ray Disc or are available for download on the PlayStation Network.

High definition and enhanced definition video

Both the PlayStation 3 and the Xbox 360 support 1080p high definition video output. However, the output signal may be protected by digital rights management and may require an HDCP-compliant display if HDMI is used. The Xbox Live Marketplace service and the PlayStation Store offer HD movies, TV shows, movie trailers, and clips for download to the console's HDD. Other regional PlayStation Stores only allow download of movie trailers and short segment clips. As of November 2009, the Video Download service present on the American PlayStation Store will be available for select European countries.

While only a small number of games render video in native 1080p, many games can be automatically scaled to output this resolution. The Wii is capable of outputting 480p for the Wii Menu and most games through a component cable, which must be purchased separately.

Reliability

In the September 2009 issue of Game Informer magazine, survey results were published in which among nearly 5000 readers who responded, 54.2% of those who owned an Xbox 360 had experienced a console failure for that system, compared with 10.6% for PlayStation 3, and 6.8% for Wii.

In August 2009, warranty provider SquareTrade published console failure rate estimates, in which the proportion of its customers reporting a system failure in the first two years is 23.7% for Xbox 360, 10.0% for PlayStation 3, and 2.7% for Wii.

Handheld systems

For video game handhelds, the seventh generation began with the release of the Nintendo DS on November 21, 2004. This handheld was based on a design fundamentally different from the Game Boy and other handheld video game systems. The Nintendo DS offered new modes of input over previous generations such as a touch screen, the ability to connect wirelessly using IEEE 802.11b, as well as a microphone to speak to in-game NPCs. On December 12, 2004, Sony released its first handheld, PlayStation Portable. The PlayStation Portable was marketed at launch to an above-25-year-old or "core gamer" market, while the Nintendo DS proved to be popular with both core gamers and new customers.

Nokia revived its N-Gage platform in the form of a service for selected S60 devices. This new service launched on April 3, 2008. Other less-popular handheld systems released during this generation include the Gizmondo (launched on March 19, 2005 and discontinued in February 2006) and the GP2X (launched on November 10, 2005 and discontinued in August 2008). The GP2X Wiz, Pandora, and Gizmondo 2 were scheduled for release in 2009.

Another aspect of the seventh generation was the beginning of direct competition between dedicated handheld gaming devices, and increasingly powerful PDA/cell phone devices such as the iPhone and iPod Touch, and the latter being aggressively marketed for gaming purposes. Simple games such as Tetris and Solitaire had existed for PDA devices since their introduction, but by 2009 PDAs and phones had grown sufficiently powerful to where complex graphical games could be implemented, with the advantage of distribution over wireless broadband.

Sony announced in 2014 that they had discontinued the production of the PlayStation Portable worldwide, this follows Nintendo's announcement in 2014 that it had discontinued its original line of DS family devices to move onto the 3DS line.

Handheld comparison

Note: First year of release is the first year of the system's worldwide availability.

Other systems

There were also other consoles released during the seventh generation time period. Generally, they are either niche products or less powerful.

