Sildenafil

Sildenafil, sold under the brand name Viagra, among others, is a medication used to treat erectile dysfunction and pulmonary arterial hypertension.[4][8] It is unclear if it is effective for treating sexual dysfunction in women.[8] It is taken by mouth or by injection into a vein.[8] Onset is typically within twenty minutes and lasts for about two hours.[8]

Sildenafil
Clinical data
Pronunciation/sɪlˈdɛnəfɪl/ sil-DEN-ə-fil
Trade namesViagra, Revatio, others
AHFS/Drugs.comMonograph
MedlinePlusa699015
License data
Pregnancy
category
Routes of
administration		By mouth (tablets), intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability41% (mean)[7]
Protein binding~96%
MetabolismLiver: CYP3A4 (major route), CYP2C9 (minor route)
MetabolitesN-desmethylsildenafil (~50% potency for PDE5)
Onset of action20 minutes
Elimination half-life3–4 hours
ExcretionFeces (~80%), urine (~13%)[4]
Identifiers
IUPAC name
  • 5-{2-Ethoxy-5-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.122.676
Chemical and physical data
FormulaC22H30N6O4S
Molar mass474.58 g·mol−1
3D model (JSmol)
  • CCCC1=NN(C2=C1N=C(NC2=O)C3=C(C=CC(=C3)S(=O)(=O)N4CCN(CC4)C)OCC)C
  • InChI=1S/C22H30N6O4S/c1-5-7-17-19-20(27(4)25-17)22(29)24-21(23-19)16-14-15(8-9-18(16)32-6-2)33(30,31)28-12-10-26(3)11-13-28/h8-9,14H,5-7,10-13H2,1-4H3,(H,23,24,29) N
  • Key:BNRNXUUZRGQAQC-UHFFFAOYSA-N N
 NY (what is this?)  (verify)

Common side effects include headaches, heartburn, and flushed skin.[8] Caution is advised in those with cardiovascular disease.[8] Rare but serious side effects include a prolonged erection (priapism) that can lead to damage to the penis, vision problems, and hearing loss.[8] Sildenafil should not be taken by people on nitrates such as nitroglycerin (glycerin trinitrate), as this may result in a serious drop in blood pressure.[8] Sildenafil should not be taken within four hours of taking an alpha blocker.

Sildenafil acts by blocking phosphodiesterase 5 (PDE5), an enzyme that promotes breakdown of cGMP, which regulates blood flow in the penis.[8] It requires sexual arousal to work.[8] It also results in dilation of the blood vessels in the lungs.[8]

Pfizer originally discovered the medication in 1989 while looking for a treatment for heart-related chest pain.[9] It was approved for medical use in the United States and in the European Union in 1998.[5][8][9][10] In 2017, it was the 217th-most commonly prescribed medication in the United States, with more than two million prescriptions.[11][12] That same year, it also became available as a generic medication after final patents by Pfizer expired.[13] In the United Kingdom, it is available over the counter.[14] Most of the Active Pharmaceutical Ingredient (API) in Sildenafil, Sildenafil citrate, is produced in Pfizer's Ringaskiddy complex, County Cork, which is Pfizer's largest production facility outside of the United States.[15]

Medical uses
Pfizer Viagra tablet in the trademark blue diamond shape

Sexual dysfunction

The primary indication of sildenafil is treatment of erectile dysfunction (inability to sustain a satisfactory erection to complete sexual intercourse). Its use is now one of the standard treatments for erectile dysfunction, including for men with diabetes mellitus.[16]

Antidepressant-associated sexual dysfunction

Tentative evidence suggests that sildenafil may help men who experience antidepressant-induced erectile dysfunction.[17]

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.[18]

Raynaud's phenomenon

Sildenafil and other PDE5 inhibitors are used off-label to alleviate vasospasm and treat severe ischemia and ulcers in fingers and toes for people with secondary Raynaud's phenomenon;[19][20] these drugs have moderate efficacy for reducing the frequency and duration of vasospastic episodes.[19] As of 2016, their role more generally in Raynaud's was not clear.[20]

High-altitude pulmonary edema

Sildenafil has been studied for high-altitude pulmonary edema, but its use is currently not recommended for that indication.[21]

