The iPhone has become such a trend that everyone wants to buy it and utilize it’s fantastic features like being able to download iPhone movies, iPhone games, iPhone software and iPhone music. In this article, will discuss some of the best places to get free iPhone downloads.

Before choosing an iPhone downloads site the most important thing to consider is the type of service you want. The two most popular types of iPhone downloads sites are pay per download sites and unlimited free iPhone downloads membership sites.

If you choose a site with pay per download fees, this means you will be charged about $0.90 for each and every one of your movie, music and game downloads. This type of iPhone downloads site can become very costly if you plan on downloading a lot of movies, music and games.

Your other option would be to join an unlimited free iPhone downloads membership site. Once you pay a one time lifetime membership fee of about $30-$35, all the downloads would be free of cost for you forever, which would include unlimited free iPhone movie downloads, unlimited free iPhone game downloads, unlimited free iPhone music downloads, unlimited free iPhone software downloads and much more. So, instead of paying for each and every one of your downloads for your iPhone, all you need to do is pay a one time lifetime membership fee. Most of the good free iPhone download sites also offer a one or two year option. Without question, the unlimited free iPhone downloads membership site seems the best deal by far.

At this moment, the iPhone seems to be the hottest gadget in the world, and as an Internet device, it has soared miles ahead of its competition. So, if movies are your thing, you can now enjoy watching all your favorites by using your iPhone. It goes without question that iPhones are expensive, yet, the amazing features that comes as part of the entire iPhone package make it well worth the extra expense. If you are wise enough to take advantage of the iPhones fantastic features, you’ll join an unlimited free iPhone downloads membership site too.

While having the ability to watch movies or play games on your iPhone is great, its even better if your iPhone’s movie downloads and iPhone game downloads are free. But please don’t trust everything on blind faith. That can get you into deep trouble. Remember to always be careful about your iPhone. There are some iPhone download sites out there that are pure scams. If you want to protect your iPhone from malicious viruses and spy ware then check out the iPhone review sites to find out the best sites to get your unlimited free iPhone downloads from.

The financial income of the people is greatly affected because of the financial crises. All the markets are sinking because they are suffering too much lose. But, humans can not live without the medications if they have the ill health. Thus, to all these men generic drugs could be a best option to save the money. Reasons for the cheap price of the generic drug are— the cost of production of generic drug is very less as compared with the original brand name companies, no investment is done for the research on generic drug as the research is already conducted by the brand name manufacturer, clinical trials are not conducted by the generic drug manufacturer because they are previously conducted by the brand name manufacturer, and no cost is involved in the advertising and marketing of the generic drug because they get the benefit of the advertising and marketing done by the original drug manufacturer. Thus, generic drug allows the manufacturer to earn lots of profits.

Generic drugs not only save the money of the customers but also save the investment of the government in the pharmaceutical sector. US govt. has saved about 1 Billion dollars because of the generic drugs in the year 2007-08. Insurers are also very beneficial due to the use of the generic drugs. Insurance companies are asking the doctors to follow the step therapy that means doctors should first prescribe the generic drugs and if these drugs fail to produce the required effect then they should prescribe the more expensive brand-name drugs. FDA is sending pamphlets to the big pharmacy chain in US to promote the generic drugs. FDA is even asking these pharmacies to promote the sale of generic drugs. FDA says that all drugs must work well and be safe. FDA makes sure that before approving that generic drugs are of high quality, strong, pure, and stable as their respective brand-name drugs.

Generic drugs are allowed to be sold in the market only after they satisfy the following criteria:

Generic drug should have the same ingredient as the original drug.

Generic drug must be identical or bioequivalent to the original drug.

The pharmacokinetic and pharmacodynamic properties of the generic drugs should be similar to the original drugs.

Generic drugs should be similar in strength in comparison with the original brand name drug.

The side-effects of the generic drug are less or more than the original brand name drug.

Generic drugs are manufactured in the world class units that are checked and then approved by the FDA. The safety of the generic drugs is not at all in doubt because no casualties till date are noted by the intake of the generic drugs. Thus even the pharmacy distributors believe in the generic drug manufacturer and thus the sale of generic drug increases. Customer is using generic drugs because of the cost benefits and he is enjoying the same effects that he used to get by the original branded drugs. Hence, we can conclude that generic drugs perfectly match the demand of time.

The best iPhone add ons are the ones that suit your lifestyle and are things you feel would enhance the usage of your iPhone. When buying iPhone add ons ask yourself what you use your iPhone most for and what you’d like your add ons to do primarily. This will help you select the best add on iPhone products for your lifestyle.

Apple iPhone Bluetooth Headset. Bluetooth technology comes to the iPhone! You can easily answer your calls wirelessly using this lightweight headset that sits on your ear. The iPhone Bluetooth Headset comes with an iPhone Dual Dock and a Bluetooth Travel Cable. This is a great set for the iPhone user who wants to embrace wireless technology while using their iPhone.

Apple USB Power Adapter. This compact adapter is perfect to use to charge up your iPhone so it will be ready to use whenever you want to use it. You can also use this power adapter to charge up your iPod as well. This is a very popular add on for the iPhone that many users prefer to use for its convenience.