Home consoles

Handhelds

Released in China only

Released in South Korea only

Resembles

Cloud gaming/Gaming on demand services

Software

Milestone titles

• Assassin's Creed II (PC, PS3, Xbox 360) by Ubisoft Montreal and Ubisoft was met with widespread critical acclaim. Its success spawned two direct sequels, Assassin's Creed: Brotherhood, and Assassin's Creed: Revelations. It garnered Metacritic scores of 91, 90, and 86 respectively. The game was praised for its stronger emphasis on open-world exploration and interaction, non-linear gameplay and greater mission variety compared to the first Assassin's Creed.
• Batman: Arkham Asylum (PC, PS3, Xbox 360) by Rocksteady Studios, Eidos Interactive, and Warner Bros. Interactive Entertainment has been praised for its innovation, gameplay, and compelling storyline. It won a Guinness World Record for 'Most Critically Acclaimed Superhero Game Ever'. It broke the record in this category by achieving an average score of 91.67 from reviews around the world. Its sequel Batman: Arkham City (PC, PS3, Xbox 360, Wii U) would later become even more critically acclaimed than its predecessor, becoming the highest-rated game of 2011. It received universal acclaim for its narrative, character and world designs, and Batman's combat and navigation abilities and was the recipient of several awards including: Game of the Year, Best Action Game, Best Action Adventure Game, Best Adventure Game, and Best Original Score from different media outlets.
• Bayonetta (PS3, Xbox 360) by Platinum Games and Sega received universal critical acclaim, including perfect scores from Famitsu and Edge, and is considered to have surpassed peers in its genre.
• BioShock (PC, PS3, Xbox 360) by Irrational Games and 2K Games is considered a major influential and artistic game of this generation with a plot that quickly created controversy with the decisions the player makes during the gameâ€"such as making moral choices as to whether to save or kill children. BioShock 2 (PC, PS3, Xbox 360) and BioShock Infinite (PC, PS3, Xbox 360), the franchise's subsequent titles, have received mostly positive reviews from critics and players alike. BioShock Infinite in particular received universal acclaim upon release, with reviews singling out the game's plot and visual aesthetics as the main standouts, becoming the highest rated first-person shooter of 2013. It was also favorably compared to the first BioShock game, with some critics even considering Infinite had surpassed it.
• Call of Duty 4: Modern Warfare (PC, PS3, Xbox 360) by Infinity Ward and Activision garnered universal critical acclaim and is considered among the best games in its genre. With the release of its direct sequel and every single installment up until the launch of the PlayStation 4 and Xbox One, the Call of Duty franchise quickly propelled into the fastest and best selling video game franchise of the seventh generation of video games.
• Dark Souls (PS3, Xbox 360) by From Software generated universal critical acclaim upon release. Known for its brutally challenging gameplay, critics consider Dark Souls to be one of the most influential and rewarding video games of the seventh console generation.
• Donkey Kong Country Returns (Wii) by Retro Studios and Nintendo generated critical acclaim upon release for its arcade-retro platform style and highly challenging gameplay. It was awarded "Best Retro Design" and "Most Challenging" in 2010 by IGN, and was selected 5th in the top 25 Wii games.
• The Elder Scrolls V: Skyrim (PC, PS3, Xbox 360) by Bethesda Game Studios and Bethesda Softworks was one of the fastest selling games of all times, and one of the most critically acclaimed of this generation. The art style of the game world drew acclaim from many reviewers and it became the highest rated role-playing game of 2011.
• Gears of War (PC, Xbox 360) by Epic Games and Microsoft Studios had preorder sales that were second only to Halo 2 in the studio's history. Gears of War was also the first Xbox or Xbox 360 game to sell out and reach the top ten charts in Japan. On November 7, 2006â€"the day that it was releasedâ€"it became the most popular game on the Xbox Live service, overtaking Halo 2, which had held the spot since its launch in November 2004. By January 19, 2007, just ten weeks after its debut, over three million units of the game had been sold.
• Grand Theft Auto IV (PC, PS3, Xbox 360) by Rockstar Games is a sandbox-style action-adventure video game developed by Rockstar North. The game received universal acclaim, and was so popular that a few Hollywood producers set precedent by beginning to browse video-game release dates to check for conflicts with movie release dates, due to Grand Theft Auto IV's potential harm to May 2, 2008 release of Iron Man. As of January 2014, the PS3 and Xbox 360 version has taken the fourth and seventh positions of GameRankings' best-rated games of all time, respectively. GTA IV also shattered worldwide weekly sales records of any entertainment media to date by grossing over $500 million within the first week of its release.
• Grand Theft Auto V (PS3, Xbox 360) as one of the AAA titles to release initially in the seventh generation of video game consoles, it was highly anticipated preceding its release. It was acclaimed by many reviewers who praised the story, presentation and open world gameplay. It broke industry sales records by earning US $800 million in the first 24 hours of its release, and $1 billion within its first three days, making it the fastest selling entertainment product in history.
• Guitar Hero and Rock Band (Xbox 360, PlayStation 3, Wii), music game franchises which used specially designed controllers that mimicked musical instruments and allowed uses to play a large selection of licensed music, were extremely popular during the seventh generation, with over twenty different title releases across various platforms. Activision's Guitar Hero series sold more than 25 million units with over $2 billion in retail revenue, while Harmonix's Rock Band series has sold over 13 million copies; both series were augmented with a large volume of downloadable content. However, due to saturation of the market in 2009 along with the economic recess, both series have since ceased publishing, though Harmonix has stated they will bring back Rock Band to the eighth-generation when the time is right.
• Halo 3 (Xbox 360) by Bungie and Microsoft Studios broke many first day records, including preorders (1.7 million+), and first day sales (US$170 million+), surpassing its predecessor, Halo 2, in both of these fields. It also featured advanced artificial intelligence (AI) technology for enemies, though the player's allies' intelligence was less refined.
• The Last of Us (PS3) by Naughty Dog and SCE scored over 50 perfect scores from gaming publications. It has been rated as the best PlayStation 3 game of 2013 on Metacritic, and has had one of the biggest launches of the year with 1.3 million sold.
• The Legend of Zelda: Skyward Sword (Wii) by Nintendo EAD and Nintendo received perfect scores from at least 30 publications and was praised for its intuitive motion-based swordplay.
• LittleBigPlanet (PS3) by Media Molecule and Sony Computer Entertainment (SCE) was one of the most highly anticipated games of 2008. Upon release, it received high critical acclaim with a score of 95/100 on Metacritic and was the second most highly rated game of that year (behind Grand Theft Auto IV). It was praised by G4 as a game that "not only lives up to the hype but exceeds it so many ways" and IGN called it "nothing short of astounding". Its sequel, LittleBigPlanet 2 was released in 2011 to similar acclaim and is considered an improvement over its predecessor in almost every aspect.
• Mario Kart Wii (Wii) by Nintendo EAD and Nintendo received highly positive reviews which commended the wide array of characters, tracks, karts, and distinctive online gameplay. Overall, it is the second best-selling game for Wii at 35.53 million copies sold, after Wii Sports as of March 31, 2014. Mario Kart Wii is also the best-selling racing game of all time.
• Mass Effect 2 (PC, PS3, Xbox 360) by Bioware, the most acclaimed game of the Mass Effect series, set a new standard for expansive yet cohesive storytelling and character development. It remains one of the best reviewed games of the generation (96% on Metacritic for the 360 version) and won numerous awards including the BAFTA and AIAS Game of the Year awards.
• Metal Gear Solid 4: Guns of the Patriots (PS3) by Kojima Productions and Konami received widespread critical acclaim upon release, receiving a perfect 10 from IGN, GameSpot and numerous other game reviewers. It also got a 94% from Metacritic. The game was a financial driving force for Konami, reaching 5 million units sold in the financial year of 2009. It is often considered one of the best games of the generation by critics and players alike.
• New Super Mario Bros Wii (Wii) by Nintendo Entertainment Analysis and Development (Nintendo EAD) and Nintendo received critical acclaim upon release for beign the first in the Mario main series since Mario Bros. to feature simultaneous multiplayer gameplay and the first to introduce a four player multiplayer. Overall, it is the fourth best-selling game for Wii at 29.90 million copies sold, as of March 31, 2014. It's critical and commercial success helped revive the 2D platform genre for consoles.
• Portal and Portal 2 (PC, PS3, Xbox 360) by Valve Corporation were critically acclaimed and have sold millions of copies. Both games are often cited as some of the most influential games of the decade for rejuvenating the "first person puzzle" genre and have been selected, along with a few other titles, to be put in the Museum of Modern Art as an example of a work of art in video games.
• Red Dead Redemption (PS3, Xbox 360) by Rockstar is one of the most critically acclaimed games of 2010. It won numerous Game of the Year Awards and received a 95/100 on the review aggregate site Metacritic.
• Street Fighter IV (Arcade, PC, PS3, Xbox 360) by Dimps and Capcom garnered universal critical acclaim and is considered perhaps the finest 2D fighter ever made.
• Super Mario Galaxy (Wii) by Nintendo Entertainment Analysis and Development (Nintendo EAD) and Nintendo sold more copies in its first week, including over 500,000 in the US, than any other Mario title in the history of the franchise. As of November 2012, Galaxy and its sequel, Super Mario Galaxy 2, are the first and third highest rated games of all time respectively, as listed on GameRankings, along with being the recipients of many game of the year awards.
• Super Smash Bros. Brawl (Wii) by Sora Ltd. and Nintendo is the first in the series to have third-party characters, with the inclusion of Solid Snake and Sonic the Hedgehog. It dominated sales during its first week in Japan and the United States, selling 820,000 in Japan and becoming the fastest-selling video game in Nintendo of America's history with 1.4 million sold in the US. The game was critically acclaimed, receiving 93% on Metacritic.
• Uncharted 2: Among Thieves (PS3) by Naughty Dog and SCE was the most positively reviewed game of 2009 and is one of the most critically acclaimed games of the generation. It received universal critical acclaim with a Metacritic score of 96 out of 100, a GameRankings score of 96.38%. At E3 2009, Uncharted 2 won the most E3 awards of any game. Critics praised almost every aspect of the game ranging from high quality music and sound to graphics.
• Wii Sports (Wii) by Nintendo EAD and Nintendo has been attributed as a major factor in the Wii's worldwide success. The game, along with Wii Fit, has been cited as attracting a more broad mainstream audience. This is a rarity among seventh generation games, as developers tend to try to attract young men. It has also been cited as one game that can provide a bonding experience among family members, and as a means of exercising and losing weight when played regularly. As of March 31, 2014, the game has sold 82.54 million copies worldwideâ€"including bundled copies, making it the best-selling Wii game and the best-selling video game of all time.