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.[4] Some sildenafil users have complained of seeing everything tinted blue (cyanopsia).[22] This cyanopsia can be explained because Sildenafil, while selective for PDE5, does have a minor level of selectivity for PDE6, which is the phosphodiesterase found in the retina. Patients thus taking the drug may experience colorvision abnormalities. Some complained of blurriness and loss of peripheral vision. In July 2005, the U.S. Food and Drug Administration (FDA) found that sildenafil could lead to vision impairment in rare cases,[23] and a number of studies have linked sildenafil use with non-arteritic anterior ischemic optic neuropathy.[24]

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.[4] 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.[25]

Interactions

Care should be exercised by people who are also taking protease inhibitors for the treatment of HIV infection. Protease inhibitors inhibit the metabolism of sildenafil, effectively multiplying the plasma levels of sildenafil, increasing the incidence and severity of side effects. Those using protease inhibitors are recommended to limit their use of sildenafil to no more than one 25 mg dose every 48 hours.[4] 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.[26]

The use of sildenafil and an α1 blocker (typically prescribed for hypertension or for urologic conditions, such as benign prostatic hypertrophy) at the same time may lead to low blood pressure, but this effect does not occur if they are taken at least 4 hours apart.[27]

Contraindications

Contraindications include:[4]

  • Concomitant use of nitric oxide donors, organic nitrites and nitrates,[28] such as:
  • Concomitant use of soluble guanylyl cyclase stimulators, such as riociguat
  • Known hypersensitivity to sildenafil

Sildenafil should not be used if sexual activity is inadvisable due to underlying cardiovascular risk factors.[29]

Nonmedical use

Recreational use

Sildenafil's popularity with young adults has increased over the years.[30] 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.[31] The reasons behind such use include the belief that the drug increases libido, improves sexual performance,[31] or permanently increases penis size.[32] Studies on the effects of sildenafil when used recreationally are limited, but suggest it has little effect when used by those who do not have 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.[33] This study also noted a significant placebo effect in the control group.[33]

Unprescribed recreational use of sildenafil and other PDE5 inhibitors is noted as particularly high among users of illegal drugs.[34] Sildenafil is sometimes used to counteract the effects of other substances, often illicit.[31] 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".[31] Mixing it with amyl nitrite, another vasodilator, is particularly dangerous and potentially fatal.[31]

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.[35][36]

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.[37][38]

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.[39] These analogs have not undergone any of the rigorous testing that drugs like sildenafil have passed, and thus have unknown side-effect profiles.[40] 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.[41]

The U.S. Food and Drug Administration (FDA) has banned numerous products claiming to be Eurycoma longifolia that, in fact, contain only analogs of sildenafil.[42][43][44] 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.[45]

Mechanism of action
Crystal structure of human PDE5 with bound sildenafil, PDB entry 1udt[46]

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.[47] 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.

The molecular mechanism of smooth muscle relaxation involves the enzyme CGMP-dependent protein kinase, also known as PKG. This kinase is activated by cGMP and it phosphorylates multiple targets in the smooth muscle cells, namely myosin light chain phosphatase, RhoA, IP3 receptor, phospholipase C, and others.[48] Overall, this results in a decrease in intracellular calcium and desensitizing proteins to the effects of calcium, engendering smooth muscle relaxation.[48]

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 increased penile response to sexual stimulation.[47][49] 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.[50]

Route of administration
  • When taken by mouth sildenafil for erectile dysfunction results in an average time to onset of erections of 27 minutes (ranging from 12 to 70 minutes).[51]
  • Under the tongue use of sildenafil for erectile dysfunction results in an average onset of action of 15 minutes and lasting for an average of 40 minutes.[52]

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

Chemical synthesis

The preparation steps for synthesis of sildenafil are:[53]

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

History

Sildenafil (compound UK-92,480) was synthesized by a group of pharmaceutical chemists working at Pfizer's Sandwich, Kent, research facility in England. It was initially studied for use in hypertension (high blood pressure) and angina pectoris (a symptom of ischaemic heart disease). The first clinical trials were conducted in Morriston Hospital in Swansea.[54] 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.[55][56] Pfizer therefore decided to market it for erectile dysfunction, rather than for angina; this decision became an often-cited example of drug repositioning.[57][58] The drug was patented in 1996, approved for use in erectile dysfunction by the FDA on 27 March 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.[59] It soon became a great success: annual sales of Viagra peaked in 2008 at US$1.934 billion.[60]

Society and culture

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.[61][62] The Viagra name has become so well known that 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.[63] By 2007, Viagra's global share had plunged to about 50%[64] 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.[65][66] In 2008, the FDA forced Pfizer to remove Viva Cruiser, an advergame for Viagra, from appearing on Forbes.com, after the game failed to disclose risk information about the drug.[67][68]

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.[69] In 2017, the Medicines and Healthcare products Regulatory Agency (MHRA) enacted legislation that expanded this nationwide,[70] allowing a particular branded formulation of Sildenafil, Viagra Connect (50 mg), to be sold over the counter and without a prescription throughout the UK from early 2018. While the sale remains subject to a consultation with a pharmacist, the other restrictions from the trial have been removed, allowing customers over the age of 18 to purchase an unlimited number of pills.[71] The decision was made, in part, to reduce online sales of counterfeit and potentially dangerous erectile dysfunction treatments.