Power Support Crystal Film Set for iPhone. This is a very handy add on that anyone whose become attached to their iPhone will greatly appreciate. This clear film goes right over your iPod screen to protect it from any scratches or anything else that could damage it. You know just how visual and intense the iPod screen is — that is one of the best benefits of using the iPhone! Therefore, it would make perfect sense any iPhone user would want to do anything to protect it from potential damage. A Power Support Crystal Film Set will keep your iPhone from getting any scratches on its screen.

Apple iPhone Stereo Headset. For convenient use of your iPhone, these comfortable stereo headset earphones make using your system all the easier. Bring this headset with you; they are very portable and quite lightweight. The Apple iPhone Stereo Headset is also durable and will stand up to general and practical usage. Ideal for listening to music, videos or other sound on your iPhone.

iSkin Revo for iPhone. This is a great add on that any iPhone user would appreciate. The iSkin easily protects your iPhone from damage. The “skin” goes onto your iPhone, protecting the exterior of your iPhone. Made from silicone and polycarbonate, it keeps your iPhone from being vulnerable to anything that could cause it harm. It has a protective visor and easily snaps shut in the back.

There are many iPhone add ons that you can find. All of them can make using your iPhone more convenient, fun and easier. Best of all you’ll be tempted to use your iPhone more and more with the addition of these terrific add ons!

The financial income of the people is greatly affected because of the financial crises. All the markets are sinking because they are suffering too much lose. But, humans can not live without the medications if they have the ill health. Thus, to all these men generic drugs could be a best option to save the money. Reasons for the cheap price of the generic drug are— the cost of production of generic drug is very less as compared with the original brand name companies, no investment is done for the research on generic drug as the research is already conducted by the brand name manufacturer, clinical trials are not conducted by the generic drug manufacturer because they are previously conducted by the brand name manufacturer, and no cost is involved in the advertising and marketing of the generic drug because they get the benefit of the advertising and marketing done by the original drug manufacturer. Thus, generic drug allows the manufacturer to earn lots of profits.

Generic drugs not only save the money of the customers but also save the investment of the government in the pharmaceutical sector. US govt. has saved about 1 Billion dollars because of the generic drugs in the year 2007-08. Insurers are also very beneficial due to the use of the generic drugs. Insurance companies are asking the doctors to follow the step therapy that means doctors should first prescribe the generic drugs and if these drugs fail to produce the required effect then they should prescribe the more expensive brand-name drugs. FDA is sending pamphlets to the big pharmacy chain in US to promote the generic drugs. FDA is even asking these pharmacies to promote the sale of generic drugs. FDA says that all drugs must work well and be safe. FDA makes sure that before approving that generic drugs are of high quality, strong, pure, and stable as their respective brand-name drugs.

Generic drugs are allowed to be sold in the market only after they satisfy the following criteria:

•    Generic drug should have the same ingredient as the original drug.
•    Generic drug must be identical or bioequivalent to the original drug.
•    The pharmacokinetic and pharmacodynamic properties of the generic drugs should be similar to the original drugs.
•    Generic drugs should be similar in strength in comparison with the original brand name drug.
•    The side-effects of the generic drug are less or more than the original brand name drug.

Generic drugs are manufactured in the world class units that are checked and then approved by the FDA. The safety of the generic drugs is not at all in doubt because no casualties till date are noted by the intake of the generic drugs. Thus even the pharmacy distributors believe in the generic drug manufacturer and thus the sale of generic drug increases. Customer is using generic drugs because of the cost benefits and he is enjoying the same effects that he used to get by the original branded drugs. Hence, we can conclude that generic drugs perfectly match the demand of time.

For using things in the better way, it is very necessary that it should be done by the expert professionals for getting desired results. In the age of customized services in the field of information & technology, developing a mutual understanding with your hired professional is the best way of getting the things according to you. iPhone application development is the process of implementing creativity with perfect technological expertise and hiring iPhone programmer is the easiest way for the development of desired iPhone systems.

Getting connected with your hired iPhone programmer allows you to enhance your personal technological knowledge about your iPhone and different innovative ways of using the latest mobile technology in the better way. Exchanging the thoughts regularly with your hired iPhone developer not only helps you get the desired applications but it develops the relationship between you and your programmer. In the mobile industry iPhone technology is not very old concept, so it is very obvious that people are not having more expertise in short span of time. Hire special iPhone developers is a smart move to get the things done faster and learn more professionally about the technology and get the desired results according to your need.

iPhone application development is not only following the guidelines provided by Apple Inc in form of SDK (software development kit) for the error-free work. It requires professional technological expertise in mobile application development to implement the technology and practical experience to handle the process systematically for the quality results. Hiring iPhone programmer helps you to overcome the various complex situations in the mobile application development and making you aware about the new systems & process, which can help you further in the optimum use of iPhone applications easily. Hire SDK programmer is the solution for future, as technology only grows to provide more sophistication in the use of latest versions and get updated with them.

Working with the new technologies of the age in mobile industry is not easy, for nowise people, as everybody do not practice for the application development such as iPhone applications and other mobile related jobs. As iPhone technology is the latest in the mobile industry and created a large segment of iPhone users rapidly, among the large segment of iPhone users everybody is having their unique priorities for using the iPhone such as users are crazy for the dissimilar iPhone applications. In the army of iPhone lovers, there are many who use iPhone applications for business, some of them for entertainment purpose and many of them for fun of games. The demand for a variety of iPhone applications is touching sky in very short span of time.

