Sildenafil

"Viagra" redirects here. For other uses, see Viagra (disambiguation).

Sildenafil
Systematic (IUPAC) name
1-[4-ethoxy-3-(6,7-dihydro-1-methyl-
7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)
phenylsulfonyl]-4-methylpiperazine
Clinical data
Trade names Viagra, Revatio, others
AHFS/Drugs.com monograph
MedlinePlus a699015
Licence data
Pregnancy
category
  • US: B (No risk in non-human studies)
Legal status
  • Rx-only
Routes of
administration		 Oral, IV
Pharmacokinetic data
Bioavailability 40%
Metabolism Hepatic (mostly CYP3A4, also CYP2C9)
Biological half-life 3 to 4 hours
Excretion Fecal (80%) and renal (around 13%)
Identifiers
CAS Number 139755-83-2 YesY
ATC code G04BE03
PubChem CID 5281023
DrugBank DB00203 YesY
ChemSpider 56586 YesY
UNII 3M7OB98Y7H YesY
KEGG D08514 YesY
ChEBI CHEBI:58987 YesY
ChEMBL CHEMBL1737 N
PDB ligand ID VIA (PDBe, RCSB PDB)
Chemical data
Formula C22H30N6O4S
Molar mass base: 474.6 g/mol
 NYesY (what is this?)  (verify)

Sildenafil, sold as Viagra and other trade names, is a medication used to treat erectile dysfunction and pulmonary arterial hypertension.[1] Its effectiveness for treating sexual dysfunction in women has not been demonstrated.[1]

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, as this may result in a severe and potentially fatal drop in blood pressure.[1]

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

It was originally discovered by Pfizer scientists Andrew Bell, David Brown, and Nicholas Terrett.[2][3] Since becoming available in 1998, sildenafil has been a common treatment for erectile dysfunction; its primary competitors are tadalafil (Cialis) and vardenafil (Levitra).

Medical uses

Viagra

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 standard treatment for erectile dysfunction including for those with diabetes mellitus.[4]

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.[5]

Antidepressant-associated sexual dysfunction

There is tentative evidence that among men who experience antidepressant induced erectile dysfunction sildenafil may help.[6]

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.[7]

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.[8] Some sildenafil users have complained of seeing everything tinted blue (cyanopsia).[9] 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[10] and a number of studies have linked sildenafil use with nonarteritic anterior ischemic optic neuropathy.[11] 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.[8] 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.[12]

Interactions

Care should be exercised by people who are also taking protease inhibitors for the treatment of HIV. 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.[13] 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 alpha blocker at the same time may lead to low blood pressure, but this effect does not occur if they are taken at least four hours apart.[14]

Contraindications

Contraindications include:[8](p11)

Nonmedical use

Recreational use

Sildenafil's popularity with young adults has increased over the years.[16] 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.[17] The reasons behind such use include the belief that the drug increases libido, improves sexual performance,[17] or permanently increases penis size.[18] 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.[19] This study also noted a significant placebo effect in the control group.[19]

Unprescribed recreational use of sildenafil and other PDE5 inhibitors is noted as particularly high among users of illegal drugs.[20] Sildenafil is sometimes used to counteract the effects of other substances, often illicit.[17] 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".[17] Mixing with amyl nitrite is particularly dangerous and potentially fatal.[17]

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.[21][22]

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.[23][24]

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.[25] These analogs have not undergone any of the rigorous testing that drugs like sildenafil have passed, and thus have unknown side-effect profiles.[26] 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.[27]

The US FDA has banned numerous products claiming to be Eurycoma longifolia that, in fact, contain only analogs of sildenafil.[28][29][30] 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.[31]

Mechanism of action

Crystal structure of human PDE5 with bound sildenafil, PDB entry 1udt[32]

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.[33] 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.[33] 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.[34]

Route of administration

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

Chemical synthesis

The preparation steps for synthesis of sildenafil are:[37]

  1. Methylation of 3-propylpyrazole-5-carboxylic acid ethyl ester with hot dimethyl sulfate
  2. Hydrolysis with aqueous 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
  6. Acylation with 2-ethoxybenzoyl chloride
  7. Cyclization
  8. Sulfonation to the chlorosulfonyl derivative
  9. Condensation with 1-methylpiperazine.

