Sildenafil by Anthony Crasto


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Sildenafil by Anthony Crasto

  2. 2. DEDICATED TO MY SON LIONEL CRASTO,He was only in first standard in school (Dec2007) when I was Paralysed head to toe.His smiling face sees me through day in and day out.Vast readership from academia and industry motivates me, and keeps megoing.Helping millions with free advertisement free websites and has millionhits on googleThanks for helping me to keep lionel smiling
  3. 3. SHORE Your own will power and determination will reachyou to the shore even if you are drowned in themiddle of a storm
  4. 4.  Erectile dysfunction (or ED), also called maleimpotence, describes a mans inability to achieveand maintain an erection sufficient for mutuallysatisfactory sexual intercourse with his partner. Byitself, ED is not a disease but more of a signal thatsomething else may be a problem.
  5. 5.  Viagra works best if taken 30-60 minutes beforesexual activity. Only 1 tablet should be taken perday. It should be taken on an empty stomach.Increasing the dosage beyond the recommendedamounts will not improve the response and will onlyresult in greater side effects.
  6. 6.  Sildenafil is a vasoactive agent used to treat erectiledysfunction and reduce symptoms in patients withpulmonary arterial hypertension (PAH). Sildenafil elevates levels of the second messenger,cGMP, by inhibiting its breakdown viaphosphodiesterase type 5 (PDE5). PDE5 is found inparticularly high concentrations in the corpuscavernosum, erectile tissue of the penis. It is also found in the retina and vascular endothelium. Increased cGMP results in vasodilation which facilitatesgeneration and maintenance of an erection. Thevasodilatory effects of sildenafil also help reducesymptoms of PAH.
  7. 7.  In simple terms, Sildenafil Citrate works by increasing the amount of blood that flows to thepenis. This causes a healthy erection, something the users of the drug want. Most men, up to a certain age at least, take their ability to achieve a healthy erection forgranted. They do not consider that impotence may be a problem for them, and when it doeshappen, it can be a distressing experience, and can even cause families to fall apart. Theproblem can cause depression in men. The idea that sexual potency is limited and may even begone forever from a man’s life is one that many men do not even want to contemplate. Theemotional impact of erectile dysfunction can be devastating, with many sufferers reportingfeelings linked to depression. Some sufferers fear intimacy in their relationships. Others sufferfrom high anxiety. The problem is quite common. In fact, over 50% of men between the age of 40 and 70 reportedrecently that they have had at least one incidence of erectile dysfunction. This problem getseven worse as men get older, with one in three 70 year olds reporting the problem. Men who smoke are more likely to suffer from erectile dysfunction, as are men who areoverweight. Those who suffer from any kind of hypertension or heart disease are even morelikely to suffer from impotence, since such conditions restrict the flow of blood to organs. When a man is sexually excited, Sildenafil works to create an erection by increasing blood flow.As the sexual experience finishes, the erection dies away. The erection process takes place when nitric oxide is released to the penile corpuscavernosum. This process then activates an enzyme known as guanylate cyclase. All of thisleads to some relaxation of the smooth muscles in this area of the penis, which results inerection. Sildenafil Citrate does not work without sexual stimulation
  8. 8. GENERAL Sildenafil (compound UK-92,480) was synthesized by a group ofpharmaceutical chemists working at Pfizers Sandwich, Kent, researchfacility in England. It was initially studied for use in hypertension (highblood pressure) and angina pectoris (a symptom of ischaemic heartdisease). The first clinical trials were conducted in Morriston Hospital inSwansea. Phase I clinical trials under the direction of Ian Osterlohsuggested that the drug had little effect on angina, but that it couldinduce marked penile erections.[1][47] Pfizer therefore decided to market itfor erectile dysfunction, rather than for angina. The drug was patented in1996, approved for use in erectile dysfunction by the United States Foodand Drug Administration on March 27, 1998, becoming the first oraltreatment approved to treat erectile dysfunction in the United States, andoffered for sale in the United States later that year.[48] It soon became agreat success: annual sales of Viagra peaked in 2008 at US$1,934million. The British press portrayed Peter Dunn and Albert Wood as the inventorsof the drug, a claim that Pfizer disputes. Their names are on themanufacturing patent application, but the original patent on the synthesisof the drug was filed by Nicholas Terrett and Peter Ellis.