Hence, hire iPhone application developer is the ultimate option for those who want optimum and customized use of their latest communicative device called “iPhone”.

Drug-drug interactions that affect the travel of drugs in the body can be further understood as those that affect absorption into the bloodstream, distribution within the body, breakdown into different products or removal from the body.

Absorption interactions can occur when one drug’s particles have a large enough surface area to cause another drug’s particles to stick to them, both drugs may also bind to each other, or one drug alters the acidity of the stomach contents or the rate at which the stomach moves it’s contents. These interactions can alter the ability of one or both drugs to get into the bloodstream. When a drug only reduces the rate of absorption of another, a patient on regular use of both drugs is usually unaffected. However, if one drug reduces the extent of absorption of the other, the patient can be exposed to lower levels of the second drug than required and the second drug may hence be ineffective in treatment.

Distribution interactions may occur when drugs reach the bloodstream and the tissues. Competition between two drugs can arise for binding to the same proteins in the blood or one drug may dislodge another from it’s connection with tissues. It is more common in the second instance when one drug displaces another from the tissues, to find that the displaced drug accumulates in the blood leading to a greater risk of an affected patient experiencing toxicity. An example is when the heart medications quinidine and Lanoxin® (digoxin) are taken concurrently, digoxin blood levels can rise and adversely affect the patient if not monitored appropriately.

While drugs can be broken down at many different sites in the body, the most common site is the liver. Here, a system of enzymes can be up-regulated or down-regulated by one drug to result in the quicker or slower breakdown of the other respectively. Examples of drugs that up-regulate specific enzymes in the liver, include the anti-epileptics Dilantin® (phenytoin) and Tegretol® (carbamazepine). The enzyme up-regulation effect usually takes place gradually with maximal effects observed in 7 to 10 days of starting the drug. It may also take an equal or longer time before normalcy is regained upon discontinuing the drug. Examples of drugs that down-regulate specific enzymes in the liver, include the antibiotics erythromycin and ciprofloxacin. The onset of enzyme down-regulation is usually faster than up-regulation.

The majority of broken down drug products as well as whole drugs are removed from the body through the passing of urine. When one drug affects the pH of the urine, this can affect another drug’s ability to get into the urine depending on how it’s form changes during the filtering process in the kidneys. Transporter molecules in the kidney that facilitate drug removal may also become more or less available to one drug as a result of the presence of another.

Drugs can also interact and exert a net effect by their direct actions on the body. Two drugs with similar effects when administered together can display synergism in action although acting at different sites or receptors in the body. An example is the drowsiness that can be experienced when a sedative like Valium® (diazepam) is taken concurrently with an antihistamine like Polaramine® (dexchlorpheniramine). Conversely when two drugs that have opposing effects are taken concurrently, the response to either or both can be reduced. An example is the opposing wakefulness and drowsiness that can result from consuming a caffeine-based anti-migraine preparation and a sedative.

Another set of action-related drug-drug interactions occurs when two drugs exert toxicity towards the same organ or tissue in the body. Concurrent administration of the two drugs can result in damage to the corresponding organ or tissue despite the individual dose of each drug alone not being enough to result in toxicity under normal circumstances. The common organs that are most often affected by such drug-drug toxicity interactions are the kidneys and the liver. Of note is also that one drug can increase the organ-toxic effect of another even though it does not exert any direct toxicity towards that organ by itself.

Because of the numerous drugs available and the many more that are constantly arriving, drug-drug interactions can be quite common. However, the adverse effects can be minimized through consultation with an experienced medication expert. When such interactions are anticipated early, the most appropriate countermeasures can be readied to maintain well being.

Here comes another side-by-side comparison of Apple’s iPhone 3G with RIM’s BlackBerry Storm, which is considered as another iPhone Killer.

BlackBerry Storm is expected to be released some time in November exclusively by Verizon in the US and Vodafone in UK.

Hardware Spec
Dimension:
Storm = 4.4 x 2.4 x 0.6 inches
iPhone 3G = 5.5 x 2.4 x 0.48 inches
Weight:
Storm = 155g
iPhone = 133g
Screen Size:
Storm = 3.2 inches
iPhone = 3.5 inches
Camera:
Storm = 3.2M pixel
iPhone = 2M pixel
Memory:
Storm = 1GB on board + 16GB expandable with MicroSD
iPhone = 8GB / 16GB (No expansion)
Battery:
Storm = 5.5hrs talk time / 360 hrs standby
iPhone = 5hrs talk time / 300 hrs standby

Unlike T-Mobile G1 that we have reviewed earlier, BlackBerry Storm “steals” the design and looks much like the iPhone 3G. However, it does not look as sleek as iPhone 3G. It’s a little bit thicker (0.14inches more) and heavier (22g more) than iPhone 3G. And, surprisingly, BlackBerry Storm does not come with Wi-Fi support or they probably consider Verizon’s 3G network is good enough.

BlackBerry Storm’s screen is also a little bit smaller (3.2 inch) as compared to iPhone 3G (3.5 inch), however it sports a slightly higher resolution (460×360 pixels) than iPhone 3G (460×360 pixels).