On 6 May 2013, Pfizer, which manufactures Viagra, told the Associated Press they will begin selling the drug directly to people on its website.[72]

Pfizer's patents on Viagra expired outside the US in 2012; in the US they were set to expire, but Pfizer settled litigation with each of Mylan and Teva which agreed that both companies could introduce generics in the US on 11 December 2017.[73][74] In December 2017, Pfizer released its own generic version of Viagra.[75][76]

As of 2018, the U.S. Food and Drug Administration has approved fifteen drug manufacturers to market generic sildenafil in the United States. Seven of these companies are based in India. This is likely to lead to dramatic price reductions.[77][78]

Counterfeits

Counterfeit Viagra, despite generally being cheaper,[79] can contain harmful substances or substances that affect how Viagra works, such as blue printer ink, amphetamines, metronidazole, boric acid, and rat poison.[80]

Viagra is one of the world's most counterfeited medicines.[81][82] According to a Pfizer study, around 80% of sites claiming to sell Viagra were selling counterfeits.[80]

Brazil

Pfizer's patent on sildenafil citrate expired in Brazil in 2010.[83]

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.[84][85]

On 8 November 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."[86]

Teva Canada launched Novo-Sildenafil, a generic version of Viagra, on the day the Supreme Court of Canada released its decision.[87][88][89] To remain competitive, Pfizer then reduced the price of Viagra in Canada.[90] However, on 9 November 2012, Pfizer filed a motion for a re-hearing of the appeal in the Supreme Court of Canada,[91] on the grounds that the court accidentally exceeded its jurisdiction by voiding the patent.[92] Finally, on 22 April 2013, the Supreme Court of Canada invalidated Pfizer's patent altogether.[93]

China

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

Egypt

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.[94]

European Union
Sildenafil 100 milligram tablets - (prescription in the 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.[95][96][97] 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.[98][99]

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), Manly (Cooper Pharma) and Zenegra (Alkem Laboratories).

New Zealand

Sildenafil was reclassified in New Zealand in 2014 so it could be bought over the counter from a pharmacist. It is thought that this reduced sales over the Internet and was safer as men could be referred for medical advice if appropriate.[100]

South Korea

In 1999 South Korea granted two patents to Pfizer related to sildenafil. The first document guaranteed sole production and sale of the substance until 2012, while the second gave Pfizer the exclusive use to treating erectile dysfunction with sildenafil until 2014.[101] In 2011 Hanmi Pharmaceutical and CJ CheilJedang launched a suit against the exclusive use patent. The Korean Court system made a ruling against Pfizer in June 2012, allowing for the unhindered domestic production of generic prescription sildenafil.[102]

During 2012 Viagra lost its position as the top selling erectile dysfunction treatment in South Korea. This development was credited largely "due to the introduction of generic products." Generic sildenafil became publicly available in May. Sales of PalPal by Hanmi Pharmaceuticals totalled ₩22 billion or about 86% the market share of Viagra that year.[103] By 2017 there were over 50 generic sildenafil pills available. During that year Viagra sales slumped to 38% that of Palpal.[104]

United Kingdom

There were 2,958,199 prescriptions for Sildenafil in 2016 in England, compared with 1,042,431 in 2006.[105]

In 2018, Viagra Connect, a particular formulation of Sildenafil marketed by Pfizer, became available for sale without a prescription in the UK,[71] in an attempt to widen availability and reduce demand for counterfeit products.