  9. 9.  Sildenafil citrate, sold as Viagra, Revatio andunder various other trade names, is adrug used totreat erectile dysfunction and pulmonary arterialhypertension (PAH). It was originally developed by British scientists andthen brought to market by the US-basedpharmaceutical company Pfizer.
  10. 10.  It acts by inhibiting cGMP-specificphosphodiesterase type 5, an enzyme thatpromotes degradation of cGMP, which regulatesblood flow in thepenis. Since becoming available in 1998, sildenafil hasbeen the prime treatment for erectile dysfunction;its primary competitors on the marketare tadalafil (Cialis) and vardenafil (Levitra).
  11. 11. SILDENAFILSildenafil citrate, commonly called as “Viagra” was first discovered by Pfizercompany in U.K.It was initially used to study its effects for the treatment of angina pectorisand hypertension.It was found to be effective for penile errections than on cardiovasculardiseases.First clinical trials were conducted in Morriston Hospital in Swansea underthe guidance of Prof. Lan Osterloh.The drug was patented in 1996 and approved by U.S FDA on March 27th1998.
  12. 12. SEXUAL DYSFUNCTION The primary indication of sildenafil is treatmentof erectile dysfunction (inability to sustain asatisfactory erection to complete intercourse). Itsuse is now standard treatment for erectiledysfunction in all settings, including diabetes. People on antidepressants may experience sexualdysfunction, either as a result of their illness or as aresult of their treatment. A 2003 study showed thatsildenafil improved sexual function in men in thissituation. Following up reports from 1999,[4] thesame researchers found that sildenafil improvedsexual function in female patients onantidepressants as well.
  13. 13. DOSAGE Viagra Viagra pills are blue and diamond-shaped with theword "Pfizer" engraved on one side, and "VGR xx"(where xx stands for "25", "50" or "100", the dose ofthat pill in milligrams) engraved on the other. It istaken not more than once per day between30 minutes and 4 hours prior to sexual intercourse. The dosage for pulmonary arterial hypertension(Revatio) is three times a day. Revatio pills arewhite, round, film-coated tablets imprinted with"RVT 20" embossed on one side
  14. 14. STRUCTURE1-[4-ethoxy-3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenylsulfonyl]-4-methylpiperazine citrate
  15. 15. TARGET Target is cyclic guanosine monophosphatephosphodiesterase type 5 receptor. Fluforma is a company which found the genomeexplorations and target identification through affymetrixmicroarrays. High throughput functional assays of Si Rna’s inhibit theexpression of target, chromatographic techniques,spectrophotometric methods, adsorptive strippingvoltametry. Gingel showed that a 50mg dose given daily for 28days consecutively improved errections in almost 90%of patients. Structural validation techniques are NMR technique,Infrared spectrum, HPLC, Mass spectroscopy andLiquid chromatography.
  17. 17.  Erections are controlled by the parasympathetic nervous system. Uponsexual stimulation, a decrease in vascular resistance is mediated byacetylcholine and nitric oxide resulting in vasodilation. The hemodynamicmechanism of an erection is comprised of five stages. During the latentstage, arterial and carvernous smooth muscle relaxation occurs.Vasodilation results in high levels of blood flow causing the penis to growto its full size. This stage is called tumescence. During the full-erectionstage, blood flow fills penis sinusoids and outflow is restricted. This isfollowed by the rigid-erection phase during which the cavernous musclescontract causing the penis to become rigid. Little blood flow occursduring this stage. During the final stage, detumescence, the cavernousmuscles relax and blood flows out of the penis. Erectile dysfunction mayoccur when there is insufficient blood supply to the penis or when thepenis is unable to prevent outflow of blood from the penis. Sildenafil is aspecific inhibitor of PDE5, an enzyme responsible for the breakdown ofcGMP to 5’-GMP. Increased levels of cGMP stimulate vasodilation andfacilitate the generation and maintenance of erections. Thesevasodilatory effects also help decrease symptoms of PAH. Sildenfail alsoexhibits some activity against PDE6 (10 times less potentcy compared toPDE5), a PDE isoform found predmoninantly in the retina. This activity isresponsible for the blue tinged vision experienced by users of sildenafil.
