Pfizer to buy King Pharmaceuticals for $3.6 billion

Pfizer announced Tuesday an agreement to acquire King Pharmaceuticals for $3.6 billion in cash, or $14.25 per share, representing a premium of approximately 40 percent over the company’s closing share price on October 11. Pfizer CEO Jeffrey Kindler noted that the deal will allow the drugmaker “to offer a fuller spectrum” of pain treatments, and further diversifying the company’s business.

The agreement, which was approved by the boards of both companies, will give Pfizer access to such pain drugs as Avinza (morphine), Embeda (morphine sulfate/naltrexone hydrochloride) and the Flector Patch (diclofenac epolamine). King is also currently developing the tamper-resistant Remoxy (oxycodone), as well as a short-acting version of the drug, Acurox (oxycodone/niacin), which < a href=” http://www.firstwordplus.com/Fws.do?articleid=A2AACAE25AF042CB86175DCC0D39CE16″>failed to win an FDA panel’s support in April.

King, which generated annual revenues last year of nearly $1.8 billion, also makes specialty pharmaceuticals and animal health products. Pfizer noted that “King’s three key businesses are not only complementary…but are also strategically aligned with Pfizer’s Primary Care, Established Products and Animal Health business units, enabling a seamless combination.”

Pfizer expects the acquisition to be accretive to earnings by approximately $0.02 in 2011 and 2012, and approximately $0.03 to $0.04 between 2013 and 2015. The transaction is also expected to lead to cost savings of at least $200 million to be realised by the end of 2013, Pfizer noted. The deal, which is expected to close later in this quarter or in the first quarter of 2011, will not impact Pfizer’s 2010 annual guidance or its financial targets for 2012.

Joel Levington of Brookfield Investment Management said that the “transaction should modestly help Pfizer’s growth profile in 2012 through 2013.” The analyst called King “a solid asset,” although he noted that Pfizer was paying “a somewhat elevated price” for the company.

treatment and prophylaxis of swine flu

In the wake of the recent development and the upgrade of the swine flu to the pandamic status, let us review the medications that is used to treat it.
Will start by the Tamiflu






Treatment of Influenza


TAMIFLU (oseltamivir phosphate) is indicated for:

• The treatment of uncomplicated acute illness due to influenza infection in adults and adolescents (>13 years) who have been symptomatic for no more than 2 days.
  
  The treatment indication is based on two Phase III clinical studies of naturally occurring influenza in adults in which the predominant infection was influenza A (95%) and a limited number with influenza B (3%) and influenza of unknown type (2%), reflecting the distribution of these strains in the community. The indication is also supported by influenza A and B challenge studies. No data are available to support the safety and efficacy of TAMIFLU in adult patients who commenced treatment after 40 hours of onset of symptoms.
• The treatment of uncomplicated acute illness due to influenza in pediatric patients 1 year and older who have been symptomatic for no more than 2 days.
  
  The pediatric indication is based on one Phase III clinical study of naturally occurring influenza in pediatric patients aged 1 to 12 years in which 67% of influenza infected patients were infected with influenza A and 33% with influenza B.
  
  TAMIFLU, when taken as recommended for the treatment of influenza, alleviates the symptoms and reduces their duration.

Prevention/Prophylaxis of Influenza


The decision to administer TAMIFLU for prophylaxis to close contacts should be based on the knowledge that influenza is circulating in the area and the index case demonstrates characteristic symptoms of influenza. TAMIFLU is not effective in providing prophylaxis for respiratory infections other than influenza therefore a proper diagnosis of the index case is important.

TAMIFLU is not a substitute for influenza vaccination. Vaccination is the preferred method of prophylactic prevention against influenza.
The use of antivirals for the treatment and prevention of influenza should be determined on the basis of official recommendations taking into consideration variability of epidemiology and the impact of the disease in different geographical areas and patient populations.


TAMIFLU is indicated for:

• The prevention of influenza illness in adults and adolescents 13 years and older following close contact with an infected individual (the index case).
  
  The prevention indication is based on a phase III clinical study programme consisting of 4 Phase III clinical trials.
• The prevention of influenza illness in pediatric patients 1 year and older following close contact with an infected individual (the index case).
  
  This indication is based on a substudy of pediatric patients in a Phase III clinical trial.

Contraindications

• TAMIFLU (oseltamivir phosphate) is contraindicated in patients with known hypersensitivity to any of the components of the product. For a complete listing, see Dosage Forms, Composition and Packaging.
• Use of TAMIFLU in children under 1 year of age is contraindicated. TAMIFLU may be safely administered only once the blood-brain barrier is fully developed.