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Avis is an American car rental company headquartered in Parsippany-Troy Hills, New Jersey, United States. Avis, Budget Rent a Car and Budget Truck Rental are all units of Avis Budget Group.

Avis Budget Group operates the Avis brand in North America, South America, India, Australia and, New Zealand. Recently Avis has acquired Avis Europe plc which once was a separate corporation licensing the Avis brand. Avis is the third largest car rental agency in the world trailing behind Hertz Corporation.

Since the late 1970s, Avis has featured mainly General Motors (GM) vehicles such as Chevrolet and Cadillac, but today also rents popular non-GM brands including Ford and Toyota.

Avis is a leading rental car provider to the commercial segment serving business travelers at major airports around the world, and to leisure travellers at off-airport locations. Many of the off-airport locations are franchised operations rather than company-owned and -operated, as is the case with most airport locations. Avis was the first car rental business to be located at an airport.

In January 2013, the company agreed to acquire Zipcar for $491 million.

History

The company was founded in 1948 with three cars at Willow Run Airport, Ypsilanti, Michigan, by Warren Avis (August 4, 1915 â€" April 24, 2007). It established branch operations across the United States over the next few years, becoming the second largest car rental company in the country by 1953. By its tenth anniversary in 1956 it had opened its first international offices in Europe, Canada and Mexico.

Their corporate motto is "We Try Harder" It was adopted in 1962 (during the tenure of Robert Townsend as its CEO) to make a more positive reference of Avis' status as the second largest car rental company in the United States, at the expense of its larger competitor The Hertz Corporation. The slogan was used for 50 years before a re-branding in 2012, in which Avis received a new slogan, "It's Your Space." In 1972, Avis introduced Wizard, the first computer-based information and reservations system to be used in the United States car rental business; to this day, almost all frequent Avis customers are identified by their unique "Wizard number". In 1981, the company instituted its system of vehicle tracking, that was not coincidentally named Advanced Vehicle Identification System (AVIS).

Avis has been owned by a number of other companies over the years, along with several periods of being a public company. These include:

• 1956 - The Amoskeag Company
• 1962 - Investment group Lazard Freres
• 1965 - ITT Corporation
• 1977 - Norton Simon
• 1983 - Esmark
• 1984 - Beatrice Foods
• 1986 - Investment firm Wesray Capital Corporation
• 1987 - Majority ownership under an Employee Share Ownership Plan
• 1989 - General Motors (acquires 29% stake)
• 1996 - HFS Corporation
• 2001 - Cendant
• 2006 - Avis Budget Group

Fleet

While Avis generally rents vehicles manufactured by General Motors, their fleet is diverse. This is their current fleet guide as of November, 2014:

Subcompact: Hyundai Accent Sedan Compact: Ford Focus Intermediate: Chevrolet Cruze Standard: Nissan Altima Coupe Full-Size: Chevrolet Impala or Chevrolet Impala Limited Specialty: Ford Mustang Coupe Specialty: Toyota Prius Specialty: Chevrolet Camaro SS Coupe Specialty: Mercedes-Benz E Class E350 Specialty: Ford F-150 Specialty: Mercedes-Benz GL GL450 Premium: Chrysler 300 Luxury: Lincoln MKS Convertible: Ford Mustang Convertible Standard Elite SUV: Chevrolet Traverse Minivan: Dodge Grand Caravan Intermediate SUV: Ford Escape Full-Size SUV: Chevrolet Tahoe Standard SUV: Ford Edge Premium SUV: Chevrolet Suburban 1500 Passenger Van: Ford E-Series Econoline E350 Super Duty

Avis also rents cars in their Signature Series, with such cars as:

-BMW 5 Series Sedan 528i -BMW X3 -BMW X5 -Chevrolet Corvette Coupe -BMW 7 Series 740i -BMW 3 Series Sedan 328i -Cadillac XTS -Jeep Wrangler -Lincoln Navigator -BMW Z4

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Sildenafil, sold as the brand name Viagra among others, is a medication used to treat erectile dysfunction and pulmonary arterial hypertension. Its effectiveness for treating sexual dysfunction in women has not been demonstrated.

Common side effects include headaches and heartburn, as well as flushed skin. Caution is advised in those who have cardiovascular disease. Rare but serious side effects include prolonged erections, which can lead to damage to the penis, and sudden-onset hearing loss. Sildenafil should not be taken by people who take nitrates such as nitroglycerin (glycerin trinitrate), as this may result in a severe and potentially fatal drop in blood pressure.

Sildenafil acts by inhibiting cGMP-specific phosphodiesterase type 5 (phosphodiesterase 5, PDE₅), an enzyme that promotes degradation of cGMP, which regulates blood flow in the penis.

Pfizer scientists Andrew Bell, David Brown, and Nicholas Terrett originally discovered sildenafil as a treatment for various cardiovascular disorders. Since becoming available in 1998, sildenafil has been a common treatment for erectile dysfunction; its primary competitors are tadalafil (trade name Cialis) and vardenafil (Levitra).