History

Origins

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.[38] 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.[3][39] 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.[40] It soon became a great success: annual sales of Viagra peaked in 2008 at US$1,934 million.[41]

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.[2]

Marketing and sales

Bulk bag of counterfeit Viagra

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.[42][43] 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.[44] By 2007, Viagra's global share had plunged to about 50%[45] 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.[46][47]

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.[48]

On May 6, 2013, Pfizer, which manufacturers Viagra, told the Associated Press they will begin selling the drug directly to patients on its website.[49]

Patents

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.[50][51][52] 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.[53][54]

United States

In 1992, Pfizer filed a patent covering the substance sildenafil and its use to treat cardiovascular diseases.[55] This patent was published in 1993 and expired in 2012. In 1994, Pfizer filed a patent covering the use of sildenafil to treat erectile dysfunction.[56] 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.[57]

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.[58] No legal barrier exists to doctors prescribing this form of sildenafil "off label" for erectile dysfunction, although the dosage typically required for treating ED requires patients to take multiple pills.

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.[59][60]

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."[61]

Teva Canada launched Novo-Sildenafil, a generic version of Viagra, on the day the Supreme Court of Canada released its decision.[62][63][64] To remain competitive, Pfizer then reduced the price of Viagra in Canada.[65] However, on November 9, 2012, Pfizer filed a motion for a re-hearing of the appeal in the Supreme Court of Canada,[66] on the grounds that the court accidentally exceeded its jurisdiction by voiding the patent.[67] Finally, on April 22, 2013, the Supreme Court of Canada invalidated Pfizer's patent altogether.[68]

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.[69]

Pfizer's patent on sildenafil citrate expired in Brazil in 2010.[70]