Winner: iPhone 3G

Tips: How to convert DVD to iPhone 3G


Input Method

With the success of iPhone’s multi-touch interface, touch is now the standard for any new smartphone. Like iPhone, Storm does not have physical slide-out keyboard and uses the screen as input, in fact its RIM’s first smartphone to feature a touch screen. However, RIM highlights that the touch technology developed on Storm is somewhat different to other touch screen smartphone available. RIM refers its touch technology as “Clickable Screen”. That means, when users press key on screen, they can actually feel the key pressed and release, just like you press the mouse button. They call it a game changing touch technology that makes on-screen keyboard more appealing.

Also, like T-Mobile G1, it will have built-in cut and paste capability across applications a feature missing from iPhone 3G.

Winner:Its difficult to call a winner on this one, until we get feedback from users on RIM’s touch technology. We love iPhone 3G’s revolutionary multi-touch interface.

Multimedia
Multimedia support is not the strong area of RIM smartphones, as they predominantly targets business users. Storm is developed with multiple support in mind to lure more casual users. Standard feature like music and video playback is included. A wide range of audio format (including MP3, AAC, WMA, etc) and video format (including MPEG4, WMV, etc). Storm also allows you to sync iTunes music files via BlackBerry Media Sync and has its own media software to manage your music.

iPhone 3G is the best iPod Apple has ever created. The music and video playback experience is awesome. And, Apple continues to update features like Genius Playlist into iPhone makes iPhone’s multimedia support nearly unbeatable. With its seamless integration with iTunes Store, you can download songs wirelessly or sync it between desktop using iTunes. iPhone 3G also supports a wide range of music formats but only plays Quick Time video.

Winner: iPhone 3G

Camera & Video Recording

Apple did not upgrade the camera in iPhone 3G, its still a basic 2 megapixel camera while Storm comes with 3.2 megapixel camera and includes video recording capability. Storm also includes a flash and auto focus for its camera.

Winner: BlackBerry Storm

Modem Capability
iPhone 3G does not support tethering and Apple tends to ban any applications in App Store that adds this capability. The only option you have is to jailbreak the iPhone and use jailbreak apps such as PDANet, iPhoneModem etc. BlackBerry Storm, on the other hands, comes with tethering built-in.

Winner: BlackBerry Storm
Tips: How to convert DVD to Blackberry with Daniusoft DVD BlackBerry Converter?

Enterprise Feature

Apple has made quite a few strides to take market share from RIM in the enterprise area. iPhone 3G, with built-in support for Microsoft’s ActiveSync protocol, lets enterprise users to access Microsoft Exchange’s services. Also, it takes a great step forwards to support Cisco IPsec VPN, which is a standard in enterprise wireless security. Further, it incorporates a feature to let administrator to wipe data remotely, in case the iPhone is lost or stolen.

RIM is always the leader in enterprise wireless devices. Storm, by no means, continues to lead in this area. The enterprise support is outstanding that different security policies can be defined, such that administrator may enable or shutdown specific bluetooth profiles; and even, to disable its digital camera access.

Winner: BlackBerry Storm

To sum up, BlackBerry strikes a balance between business and causal use. It’s, by far, the sleekest BlackBerry; which should help RIM lure causal customers.

Is it another iPhone killer? Its difficult to conclude. iPhone 3G and BlackBerry both come with some unique features that neither have and they are positioned differently in the market.
However, I still fail to understand the omission of Wi-Fi in BlackBerry Storm, its true that BlackBerry is targeted at the business users who use it primarily for email, but still it seems like a major disadvantage over iPhone 3G.

As a consumer device, iPhone will definitely win thanks to the iPod application, its Safari browser which is easily the most advanced web browser on a portable device which makes browsing the internet on the iPhone a treat and overall for its cool factor. But if you turn to some business-savvy users and enterprise, BlackBerry is still the de-facto choice.

RIM has also not disclosed the pricing or the official shipping date.

You can checkout the demo video of BlackBerry Storm to get an overview:

BlackBerry Storm, T-Mobile G1 and soon to be released Nokia’s XpressMusic phone (Nokia’s first touch screen phone) might or might not end up being iPhone killers but they are healthy competition to Apple’s iPhone 3G that will ensure that Apple constantly innovates which in the end is beneficial for consumers like us.

Let us know which one is a winner from your point of view and why?

Features of urine and saliva drug testing
Both the urine drug testing and the saliva drug testing have their own advantages as well as some disadvantages.

Collection of specimen:
The major advantage of saliva drug testing over urine drug testing is its least invasiveness of privacy while collecting specimen. This has been a controversy since a long time in all the places of drug testing. The process of collecting saliva for a drug test is obviously less invasive compared to the case of urine drug test.

Chances of adulteration:
The chances of adulteration in saliva drug test are very less, compared to urine drug test. In case of saliva drug test, it is feasible to collect the specimen under legible supervision. Thus, minimizing the chances of tampering the specimen. This is not possible in case of urine drug testing. However, saliva drug test is not completely free from adulteration.

Detection period of drug abuse:
The detection period of drug abuse through saliva drug test is shorter, compared to urine drug test. The detection period in case of saliva drug test is around 20 hours to 1 day approximately, whereas it is around 3 days in case of urine drug test.