Medical uses

Sexual dysfunction

The primary indication of sildenafil is treatment of erectile dysfunction (inability to sustain a satisfactory erection to complete intercourse). Its use is now one of the standard treatment for erectile dysfunction, including for men with diabetes mellitus.

Pulmonary hypertension

While sildenafil improves some markers of disease in people with pulmonary arterial hypertension, it does not appear to affect the risk of death or serious side effects as of 2014.

Antidepressant-associated sexual dysfunction

Tentative evidence suggests that sildenafil may help men who experience antidepressant-induced erectile dysfunction.

Altitude sickness

Sildenafil appears to improve some risk factors for high-altitude pulmonary edema but it is unclear whether or not it affects the rate of the condition itself as of 2008.

Adverse effects

In clinical trials, the most common adverse effects of sildenafil use included headache, flushing, indigestion, nasal congestion, and impaired vision, including photophobia and blurred vision. Some sildenafil users have complained of seeing everything tinted blue (cyanopsia). Some complained of blurriness and loss of peripheral vision. In July 2005, the FDA found that sildenafil could lead to vision impairment in rare cases and a number of studies have linked sildenafil use with non-arteritic anterior ischemic optic neuropathy.

Rare but serious adverse effects found through postmarketing surveillance include prolonged erections, severe low blood pressure, myocardial infarction (heart attack), ventricular arrhythmias, stroke, increased intraocular pressure, and sudden hearing loss. In October 2007, the FDA announced that the labeling for all PDE5 inhibitors, including sildenafil, required a more prominent warning of the potential risk of sudden hearing loss.

Interactions

Care should be exercised by people who are also taking protease inhibitors for the treatment of HIV infection. Protease inhibitors inhibit the metabolism of sildenafil, effectively multiplying the plasma levels of sildenafil, increasing the incidence and severity of side effects. Those using protease inhibitors are recommended to limit their use of sildenafil to no more than one 25 mg dose every 48 hours. Other drugs that interfere with the metabolism of sildenafil include erythromycin and cimetidine, both of which can also lead to prolonged plasma half-life levels.

The use of sildenafil and an α₁ blocker (typically prescribed for hypertension or for urologic conditions, such as benign prostatic hypertrophy) at the same time may lead to low blood pressure, but this effect does not occur if they are taken at least 4 hours apart.

Contraindications

Contraindications include:

• Concomitant use of nitric oxide donors, organic nitrites and nitrates, such as:
  • nitroglycerin
  • isosorbide mononitrate
  • isosorbide dinitrate
  • sodium nitroprusside
  • alkyl nitrites (commonly known as "poppers")
• Concomitant use of soluble guanylyl cyclase stimulators, such as riociguat
• Known hypersensitivity to sildenafil

Sildenafil should not be used if sexual activity is inadvisable due to underlying cardiovascular risk factors (such as recent heart surgery, stroke or heart attack, etc.).

Nonmedical use

Recreational use

Sildenafil's popularity with young adults has increased over the years. Sildenafil's trade name, Viagra, is widely recognized in popular culture, and the drug's association with treating erectile dysfunction has led to its recreational use. The reasons behind such use include the belief that the drug increases libido, improves sexual performance, or permanently increases penis size. Studies on the effects of viagra when used recreationally are limited, but suggest it has little effect when used by those not suffering from erectile dysfunction. In one study, a 25-mg dose was shown to cause no significant change in erectile quality, but did reduce the postejaculatory refractory time. This study also noted a significant placebo effect in the control group.

Unprescribed recreational use of sildenafil and other PDE5 inhibitors is noted as particularly high among users of illegal drugs. Sildenafil is sometimes used to counteract the effects of other substances, often illicit. Some users mix it with methylenedioxymethamphetamine (MDMA, ecstasy), other stimulants, or opiates in an attempt to compensate for the common side effect of erectile dysfunction, a combination known as "sextasy", "rockin' and rollin'" or "trail mix". Mixing with amyl nitrite is particularly dangerous and potentially fatal.

Jet lag research

The 2007 Ig Nobel Prize in Aviation went to Patricia V. Agostino, Santiago A. Plano, and Diego A. Golombek of Universidad Nacional de Quilmes, Argentina, for their discovery that sildenafil helps treat jet lag recovery in hamsters.

Sports

Professional athletes have been documented using sildenafil, believing the opening of their blood vessels will enrich their muscles. In turn, they believe it will enhance their performances.

Analogs

Acetildenafil and other synthetic structural analogs of sildenafil which are PDE5 inhibitors have been found as adulterants in a number of "herbal" aphrodisiac products sold over-the-counter. These analogs have not undergone any of the rigorous testing that drugs like sildenafil have passed, and thus have unknown side-effect profiles. Some attempts have been made to ban these drugs, but progress has been slow so far, as, even in those jurisdictions that have laws targeting designer drugs, the laws are drafted to ban analogs of illegal drugs of abuse, rather than analogs of prescription medicines. However, at least one court case has resulted in a product being taken off the market.

The US FDA has banned numerous products claiming to be Eurycoma longifolia that, in fact, contain only analogs of sildenafil. Sellers of such fake herbals typically respond by just changing the names of their products.

Detection in biological fluids

Sildenafil and/or N-desmethylsildenafil, its major active metabolite, may be quantified in plasma, serum, or whole blood to assess pharmacokinetic status in those receiving the drug therapeutically, to confirm the diagnosis in potential poisoning victims, or to assist in the forensic investigation in a case of fatal overdose.

Mechanism of action

Sildenafil protects cyclic guanosine monophosphate (cGMP) from degradation by cGMP-specific phosphodiesterase type 5 (PDE5) in the corpus cavernosum. Nitric oxide (NO) in the corpus cavernosum of the penis binds to guanylate cyclase receptors, which results in increased levels of cGMP, leading to smooth muscle relaxation (vasodilation) of the intimal cushions of the helicine arteries. This smooth muscle relaxation leads to vasodilation and increased inflow of blood into the spongy tissue of the penis, causing an erection. Robert F. Furchgott, Ferid Murad, and Louis Ignarro won the Nobel Prize in Physiology or Medicine in 1998 for their independent study of the metabolic pathway of nitric oxide in smooth muscle vasodilation.