United States

Sildenafil is available as a generic drug in the United States, labeled for pulmonary arterial hypertension.[106] As of 2016 branded pills cost about 50 times more than generic ones.[106] In the United States as of 2015 the branded 50 mg pill cost is between 25.17 and US$37.88.[107]

In the United States, Pfizer received two patents for sildenafil: one for its indication to treat cardiovascular disease (marketed as Revatio) and another for its indication to treat erectile dysfunction (marketed as Viagra). The substance is the same under both trade names.[106]

In 1992, Pfizer filed a patent covering the substance sildenafil and its use to treat cardiovascular diseases.[108] This would be marketed as Revatio. The patent was published in 1993 and expired in 2012. The patent on Revatio (indicated for pulmonary arterial hypertension rather than erectile dysfunction) expired in late 2012. Generic versions of this low-dose form of sildenafil have been available in the U.S. from a number of manufacturers, including Greenstone, Mylan, and Watson, since early 2013.[109] Health care providers may prescribe generic sildenafil for erectile dysfunction.[106] However, the generic is not available in the same dosages as branded Viagra, so using dosages typically required for treating ED requires patients to take multiple pills.[106]

In 1994, Pfizer filed a patent covering the use of sildenafil to treat erectile dysfunction.[110] This would be marketed as Viagra. This patent was published in 2002 and will expire in 2019. Teva sued to have the latter patent invalidated, but Pfizer prevailed in an August 2011 federal district court case.[111] An agreement with Pfizer allowed Teva to begin to provide the generic drug in December 2017.[106]

