Pfizer’s Blue Pill.pptx

7/21/2019 Pfizer’s Blue Pill.pptx

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The Big Implications of

Pzer’s Little Blue Pill

Sildenal citrate: The

Revolutionary Bloc!uster"rug of the #$$%s



&rticle Titles

Sildenafl or Treatment o Erectile Dysunction inMen With Diabetes: A Randomized Controlled Trial

Rendell MS, Raer !, Wic"er #A, Smith MD, or theSildenafl Diabetes Study$rou%& JAMA.()))*+(-./:0+(10+2&doi:(3&(33(4ama&+(&.&0+(&

• 5ral Sildenafl in the Treatment o ErectileDysunction

Ir'in (oldstein) *+"+) Tom ,+ Lue) *+"+) -arin Padma./athan)

*+"+) Raymond 0+ Rosen) Ph+"+) 1illiam "+ Steers) *+"+) andPierre &+ 1icer) *+"+ for the Sildenal Study (roup

/ 3ngl 4 *ed #$$56 775:#7$8.#9%9*ay #9) #$$5"I:

#%+#%;<=/34*#$$5%;#9775>%%#

http://www.nejm.org/toc/nejm/338/20/

http://www.nejm.org/toc/nejm/338/20/



*ay 0ause Informationverload



1hat 'e’re going to do

• Part #6 The #% . minute Ph":"iscussion on the history of Pzer)the discovery of sildenal) drug

research and clinical trials) synthesisand !iochemistry of sildenal

• Part >6 The #% ? minute *":

&natomy and Physiology) Pathology)Biochemistry and Pharmacology ofsildenal6 Therapeutics



@Aitamin A



The Biggest /e's of #$$5



The Little Blue Pill

• P"3 inhi!itor used for the treatmentof erectile dysfunction C3"D andpulmonary arterial hypertension

CP&-D

• riginally a antiangial medication

• 0omes in >; mg) ;% mg and #%%mgvariants

• Taen # hour !efore intercourse6once daily



Aiagra Sales

• $>E of all 3" medications

Based on the 9th

Fuarterly ,iscalReport of Pzer

• G7%% million in sales

•

9%% %%% units sold



Pzer

#6ARMACE7T8CA9SRA;ED +D $95<A99= A>TER

!56S5 ? !56S5

6EAD@7ARTERS8 EW =5R;

C8T= CE5: 8A C&READ

.(&2<89985

>57DERs:C6AR9ES #>8BER ?

C6AR9ES ER6ART>57DED: (0),



The discovery of Sildenal

Daid

<ron

icholas

Terrett

Andre

<ell



The Story of Aiagra: &n vervie' of"rug Research and 0linical Trials



-o' much is needed to produce a

ne' drugH

• This is uite a hard uestion toans'er) !ut a study !y 4oe "i*asiJestimated that it cost on average

G5%%)%%%)%%% to develop a ne' drug• &lthough not conrmed) estimates

for development of a ne' drug are

no' in the order of G%+; . > !illionJJJ"i*asi 4&) -ansen R1) (ra!o'si -(+ 4 -ealth 3con+ >%%7>>C>D:#;#.5;JJ&dams 0) Brantner A C>%%<D+ Health Af (Millwood) +. C>D: 9>%?5



The "rug Pipeline



Really) all in all) ho' much does it

costH

• Broen do'n) the cost !roadly 'orsout at

– &round G77; million in the preclinicalphases

– &round G9<8 million in the clinical trialphases

–&round G#%% million in Post approval



The 3ntire Process



*ore on 0linical Trials

• Clinical Trials hae a lon historyF een i not ac"noleded asClinical trials

• >ormal record o clinical trialsdates bac" to the time o the“Trialists”:• Dr& Gan 6elmontHs %ro%osal or a

thera%eutic trial o bloodlettin oreers I(2+J

•

Dr& 9indHs, a shi% sureon, trial ooran es ? limes or scur (K0K



3ven *ore on 0linical Trials

6istorical 6ihlihts o Dru Trials

• ()3): #aul Ehrlich 1 Ars%henamine

• ()+): AleLander >lemin 1 #enicillin

• ().: $erhard Doma" 1 Sulonamide• ()00: Schatz4<uie4Wa"sman F

Stre%tomycin

• <y ().3, the <ritish Medical Res& Councildeelo%ed a systematic methodoloy orstudyin ? ealuatin thera%euticinterentions



0ore 0omponents of 0linical Trials

• 8nole human subects

• Moe orard in time

• Most hae a com%arison C5TR59 rou%

• Must hae method to measureinterention

• >ocus on un"nons: eNect o medication

• Must be done beore medication is %arto standard o care

• Conducted early in the deelo%ment othera%ies



*ore 0omponents

• Must reie eListin scientifcdata ? build on that "nolede

• Test a certain hy%othesis

• Study %rotocol must be built onsound ? ethical science

• Control or any %otential biases

• Most study medications,%rocedures, and4or otherinterentions



Recruiting (uinea Pigs+++er+++Patients

• 8dentiy eliible%artici%ants

• EL%lain study

• #roide inormedconsent

• Reassess

eliibility• Assin to one

rou%

#artici%ants shouldbe told:

• May hae side

eNects -aderseeNects/

• Time commitment

•

<enefts ? ris"s• May ithdra at

any time

• Enrollment (33O

oluntary



Phases of 0linical Trials

• Most trials that inole nedrus o throuh a series oste%s:

–P(: EL%eriments in thelaboratory

–P+: 5nce deemed sae, o

throuh (10 %hases




• #hase 8: Small group K>%.5% for #sttime to evaluate safety) determinesafe dosage range M identify S3

• #hase 88: RL4tL ien to larerrou% I(33133J to confrmeNectieness, monitor SE, ?

urther ealuate saety




• #hase 888: RL4tL ien to een larerrou% I(,3331,333J to ulfll all o#hase 88 obecties ? com%are it to

other commonly used tLs ? collectdata that ill allo it to be used saely

• #hase 8G: Done ater rL4tL has beenmar"eted 1 studies continue to test

rL4tL to collect data about eNects inarious %o%ulations ? SE rom lonterm use&



Summary of Phases I.III

# Subs. Length Purpose % Drugs

Successfully

Tested

Phase I20 – 100 Seeral

!onths"anly Safety $0%

Phase II p toseeral100

Seeral!onths&2 yrs.

Short ter!safety' !anlyeffecteness

((%

PhaseIII

100s –seeral1000

1&) yrs. Safety* dosage+ effecteness

2,&(0%



Standards

ethical %rinci%les uide clinicalresearch:

• Res%ect or #ersons: Treatmento %erson as autonomous

• <enefcence: 8ssue re: %otentialconQict beteen ood o society

s& indiidual

• !ustice: Treatment o all airly ?all eually share benefts ? ris"s



3thical /orms

Sound study desins ta"e into account:

• Randomization or sharin o ris"s

• #ro%er use o %lacebo

• #rocesses to monitor saety o rL4tL

• Com%etent inestiators

• 8normed consent

• Euitable selection o %artici%ants• Com%ensation or study related

inuries



Bac to Aiagra



The Surprising 3Nects on Test

Su!Oects

• Studies 'ere done to see 'hat sideeNects 'ould come from increaseddosages+ Aolunteers reported !ac

'ith side eNects lie head aches)visual pro!lems) and prolonged

penile erections+



Sildenal citrate



IP&0 /omenclature

#.K9.ethoQy.7.C<)8.dihydro.#.methyl.8.oQo.7.propyl.#HpyrazoloK9)7.dpyrimidin.;.ylDphenylsulfonyl.9.methylpiperazine



Synthesis of Sildenal

#+ *ethylation of 7.propylpyrazole.;.car!oylicacid ethyl ester 'ith hot dimethy sulfate+

>+ -ydrolysis 'ith /a-

7+ /itration 'ith fuming /itric &cid

9+ 0ar!oQamide formation 'ith reuQing thionylchloride= /-9-

;+ Reduction of /itro group to &mino

<+ &cylation 'ith >.ethoQy!enzoyle chloride

8+ 0yclization

5+ Sulfonation to the chlorosulfonyl derivative

$+ 0ondesation 'ith #.methylpiperazine

* th l ti f 7 l l ;



*ethylation of 7.propylpyrazole.;.car!oylic acid ethyl ester 'ith hot

dimethy sulfate



-ydrolysis 'ith /a-



/itration 'ith oleum



0ar!oQamide formation 'ith reuQing thionyl chloride= /-9-



Reduction of /itro group toamino



&cylation 'ith >.ethoQy!enzoyle chloride



0yclization



Sulfonation to the chlorosulfonyl derivative



0ondesation 'ith #.methylpiperazine



Synthesis



0itric acid



1hy add citric acidH

• Sildenal is !asic+

• Reacting it 'ith citric acid yields thesalt sildenal citrate+

• &s a salt) it is solu!le in 'ater !roendo'n into citrate and sildenal ions+

• Ions are more reactive than non.ionsin the cytoplasm) therefore)sildenal’s !ioavaila!ility is greatlyincreased+



Sildenal citrate



#ART ( 5> T6E (31M87TEMED SC6559: S5ME <AS8C

67MA AAT5M=



Types of *uscles



The -eart

I t l St t f th



Internal Structures of the-eart



The 0irculatory System



The Brain



The /ervous System



&natomy of the *ale (enitals



The Internal Structures



Part > of the #% ? minute *":