Accuracy of results:
The accuracy rate of both, urine and saliva drug tests are deemed by the United States court system. However, the accuracy rate of urine drug test results is much higher than that of saliva drug test results, the risk of false negatives is high in both the drug tests.

Cost of drug test
Cost-effectiveness is the major advantage of urine drug tests compared to any type of drug tests. The cost of saliva drug test is a little higher, compared to urine drug test. However, the cost of saliva drug testing complies with the quality of the drug test.

As both saliva drug test and urine drug test, have their own advantages and disadvantages it is not feasible to use any one of them in all the situations. Based on the comparison of features mentioned above, it will be easier to analyze and choose a drug test according to the situation.

We all know how the iPhone frenzy has grabbed popular imagination since it was first announced in Jan 2007. With its cool feature set, slick appearance, powerful computing capabilities, beautiful display and intuitive touch navigation, this poster boy of the mobile generation has captured the imagination of gizmo freaks and tech phobics alike. To get some measure of iPhone’s success, one only needs refer to Tim Cook’s (Apple’s COO) recent statement at a conference – he said that the company had “really good confidence” the company would hit 10 million iPhones sold by the end of 2008.

According to a research from IDC, 70 percent of those polled who own, or plan to purchase an iPhone in the next year, consider it to be for both personal and business use.

Considering the vast proliferation of iPhones in such a short span, it is natural that all those who own a iPhone would want to extend its use to business as well. And it is no joy carrying around a Blackberry and iPhone in either pocket. All that does is to exert extra downward pressure on the belt. It is no wonder then, that iPhone’s usability in a business context is a raging debate nowadays. That is still a secondary question, because the fact remains that present and future end users of iPhone see is as something they want to use for business.

The Bad News

Unfortunately for corporates, iPhone was created mainly for the meatier consumer market, and never really meant to be a business tool.

What Obstructs “iPhone for Business”

-   It’s mainly a PIM

-   Third party applications not supported

-   Lack of Exchange Support

Mainly a PIM – iPhone mainly has PIM(personal information manager) capabilities (email, contacts, calendars, calendars, notes) and not meant to be used for team collaboration, which requires the ability to share and work togather on information.

Sorry Third Party Developers – iPhone runs on a custom built operating system called the “iPhone OS”, and at this point does not allow third party applications to be built & installed on this native OS. Users are restricted to applications prebuilt into the system (mail, sms,  calendar, photos, etc). This meant no special business centric applications could be created to make use of iPhone’s computing & display capabilities and internet-ability.  

No Exchange Support – The gravest ommision was a lack of support for MS Exchange, which meant that users could not view even the most most elementary business information – business mail, contacts, tasks, and calendars, on their iPhones, what to speak of advanced collaboration. The only way to achieve this was complicated and unreliable workarounds.

The Good News

iPhone’s Business Friendly Features

-   Rich Safari Browser

-   Web 2.0 Applications Allowed

-   Internet Friendly

-   Recent Apple Announcements

Hurray for Web 2.0 – The good news is that they allowed a small window, through which an elephant could be pushed. Soon after its launch, Apple announced that it would allow third party web applications supporting web 2.0 standards, to run on iPhone though its rich Safari browser. This effectively meant that iPhone could be part of the web 2.0 revolution, and access all the rich applications therein.

The Safari Browser – iPhones web browser Safari, is a full web browser with the works. It is light years ahead of the custom made web browsers of traditional corporate handhelds like Palm’s Blazer browser, Blackberry browser, etc. It is not just comparable to a desktop browser, but is a desktop browser. This allows iPhone to ride high on the current web 2.0 wave, rather than just being a bystander.

According to AT&T and Google, iPhone generated 50 times more search requests than any other mobile handset.

Internet-ability- iPhone allows internet access through wi-fi or wide area EDGE networks. One important prerequisite for a mobile to be an effective remote collaboration tool is the willingness and comfort level of users to use the device for web access. With no little thanks to the large display & the safari browser, the iPhone has been a huge success as a device for web access. The iPhone increased the average wireless data usage as much as 30 times higher than on other phones.

Apple finally Awakens from its Slumber – Only lately has Apple has woken up to the previously ignored aspect of business usage. This was largely caused by the hue and cry raised by the media and users over its frustrating lack of business friendlyness. Even as I write, there is news of iPhone finally offering Exchange support, and an iPhone SDK (software development kit) which will allow programmers to develop applications specifically to be installed on the iPhone.

But these new developments are not just in their infancy, but even foetal stage. It will be some time before these new applications find their feet, an truly provide trouble free functionality to businesses.

Exchange support at this time is issue riddled and works only for companies that support Exchange 2007 or Direct Push on Exchange 2003. Moreover, this and the launch of installed applications for iPhone wont take place until a firmware update slated for June 2008.

Webapps to the Rescue : HyperOffice as a case in study

Amongst the first companies to regonise the oppurtunity presented by iPhone for rich business applications was HyperOffice. Already well experienced in the web based business collaboration domain, they developed HyperOffice for iPhone, an iPhone specific version of their flagship product, HyperOffice.