References
  1. "Sildenafil Use During Pregnancy". Drugs.com. 7 October 2019. Retrieved 6 October 2020.
  2. "Viagra 25mg film-coated tablets - Summary of Product Characteristics (SmPC)". (emc). 7 August 2020. Retrieved 6 October 2020.
  3. "Viagra Connect 50 mg film-coated tablets - Summary of Product Characteristics (SmPC)". (emc). 5 December 2017. Retrieved 6 October 2020.
  4. "Viagra- sildenafil citrate tablet, film coated". DailyMed. Retrieved 6 October 2020.
  5. "Viagra EPAR". European Medicines Agency. Retrieved 6 October 2020.
  6. "Revatio EPAR". European Medicines Agency. Retrieved 6 October 2020.
  7. Nichols DJ, Muirhead GJ, Harness JA (6 March 2002). "Pharmacokinetics of sildenafil after single oral doses in healthy male subjects: absolute bioavailability, food effects and dose proportionality". British Journal of Clinical Pharmacology. 53 (Suppl 1): 5S–12S. doi:10.1046/j.0306-5251.2001.00027.x. PMC 1874258. PMID 11879254.
  8. "Sildenafil Citrate". The American Society of Health-System Pharmacists. Retrieved 1 December 2014.
  9. Goldstein I, Burnett AL, Rosen RC, Park PW, Stecher VJ (January 2019). "The Serendipitous Story of Sildenafil: An Unexpected Oral Therapy for Erectile Dysfunction". Sexual Medicine Reviews. 7 (1): 115–128. doi:10.1016/j.sxmr.2018.06.005. PMID 30301707. S2CID 52945888.
  10. "Drug Approval Package: Viagra (sildenafil citrate) NDA #020895". U.S. Food and Drug Administration (FDA). 27 March 1998. Retrieved 15 February 2021.
  11. "The Top 300 of 2020". ClinCalc. Retrieved 11 April 2020.
  12. "Sildenafil - Drug Usage Statistics". ClinCalc. Retrieved 11 April 2020.
  13. Gordon S (11 December 2017). "Generic Viagra: Two versions of sildenafil hit the market today". CBS News. Retrieved 24 November 2018.
  14. LaMattina J. "With Viagra Now Available Over-The-Counter In The U.K., Will The U.S. Follow Suit?". Forbes. Retrieved 24 November 2018.
  15. "Pfizer Synthesis Facility, Ringaskiddy, Ireland - Pharmaceutical Technology". www.pharmaceutical-technology.com. Retrieved 10 April 2021.
  16. Vardi M, Nini A (January 2007). "Phosphodiesterase inhibitors for erectile dysfunction in patients with diabetes mellitus". The Cochrane Database of Systematic Reviews. 2009 (1): CD002187. doi:10.1002/14651858.CD002187.pub3. PMC 6718223. PMID 17253475.
  17. Taylor MJ, Rudkin L, Bullemor-Day P, Lubin J, Chukwujekwu C, Hawton K (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.
  18. Wang RC, Jiang FM, Zheng QL, Li CT, Peng XY, He CY, et al. (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. Retrieved 5 November 2016.
  19. Roustit M, Blaise S, Allanore Y, Carpentier PH, Caglayan E, Cracowski JL (October 2013). "Phosphodiesterase-5 inhibitors for the treatment of secondary Raynaud's phenomenon: systematic review and meta-analysis of randomised trials". Annals of the Rheumatic Diseases. 72 (10): 1696–9. doi:10.1136/annrheumdis-2012-202836. PMID 23426043. S2CID 33666968. PDE-5 inhibitors appear to have significant but moderate efficacy in secondary [Raynaud's phenomenon].
  20. Linnemann B, Erbe M (2016). "Raynaud's phenomenon and digital ischaemia--pharmacologic approach and alternative treatment options". VASA. Zeitschrift für Gefasskrankheiten. 45 (3): 201–12. doi:10.1024/0301-1526/a000526. PMID 27129065. Phosphodiesterase inhibitors (e.g., sildenafil) can also improve [Raynaud's phenomenon] symptoms and ulcer healing
  21. Nieto Estrada VH, Molano Franco D, Medina RD, Gonzalez Garay AG, Martí-Carvajal AJ, Arevalo-Rodriguez I (June 2017). "Interventions for preventing high altitude illness: Part 1. Commonly-used classes of drugs". The Cochrane Database of Systematic Reviews. 6 (12): CD009761. doi:10.1002/14651858.CD009761.pub2. PMC 6481751. PMID 28653390.
  22. "Viagra and Vision". VisionWeb. 29 October 2001. Archived from the original on 10 June 2017. Retrieved 5 November 2016.
  23. "FDA Updates Labeling for Viagra, Cialis and Levitra for Rare Post-Marketing Reports of Eye Problems" (Press release). U.S. Food and Drug Administration. 8 July 2005. Archived from the original on 22 October 2016. Retrieved 5 November 2016.
  24. Laties AM (January 2009). "Vision disorders and phosphodiesterase type 5 inhibitors: a review of the evidence to date". Drug Safety. 32 (1): 1–18. doi:10.2165/00002018-200932010-00001. PMID 19132801. S2CID 207296076.
  25. "FDA Announces Revisions to Labels for Cialis, Levitra and Viagra". U.S. Food and Drug Administration (FDA). 18 October 2007. Archived from the original on 22 October 2016. Retrieved 5 November 2016.