Physiology and Biochemistry



-o' the heart pumps !lood



*ale -uman SeQual Response 0ycle

•30IT3*3/T

•

PL&T3&•R(&S*

•R3SLTI/

So 'hat are erections



So) 'hat are erectionsany'ayH



*edical denition

• &n erection Cclinically: %enileerection or %enile tumescenceD is aphysiological phenomenon of the male genitalia ofmany species) in 'hich the penis !ecomes rmer)

engorged and enlarged+ Penile erection is theresult of a compleQ interaction of psychological)neural) vascular and endocrine factors) and isoften associated 'ith seQual arousal or

seQual attraction) although erections can also !espontaneous+ The shape) angle and direction of anerection varies considera!ly in humans+

http://en.wikipedia.org/wiki/Male_genitalia

http://en.wikipedia.org/wiki/Penis

http://en.wikipedia.org/wiki/Sexual_arousal

http://en.wikipedia.org/wiki/Sexual_attraction

http://en.wikipedia.org/wiki/Sexual_attraction

http://en.wikipedia.org/wiki/Sexual_arousal

http://en.wikipedia.org/wiki/Penis

http://en.wikipedia.org/wiki/Male_genitalia



-o' erections occur

• pon seQual stimulation) theterminals of parasympathetic nervesrelease nitric oQide+

• The nitric oQide diNuses into thesmooth muscle cells and !ind 'iththe enzyme guanylate cyclase+

• (uanylate cyclase convertsguanosine triphosphate C(TPD intocyclic guanosine monophosphate

Cc(*PD+



-o' erections occur

• c(*P !inds to Protein inase ( CP(D'hich causes the smooth musclecells to relaQ) allo'ing for an ino'

of !lood+ P( 'ors !y manymechanisms) including lo'ering thecellular 0aU> levels+

• The ino' of !lood causes thesinusoids of the corpus cavernosumto enlarge) 'hich compresses the

penile veins+



-o' erections occur

• Therefore) there !ecomes acollection of !lood inside the penissmooth muscle tissue+



-o' does Aiagra 'orH

• Phosphodiesterase ; CP"3 ;D is the enzymethat catalyzes the hydrolysis of c(*P !acinto (TP+

•

Aiagra acts competitively 'ith c(*P at theactive site of P"3 ;+

• So) if Aiagra inhi!its P"3 ;) then there 'ill!e an accumulation of c(*P in smooth

muscle cells until the Aiagra is meta!olizedCmainly !y cytochromes in hepaticmeta!olismD+



Viagra shows good competitive kinetics with



Viagra shows good competitive kinetics withcGMP because of the structural similarities



Pharmacology

• Aiagra is rapidly a!sor!ed after oraladministration . Total Bioavaila!ility:9%E

• Its pharmacoinetics are doseproportional over the recommendedrange

• Aiagra is meta!olized mainly !yhepatic meta!olism and eQcretedmainly in the feces+

-o' Scientists Tested



-o' Scientists TestedSu!Oects

• Scientists assessed erections using aninstrument called Rigiscan) 'hich measureshardness and duration of erections+

• &lso) each su!Oect 'as given a survey)'hich measured the a!ility to achieveerections for suVcient seQual intercourse)and the a!ility to maintain erections afterpenetration+

• &lso) some su!Oects 'ere ased to create adiary to 'rite do'n any feelings or sideeNects they might have had+



0linical Results

• 3rectile dysfunction 'as attri!uted toorganic C;5ED) psychogenic C#8ED) ormiQed etiologies C>9ED+

• &fter < months of Aiagra treatment) thepercentages of men reportingimprovement in their erections are !elo':

rganic W <7EPsychogenic W 89E

*iQed W 5>E

Is this a 'onder drug or are there



Is this a 'onder drug) or are there

side eNectsH

• ne side eNect of Aiagra comes fromthe relatively high selectivity for P"3<+ &t pea plasma levels of Aiagra)

some su!Oects cannot distinguish!et'een green and !lue+

• In place!o controlled studies) only

>+;E of users discontinued the use ofAiagra !ecause of negative sideeNects+



Side 3Nects

• Some side eNects of Aiagra:

-eadache

,lushing

"yspepsia

/asal 0ongestion

"iarrhearinary Tract Infections



*aOor 0oncerns

• Because Aiagra is a vasodilator Calthough mainlylocallyD) it needs to !e used cautiously !ecause itlo'ers !lood pressure+

• Aiagra should not !e given to patients 'ho are taingnitrates) !ecause nitrates are also a strong vasodilator+

The use of !oth could cause maOor heart pro!lems+• &lso) the use of 0XP7&9 or P9;% inhi!itors C'hich are

the cytochromes responsi!le for Aiagra meta!olismD)greatly increases the ris of negative side eNects+

Some 0XP7&9 inhi!itors include 3rythromycin)0imetidine+

ne maOor P9;% inhi!itor is Ritonavir

Pfizer’s Blue Pill.pptx

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