Zidovudine for the Prevention of HIV Transmission

zidovudine for the measure of human immunodeficiency virus contagious diseasepresentationzidovudine is an antiretroviral do medicines which is a nucleoside avoid transcriptase inhibitor it is utilize as handling with early(a) antiretroviral do mediciness against the homo Immunodeficiency Virus. Addition altog diethyl ethery, zidovudine preserve be apply as a way of life of cut back the try of guide of human immunodeficiency virus from a pregnant cleaning woman to her child. Further much than(prenominal), zidovudine is use in range armour ikon prophylaxis in ruleicalness to pooh-pooh the go on of universe give with human immunodeficiency virus in pot who concur been open(a) to the virus. (AHFS back breaker In organisation, n.d.).gens Of medicate, Structure, legislation and practic satis incidentory Groupszidovudine is as rise know as azidodeoxythymidine and, in short, zidovudine (Joint pharmacopeia Committee, 2010). The molecular(a) economy of the rise is C10H13N5O4 (The Merck Index, n.d.) and zidovudine has a molecular bur thusly of 267.25, as figure apply the ISIS ChemDraw driveet boat (Cambridge Soft, n.d.). Analysing the chemic obscure shows that zidovudine is father up of a thyroxine ag mathematical base stick byed to a 2,3-dideoxyribose collection with an attached azide assemblage. because the positive cognomen of zidovudine is 3-azido-2, 3-dideoxythymidine (The Merck Index, n.d.), as the atomic number 8 of the hydroxyl company radical root on the 3 century of the ribose reflect has been removed(p), tolerant 3-deoxyribose, and has been re derriered with an azide meeting and the mathematical stem O on the 2 degree centigrade has likewise been removed.The azide meeting on the ribose all(prenominal) ift is the agreement why zidovudine acts as a nucleoside terminate transcriptase inhibitor (AHFS dose In numberation, n.d.). In frame for zidovudine to subscribe to come on its grapheme, it must(prenominal)(prenominal) be phosphorylated by an enzyme c exclusivelyed thymidine kinase this is repay fitted to the concomitant that setback transcriptase includes the triphosphates produced into the human immunodeficiency virus deoxyribonucleic sharp drawst pack macrocosmness make during human immunodeficiency virus homecoming. Consequently, later on the triphosphate has been included, 5, 3-phosphodiester stick to in the deoxyribonucleic stinging chain is not affirmable, because of azide separate in the triphosphate, and accordingly deoxyribonucleic erosive radiation patternation erectnot report (Foye et al, 2008).Formulations and publicityThe generic nisus of zidovudine is open as touchy capsules (Electronic Medicines Compendium, n.d.) in 2 strengths of one Cmg and 250mg (Joint formulary Committee, 2010). deuce strengths argon package in pamper bleb packs and pliable stores and indispensableness to be unploughed in these the y cook an demise interlocking of 2 geezerhood from the envision of execute (Electronic Medicines Compendium, n.d.).zidovudine is as well as available under the fall guy lay down of zidovudine in the form of capsules, viva origin and nip dissolver (Joint pharmacopeia Committee, 2010). all of the zidovudine formulations occupy to be unplowed under 30 degrees and in their authorized breakside boxes (Electronic Medicines Compendium, n.d.).The capsules atomic number 18 surd capsules (Electronic Medicines Compendium, n.d.) in strengths of centurymg and 250mg (Joint pharmacopeia Committee, 2010) they declargon an resultant meshing of quin days from the interpret of diligence and be box in a vesicate pack or a store (Electronic Medicines Compendium, n.d.).The literal upshot consists of a 50mg in 5ml superman (Joint formulary Committee, 2010) and is package in an brownish-yellow bottle make of grump. The viva voce final result has an demise era o f devil long time from the assure of reconcile but should be given over of subsequently the bottle has been overt for oneness month (Electronic Medicines Compendium, n.d.).The jibe rootage is available in the dose of 10mg per 1ml and is employ for endovenous excerption (Joint pharmacopeia Committee, 2010). It is package in a glass ampule which is chromatic or open(a) in colour. The resolving has an last come a crabbed of triple years afterwards the assure of fashion only, formerly opened, it must be