  26. Schwartz BG, Kloner RA (July 2010). "Drug interactions with phosphodiesterase-5 inhibitors used for the treatment of erectile dysfunction or pulmonary hypertension". Circulation. 122 (1): 88–95. doi:10.1161/CIRCULATIONAHA.110.944603. PMID 20606131. S2CID 13207143.
  27. Kloner RA (December 2005). "Pharmacology and drug interaction effects of the phosphodiesterase 5 inhibitors: focus on alpha-blocker interactions". The American Journal of Cardiology. 96 (12B): 42M–46M. doi:10.1016/j.amjcard.2005.07.011. PMID 16387566.
  28. Cheitlin MD, Hutter AM, Brindis RG, Ganz P, Kaul S, Russell RO, Zusman RM (January 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.
  29. "Viagra (Sildenafil Citrate): Side Effects, Interactions, Warning, Dosage & Uses". RxList. Retrieved 11 July 2018.
  30. Peterson K (21 March 2001). "Young men add Viagra to their drug arsenal". USA Today.
  31. Smith KM, Romanelli F (2005). "Recreational use and misuse of phosphodiesterase 5 inhibitors". Journal of the American Pharmacists Association. 45 (1): 63–72, quiz 73–5. doi:10.1331/1544345052843165. PMID 15730119.
  32. "Sildenafil Will Not Affect Libido - Fact!". Retrieved 15 July 2016.
  33. 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". International Journal of Impotence Research. 15 (3): 225–8. doi:10.1038/sj.ijir.3901005. PMID 12904810.
  34. McCambridge J, Mitcheson L, Hunt N, Winstock A (March 2006). "The rise of Viagra among British illicit drug users: 5-year survey data". Drug and Alcohol Review. 25 (2): 111–3. doi:10.1080/09595230500537167. PMID 16627299. S2CID 40250895.
    - 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?". The Journal of Family Practice. 56 (11): E1-4. PMID 17976333.
  35. "The 2007 Ig Nobel Prize Winners". Improbable Research. 4 October 2007. Archived from the original on 26 January 2013. Retrieved 10 February 2009.
  36. Agostino PV, Plano SA, Golombek DA (June 2007). "Sildenafil accelerates reentrainment of circadian rhythms after advancing light schedules". Proceedings of the National Academy of Sciences of the United States of America. 104 (23): 9834–9. Bibcode:2007PNAS..104.9834A. doi:10.1073/pnas.0703388104. PMC 1887561. PMID 17519328.
  37. Thompson T, Red C, O'Keefffe M, Vinton N (10 June 2008). "Source: Roger Clemens, host of athletes pop Viagra to help onfield performance". Daily News. Archived from the original on 14 August 2020. Retrieved 10 February 2009.
  38. Busbee J (28 November 2012). "Bears' Brandon Marshall says some NFL players use Viagra … ON THE FIELD". Yahoo! Sports. Archived from the original on 5 March 2016. Retrieved 28 November 2012.
  39. Venhuis BJ, de Kaste D (October 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.
  40. Oh SS, Zou P, Low MY, Koh HL (November 2006). "Detection of sildenafil analogues in herbal products for erectile dysfunction". Journal of Toxicology and Environmental Health. Part A. 69 (21): 1951–8. doi:10.1080/15287390600751355. PMID 16982533. S2CID 40831895.
  41. Venhuis BJ, Blok-Tip L, de Kaste D (May 2008). "Designer drugs in herbal aphrodisiacs". Forensic Science International. 177 (2–3): e25-7. doi:10.1016/j.forsciint.2007.11.007. PMID 18178354.
  42. "FDA letter to Libidus distributor". US FDA. 11 July 2006. Archived from the original on 4 March 2016.
  43. "FDA Warns Consumers About Dangerous Ingredients in "Dietary Supplements" Promoted for Sexual Enhancement". US FDA. 12 July 2006. Archived from the original on 18 January 2017.
  44. "Hidden Risks of Erectile Dysfunction 'Treatments' Sold Online". US FDA. 21 February 2009. Retrieved 8 December 2020.
  45. R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 9th edition, Biomedical Publications, Seal Beach, CA, 2011, pp. 1552–53. "Sildenafil" (PDF). Biomedical Publications. Archived from the original (PDF) on 10 September 2011. Retrieved 1 July 2011.
  46. Sung BJ, Hwang KY, Jeon YH, Lee JI, Heo YS, Kim JH, et al. (September 2003). "Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules". Nature. 425 (6953): 98–102. Bibcode:2003Natur.425...98S. doi:10.1038/nature01914. PMID 12955149. S2CID 4404590.
  47. Webb DJ, Freestone S, Allen MJ, Muirhead GJ (March 1999). "Sildenafil citrate and blood-pressure-lowering drugs: results of drug interaction studies with an organic nitrate and a calcium antagonist". The American Journal of Cardiology. 83 (5A): 21C–28C. doi:10.1016/S0002-9149(99)00044-2. PMID 10078539.
  48. Francis SH, Busch JL, Corbin JD, Sibley D (September 2010). "cGMP-dependent protein kinases and cGMP phosphodiesterases in nitric oxide and cGMP action". Pharmacological Reviews. 62 (3): 525–63. doi:10.1124/pr.110.002907. PMC 2964902. PMID 20716671.
