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* [http://www.viagra.co.uk/ Official Viagra UK Website]
* [http://www.viagra.co.uk/ Official Viagra UK Website]
* [http://www.revatio.com/ Official Revatio Website]
* [http://www.revatio.com/ Official Revatio Website]
* [http://www.kwikmed.com/ Official KwikMed Website]
* [http://www.pfizer.com/files/products/uspi_viagra.pdf prescribing information for Viagra] and [http://www.pfizer.com/files/products/uspi_revatio.pdf prescribing information for Revatio] from [[Pfizer]]
* [http://www.pfizer.com/files/products/uspi_viagra.pdf prescribing information for Viagra] and [http://www.pfizer.com/files/products/uspi_revatio.pdf prescribing information for Revatio] from [[Pfizer]]
* [http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm162833.htm FDA Information]
* [http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm162833.htm FDA Information]

Revision as of 19:11, 30 July 2010

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

Template:Pp-pending

Sildenafil
Clinical data
License data
Routes of
administration		Oral
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability40%
MetabolismHepatic (mostly CYP3A4, also CYP2C9)
Elimination half-life3 to 4 hours
ExcretionFecal (80%) and renal (around 13%)
Identifiers
  • 1-[4-ethoxy-3-(6,7-dihydro-1-methyl-
    7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)
    phenylsulfonyl]-4-methylpiperazine citrate
CAS Number
PubChem CID
DrugBank
ChemSpider
CompTox Dashboard (EPA)
ECHA InfoCard100.122.676 Edit this at Wikidata
Chemical and physical data
FormulaC22H30N6O4S
Molar massbase: 474.6 g/mol g·mol−1
3D model (JSmol)
  • O=S(=O)(N1CCN(C)CC1)c4cc(C=2NC(=O)c3n(C)nc(CCC)c3N=2)c(OCC)cc4
  (verify)

Sildenafil citrate, sold as Viagra, Revatio and under various other trade names, is a drug used to treat erectile dysfunction and pulmonary arterial hypertension (PAH). It was developed and is being marketed by the pharmaceutical company Pfizer. It acts by inhibiting cGMP specific phosphodiesterase type 5, an enzyme that regulates blood flow in the penis. Since becoming available in 1998, sildenafil has been the prime treatment for erectile dysfunction; its primary competitors on the market are tadalafil (Cialis) and vardenafil (Levitra).

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.[1] Phase I clinical trials under the direction of Ian Osterloh suggested that the drug had little effect on angina, but that it could induce marked penile erections.[2][3] 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 US Food and Drug Administration 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.[4] It soon became a great success: annual sales of Viagra in the period 1999–2001 exceeded $1 billion.[citation needed]

The British press portrayed Peter Dunn and Albert Wood as the inventors of the drug, a claim that Pfizer disputes.[5] Their names are on the manufacturing patent application drug, but Pfizer claims this is only for convenience.[citation needed]

Even though sildenafil is available only by prescription from a doctor, it was advertised directly to consumers on U.S. TV (famously being endorsed by former United States Senator Bob Dole and soccer star Pelé). Numerous sites on the Internet offer Viagra for sale after an "online consultation", often a simple web questionnaire."Missouri fines internet pharmacy". British Medical Journal. Retrieved 2010-07-07. 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", as well as various other nicknames.[6]

In 2000, Viagra sales accounted for 92 percent of the global market for prescribed erectile dysfunction pills.[7] By 2007, Viagra's global share had plunged to about 50 percent[8] 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.[9][10]

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 aged between 30 and 65 would be eligible to buy four tablets after a consultation with a pharmacist.[11]

Pfizer's worldwide patents on sildenafil citrate will expire in 2010–2013.[12] The 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.[13][14]

Mechanism of action

The mechanism of action of Sildenafil citrate involves the protection of 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 the receptors of an enzyme called guanylate cyclase 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.[15] Robert F. Furchgott won the Nobel Prize in Physiology or Medicine in 1998 for his discovery and analysis of endothelium-derived relaxing factor or "EDRF", later identified with NO itself or a closely-related compound.