  18. 18. Crystal structure of human PDE5 with boundsildenafil
  19. 19. PHARMAKOKINETICS Sildenafil is rapidly absorbed with absolutebioavailability of 40%, it is cleared by hepaticmicrosomal isoenzymes CYP3A4 and CYP2C9 andexcreted. Sildenafil is available in 25mg, 50mg, 100mg. Efficacy of erectile function can be scored by fivedomains, namely erectile function, orgasmicfunction, sexual desire, intercourse satisfaction,overall satisfaction by international
  20. 20. SYNTHESIS
  21. 21. PATENT ISSUES AND EXPIRATIONS A UK patent held by Pfizer on the use of PDE5 inhibitors (seebelow) as treatment of impotence was invalidated in 2000because of obviousness; this decision was upheld on appealin 2002. But there are two other patents covering the methodsfor manufacturing Viagra, and Pfizer has maintained itsmonopoly on the drug in the UK. Egypt approved Viagra for sale in 2002, but soon afterwardsallowed local companies to produce generic versions of thedrug, citing the interests of poor people who would not be ableto afford Pfizers price. Pfizers patent on sildenafil citrate expired in Brazil in 2010. Itwas originally believed that Pfizers patents would expire inthe United States in March 2012, but an August 2011 federaldistrict court case raises the prospect that at least one ofPfizers patents will be valid until 2019.
  22. 22.  In Canada, Pfizers patent 2,324,324 for Revatio (sildenafil used to treatpulmonary hypertension) was found invalid by the Federal Court in June2010, on an application by Ratiopharm Inc. On November 8, 2012 the Supreme Court of Canada ruled that Pfizerspatent 2,163,446 on Viagra was invalid from the beginning because thecompany did not provide full disclosure in its application. The decision,Teva Canada Ltd. v. Pfizer Canada Inc., pointed to section 27(3)(b) ofThe Patent Act which requires that disclosure must include sufficientinformation "to enable any person skilled in the art or science to which itpertains" to produce it. It added further: "As a matter of policy and soundstatutory interpretation, patentees cannot be allowed to “game” thesystem in this way. This, in my view, is the key issue in this appeal." Teva Canada launched Novo-Sildenafil, a generic version of Viagra, onthe day the Supreme Court of Canada released its decision. To remaincompetitive, Pfizer then reduced the price of Viagra in Canada. However,on November 9, 2012, Pfizer filed a motion for a re-hearing of the appealin the Supreme Court of Canada on the grounds that the courtaccidentally exceeded its jurisdiction by voiding the patent.
  23. 23. INDIA Manufacture and sale of sildenafil citrate drugsknown as "generic viagra" is common in India,where Pfizers patent claim does not apply. Tradenames include Kamagra (Ajanta Pharma), Silagra(Cipla), Edegra (Sun Pharmaceutical), Penegra(Zydus Cadila), and Zenegra (Alkem Laboratories).
  24. 24. LINK is the link to my blog which tracks drugs worldwide US, CANADA, JAPAN, EU CHINA ETC
  25. 25. SITE NEEDS=
  26. 26. Join my process development group on google
  28. 28. THANKSDR ANTHONY MELVIN CRASTO Ph.Damcrasto@gmail.comMOBILE-+91 9323115463GLENMARK SCIENTIST , NAVIMUMBAI,INDIAweb link! Your presentation titled "Anthony Crasto Glenmarkscientist, helping millions with websites" has justcrossed MILLION views.
  29. 29. THANKS