  49. Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA (May 1998). "Oral sildenafil in the treatment of erectile dysfunction. Sildenafil Study Group". The New England Journal of Medicine. 338 (20): 1397–1404. doi:10.1056/NEJM199805143382001. PMID 9580646.
  50. "Viagra Clinical Pharmacology". RxList.com. 2008. Retrieved 20 August 2008.
  51. Eardley I, Ellis P, Boolell M, Wulff M (2002). "Onset and duration of action of sildenafil for the treatment of erectile dysfunction". British Journal of Clinical Pharmacology. 53 (Suppl 1): 61S–65S. doi:10.1046/j.0306-5251.2001.00034.x. PMC 1874251. PMID 11879261.
  52. Deveci S, Peşkircioğlu L, Aygün C, Tekin MI, Dirim A, Ozkardeş H (November 2004). "Sublingual sildenafil in the treatment of erectile dysfunction: faster onset of action with less dose". International Journal of Urology. 11 (11): 989–92. doi:10.1111/j.1442-2042.2004.00933.x. PMID 15509203. S2CID 28302024.
  53. Dunn PJ (2005). "Synthesis of Commercial Phosphodiesterase(V) Inhibitors". Org Process Res Dev. 2005 (1): 88–97. doi:10.1021/op040019c. S2CID 93589067.
  54. "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!
  55. Boolell M, Allen MJ, Ballard SA, Gepi-Attee S, Muirhead GJ, Naylor AM, et al. (June 1996). "Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction". International Journal of Impotence Research. 8 (2): 47–52. PMID 8858389.
  56. 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): 1819–24. doi:10.1016/0960-894X(96)00323-X.
  57. Ashburn TT, Thor KB (August 2004). "Drug repositioning: identifying and developing new uses for existing drugs". Nature Reviews. Drug Discovery. 3 (8): 673–83. doi:10.1038/nrd1468. PMID 15286734. S2CID 205475073.
  58. Institute of Medicine (2014). Drug Repurposing and Repositioning: Workshop Summary. National Academies Press. ISBN 9780309302043.
  59. Kling J (1998). "From hypertension to angina to Viagra". Mod. Drug Discov. 1: 31–38. ISSN 1532-4486. OCLC 41105083.
  60. "Portions of the 2010 Financial Report". Retrieved 15 July 2016.
  61. Ciment J (November 1999). "Health situation in former communist bloc is dire, says Unicef". BMJ. 319 (7221): 1324. doi:10.1136/bmj.319.7221.1324g. PMC 1174637. PMID 10567131.
  62. Devine A (29 September 2008). "Chemists plan to sell Viagra on the internet". Daily Record. Retrieved 30 April 2012.
  63. Keith A (2000). "The economics of Viagra". Health Affairs. 19 (2): 147–57. doi:10.1377/hlthaff.19.2.147. PMID 10718028.
  64. McGuire S (1 January 2007). "Cialis gaining market share worldwide". Medical Marketing & Media. Haymarket Media. Archived from the original on 3 January 2009. Retrieved 10 February 2009.
  65. Mullin R (20 June 2005). "Viagra". Chemical & Engineering News. 83 (25). Retrieved 20 August 2008.
  66. Berenson A (4 December 2005). "Sales of Impotence Drugs Fall, Defying Expectations". The New York Times. Retrieved 20 August 2008.
  67. "Pfizer Courting More Controversy with Viagra 'Advergaming'". www.cbsnews.com. Retrieved 19 December 2019.
  68. "FDA gave Pfizer hard time over Viagra game". Engadget. Retrieved 19 December 2019.
  69. "Over-the-counter Viagra piloted". BBC News. 11 February 2007. Retrieved 10 February 2009.
  70. "Viagra can be sold over the counter". BBC News. 28 November 2017. Retrieved 5 April 2018.
  71. "Viagra now available over the counter without prescription in the UK". The Independent. 27 March 2018. Retrieved 5 April 2018.
  72. "Pfizer to sell Viagra online, in first for Big Pharma: AP". CBS News. Associated Press. Retrieved 6 May 2013.
  73. Helfand C (14 April 2015). "The coming generics threat to Pfizer's Viagra brand just got scarier". FiercePharma.
  74. "Viagra to go generic in 2017 according to Pfizer agreement". CBS News. 17 December 2013.
  75. Nocera J (6 December 2017). "Sex, Drugs and That Little Blue Pill". Bloomberg. Retrieved 10 December 2017.
  76. Mukherjee S (6 December 2017). "Why Pfizer Is About to Slash Viagra's Price in Half". Fortune. Retrieved 6 December 2017.
  77. Chandna H (7 August 2018). "Pfizer to lose patent of drug Viagra, Indian companies gear up with copycat versions: Pfizer's patent for the formulation of Viagra, used to treat impotence in men, ends in the US in 2020". Hindustan Times. New Delhi. Retrieved 10 August 2018.
  78. "Set to conquer US, Indian 'Viagras' may give Pfizer a hard Time". The Economic Times. Mumbai. 3 August 2018. Retrieved 10 August 2010.