This allowed business users to use almost the entire feature set HyperOffice right from their iPhones. Rather than an isolated personal information manager, HyperOffice allowed iPhone to be used as a dynamic collaboration tool through which users could access the company intranet, share contacts and calendars, plan projects, share and edit documents, schedule meetings, & many other things.

They also realised early on that a major pain point for users looking to use iPhone for business was a lack of Exchange support. HyperOffice allows users to get past this hurdle easily by acting as a bridge between Exchange and iPhone. It allows users to receive information directly from Exchange, or access Outlook information (mail, contacts, calendars, tasks) right on iPhone, with or without Exchange. No matter where users access mail and other information – Outlook, iPhone’s email client or on any other web device, information is automatically synched. Users always get updated information.

A drug that is structurally very similar to already known drugs, with only minor differences. The term “me-too” carries a negative connotation. However, me-too products may create competition and drive prices down1.

The majority of the new products the industry puts out, are “me-too” drugs, which are almost identical to current treatments but “no better than drugs already on the market to treat the same condition.” Around 75 percent of new drugs approved by the FDA are me-too drugs. They can be less effective than current drugs, but as long as they’re more effective than a placebo, they can get the regulatory green light2.

This isn’t surprising at all, as someone who works in the field, but these so-called “me-too” drugs, which are reportedly better than their forebears, is driving costs. A “me-too” drug is a drug that has its origins in another drug. Probably the most famous example of this is Prilosec (“The Purple Pill”) and Nexium (“Today’s Purple Pill”). Prilosec’s active ingredient is omeprazole. Nexium’s active ingredient is called esomeprazole. The difference is that Nexium is the left-handed version of omeprazole. In chemistry, S stands for sinister, which means the molecular conformation has a left-handed orientation. (D would be right handed.) So this S-omeprazole is one half of the mixture that comprises its predecessor. By specifically picking only the S conformation, the drug is made more potent. This sounds great, but its efficacy is only marginally better than Prilosec-, which has a generic version, and costs about a third less than Nexium. Some other “me-too” drugs are: Claritin (loratidine) and Clarinex (desloratidine), Celexa (citalopram) and Lexapro (escitalopram)3.

What are “Me-Too” drugs?

Ever since the advent of modern chemotherapy, when drugs were discovered and developed through the process of screening thousands of molecules for a variety of disease conditions, using animal models, there has been a growing criticism that too many molecules were developed with similar chemical structure and the same pharmacological profile, with very little to distinguish them from each other in terms of their therapeutic utility. In other words, once the first breakthrough discovery is made of a new pharmacological activity for a new molecule, subsequent years saw the emergence of a host of new molecules or “me-too” drugs from the same chemical class and possessing the same pharmacological profile.

Such follow-up drugs have been termed molecular modifications, molecular roulettes or copycats, the development of which are alleged to be motivated by purely commercial considerations. They are also deemed to involve lower levels of innovation, compared to the original molecule. It is important to analyze in a historical perspective the end results of such efforts in different therapeutic areas of developing new molecular entities, as later generation products, after an initial breakthrough discovery has been made and the technical, medical and commercial merits of developing such drugs.

Development of “Me-Too” drugs

The success rate in the discovery of new chemical entities with fundamentally new chemical and biological profiles of activity are very low. In fact, even chemical entities within the same structural class of an approved drug are becoming rare now, compared to the period of sixties to eighties. In 2001, $ 26 billion was spent on developing new drugs and the U.S. FDA approved only 9 new chemical entities. At the same time, two thirds of the drugs approved from 1989 to 2000 were modified versions of existing drugs or even identical to those, in newer forms and formulations4.

Of the 1,035 drugs approved by FDA during 1989 to 2000, only 361 or 35% contained new active ingredients. Of these, only fewer than half were granted priority review status by the FDA. One impression is that these drugs are slightly altered versions of existing drugs, with little to offer in terms of better activity or tolerance, let alone new pharmacological profiles. The implication is that such drugs are developed, as patents on top-selling original drugs run out and not many truly new medicines are discovered. The indication that many of these drugs do not offer any major advantages over existing drugs is given by FDA’s unwillingness to grant priority review for most of them.

On the other hand, conventionally, the Regulatory Agencies, including the FDA, are not obliged to consider better efficacy over existing drugs as a criterion for approval; rather, they require only the establishment of efficacy and safety of the new drug over a placebo.

How good are they?

Notwithstanding such perceptions, historically, many “me-too” drugs have proved to be considerably better than their original counterparts. Examples are a series of generations of beta-blockers, which came up after the original drug Propanalol was discovered by ICI, with most of them having merits in terms of better efficacy, cardio-selectivity and safety. Ranitidine, the first follow-up drug after the introduction of the first H-2 receptor antagonist, Cimetidine, was followed by Famotidine and in each case these “me-too” drugs had notable merits over the original drug.

Apart from the major breakthrough in the development of orally active beta lactam antibiotics of the Penicillin and Cephalosporin class, within the same oral derivatives, there have been considerable improvements brought about by change in the side chains incorporated by condensation of specific agents with 6-APA, 7-ADCA and 7-ACA. A whole new range of broad-spectrum antibiotics of these structural classes could thus be developed. In each of the major classes of antibiotics, classified according to the mechanisms of their action, namely inhibition of cell wall synthesis (Beta Lactams, Vancomycin), inhibition of bacterial protein synthesis (Erythromycin, Tetracycline, Streptomycin), inhibitors of DNA or RNA replication (Quinolones, Rifamycins), inhibition of Folate Coenzyme biosynthesis (Sulfa drugs, Trimethoprim), there have been several “me-too” drugs marketed.