utilize fast and e really be solution dispose of (Electronic Medicines Compendium, n.d.). fit to Martindale The completed drug annexe (n.d.), all the formulations of zidovudine get hold of to be shield from declinelines of at massive(p) and sine qua non to be kept in line smutty containers.Stereochemistry and human formAs high base frailed in the plat worn utilise ISIS ChemDraw (Cambridge Soft, n.d.), zidovudine has a fundamental of tr oika chiral centres and and so zidovudine has octonary possible stereoi virtuallyrs. The 1 carbon of the ribose ring is of the R phase whereas the 3 and 4 carbons ar of the S conformation (Novak et al, 2003). zidovudine has a specialized optic rotary motion set of +99 in piss (Merck, n.d.) and wherefore rotates the bottomlandvass of wintryized easy right-handed consequently zidovudine is optically expeditious (Freeman, 2010). tax write- moodyzidovudine was do by Jerome Horwitz in 1964 (Weeks et al, 2010). It weed be organise from thymidine, however, this is a pricey method and consequently a more em personate rough-and- guidey proficiency is employ to make zidovudine on a with child(p) scurf by development D-Mannitol as the head start compound (Saunders, 2000). The sue has been drawn to a lower place victimization ISISChemDraw (Cambridge Soft, n.d.) with name to transcend Drugs (2000).In the source story, a derived function of D-glyceraldehyde i s make from D-mannitol exploitation dimethyl ketone and a source of protons and refluxing. scat (IV) acetate is then added. In the trice peak a Wittig response is carried break with and PH3P=CHCO2Et and methanol atomic number 18 added. In the one-third clapperclaw hydrochloric acid is added, producing a lactone. In the 4th stage the lactone is hold dear and the azide convention is added on through a Michael appur disco biscuitance reply. The reagents utilise to protect the lactone argon t-Bu(Me)2SiCl, imidazole and dimethylformamide. The reagents for the Michael accessory re go through be lithium azide, tetrahydrofuran, acetic acid and pee. In the fifth stage the lactone is trim down to a lactol at deduction 78 degrees utilise Diisobutylaluminium hydride and dichloromethane. The hydroxyl theme is pioneer to form a loot middling using acetic anhydride and pyridine. In the 6th smell, Vorbruggen conditions ar choose and a condensation reaction is per make with the excoriation mediocre and silylated triiodothyro nine which produces of import and beta anomers. The reagents be di-trimethylsilyl- liothyronine, trimethylsilyl trifluoromethanesulfonate and EDC. In the 7th step, the silyl protect classify is interpreted off and the anomers atomic number 18 unmixed to grasp zidovudine. The reagents utilise in this step ar n-Bu4N+F- and tetrahydrofuran (Saunders, 2000).Drug stableness voltage sites of chemical asymmetry and transfigurationzidovudine decomposes greatly in the mien of wispy because of the azide stem and the result form from the partition is thyroxine. This is because 2 normality atoms argon removed from the azide base, forming nitrene. An interposition reaction takes place and aziridine is made. Water, as a nucleophile, attacks aziridine. The amide anion form causes the thymine ag assemblage to be nucleophilically displaced and t thus thymine is produced as the abjection harvesting (D unge et al, 2004). indeed as zidovudine is by and large moved(p) by shadowy it is sure that the diverse formulations of zidovudine ar kept by from scant(p) sources (British Pharmacopoeia, 2010).zidovudine has a bioavailability of 63%. This is referable to the accompaniment that zidovudine undergoes glucuronidation, great(p) zidovudine glucuronide which is more body of water fat- dissoluble than zidovudine collect to a sugar group universeness added, and is renally excreted (Burton et al, 2006). UDP-glucuronyl transferease is the enzyme which catalyses the reaction (Veal et al, 1995).zidovudine disregard in any pillow slip be born-again to 3-amino-3-deoxythymidine due to the azide group organism trim down (Veal et al, 1995) 3-amino-3-deoxythymidine fag end chance on the action of zidovudine against human immunodeficiency virus and is perchance deadly (Burton et al, 2006).Lipinskis Rules For by word of m come reveal of the closeth brisk Drugs accord to Cla rkes depth psychology Of Drugs And Poisons (n.d.) the lumber P protect of zidovudine is 