References

  1. 1 2 3 "Sildenafil Citrate". The American Society of Health-System Pharmacists. Retrieved Dec 1, 2014.
  2. 1 2 "Patent US5250534 - Pyrazolopyrimidinone antianginal agents - Google Patents".
  3. 1 2 Boolell M, Allen MJ, Ballard SA, Gepi-Attee S, Muirhead GJ, Naylor AM, Osterloh IH, Gingell C (June 1996). "Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction". Int. J. Impot. Res. 8 (2): 47–52. PMID 8858389.
  4. ↑ Vardi M, Nini A (2007). Vardi, Moshe, ed. "Phosphodiesterase inhibitors for erectile dysfunction in patients with diabetes mellitus". Cochrane Database Syst Rev (1): CD002187. doi:10.1002/14651858.CD002187.pub3. PMID 17253475.
  5. ↑ Wang, RC; Jiang, FM; Zheng, QL; Li, CT; Peng, XY; He, CY; Luo, J; Liang, ZA (March 2014). "Efficacy and safety of sildenafil treatment in pulmonary arterial hypertension: a systematic review.". Respiratory medicine 108 (3): 531–7. doi:10.1016/j.rmed.2014.01.003. PMID 24462476.
  6. ↑ Taylor, MJ; Rudkin, L; Bullemor-Day, P; Lubin, J; Chukwujekwu, C; Hawton, K (31 May 2013). "Strategies for managing sexual dysfunction induced by antidepressant medication.". The Cochrane database of systematic reviews 5: CD003382. doi:10.1002/14651858.CD003382.pub3. PMID 23728643.
  7. ↑ Stream, JO; Grissom, CK (2008). "Update on high-altitude pulmonary edema: pathogenesis, prevention, and treatment.". Wilderness & environmental medicine 19 (4): 293–303. doi:10.1580/07-weme-rev-173.1. PMID 19099331.
  8. 1 2 3 "Viagra Prescribing Information". Pfizer. October 2007. Archived from the original (PDF) on 14 November 2012. Retrieved 14 November 2012.
  9. ↑ "Viagra and vision". VisionWeb. 29 October 2001. Retrieved 2009-02-10.
  10. ↑ "FDA Updates Labeling for Viagra, Cialis and Levitra for Rare Post-Marketing Reports of Eye Problems". United States Food and Drug Administration. 8 July 2005. Archived from the original on February 23, 2008. Retrieved 2009-02-10.
  11. ↑ Laties AM (2009). "Vision disorders and phosphodiesterase type 5 inhibitors: a review of the evidence to date". Drug Saf 32 (1): 1–18. doi:10.2165/00002018-200932010-00001. PMID 19132801.
  12. ↑ "FDA Announces Revisions to Labels for Cialis, Levitra and Viagra". United States Food and Drug Administration. 18 October 2007. Archived from the original on 11 July 2007. Retrieved 10 February 2009.
  13. ↑ "Viagra (sildenafil citrate) tablets" (PDF). page 29: Pzifer. October 2007. Retrieved 2009-10-25.
  14. ↑ Kloner RA (2005). "Pharmacology and drug interaction effects of the phosphodiesterase 5 inhibitors: focus on alpha-blocker interactions". Am J Cardiol 96 (12B): 42M–46M. doi:10.1016/j.amjcard.2005.07.011. PMID 16387566.
  15. ↑ Cheitlin MD, Hutter AM Jr, Brindis RG, Ganz P, Kaul S, Russell RO Jr, Zusman RM (1999). "ACC/AHA expert consensus document. Use of sildenafil (Viagra) in patients with cardiovascular disease. American College of Cardiology/American Heart Association". Journal of the American College of Cardiology 33 (1): 273–82. doi:10.1016/S0735-1097(98)00656-1. PMID 9935041.
  16. ↑ Peterson K (2001-03-21). "Young men add Viagra to their drug arsenal". USAToday.
  17. 1 2 3 4 5 Smith KM, Romanelli F (2005). "Recreational use and misuse of phosphodiesterase 5 inhibitors". J Am Pharm Assoc (2003) 45 (1): 63–72; quiz 73–5. doi:10.1331/1544345052843165. PMID 15730119.
  18. ↑ Sildenafil Will Not Affect Libido - Fact!
  19. 1 2 Mondaini N, Ponchietti R, Muir GH, Montorsi F, Di Loro F, Lombardi G, Rizzo M (June 2003). "Sildenafil does not improve sexual function in men without erectile dysfunction but does reduce the postorgasmic refractory time". Int. J. Impot. Res. 15 (3): 225–8. doi:10.1038/sj.ijir.3901005. PMID 12904810.
  20. ↑ McCambridge J, Mitcheson L, Hunt N, Winstock A (March 2006). "The rise of Viagra among British illicit drug users: 5-year survey data". Drug Alcohol Rev 25 (2): 111–3. doi:10.1080/09595230500537167. PMID 16627299.