An important recent example to show that ‘me-too” drugs need to be developed is the case of the oral hypoglycemic drug Troglitazone, approved as an anti-diabetic drug in 1997. The drug was withdrawn from the market following reports of unacceptable hepato-toxicity. The follow-up “me-too” drugs, Rosiglitazone and Pioglitazone are much less toxic and are today widely used. If these drugs were not developed, the withdrawal of Troglitazone would have left a major therapeutic gap in anti-diabetic therapy.

“Me-Too” drugs: Strategies for New Drug Research for Indian Companies

Breakthrough innovations in pharmaceutical industry, of new drugs, such as the first beta blocker, the first NSAID, the first of each class of Antibiotics, Calcium Channel blockers, ACE inhibitors, Sulfonyl Ureas, Biguanides, Insulin, Glitazones, Glinides, Tricyclic Anti Depressants,major and minor Traquillisers, Selective Serotonin Receptor inhibitors, H-1 and H-2 Receptor antagonists, Proton Pump inhibitors etc are relatively rare and even though a few of the original drugs under these classes are still very much in use, they have been superceded in most cases, by later generation products, many of them “me-too”. The newer drugs are discovered both through incremental innovations on the original drugs as well as through new research.

Generally the original discovery leads to feverish activity both within the innovator company as well as in Competitors’ laboratories, to develop better products in the same therapeutic category. The essential caveat for commercial success, however, is that the newly discovered molecules should meet the minimum standards of patentability. For example within three years of the discovery of the highly successful Sildinafil Citrate (Viagra), three more new versions for the same indications have been patented and developed5.

Me-too drugs also provide therapeutic advantage6. For the practicing physicians, there’s the benefit of established drug MoA with a “me-too” medication, coupled with clinical studies that – hopefully – show patient-centered benefits such as better adverse events profiles, less frequent dosing, less bothersome potential for drug/drug interactions, and so forth. A “me-too” drug is a helluva lot easier to incorporate in practice than a totally novel medication7.

“Me-Too” drugs: The hidden dynamics

The most common criticism of drug development centers on the so-called “me-too” drugs that employ the same biological mechanism as pioneer brands. This involves a lot more than such high-profile targets as the anti-ulcer drug Nexium. We should be thinking about antidepressants, cholesterol-reducing drugs, diabetes treatments, anti-psychotics, and other therapeutic categories that have seen both blockbuster sales and rapid innovation. There is quite a bit of evidence that follow-on drugs do a lot of patients a lot of good. The newer statins, for example, often out-perform the older ones in clinical trials where the endpoints are the number of heart attacks and deaths prevented.

Me-too drugs are also a powerful tool for cutting health care costs. We should be glad that our research industry does not target only brand new biological mechanisms. That would be a very expensive business model indeed. Fortunately, the industry also works on marginal improvements, exploiting opportunities to make drug therapy better and sometimes opening the door to really radical improvements that happen to lie more or less next-door, scientifically speaking. In the meantime, we get price competition as a by-product. Me-too’s almost always undercut the prices of the pioneer drugs.

Another part of the me-too story gets almost completely ignored even though it is extraordinary important. For me-too manufacturers, advancing the science is a way to gain a competitive advantage. The classic example is the statin class of cholesterol drugs. Research on one of the follow-on drugs (Pravachol) demonstrated for the first time that using a statin to reduce cholesterol would actually prevent deaths from heart attacks, something that had previously been assumed without proof. Additional trials for several statins, including Lipitor, the formidable challenger to Zocor and Pravachol, have demonstrated that serum cholesterol is far more important than almost anyone thought (for preventing strokes, for example).

There are lots of other stories about the benefits of new research from me-too drugs, but they are part of a larger story: new uses for old drugs. The data showing a slowdown in new drug approvals exclude essential information: discoveries of new uses for old drugs. This kind of discovery has become so common that it amounts to a “new-use” revolution. One of the scientific ironies of the new era of pharmaceutical research is that as drugs become more tightly targeted on biological mechanisms, their uses actually become more diverse. This is because the body typically uses specific mechanisms over and over again, sometimes in what appear to be completely unrelated ways.

Consider the SSRI antidepressants. A recent Science article on the diverse and unexpected applications of drugs that fiddle with serotonin reuptake which is what the SSRIs do concluded that the very term “antidepressant” is misleading because there is no scientific reason to think of this drug as being just for depression. Fighting depression just happened to be the first really useful condition that was explored for this very interesting class of drugs.