Sildenafil is a potent and selective inhibitor of cGMP-specific phosphodiesterase type 5 (PDE5), which is responsible for degradation of cGMP in the corpus cavernosum. The molecular structure of sildenafil is similar to that of cGMP and acts as a competitive binding agent of PDE5 in the corpus cavernosum, resulting in more cGMP and better erections. Without sexual stimulation, and therefore lack of activation of the NO/cGMP system, sildenafil should not cause an erection. Other drugs that operate by the same mechanism include tadalafil (Cialis) and vardenafil (Levitra).

Sildenafil is broken down in the liver by hepatic metabolism using cytochrome p450 enzymes, mainly CYP450 3A4(major route), but also by CYP2C9 (minor route) hepatic isoenzymes. The major product of metabolisation by these enzymes is N-desmethylated sildenafil, which is metabolised further. This metabolite also has an affinity for the PDE receptors, about 40% of that of sildenafil. Thus, the metabolite is responsible for about 20% of sildenafil's action. Sildenafil is excreted as metabolites predominantly in the feces (about 80% of administered oral dose) and to a lesser extent in the urine (around 13% of the administered oral dose). If taken with a high-fat meal, absorption is reduced; the time taken to reach the maximum plasma concentration increases by around one hour, and the maximum concentration itself is decreased by nearly one-third.

Route of administration

• When taken by mouth sildenafil for erectile dysfunction results in an average time to onset of erections of 27 minutes (ranging from 12 to 70 minutes).
• Under the tongue use of sildenafil for erectile dysfunction results in an average onset of action of 15 minutes and lasting for an average of 40 minutes.

There are also mouth spray preparations of sildenafil for faster onset of action.

Chemical synthesis

The preparation steps for synthesis of sildenafil are:

1. Methylation of 3-propylpyrazole-5-carboxylic acid ethyl ester with hot dimethyl sulfate
2. Hydrolysis with aqueous sodium hydroxide (NaOH) to free acid
3. Nitration with oleum/fuming nitric acid
4. Carboxamide formation with refluxing thionyl chloride/NH₄OH
5. Reduction of nitro group to amino group
6. Acylation with 2-ethoxybenzoyl chloride
7. Cyclization
8. Sulfonation to the chlorosulfonyl derivative
9. Condensation with 1-methylpiperazine.

History

Sildenafil (compound UK-92,480) was synthesized by a group of pharmaceutical chemists working at Pfizer's Sandwich, Kent, research facility in England. It was initially studied for use in hypertension (high blood pressure) and angina pectoris (a symptom of ischaemic heart disease). The first clinical trials were conducted in Morriston Hospital in Swansea. Phase I clinical trials under the direction of Ian Osterloh suggested the drug had little effect on angina, but it could induce marked penile erections. Pfizer therefore decided to market it for erectile dysfunction, rather than for angina. The drug was patented in 1996, approved for use in erectile dysfunction by the FDA on March 27, 1998, becoming the first oral treatment approved to treat erectile dysfunction in the United States, and offered for sale in the United States later that year. It soon became a great success: annual sales of Viagra peaked in 2008 at US$1.934 billion.

The British press portrayed Peter Dunn and Albert Wood as the inventors of the drug, but only Andrew Bell, David Brown, and Nicholas Terrett are listed on the original composition of matter patent.

Society and culture

Marketing and sales

In the US even though sildenafil is available only by prescription from a doctor, it was advertised directly to consumers on TV (famously being endorsed by former United States Senator Bob Dole and football star Pelé). Numerous sites on the Internet offer Viagra for sale after an "online consultation", often a simple web questionnaire. The Viagra name has become so well known, many fake aphrodisiacs now call themselves "herbal viagra" or are presented as blue tablets imitating the shape and colour of Pfizer's product. Viagra is also informally known as "vitamin V", "the blue pill", or "blue diamond", as well as various other nicknames.

In 2000, Viagra sales accounted for 92% of the global market for prescribed erectile dysfunction pills. By 2007, Viagra's global share had plunged to about 50% due to several factors, including the entry of Cialis and Levitra, along with several counterfeits and clones, and reports of vision loss in people taking PDE5 inhibitors.

In February 2007, it was announced that Boots, the UK pharmacy chain, would try over-the-counter sales of Viagra in stores in Manchester, England. Men between the ages of 30 and 65 would be eligible to buy four tablets after a consultation with a pharmacist.

On May 6, 2013, Pfizer, which manufacturers Viagra, told the Associated Press they will begin selling the drug directly to patients on its website.

Counterfeits

Counterfeit Viagra, despite generally being cheaper, can contain harmful substances or substances that affect how Viagra works, such as blue printer ink, amphetamines, metronidazole, boric acid, and rat poison, as well as talcum powder and commercial paint. The annual counterfeit Viagra trade is worth an estimated $75 billion per year.

Viagra is one of the world's most counterfeited medicines. According to a Pfizer study, around 80% of sites claiming to sell Viagra were selling counterfeits.

Regional issues

European Union

Pfizer's patent on sildenafil citrate expired in some member countries of the EU, Austria, Denmark, France, Germany, Ireland, Italy, The Netherlands, Spain, Sweden, the United Kingdom and Switzerland on 21 June 2013. A UK patent held by Pfizer on the use of PDE5 inhibitors (see below) as treatment of impotence was invalidated in 2000 because of obviousness; this decision was upheld on appeal in 2002.

United States

Sildenafil is available as a generic drug in the United States. As of 2016 branded pills cost about 50 times more than generic ones. In the United States as of 2015 the branded 50 mg pill cost is between 25.17 and 37.88 USD.

In the United States, Pfizer received two patents for sildenafil: one for its indication to treat cardiovascular disease (marketed as Revatio) and another for its indication to treat erectile dysfunction (marketed as Viagra). The substance is the same under both trade names.

In 1992, Pfizer filed a patent covering the substance sildenafil and its use to treat cardiovascular diseases. This would be marketed as Revatio. The patent was published in 1993 and expired in 2012. The patent on Revatio (indicated for pulmonary arterial hypertension rather than erectile dysfunction) expired in late 2012. Generic versions of this low-dose form of sildenafil have been available in the U.S. from a number of manufacturers, including Greenstone, Mylan, and Watson, since early 2013. Health care providers may prescribe generic sildenafil for erectile dysfunction. However, the generic is not available in the same dosages as branded Viagra, so using dosages typically required for treating ED requires patients to take multiple pills.