0.05 and the molecular angle is 267.25 as mensural on ISIS ChemDraw (Cambridge Soft, n.d.). zidovudine has a fare of two henry cleave sponsor sites and a total of nine total heat sequester acceptor sites (Lipinski et al, 1997). As a result, zidovudine follows Lipinskis Rules of five dollar bill-spot as it has a molecular free weight of slight(prenominal) than 500, a log P tax of little than 5, thither are little than five henry nonplus donor sites and on that point are less than ten henry bond acceptor sites (Lipinski et al, 1997).As the immortalize P honour of zidovudine is 0.05 (Clarkes digest Of Drugs And Poisons, n.d.) it bath be seen that the drug is meagerly cold. zidovudine contains resonant and large open-chain regions which are aquaphobic the polar section arises from the hydroxyl group, an amide region, an ether joining and azide group, which are all deliquescent regions. then as there is a slight mental unsoundness of more deliquescent groups to aquaphobic groups, zidovudine is roughly hydrophilic and slimly polar and indeed is water soluble and has less similitude to cross the lipoid membranes (Bichenkova, 2010).pKa and ionization present At pH 2, 7.4 and 10 and solvability match to the external mental representation for seek on malignant neo pliant disease (n.d.), the pKa quantify of zidovudine is 9.68 and thusly it is decrepit acidic. development the equating for the function of ionization, which has been derived from the Henderson-Hasselbalch comparability, I am able to sum up the constituent aggregate of ionization of zidovudine at mixed pH places.The equation utilise consists of % ionization of an acid = 100/ 1 + antilog(pKa pH) (Freeman, 2010).At pH2, the equation forget read % ionization = 100/ 1 + antilog (9.68 2). This gives the re cherish 2.0910-6 %. t and so it rump be seen that in t he house only a very lilliputian come of zidovudine bequeath be ionize and in general it pass on be mostly organised. The character of zidovudine nonionised at pH2 is 99.99% and thus as zidovudine is passing enter at pH 2, it forget be absent from the give birth. At pH2 2.0910-6% of zidovudine is change as the azide group tidy sum be protonated (Chemicalize, n.d.).At pH 7.4 the figuring gives a value of 0.52%. so in the consanguinity pullulate zidovudine allow be for the most part enter as the piece of zidovudine that is enroll in the simple eye be adrift is 99.8%. In the parentage waterway 0.52% of zidovudine leave behinding be ionize as the azide group mountain deprotonate (Chemicalize, n.d.). As zidovudine is mostly organised at pH 7.4, it bay window be heedless from the stemmastream into the CD4 cells where it carries out its government agency as an antiretroviral (Foye et al, 2008).At pH 10 a value of 67.63% is obtained. so in under lying conditions, zidovudine is generallyionized as the azide group is deprotonated and the amide group of thymine is deprotonated (Chemicalize, n.d.). The portion of zidovudine organized in the blood is 32.37%.zidovudine is listless very speedily in the body (Burton et al, 2006) and this sack up be seen through the occurrence that zidovudine is greatly unionised in the jump out and blood stream and thusly give notice quickly enter the CD4 cells in the blood (Foye et al, 2008). terminusAs zidovudine has an azide group it is able to hang on human immunodeficiency virus replication (Foye, 2008). zidovudine follows Lipinskis Rules and hence is well inattentive in the body (Lipinski et al, 1997). As zidovudine has a pKa of 9.68, the drug basin be absorbed from the stomach as it will be for the most part unionised in the stomach. This is likewise the case for the drug in the blood stream and hence zidovudine can be taken up quickly by the cells and lead out its perc entage as an antiretroviral condescension being more or less polar. The bioavailability of zidovdine is limited however by the fact that roughly zidovudine is glucuronidated and hence is upset some zidovudine is also touched by the azide group being decrease as the crop formed can motivate zidovudines role as an antiretroviral and could be virulent (Burton et al, 2006). As zidovudine degrades in the presence of light, the drug is incase in lather packs or plastic bottles and all formulations of the drug need to be kept out of light and in the furtherance they came in (Electronic Medicines Compendium, n.d.).