Another example is the Cox-2 inhibitors like Celebrex (and Vioxx, which is important in this story and may return to the market partly for this reason). These were invented to relieve arthritis pain. But the Cox-2 enzyme turns out to be important for lots of things including cancer and Alzheimer’s. Clinical trials to exploit these leads have been underway for years. Celebrex has already been approved for reducing the risk of colorectal cancer, and Vioxx has also achieved promising results. Of course, the big news recently has been that these drugs may cause heart attacks. But even here, me-too economics is of surpassing importance. The traditional NSAIDS (non-steroidal anti-inflammatory drugs) like Alleve and Advil may have the same heart attack risks. The potential risk has been there for decades, but only the new drugs-the Cox-2s-have been put through large-scale long-term clinical trials because those are the only ones still under patent. This is an example of how me-too drug development adds importantly to the research base. Thanks to the me-too’s, we are learning about NSAIDs, heart attacks, cancer and probably much more.

Also dominated by new uses are the new-targeted cancer drugs, which attack such specific biological mechanisms that they avoid killing every fast-growing cell in sight (as traditional chemotherapy tends to do).

The implications are clear. The annual count of new drug approvals will only show a tick when a new cancer drug or a new statin gets its very first approval. But a new use for an old drug can be as valuable as an entirely new drug, or even more valuable when you consider that we know more about the safety profile of old drugs and one drug will sometimes do the work of two (preventing both heart attacks and strokes, for example)8.

Me-too products can sometimes have important advantages on tolerability or dosing. It could help create more competition and lower the price. If you have five me-toos, possibly the sixth is something that is a little better. That is for the plans to decide on behalf of their patients. And even if it has the same mechanism of action, more competition could help drive down the price of the entire class. That’s an important influence, with potentially an improvement in health from greater access.

How bad are they?

Even though the major problem of antibiotic therapy, namely drug resistance cannot be addressed by the development of “me-too” drugs, due to the propensity of the same class to develop cross resistance; in most cases, the new semi-synthetic derivatives had distinct advantages over the earlier ones. Thus, for example, the first generation Cephalosporins are useful for gram-positive infections, while the second-generation drugs cover a broader spectrum including gram-negative organisms. The third generation drugs provide resistance against the beta lactamase enzyme, as well as acting against some of the most intractable infections, such as those caused by Pseudomonas and Klebsiella strains.

Even while the pharmaceutical industry turns out families of me-too drugs for relatively mild conditions in affluent people, it pays almost no attention to serious diseases, such as malaria, affecting impoverished people. It also gives short shrift to less profitable drugs, so there now are shortages of some vaccines and life-saving drugs9.

The big problem with me-too drugs is that they are chemically very similar to other drugs already available, yet they are marketed as if they were important new breakthroughs, with very high prices. Many new, expensive me-too drugs are not necessarily better than older and less expensive drugs. Most of the time they are compared with placebos and not older drug comparisons.

“Me-too” drugs are responsible for 80% of increased spending in recent years, and on average they are four times more expensive than the comparable, older alternatives10. By Patented Medicines Pricing Review Board’s (PMPRB) definitions, at the time of their introduction “me-too” drugs were judged to provide moderate, little or no improvement – in terms of effectiveness and safety – compared to older alternatives. However, on average, “me-too” drugs cost about 2.5 times as much per prescription as comparable older drugs. The question is whether the perceived or real differences justify the increased costs. New drugs do have a role in some situations and for some patients. However, it makes sense to use the older equally effective drugs whenever possible11.

Changing FDA rules to discourage me-too drug approvals would make R&D far more expensive, would discourage competition and therefore raise healthcare costs, and would forestall the wave of new research that has revolutionized our scientific understanding of the therapeutic categories where competition has been most intense.

Conclusion

New drugs are not required to improve on old ones, and there’s usually no way to know whether they do. Although the FDA must test drugs before they are marketed, they don’t need to be compared with similar drugs already on the market. The FDA only requires they be reasonably safe and better than nothing-a low standard indeed. This loophole in FDA regulations opens the door for an unlimited number of me-too drugs, which are easier to develop than innovative drugs.

Given everything, it should come as no surprise that these more expensive “me-too” drugs cost the medical industry money. The prevalence of the me-too’s really says an awful lot about the lack of innovation within the pharmaceutical industry. If you look at the new drugs marketed over the last six years, 78 percent weren’t even new chemical compounds. They were just new combinations or different formulations of old drugs. And 68 percent were classified by the F.D.A. as unlikely to be improvements over drugs already on pharmacy shelves.

At the same time, there are shortages of some important drugs that the pharmaceutical companies aren’t much interested in making because they are not as profitable as the me-too’s. But the companies don’t have to turn out needed drugs, if they are not lucrative. And they don’t.

References

1. http://www.medterms.com/script/main/art.asp?articlekey=33748

2. http://www.motherjones.com/news/qa/2004/09/09_401.html

3. http://polyscience.org/2005/09/me-too-drugs

4. http://www.shvoong.com/books/465475-me-too-drugs

5. http://www.pharmabiz.com/article/detnews.asp?SecArch=&articleid=14604&sectionid=46

6. http://direct.bl.uk/bld/PlaceOrder.do?UIN=162532605&ETOC=RN&from=searchengine

7. http://www.archivum.info/sci.med/2005-09/msg00257.html

8. http://www.aei.org/publications/filter.all,pubID.27443/pub_detail.asp

9. http://blogs.wsj.com/health/2007/05/17/in-praise-of-me-too-drugs

10. http://www.chepa.org/KnowledgeExchange/LabelleLectureship/tabid/84/Default.aspx

11. http://www.ti.ubc.ca/pages/letter59.html