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.[15] 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 metabolised by liver enzymes and excreted by both the liver and kidneys. 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.[16]

Uses

Sexual dysfunction

The primary indication of sildenafil is treatment of erectile dysfunction (inability to sustain a satisfactory erection to complete intercourse). Its use is now standard treatment for erectile dysfunction in all settings, including diabetes.[17]

People on antidepressants may experience sexual dysfunction, either as a result of their illness or as a result of their treatment. A 2003 study showed that sildenafil improved sexual function in men in this situation.[18] Following up to earlier reports from 1999,[19] the same researchers found that sildenafil was able to improve sexual function in female patients on antidepressants as well.[20]

Pulmonary hypertension

As well as erectile dysfunction, sildenafil citrate is also effective in the rare disease pulmonary arterial hypertension (PAH). It relaxes the arterial wall, leading to decreased pulmonary arterial resistance and pressure. This, in turn, reduces the workload of the right ventricle of the heart and improves symptoms of right-sided heart failure. Because PDE-5 is primarily distributed within the arterial wall smooth muscle of the lungs and penis, sildenafil acts selectively in both these areas without inducing vasodilation in other areas of the body. Pfizer submitted an additional registration for sildenafil to the FDA, and sildenafil was approved for this indication in June 2005. The preparation is named Revatio, to avoid confusion with Viagra, and the 20 milligram tablets are white and round. Sildenafil joins bosentan and prostacyclin-based therapies for this condition.[21]

Altitude sickness

Sildenafil has been shown to be useful for the prevention and treatment of high-altitude pulmonary edema associated with altitude sickness such as that suffered by mountain climbers.[22][23] While this effect has only recently been discovered, sildenafil is already becoming an accepted treatment for this condition, in particular in situations where the standard treatment of rapid descent has been delayed for some reason.[24]

Use in sports

Professional sports players have been documented using drugs such as Viagra, with the thinking that the opening of their blood vessels will enrich their muscles. In turn, they[who?] believe that it will enhance their performance.[25]

Non-medical use

Recreational use

Sildenafil's popularity with young adults has increased over the years.[26] 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.[27] The reasons behind such use include the belief that the drug increases libido, improves sexual performance,[27] or permanently increases penis size[citation needed]. Studies on the effects of viagra when used recreationally are limited, but suggest that it has little effect when used by those not suffering from erectile dysfunction, and having sex within a stable relationship. In one study, a 25 mg dose was shown to cause no significant change in erectile quality, but did reduce the post-ejaculatory refractory time.[28] This study also noted a significant placebo effect in the control group.[28]

Unprescribed recreational use of Sildenafil and other PDE-5 Inhibitors is noted as particularly high among users of illegal drugs.[29][30] Sildenafil is sometimes used to counteract the effects of other substances, often illicit.[27] 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."[27] Mixing with amyl nitrite is particularly dangerous, and is potentially fatal.[27]

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 Viagra aids jet lag recovery in hamsters.[31] Their research was published in the Proceedings of the National Academy of Sciences.[32]

Analogues

Acetildenafil is a structural analogue of sildenafil, one of the PDE5 inhibitors found in a number of "herbal" aphrodisiac products sold over-the-counter. This class of analogues have not undergone any of the rigorous testing that drugs like sildenafil have passed, and thus have an unknown side effect profile.[33] 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 analogues of illegal drugs of abuse, rather than analogues of prescription medicines. However, at least one court case has resulted in a product being taken off the market.[34]

Dosage

Viagra

Viagra pills are blue and diamond-shaped with the words "Pfizer" engraved on one side, and "VGR xx" (where xx stands for "25", "50" or "100", the dose of that pill in milligrams) engraved on the other. The dose of sildenafil for erectile dysfunction is 25 mg to 100 mg taken not more than once per day between 30 minutes and 4 hours prior to sexual intercourse.

The dosage for pulmonary arterial hypertension (Revatio) is one 20 mg tablet three times a day. Revatio pills are white, round, film-coated tablets imprinted with "RVT 20" embossed on one side.[35]

Contraindications

Contraindications include:[citation needed]

Side effects

In clinical trials, the most common adverse effects of sildenafil use included headache, flushing, dyspepsia, nasal congestion and impaired vision, including photophobia and blurred vision.[37] Some sildenafil users have complained of seeing everything tinted blue (cyanopsia).[38] Some complained of blurriness and loss of peripheral vision. In July 2005, the U.S. Food and Drug Administration found that sildenafil could lead to vision impairment in rare cases[39] and a number of studies have linked sildenafil use with nonarteritic anterior ischemic optic neuropathy.[40][41][42][43][44][45]

Rare but serious adverse effects found through postmarketing surveillance include priapism, severe hypotension, myocardial infarction (heart attack), ventricular arrhythmias, stroke, increased intraocular pressure, and sudden hearing loss.[37] As a result of these postmarketing reports, 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.[46]

Interactions

Care should be exercised by patients that 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. It is recommended that patients using protease inhibitors limit their use of sildenafil to no more than one 25 mg dose every 48 hours.[47]

Concomitant use of sildenafil and an alpha blocker may lead to low blood pressure, but this effect does not occur if they are taken at least four hours apart.[48]

Detection in biological fluids

Sildenafil and/or N-desmethylsildenafil, its major active metabolite, may be quantitated in plasma, serum or whole blood in order 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 overdosage.[49]

Chemical synthesis

The preparation steps for synthesis of sildenafil are as follows:[50]

  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.