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Icariin from horny goat weed is structurally unrelated to sildenafil (Viagra^®)

In our last post we discussed a recent USPTO ruling that rejected a claim of the Pfizer patent on the erectile dysfunction drug, sildenafil (Viagra^®), to a novel oral treatment for the disorder. The patent appeals panel ruled that the existence of horny goat weed, a traditional Chinese medicine used orally for impotence, was grounds for rejection of the claim.

Frequent commenter daedalus4u pulled out US Patent #6,469,012 (filed Mar 4 1996, issued Oct 22 2002) wherein the relevant claim 24 reads:

A method of treating erectile dysfunction in a male human, comprising orally administering to a male human in need of such treatment an effective amount of a selective cGMP PDE inhibitor, or a pharmaceutically acceptable salt thereof, of a pharmaceutical composition containing either entity.

The claim should never have been allowed in the first place, said daedalus4u, and if upheld would have allowed Pfizer to block sales of horny goat weed. I'm also assuming that upholding claim 24 would have also allowed Pfizer to block sales of follow-on PDE5 inhibitors such as Lilly's Cialis^®. But again, I'm not a patent attorney so I welcome further discussion on this point.

We also heard from my dear old colleague from Adelaide, Professor Ian Musgave. Ian is a pharmacologist who is probably better known in the blogosphere for his astronomy expertise (Astroblog, Southern Sky Watch, and contributing editor to Sky & Space).

But Ian is first and foremost a pharmacologist and raised this point:

Wait a minute, let me get this straight. The patent on Sildenafil, a compound that was rationally designed to specifically inhibit PDE (1) and developed prior to 1996 was invalidated because of a structurally unrelated component of a herbal extract that wasn't even shown to act on the cGMP/NO system before 2001? (2)

Pfizer is supposed to have time travel? The fact that a herbal treatment alleged to help sexual function would turn out, 5 years after the sildenafil patent had been granted (and the concept of PDE5 inhibitors as treatment for erectile dysfunction wide spread) to have effects on PDE5 could not possibly count as prior art. If so, the 1983 demonstration that the PDE inhibitor papaverine could produce erections would have invalidated the sildenafil patent.

The patent boards ruling is patently rubbish. How can sildenafil "logically flow" from a compound that wasn't even known to really work, let alone known to inhibit PDE?

(1)Nicholas K. Terrett, Andrew S. Bell, David Brown and Peter Ellis. Sildenafil (VIAGRATM), a potent and selective inhibitor of type 5 cGMP phosphodiesterase with utility for the treatment of male erectile dysfunction. Bioorganic & Medicinal Chemistry Letters
Volume 6, Issue 15, 6 August 1996, Pages 1819-1824
(2)Xin ZC. Kim EK, Tian ZJ, Lin GT, Guo YL. Icariin on relaxation of corpus cavernosm smooth muscle. Chin Sci Bulle 2001; 46: 485-9.

Prof Musgrave is indeed correct in the argument but daedalus4u points out the ruling did not invalidate the Pfizer patent, just the single claim to the pharmaceutical indication.

So that makes more sense to me and now I think I understand.

But in the discussion, Ian gave us another gem in response to a commenter who argued there was a structural resemblance between sildenafil and icariin, the active flavonol glycoside constituent of horny goat weed:

No, not at all. You can stick the benzofuran of the flavonol on top of the methylxanthine moiety of the sildenafil, but the charge distribution and 3D structure is all wrong, the flavonol has these huge sugar moieties which have the wrong charge and stick out in places that should inhibit binding, it lacks the bulky positively charged ring that fits into the PDE5 specific binding pocket. (I have the an image of the 3D structural overlay if anyone want to see them).

Looking at it, icariin does not scream either methylxanthine mimetic or "PDE inhibitor", in fact I would guess it would be worthless. However, flavonols and flavinoids have a habit of doing things we don't expect, such as resveratrol being a very decent cannaboid receptor anatgonist, despite looking nothing like cannabinoids of the synthetic antagonists.

In fact, Ian was kind enough to send us two molecular modeling images of the two compounds which I failed to get posted last night that illustrate the vast difference between sildenafil and icariin. This overlay image was generated with RASMOL, with icariin in the wireframe format and sildenafil in stick format:

We reported yesterday that icariin has only 1/80th the potency of sildenafil in inhibiting PDE5 and its maximal effect on cGMP accumulation in an rabbit tissue model is 1/10th that of sildenafil. One doesn't need to be a computational chemist to see from Ian's overlay why this difference in potency and efficacy exists.