In 1994, Pfizer filed a patent covering the use of sildenafil to treat erectile dysfunction. This would be marketed as Viagra. This patent was published in 2002 and will expire in 2019. Teva sued to have the latter patent invalidated, but Pfizer prevailed in an August 2011 federal district court case. In an agreement with Pfizer, Teva will begin to provide the generic drug in 2017.

Canada

In Canada, Pfizer's patent 2,324,324 for Revatio (sildenafil used to treat pulmonary hypertension) was found invalid by the Federal Court in June 2010, on an application by Ratiopharm Inc.

On November 8, 2012, the Supreme Court of Canada ruled that Pfizer's patent 2,163,446 on Viagra was invalid from the beginning because the company did not provide full disclosure in its application. The decision, Teva Canada Ltd. v. Pfizer Canada Inc., pointed to section 27(3)(b) of The Patent Act which requires that disclosure must include sufficient information "to enable any person skilled in the art or science to which it pertains" to produce it. It added further: "As a matter of policy and sound statutory interpretation, patentees cannot be allowed to 'game' the system in this way. This, in my view, is the key issue in this appeal."

Teva Canada launched Novo-Sildenafil, a generic version of Viagra, on the day the Supreme Court of Canada released its decision. To remain competitive, Pfizer then reduced the price of Viagra in Canada. However, on November 9, 2012, Pfizer filed a motion for a re-hearing of the appeal in the Supreme Court of Canada, on the grounds that the court accidentally exceeded its jurisdiction by voiding the patent. Finally, on April 22, 2013, the Supreme Court of Canada invalidated Pfizer's patent altogether.

India

Manufacture and sale of sildenafil citrate drugs known as "generic Viagra" is common in India, where Pfizer's patent claim does not apply. Trade names include Kamagra (Ajanta Pharma), Silagra (Cipla), Edegra (Sun Pharmaceutical), Penegra (Zydus Cadila), and Zenegra (Alkem Laboratories).

China

Manufacture and sale of sildenafil citrate drugs is common in China, where Pfizer's patent claim is not widely enforced.

Other countries

Egypt approved Viagra for sale in 2002, but soon afterwards allowed local companies to produce generic versions of the drug, citing the interests of poor people who would not be able to afford Pfizer's price.

Pfizer's patent on sildenafil citrate expired in Brazil in 2010.

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Beggin’ Strips is a brand of pet food and pet snack manufactured by Nestlé Purina PetCare. The product was first manufactured by Ralston Purina. The product's tagline is "Dogs Don’t Know It’s Not Bacon", which appeared in U.S. television commercials in the 1990s. The product is manufactured to resemble bacon strips.

History

Beggin' Strips were first sold in 1993. Nestlé Purina started off by selling this product in North America. It is marketed as being "more healthy than table scraps." This is supported by Nestlé Purina PetCare, who offers various coupons and other savings for Beggin' Strips.

Nutrition

Purina Beggin' Strips are made of real bacon but are enhanced with artificial ingredients. According to Purina's Beggin' Strip website the initial bacon is preserved with sodium nitrite and BHA. Base ingredients for additional additives include ground wheat, corn gluten meal, wheat flour, ground yellow corn, water, sugar, glycerin, soybean meal, hydrogenated starch hydrolysate, meat phosphoric acid, sorbic acid, natural and artificial smoke flavors. Depending on the flavor, artificial coloring is also added. There are six flavors currently available.

Purina products are made in the United States; however, they buy some of the ingredients from other countries with the biggest supplier being China. This data comes directly from Purina as stated on their Facebook page.

Marketing

Beggin' Strips are mostly famous for their television advertising, beginning in 1994, after they began selling their product in 1993. Shown from a dog's perspective, the excited pet smells Beggin' Strips and is convinced that he is smelling real bacon, exclaiming, "It's BACON!" The voice of the dog was provided by Bill Tullis. More recently, a new commercial was written and voiced by New York comedian Alex Bloom. The product's catchphrase is "It's no time like Beggin' time!"

The trademark bag for the product features a cartoon dog licking his chops while awaiting a treat. Drawn up in 1994, the dog was named "Hamlet." Hamlet was chosen to appear in Nestlé Purina's advertising for Beggin' Strips, and to represent the product.

Shortly after the initial sale of Beggin' Strips, coupons for the product were released to try to build support for the treats.

Purina also hosts an annual Pet Parade around the time of Mardi Gras. It is held every year in Soulard, a historic French neighborhood in St. Louis, Missouri with over 5,000 pets and their owners in attendance. St. Louis' Waterloo Courier also covered the Beggin' Strips Stupid Dog Contest on July 4, 1999. This contest offers multiple monetary prizes, the grand prize being a $5,000 supply of Beggin' Strips per year and a trip to see the Late Show with David Letterman in New York.

Beggin' Strips made its way into social media by launching a Facebook page in 2011, and most recently in 2012, launching an iPhone and iPad application allowing users to film their own version of the famous commercial.

References

Further reading

• Guide to Trademark Trial and Appeal Board Practice. Wolters Kluwer Law & Business. 2007. p. 6-96.2. ISBN 978-0-7355-6531-9. Retrieved December 1, 2016. 

External links

• Official website

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A macrobiotic diet (or macrobiotics), is a fad diet fixed on ideas about types of food drawn from Zen buddhism. The diet attempts to balance the supposed yin and yang elements of food and cookware. Major principles of macrobiotic diets are to reduce animal product, eat locally grown foods that are in season, and consume meals in moderation.

Macrobiotics writers often claim that a macrobiotic diet is helpful for people with cancer and other chronic diseases, although there is no good evidence to support such recommendations. Studies that indicate positive results are of poor methodological quality. Neither the American Cancer Society nor Cancer Research UK recommend adopting the diet. Suggestions that a macrobiotic diet improves cardiovascular disease and diabetes are explained by the diet being, in part, consistent with science-based dietary approaches to disease prevention.

Conceptual basis

The macrobiotic diet is associated with Zen buddhism and is based on the idea of balancing yin and yang. The diet was popularized by George Ohsawa in the 1930s and subsequently elaborated by his disciple Michio Kushi.

Macrobiotics takes a view of health which contradicts science.

According to Kushi, one goal of modern macrobiotics is to become sensitive to the actual effects of foods on health and well-being, rather than to follow dietary rules and regulations. Dietary guidelines, however, help in developing sensitivity and an intuitive sense for what sustains health and well-being.