  79. "Record amount of counterfeit Viagra seized". www.bbc.com. 12 May 2016. Archived from the original on 19 November 2016. Retrieved 26 December 2016.
  80. Amerman D (22 May 2012). "Counterfeit Viagra, Cialis, Levitra: The Ultimate Guide". AccessRx. Retrieved 10 January 2017.
  81. Moran B (20 August 2013). "Cracking Down on Counterfeit Drugs — NOVA Next | PBS". PBS NOVA Next. Retrieved 10 January 2017.
  82. Somra G (31 August 2015). "Online pharmacies suspected of counterfeit drug sales". CNN. Retrieved 10 January 2017.
  83. in-PharmaTechnologist.com. "Viagra patent expires in June, says Brazilian court". Retrieved 15 July 2016.
  84. "Revatio patent ruled invalid for lack of sound prediction and obviousness". Canadian Technology & IP Law. Stikeman Elliott. 18 June 2010. Archived from the original on 3 March 2016. Retrieved 14 November 2012.
  85. "Pfizer Canada Inc. v. Ratiopharm Inc., 2010 FC 612". CanLII.
  86. Teva Canada Ltd. v. Pfizer Canada Inc., 2012 SCC 60 at par. 80 (8 November 2012)
  87. Spears J (8 November 2012). "Supreme Court ruling could lead to cheaper versions of Viagra". Toronto Star. Retrieved 14 November 2012.
  88. Hanly K (8 November 2012). "Canadian Supreme court rules Viagra patent invalid". Digital Journal. Retrieved 14 November 2012.
  89. "Viagra patent tossed out by Supreme Court: Decision allows generic versions of drug to be produced". CBC News. 8 November 2012. Retrieved 14 November 2012.
  90. "Pfizer Canada drops Viagra price after generic versions get Supreme Court green light". Financial Post. 22 November 2012. Retrieved 9 February 2013.
  91. "SCC Case Information, Docket No. 33951". January 2001. Retrieved 14 November 2012.
  92. Makin K (15 November 2012). "In rare move, Pfizer asks Supreme Court to reconsider ruling that killed Viagra patent". The Globe and Mail. Retrieved 15 November 2012.
  93. Henderson GL, D'Iorio H (22 April 2013). "The Supreme Court of Canada holds Pfizer's Viagra patent invalid". Lexology. Retrieved 27 December 2013.
  94. Allam A (4 October 2002). "Seeking Investment, Egypt Tries Patent Laws". New York Times. Retrieved 1 April 2013.
  95. "Actavis Launches Generic Viagra in Europe as Patents Expire". Retrieved 25 October 2013.
  96. Edwards J (21 October 2009). "What Will Happen When Viagra Goes Generic?". AccessRx.com. Retrieved 25 March 2011.
  97. "Is Viagra about to lose its pulling power in the UK?". The Guardian. 3 June 2013. Retrieved 13 June 2013.
  98. Murray R (23 January 2002). "Viagra ruling upsets Pfizer". London: Telegraph Media Group Limited. Archived from the original on 22 August 2009. Retrieved 10 February 2009.
  99. "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.
  100. "Viagra from the pharmacist: insight from reclassification in New Zealand". Pharmaceutical Journal. 31 January 2018. Retrieved 2 April 2018.
  101. Herald, Korea (14 March 2012). "Generic Viagra developers queue up, but may have to wait". The Korea Herald. Retrieved 28 December 2021.
  102. "Approved Viagra copies flood drugstores in Korea". Reuters. 1 June 2012. Retrieved 28 December 2021.
  103. Herald, Korea (10 April 2013). "Viagra loses top spot in Korean market". The Korea Herald. Retrieved 28 December 2021.
  104. "Hanmi leads erectile dysfunction drug sales". KBR (in Korean). 12 December 2017. Retrieved 28 December 2021.
  105. "Viagra prescriptions almost triple in a decade". Pharmaceutical Journal. 21 August 2017. Retrieved 8 October 2017.
  106. Skinner G (4 March 2016). "Yes, There Is a Way to Get Generic Viagra". Consumer Reports. Retrieved 4 May 2016.
  107. Langreth R (29 June 2016). "Decoding Big Pharma's Secret Drug Pricing Practices". Bloomberg. Retrieved 15 July 2016.
  108. U.S. Patent 5,250,534
  109. "Pfizer's Revatio Goes Generic". Zacks Equity Research. 15 November 2012. Retrieved 5 October 2013.
  110. U.S. Patent 6,469,012
  111. Milford, Phil (15 August 2011). "Pfizer Wins Viagra Patent Infringement Case Against Teva Pharmaceuticals". Bloomberg. Retrieved 1 April 2012.
  • "Sildenafil". Drug Information Portal. U.S. National Library of Medicine.
  • "Sildenafil citrate". Drug Information Portal. U.S. National Library of Medicine.
  • Viagra at The Periodic Table of Videos (University of Nottingham)

[1]

  1. Kayık G, Tüzün NŞ, Durdagi S (October 2017). "In silico design of novel hERG-neutral sildenafil-like PDE5 inhibitors". Journal of Biomolecular Structure & Dynamics. 35 (13): 2830–2852. doi:10.1080/07391102.2016.1231634. PMID 27581752. S2CID 21682809.
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