Anyway, this has been an interesting scientific exchange on an issue that was largely only covered in the pharmaceutical business press. This also illustrates for me the fun of science blogging - we all come to the table, albeit the electronic table, with our own expertise, have a discussion and learn from one another, even if some of us are halfway around the world.

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Horny Goat Weed (Epimedium spp.) is a limp excuse for Viagra, Cialis

Reuters and Bloomberg reported earlier this week on an ongoing patent battle (read: pissing match) between Pfizer and Eli Lilly & Co. relating to their erectile dysfunction drugs Viagra and Cialis, respectively.

A US Patent and Trademark Office (USPTO) appeals committee has ruled that an element of Pfizer's patent on sildenafil, the active chemical in Viagra, is invalid because the drug is insufficiently different from a traditional Chinese medicine called Yin Yang Huo or horny goat weed.

At issue is Pfizer's claim to a method for treating male erectile dysfunction. The patent appeals panel ruled that the method did not constitute a new invention because of the precedent set by Yin Yang Huo. Moreover, the board ruled that chemicals found in the herbal medicine act by the same mechanism as sildenafil by inhibition of an enzyme called phosphodiesterase-5 (PDE5). Therefore, the panel ruled, "the patent claim was the next logical step up from using the herb."

I'm not an expert in law but there are untold number of traditional remedies touted for all sorts of sexual enhancement, none of which have the convincing efficacy of the prescription PDE5 inhibitors. We may call the condition "erectile dysfunction" today and the idea of treating it may have existed for centuries but having a compound that can actually do anything about it is an invention. However, I can see the fine distinction if Pfizer claimed that the idea of treating erectile dysfunction was an invention.

You lawyers out there can weigh in but this sounds like a bunch of posturing for market share: worldwide Viagra sales were $2 billion USD last year.

But what is this horny goat weed and why is it being singled out?

Horny goat weed is the colloquial name for any number of species of plants in the Epimedium genus. Most medicinal plant accounts describe some variation on the theme that a Chinese goat herder observed an increase in mating behavior among his flock while grazing on the plant. According to North Carolina State University Department of Horticulture webpage, it grows as a deciduous perennial ground cover in USDA Zones 6, 7, and 8.

The active compound in horny goat weed is a flavonol called icariin. As shown above, icariin (left) is about as can be from sildenafil (right). Moreover, icariin is a poor inhibitor of PDE5, with a IC50 value of 5.9 μM, making it about 80-fold less potent than sildenafil (IC50 = 75 nM) (J Nat Prod 2008; 71:1513-1517.)

And remember: that's the purified compound in an isolated enzyme assay. Let's take a look at the plant extract itself, the product sold on the internet and in health food stores as horny goat weed.

This figure comes from a 2006 paper in the International Journal of Impotence Research (2006; 18:335-342) where an extract of a specifically-selected Epimedium plant was extracted and partially purified, then tested relative to sildenafil in a tissue preparation of rabbit corpus cavernosum (the crucial penile vasculature). The extract, EP-20 was tested here for its ability to increase the levels of the second-messenger molecule cGMP in response to the nitric oxide donor, sodium nitroprusside (SNP). Erectile dysfunction agents acts to inhibit the degradation of cGMP, causing the corpus cavernosum to relax and increase blood flow to the penis.

The EP-20 extract does indeed increase SNP-stimulated cGMP concentration over SNP alone, but it tops out at about 1/10 the levels stimulated by sildenafil (note the broken y-axis for scale). More importantly, the concentrations of horny goat weed extract are tremendously high: 0.1 and 0.3 mg/mL. A direct comparison with sildenafil is difficult because it is a pure compound while the EP-20 horny goat weed extract is a mixture of all the chemicals that occur in the plant.

The take-home messages?:

• The active constituent of horny goat weed, icariin, bears no structural similarity to sildenafil.


• Sildenafil is 80 times more potent than icariin in inhibiting phosphodiesterase-5


• Horny goat weed extract must be used at unbelievably high concentrations - far more than can be achieved in the bloodstream - to cause only 1/10th the effectiveness of sildenafil in a rabbit penile blood vessel model.

So, horny goat weed is far from stiff competition for a prescription PDE5 inhibitor like sildenafil. Yes, it has the potential to target an animal model of penile vasculature in a manner similar to sildenafil but it is unlikely to occur in a real-life scenario. However, there have been no head-to-head clinical trials of horny goat weed extract and sildenafil.

Going back to the Pfizer and Eli Lilly spat, there is really little comparison between horny goat weed and the active compound in Viagra.

And as for anyone thinking that horny goat weed might be a more cost-effective substitution for Viagra? You're probably better off buying a dietary supplement intentionally adulterated with other prescription drugs.