Macrobiotics emphasizes locally grown whole grain cereals, pulses (legumes), vegetables, seaweed, fermented soy products and fruit, combined into meals according to the ancient Chinese principle of balance known as yin and yang. Whole grains and whole-grain products such as brown rice and buckwheat pasta (soba), a variety of cooked and raw vegetables, beans and bean products, mild natural seasonings, fish, nuts and seeds, mild (non-stimulating) beverages such as bancha twig tea and fruit are recommended.

Some Macrobiotic theorists, including George Ohsawa, stress the fact that yin and yang are relative qualities that can only be determined in a comparison. All food is considered to have both properties, with one dominating. Foods with yang qualities are considered compact, dense, heavy, hot, whereas those with yin qualities are considered expansive, light, cold, and diffuse. However, these terms are relative; "yangness" or "yinness" is only discussed in relation to other foods.

Brown rice and other whole grains such as barley, millet, oats, quinoa, spelt, rye, and teff are considered by macrobiotics to be the foods in which yin and yang are closest to being in balance. Therefore, lists of macrobiotic foods that determine a food as yin or yang generally compare them to whole grains.

Nightshade vegetables, including tomatoes, peppers, potatoes, eggplant; also spinach, beets and avocados are not recommended or are used sparingly in macrobiotic cooking, as they are considered extremely yin. Some macrobiotic practitioners also discourage the use of nightshades because of the alkaloid solanine, thought to affect calcium balance. Some proponents of a macrobiotic diet believe that nightshade vegetables can cause inflammation in the body and osteoporosis.

Practices

Food

Some general guidelines for the Japanese-style macrobiotic diet are the following (it is also said that a macrobiotic diet varies greatly, depending on geographical and life circumstances):

• Well-chewed whole cereal grains, especially brown rice: 40â€"60%
• Vegetables: 25â€"30%
• Beans and legumes: 5â€"10%
• Miso soup: 5%
• Sea vegetables: 5%
• Traditionally or naturally processed foods: 5â€"10%

Fish and seafood, seeds and nuts, seed and nut butters, seasonings, sweeteners, fruits, and beverages may be enjoyed occasionally, two to three times per week. Other naturally-raised animal products may be included if needed during dietary transition or according to individual needs.

Kitchenware

Cooking utensils should be made from certain materials such as wood or glass, while some materials including plastic, copper, and non-stick coatings are to be avoided. Electric ovens should not be used.

Japanese popularity and influence

The macrobiotic way of eating was developed and popularized by the Japanese. During the Edo period in Japan peasants were not allowed to eat meat and had a diet based on staples of rice and soybeans. According to some macrobiotic advocates, a majority of the world population in the past ate a diet based primarily on grains, vegetables, and other plants. Because the macrobiotic diet was developed in Japan, Japanese foods that are beneficial for health are incorporated by most modern macrobiotic eaters.

Cancer

Claims that macrobiotic diets are useful for people with cancer are not supported by good medical evidence.

The American Cancer Society recommends "low-fat, high-fiber diets that consist mainly of plant products"; however, they urge people with cancer not to rely on a dietary program as an exclusive or primary means of treatment. Cancer Research UK states, "There is no scientific evidence to prove that a macrobiotic diet can treat or cure cancer or any other disease".

Nutrition

Detailed information on the nutrients provided by a large range of foodstuffs is available in the USDA National Nutrient Database.

The following nutrients should be monitored especially in children, because of their importance in facilitating growth and function: calcium, protein, iron, zinc, vitamin D, vitamin B₁₂, riboflavin, vitamin A, omega-3 fatty acids.

People following the macrobiotic diet are at increased risk of developing scurvy.

Fish provides vitamin B₁₂ in a macrobiotic diet, as bioavailable B₁₂ analogues have not been established in any natural plant food, including sea vegetables, soya, fermented products, and algae. Although plant-derived foods do not naturally contain B₁₂, some are fortified during processing with added B₁₂ and other nutrients. Vitamin A, in the form of beta-carotene, is available from plants such as carrots and spinach. Adequate protein is available from grains, nuts, seeds, beans, and bean products. Sources of Omega-3 fatty acids are discussed in the relevant article, and include soy products, walnuts, flax seeds, pumpkin seeds, hemp seeds, and fatty fish. Riboflavin along with most other B vitamins are abundant in whole grains. Iron in the form of non-heme iron in beans, sea vegetables and leafy greens is sufficient for good health; detailed information is in the USDA database.

In 1987, the AMA stated in their Family Medical Guide: "In general, the macrobiotic diet is a healthful way of eating."

A 1999 review said the macrobiotic diet was similar to the then USDA recommendations for healthy eating.

Safety

Complications

One of the earlier versions of the macrobiotic diet that involved eating only brown rice and water has been linked to severe nutritional deficiencies and even death. Strict macrobiotic diets that include no animal products may result in nutritional deficiencies unless they are carefully planned. The danger may be worse for people with cancer, who may have to contend with unwanted weight loss and often have increased nutritional and caloric requirements. Relying on this type of treatment alone and avoiding or delaying conventional medical care for cancer may have serious health consequences.

Children

Children may also be particularly prone to nutritional deficiencies resulting from a macrobiotic diet.

Pregnancy

Macrobiotic diets have not been tested in women who are pregnant or breast-feeding, and the most extreme versions may not include enough of certain nutrients for normal fetal growth.

Malnutrition

In 1971, the AMA Council on Foods and Nutrition said that followers of the macrobiotic diet, particularly the strictest, stood in "great danger" of malnutrition. This report came half a decade after the well-publicized death of Beth Ann Simon, a young woman who had followed Ohsawa's form of the diet in spite of its disastrous effect on her body. On the other hand, in 1987, the AMA stated in their Family Medical Guide: "In general, the macrobiotic diet is a healthful way of eating."

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News America Marketing, often referred to as just News America, is a marketing business owned by News Corp. It publishes SmartSource Magazine, a weekly consumer-branded newspaper insert offering advertising and coupon promotions, delivered in over 1,600 newspapers in the U.S. and is one of three companies in the United States (the other two are Valassis Communications and Insignia Systems, Inc.) that control almost all the in-store ads and grocery coupons in the United States.