See also

Notes

  1. ^ Aubetawe Bro Morgannwg University NHS Trust (2008-07-04). "Research at ABM". Retrieved 2008-08-06.[dead link‍]
  2. ^ Boolell (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. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  3. ^ Terrett NK; et al. (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: 1819–1824. doi:10.1016/0960-894X(96)00323-X. {{cite journal}}: Explicit use of et al. in: |author= (help)
  4. ^ Kling J (1998). "From hypertension to angina to Viagra" ([dead link‍] – Scholar search). Mod Drug Discov. 1: 31–38. {{cite journal}}: External link in |format= (help)[dead link‍]
  5. ^ Bellis M. "Viagra, the patenting of an aphrodisiac". About.com. Retrieved 2009-02-10.
  6. ^ "Urban Dictionary: Vitamin V". Urban Dictionary. January 16, 2009. Retrieved 2009-02-10.
  7. ^ Keith A (2000). "The economics of Viagra" (PDF). Health Aff (Millwood). 19 (2): 147–57. doi:10.1377/hlthaff.19.2.147. PMID 10718028. Retrieved 2009-02-10.
  8. ^ McGuire, Stephen (1 January 2007). "Cialis gaining market share worldwide". Medical Marketing & Media. Haymarket Media. Retrieved 2009-02-10.
  9. ^ Mullin, Rick (June 20, 2005). "Viagra". Chemical & Engineering News. 83 (25). Retrieved 2008-08-20.
  10. ^ Berenson, Alex (December 4, 2005). "Sales of Impotence Drugs Fall, Defying Expectations". The New York Times. Retrieved 2008-08-20.
  11. ^ "Over-the-counter Viagra piloted". BBC News. BBC News. 11 February 2007. Retrieved 2009-02-10.
  12. ^ Viagra patent expires in June, says Brazilian court
  13. ^ Murray-, Rosie (23 January 2002). "Viagra ruling upsets Pfizer". London: Telegraph Media Group Limited. Retrieved 2009-02-10.
  14. ^ "Pfizer Loses UK Battle on Viagra Patent". UroToday. Thomson Reuters. 17 June 2002. Retrieved 2009-02-10.
  15. ^ a b 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  16. ^ "Viagra Clinical Pharmacology". RxList.com. 2008. Retrieved 2008-08-20.
  17. ^ Vardi M, Nini A (2007). "Phosphodiesterase inhibitors for erectile dysfunction in patients with diabetes mellitus". Cochrane Database Syst Rev (1): CD002187. doi:10.1002/14651858.CD002187.pub3. PMID 17253475.
  18. ^ Nurnberg HG, Hensley PL, Gelenberg AJ, Fava M, Lauriello J, Paine S (2003). "Treatment of antidepressant-associated sexual dysfunction with sildenafil: a randomized controlled trial". JAMA. 289 (1): 56–64. doi:10.1001/jama.289.1.56. PMID 12503977. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  19. ^ Nurnberg HG, Hensley PL, Lauriello J, Parker LM, Keith SJ (1999). "Sildenafil for women patients with antidepressant-induced sexual dysfunction". Psychiatr Serv. 50 (8): 1076–8. PMID 10445658. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  20. ^ Nurnberg HG, Hensley PL, Heiman JR, Croft HA, Debattista C, Paine S (2008). "Sildenafil Treatment of Women With Antidepressant-Associated Sexual Dysfunction". JAMA. 300 (4): 395–404. doi:10.1001/jama.300.4.395. PMID 18647982.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  21. ^ Pfizer, Inc. (June 6, 2005). "FDA Approves Pfizer's Revatio as Treatment for Pulmonary Arterial Hypertension". 2005 News Releases. Pfizer. Retrieved December 27, 2005.
  22. ^ Richalet JP, Gratadour P, Robach P; et al. (2005). "Sildenafil inhibits altitude-induced hypoxemia and pulmonary hypertension". Am. J. Respir. Crit. Care Med. 171 (3): 275–81. doi:10.1164/rccm.200406-804OC. PMID 15516532. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  23. ^ Perimenis P (2005). "Sildenafil for the treatment of altitude-induced hypoxaemia". Expert Opin Pharmacother. 6 (5): 835–7. doi:10.1517/14656566.6.5.835. PMID 15934909.
  24. ^ Fagenholz PJ, Gutman JA, Murray AF, Harris NS (2007). "Treatment of high altitude pulmonary edema at 4240 m in Nepal". High Alt. Med. Biol. 8 (2): 139–46. doi:10.1089/ham.2007.1055. PMID 17584008.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  25. ^ "Source: Roger Clemens, host of athletes pop Viagra to help onfield performance". Daily News. Daily News. 10 June 2008. Retrieved 2009-02-10. {{cite news}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  26. ^ Peterson K (2001-03-21). "Young men add Viagra to their drug arsenal". USAToday.