    - Eloi-Stiven ML, Channaveeraiah N, Christos PJ, Finkel M, Reddy R (November 2007). "Does marijuana use play a role in the recreational use of sildenafil?". J Fam Pract 56 (11): E1–4. PMID 17976333.
  21. ↑ "The 2007 Ig Nobel Prize Winners". Improbable Research. 4 October 2007. Retrieved 2009-02-10.
  22. ↑ Agostino PV, Plano SA, Golombek DA (June 2007). "Sildenafil accelerates reentrainment of circadian rhythms after advancing light schedules". Proc. Natl. Acad. Sci. U.S.A. 104 (23): 9834–9. doi:10.1073/pnas.0703388104. PMC 1887561. PMID 17519328.
  23. ↑ Teri Thompson, Christian Red, Michael O'Keefffe, and Nathaniel Vinton (10 June 2008). "Source: Roger Clemens, host of athletes pop Viagra to help onfield performance". Daily News (Daily News). Retrieved 2009-02-10.
  24. ↑ Busbee J (2012-11-28). "Bears’ Brandon Marshall says some NFL players use Viagra … ON THE FIELD". Yahoo! Sports. Retrieved 2012-11-28.
  25. ↑ Venhuis BJ, de Kaste D. (2006–2012). "Towards a decade of detecting new analogues of sildenafil, tadalafil and vardenafil in food supplements: a history, analytical aspects and health risks". Journal of Pharmaceutical and Biomedical Analysis 69: 196–208. doi:10.1016/j.jpba.2012.02.014. PMID 22464558.
  26. ↑ Oh SS, Zou P, Low MY, Koh HL. Detection of sildenafil analogues in herbal products for erectile dysfunction (2006). "Detection of sildenafil analogues in herbal products for erectile dysfunction". Journal of Toxicology and Environmental Health Part A 69 (21): 1951–1958. doi:10.1080/15287390600751355. PMID 16982533.
  27. ↑ Venhuis BJ, Blok-Tip L, de Kaste D (2008). "Designer drugs in herbal aphrodisiacs". Forensic Science International 177 (2–3): 25–27. doi:10.1016/j.forsciint.2007.11.007. PMID 18178354.
  28. ↑ FDA letter to Libidus distributor
  29. ↑ FDA Warns Consumers About Dangerous Ingredients in "Dietary Supplements" Promoted for Sexual Enhancement
  30. ↑ Hidden Risks of Erectile Dysfunction "Treatments" Sold Online
  31. ↑ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 9th edition, Biomedical Publications, Seal Beach, CA, 2011, pp. 1552–1553. http://www.biomedicalpublications.com/dt9.pdf
  32. ↑ Sung, B. J.; Hwang, K.; Jeon, Y.; Lee, J. I.; Heo, Y. S.; Kim, J.; Moon, J.; Yoon, J.; Hyun, Y. L.; Kim, E.; Eum, S.; Park, S. Y.; Lee, J. O.; Lee, T.; Ro, S.; Cho, J. (2003). "Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules". Nature 425 (6953): 98–102. doi:10.1038/nature01914. PMID 12955149.
  33. 1 2 Webb, D.J.; Freestone, S.; Allen, M.J.; Muirhead, G.J. (March 4, 1999). "Sildenafil citrate and blood-pressure-lowering drugs: results of drug interaction studies with an organic nitrate and a calcium antagonist". Am. J. Cardiol. 83 (5A): 21C–28C. doi:10.1016/S0002-9149(99)00044-2. PMID 10078539.
  34. ↑ "Viagra Clinical Pharmacology". RxList.com. 2008. Retrieved 2008-08-20.
  35. ↑ Eardley I, Ellis P, Boolell M, Wulff M (2002). "Onset and duration of action of sildenafil for the treatment of erectile dysfunction". Br J Clin Pharmacol. 53 Suppl 1: 61S–65S. doi:10.1046/j.0306-5251.2001.00034.x. PMC 1874251. PMID 11879261.
  36. ↑ Deveci S, Peşkircioğlu L, Aygün C, Tekin MI, Dirim A, Ozkardeş H (2004). "Sublingual sildenafil in the treatment of erectile dysfunction: faster onset of action with less dose". Int. J. Urol. 11 (11): 989–92. doi:10.1111/j.1442-2042.2004.00933.x. PMID 15509203.
  37. ↑ Dunn PJ (2005). "Synthesis of Commercial Phosphodiesterase(V) Inhibitors". Org Process Res Dev 2005 (1): 88–97. doi:10.1021/op040019c.
  38. ↑ "Research". ABM. Abertawe Bro Morgannwg University Health Board. 4 July 2008. Archived from the original on 26 September 2008. Retrieved 6 August 2008. Our clinicians regularly offer patients the opportunity to take part in trials of new drugs and treatments. Morriston Hospital in Swansea, was the first in the world to trial Viagra!
  39. ↑ Terrett NK, Bell AS, Brown D, Elllis P (1996). "Sildenafil (Viagra), a potent and selective inhibitor of Type 5 cGMP phosphodiesterase with utility for the treatment of male erectile dysfunction". Bioorg Med Chem Lett 6 (15): 1819–1824. doi:10.1016/0960-894X(96)00323-X.