One major division of the company is SmartSource iGroup, formed in 2000 from acquisitions and investments and runs the company’s online couponing site, www.smartsource.com, in addition to other interactive consumer businesses like sampling and direct mail. The SmartSource brand began in 1998.

History

The News America FSI was formed when News Corporation purchased the marketing divisions of two Free Standing Insert (FSI) business competitors: Quad/Marketing Inc. and Product Movers Inc., in 1988. In 1997, News America purchased Actmedia, an In-Store marketing and promotions company that operated out of Connecticut, and the company changed its name to News America Marketing.

Products

News America Marketing has three categories of products: Home-Delivered network, In-Store network, and Online-Savings network.

The Home-Delivered network contains the free standing SmartSource Magazine, door hangers, direct mail promotions, and home-delivered samples.

The In-Store products include at-shelf messaging, coupon dispensers, cart advertisements, large format entrance ads, Shelfvision video, floor messaging, and in-store sampling.

The Online Savings network includes SmartSource.com. In 2011, SmartSource began printing QR codes on its online printable coupons in order to prevent coupon fraud. The company released a free couponing application for iPad titled SmartSource Xpress in March 2012.SmartSource Xpress for iPhone was released in 2013.

On July 24, 2015 News America Marketing purchased the Canadian company Checkout 51 for an undisclosed price. Checkout 51 provides consumers with a digital means of performing coupon redemptions through smart phone enabled receipt scanning technology.

News Marketing Canada

News Marketing Canada was created in 1995 through the merger of two separate Canadian FSI companies and today publishes the coupon inserts, SmartSource Magazine and UtiliSource, the French-language version. Since News America Marketing’s 1997 purchase of Act Media, News Marketing Canada has offered in-store advertising and promotional products as well. In September 2011, it launched SmartSource.ca, a coupon website for Canadian shoppers.

Philanthropy

News America Marketing has published two Children's Miracle Network Hospitals-themed issues of their SmartSource coupon insert every year for more than 20 years, generating funds and media value for the organization. SmartSource Magazine has also featured an annual issue of an Easter Seals-themed insert. Over the course of 15 years, the Easter Seals-themed SmartSource Magazine has helped generate more than $3.3 million for Easter Seals. News America Marketing has also supported Volunteers of America’s “Toys for the Holidays” program.

Since 2009, News America Marketing has sponsored an all-expense paid trip to the Super Bowl each year for two Marines and a guest.

Each November since 2011, News America Marketing has published a special edition of SmartSource Magazine featuring Wounded Warrior Project's “Believe in Heroes” campaign. In addition, the organization has held fundraisers in its individual offices for the Wounded Warrior Project as well as Operation Gratitude.

Operations

In the fiscal year ending June 2005, the company had 28% operating margins, the highest of all News Corporation businesses. Its annual revenues were $1.1 billion, an increase of 9% from the prior year. As of 2007, News America produced the majority of revenues for News Corporation's magazines and inserts division, and it controlled an estimated 50% to 60% of the insert market and as much as 90% of the in-store business.

Legal cases

In 2005, Theme Promotions, a merchandising firm, won a $6.8 million jury verdict against News America. The California jury found News America guilty of violating civil antitrust and unfair-competition laws.

In 2006, the state of Minnesota accused News America of engaging in unfair trade practices. The company settled in 2008 by agreeing to pay costs and not to falsely disparage its competitors.

In March 2006, a News America Marketing coupon insert competitor, Valassis Communications, settled FTC charges that it had attempted to induce News America Marketing to collude on pricing by signing a consent decree that barred Valassis from engaging in, or attempting to engage in, future anticompetitive behavior. The FTC made no charges against News America Marketing in connection with its investigation. Shortly after the decree was signed, Valassis sued News America Marketing.

Between 2009 and 2011, the News Corporation paid out about $655 million to settle charges of corporate espionage and anticompetitive behavior by News America.

• In 2009, a federal case in New Jersey (Floorgraphics v. News America Marketing In-Store Services Inc, 04-cv-3500, U.S. District Court, District of New Jersey, Trenton) brought by a company called Floorgraphics went to trial, accusing News America of hacking into Floorgraphics’s password-protected computers. Much of the lawsuit was based on the testimony of Robert Emmel, a former News America executive who claimed to be a whistle-blower. After a few days of testimony, the News Corporation settled with Floorgraphics for $29.5 million; several days after that, it bought Floorgraphics. On 20 July, US Senator Frank Lautenberg wrote a letter to the Department of Justice requesting that the ongoing FBI probe include the Floorgraphics hacking allegations. On July 21, 2011, it was reported that representatives of the United States Department of Justice and the FBI had begun investigation into the Floorgraphics allegations.
• In 2010, the News Corporation paid $500 million to settle a case brought against it by Valassis Communications, after that company had won a $300 million verdict in state court in Michigan. The lawsuit by Valassis was based on claims that News America had gained market share by forcing its packaged-goods customers to sign long-term insert contracts or risk huge price increases on their in-store advertising displays The settlement included News America entering into a 10-year shared mail distribution agreement with Valassis Direct Mail, a Valassis subsidiary.
• At the beginning of 2011, in a case in Minnesota brought by Insignia Systems, News America faced more than $600 million in fines. The News Corporation paid out $125 million to settle the allegations of anticompetitive behavior and violations of antitrust laws. This was the third time that the two companies had been involved in lawsuits. In August 2000, Insignia was sued by News America regarding exclusive promotional agreements with several major supermarket retailers, a suit that was settled confidentially in November 2002. In November 2003 Insignia was sued again, regarding Insignia's right to market in-store advertising and promotional services.

In late 2011, the District Court of Atlanta granted a permanent injunction prohibiting Robert Emmel, a former News America Marketing executive, from sharing News America Marketing’s confidential information and found that Emmel was not a whistleblower and was therefore not entitled to whistleblower protection under the Dodd-Frank Act, as he had claimed. In the court’s ruling, it stated that far from harassing, or acting in a retaliatory manner towards him, News America Marketing “actually assisted Emmel in obtaining new employment after it terminated him.”

Careers

The Princeton Review voted News America Marketing's Sales Development Program as one of the "Best Entry Level Jobs" for 2008.

References

External links

• News America Marketing official website
• SmartSource official website
• SmartSource.ca official website
• Profile at Bloomberg Businessweek

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