  27. ^ a b c d e Smith, K (2005). "Recreational use and misuse of phosphodiesterase 5 inhibitors". Journal of the American Pharmacists Association. 45 (1): 63–75. doi:10.1331/1544345052843165. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  28. ^ a b Mondaini, N (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): 225–228. doi:10.1038/sj.ijir.3901005. PMID 12904810. Retrieved 2009-06-12. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  29. ^ McCambridge, J (2006). "The rise of Viagra among British illicit drug users: 5-year survey data". Drug and Alcohol Review. 25 (2): 111–113. doi:10.1080/09595230500537167. PMID 16627299. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  30. ^ Eloi-Stiven, M (2007). "Does marijuana use play a role in the recreational use of sildenafil?". Journal of Family Practice. 56 (11): 932. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  31. ^ "The 2007 Ig Nobel Prize Winners". Improbable Research. 4 October 2007. Retrieved 2009-02-10.
  32. ^ Agostino, P. V. (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. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  33. ^ Oh SS, Zou P, Low MY, Koh HL. Detection of sildenafil analogues in herbal products for erectile dysfunction. Journal of Toxicology and Environmental Health Part A. 2006 November;69(21):1951-8. PMID 16982533
  34. ^ Venhuis BJ, Blok-Tip L, de Kaste D. Designer drugs in herbal aphrodisiacs. Forensic Science International. 20 May 2008;177(2-3):e25-7. PMID 18178354
  35. ^ "Pill Identifier". Drugs.com. Retrieved 2009-02-10. This site is intended for viewing by the USA audience only. If you are in another country, local laws may not permit access to the medical information contained in this site.
  36. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  37. ^ a b "Viagra Prescribing Information" (PDF). Pfizer. 2007. Retrieved 2008-08-21. {{cite web}}: Unknown parameter |month= ignored (help)
  38. ^ "Viagra and vision". VisionWeb. 29 October 2001. Retrieved 2009-02-10.
  39. ^ "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. Retrieved 2009-02-10.
  40. ^ Pomeranz (2005). "Nonarteritic ischemic optic neuropathy developing soon after use of sildenafil (viagra): a report of seven new cases". J Neuroophthalmol. 25 (1): 9–13. PMID 15756125. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  41. ^ Egan (2000). "Sildenafil (Viagra) associated anterior ischemic optic neuropathy". Arch Ophthalmol. 118 (2): 291–2. PMID 10676804. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  42. ^ Pomeranz, H (2002). "Sildenafil-associated nonarteritic anterior ischemic optic neuropathy". Ophthalmology. 109 (3): 584–7. doi:10.1016/S0161-6420(01)00976-9. PMID 11874765. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  43. ^ Cunningham (2001). "Anterior ischemic optic neuropathy associated with viagra". J Neuroophthalmol. 21 (1): 22–5. PMID 11315976. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  44. ^ Boshier (2002). "A case of nonarteritic ischemic optic neuropathy (NAION) in a male patient taking sildenafil". Int J Clin Pharmacol Ther. 40 (9): 422–3. PMID 12358159. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  45. ^ Akash, Raj (2005). "Case report: association of combined nonarteritic anterior ischemic optic neuropathy (NAION) and obstruction of cilioretinal artery with overdose of Viagra". J Ocul Pharmacol Ther. 24 (4): 315–7. doi:10.1089/jop.2005.21.315. PMID 16117695. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  46. ^ "FDA Announces Revisions to Labels for Cialis, Levitra and Viagra". United States Food and Drug Administration. 18 October 2007. Retrieved 2009-02-10.
  47. ^ "Viagra (sildenafil citrate) tablets" (PDF). page 29: Pzifer. October 2007. Retrieved 2009-10-25.{{cite web}}: CS1 maint: location (link)
  48. ^ 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.
  49. ^ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 1427-1429.
  50. ^ Dunn PJ (2005). "Synthesis of Commercial Phosphodiesterase(V) Inhibitors". Org Process Res Dev. 2005 (1): 88–97. doi:10.1021/op040019c.
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