  40. ↑ Kling J (1998). "From hypertension to angina to Viagra". Mod. Drug Discov. 1: 31–38. ISSN 1532-4486. OCLC 41105083.
  41. ↑ Viagra sales peak at $1,934m in 2008
  42. ↑ Ciment, J (1999). "Missouri fines internet pharmacy". BMJ (British Medical Journal) 319 (7221): 1324. doi:10.1136/bmj.319.7221.1324g. PMC 1174637. PMID 10567131.
  43. ↑ Devine, Amy (September 29, 2008). "Chemists plan to sell Viagra on the internet". Daily Record. Retrieved 2012-04-30.
  44. ↑ Keith A (2000). "The economics of Viagra". Health Aff (Millwood) 19 (2): 147–57. doi:10.1377/hlthaff.19.2.147. PMID 10718028.
  45. ↑ McGuire S (2007-01-01). "Cialis gaining market share worldwide". Medical Marketing & Media. Haymarket Media. Archived from the original on 2009-01-03. Retrieved 2009-02-10.
  46. ↑ Mullin, Rick (June 20, 2005). "Viagra". Chemical & Engineering News 83 (25). Retrieved 2008-08-20.
  47. ↑ Berenson, Alex (December 4, 2005). "Sales of Impotence Drugs Fall, Defying Expectations". The New York Times. Retrieved 2008-08-20.
  48. ↑ "Over-the-counter Viagra piloted". BBC News. BBC News. 11 February 2007. Retrieved 2009-02-10.
  49. ↑ "Pfizer to sell Viagra online, in first for Big Pharma: AP". CBS News. Retrieved 6 May 2013.
  50. ↑ "Actavis Launches Generic Viagra in Europe as Patents Expire". Retrieved 2013-10-25.
  51. ↑ Jim Edwards (October 21, 2009). "What Will Happen When Viagra Goes Generic?". AccessRx.com. Retrieved 2011-03-25.
  52. ↑ "Is Viagra about to lose its pulling power in the UK?". The Guardian. Retrieved 13 June 2013.
  53. ↑ Murray-, Rosie (23 January 2002). "Viagra ruling upsets Pfizer". London: Telegraph Media Group Limited. Archived from the original on 22 August 2009. Retrieved 10 February 2009.
  54. ↑ "Pfizer Loses UK Battle on Viagra Patent". UroToday. Thomson Reuters. 17 June 2002. Archived from the original on 25 June 2007. Retrieved 10 February 2009.
  55. ↑ U.S. Patent 5,250,534
  56. ↑ U.S. Patent 6,469,012
  57. ↑ "Pfizer Wins Viagra Patent Infringement Case Against Teva Pharmaceuticals". Bloomberg. August 15, 2011. Retrieved 2012-04-01.
  58. ↑ "Pfizer's Revatio Goes Generic". Zacks Equity Research. November 15, 2012. Retrieved 2013-10-05.
  59. ↑ "Revation patent ruled invalid for lack of sound prediction and obviousness". Canadian Technology & IP Law. Stikeman Elliott. 2010-06-18. Retrieved 2012-11-14.
  60. ↑ "Pfizer Canada Inc. v. Ratiopharm Inc., 2010 FC 612". CanLII.
  61. ↑ Teva Canada Ltd. v. Pfizer Canada Inc. 2012 SCC 60 at par. 80 (8 November 2012)
  62. ↑ John Spears (2012-11-08). "Supreme Court ruling could lead to cheaper versions of Viagra". The [Toronto] Star. Retrieved 2012-11-14.
  63. ↑ Ken Hanly (2012-11-08). "Canadian Supreme court rules Viagra patent invalid". Digital Journal. Retrieved 2012-11-14.
  64. ↑ "Viagra patent tossed out by Supreme Court: Decision allows generic versions of drug to be produced". CBC News. 2012-11-08. Retrieved 2012-11-14.
  65. ↑ "Pfizer Canada drops Viagra price after generic versions get Supreme Court green light". Financial Post. 2012-11-22. Retrieved 2013-02-09.
  66. ↑ "SCC Case Information, Docket No. 33951". Retrieved 2012-11-14.
  67. ↑ Kirk Makin (2012-11-15). "In rare move, Pfizer asks Supreme Court to reconsider ruling that killed Viagra patent". The Globe and Mail. Retrieved 2012-11-15.
  68. ↑ Gowling Lafleur Henderson LLP, Hélène D'Iorio (2013-04-22). "The Supreme Court of Canada holds Pfizer’s Viagra patent invalid". Lexology. Retrieved 2013-12-27.
  69. ↑ Allam, Abeer (October 4, 2002). "Seeking Investment, Egypt Tries Patent Laws". New York Times. Retrieved April 1, 2013.
  70. ↑ Viagra patent expires in June, says Brazilian court

External links

This article is issued from Wikipedia - version of the Friday, February 12, 2016. The text is available under the Creative Commons Attribution/Share Alike but additional terms may apply for the media files.