Drug Availibe To Control Hiv Is Abacavir Biology Essay

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one of the drugs availibe to control HIV is Abacavir,this drug is a synthetic carbocyclic nucleosideanalog that has antiretroviral activity which can inhibits both HIV-1 and HIV-2, more ever it is one type of guanosine nucleoside reverse transcriptase inhibitor (NRTI) it means that it inhabits the reverse transcription of HIV , in this way it decreases the HIV virus (Kohler et al., 2010) in other words abacavir dose not cure the HIV patients but just delays and decreasses the damage of immune system further more it is also applicable in prevention of HIV when it is combined with other untiviral medications for those who have been exposed to it .(application )this drug applicable in patients how can not take non-nucleoside reverse transcriptase inhibitors or protease inhibitors treatment of children especially those how have developed toxicity to stavudine (d4T) .

Abacavir with the trade name of Ziagen . it is an enantiomer with 1S, 4R absolute configuration on the cyclopentene ring . it can be found in tow froms tablet (yellow ) or solution . (environment ) it has a solubility of 77 mg/mL in distilled water at 25°C . The tablets are coated with a film that is made of hypromellose, polysorbate 80, synthetic yellow iron oxide, titanium dioxide, and triacetin (daily med ) . this product is stable . (environment )

Abacavir has a interacellular activation pathway that was first described at 1994 (synthesis )in this pathway Abacavir will transform to carbovir triphosphate in the cell abacavir will be hosphorylated by adenosine phosphotransfrase and abacavir monophosphate will be produced , cytosolic deminase will affect this and will produce abavir monophosphate wich has 2 analog in cell triphosphate cabovir and diphosphate cabavir (Francis, 2002)

Abacavir active anabolite in cell is , carbovir triphosphate(CBV-TP) ) wich competes with an endogenous nucleotid transcriptase enzyme and inhibits transcription of HIV viral RNA to DNA and will be produced in cell by phosphorylation, acts as chain terminator for viral DNA , because it dosen't have the the 3'hydroxyl it prevents the formation of the 5' to 3' phosphodiester linkage that is essential for DNA olymerization in this way it blocks HIV replication (Achenbach et al., 2010)

FIG : Abacavir , interacellular activation pathway

Pharmacokinetic properties :

Abacavir has a bioavability of 83% and is highly absorbed in oral administration . distribution takes place mostly in vescular system and partly in CSF. It binds to about 50% in plasma proteins (Daily Med) and concentration of Abacavir has no effect in binding of drug to plasma proteins . (Daily Med) the half time of abacavir in body is about 1.5 hours ( European egency 1) . the main metabolization place for it is in liver , it is metabolized into two inactive metabolites via uridine diphosphate glucuronyl transferase and alcohol dehydrogenase , which will be then eliminated through the hepatic metabolism ( kidneys)(moheme 7 ) about 83% of abacavir dose that have been used can be found in urine as metabolist and unchanged abacavir ( European egency 1) which only 1% of it is unchanged Abacavir due to this dosage prescribed dose not need renal adjustment (Achenbach et al., 2010) .

Side effect and toxicity information :

Pharmacological Effects:

abacavir is a key component in Ziagen(R), Trizivir(R) and Epzicom(R) , studies show that abacavir has more effect when it is combined with other anti viral drugs( Mounir Ait-Khaled) .having a TNF genotype increases the risk of hypersensitivity (patent nunber WO 03018745  (A2)). The hypersensitivity reaction(AHSR ) is associated with HLA-B*5701allel that is immune system genetic variant (Hughes et al., 2004) which is a life-threatening occurring in 5-8% of those using the drug ,this factor has limited its use . the hyper sensitivity symptoms are: fever, rash, gastrointestinal (nausea, vomiting, diarrhea, or abdominal pain), constitutional (generalized malaise, fatigue, or achiness), and respiratory (dyspnea , cough, or pharyngitis) (Hughes et al., 2004), there for the risk of abacavir HSR must be considered when using abacavir for HIV treatment(Clay, 2002), an allel test is now recommended before using this product , which this will decrease its cost efficiency unless treatment with abacavir is as effective and economically efficient as alternative drugs which can be used against AIDS (Hughes et al., 2004). In some cases increase of fate in the body had been absorbed, this fate mostly accumulates in upper back and neck ("buffalo hump"), breast, and around the back, chest, and stomach area. (daily med)

Routes of Exposure (environment )

Target Organ Effects

No specific

Oral Toxicity

Not expected to be toxic

Skin Effects

In a direct contact , is not expected

Eye Effects

In direct contact , sever irritation might occur


In dermal exposure , allergic reaction might occur

Genetic Toxicity

Mutagenicity occurs in laboratory tests.


Limited evidence for this may occur In high concentrations and also depends to the period of taking the dosage

Reproductive Effects

Not expected

Interaction with other medicinal products and other forms of interaction:

abacavir has shown no clinically interaction to food or other drugs because it dose not inhabit the metabolism mediate with CYP 3A4,CYP2C9 or CYP2D6 enzymes, how ever the plasma concentration of Abacavir declines in presence of Potent enzymatic inducers.

Ethanol affects the metabolism of Abacavir by raising the AUC of abacavir to about 41%.

How ever Abacavir dose not have an impact on metabolism ethanol in body. (European egency 1)

Posology and method of administration:

Abacavir is used as a tablet or oral solution in HIV patient, the oral solution is used more in children how over 3 months are and have a body weight less than 14 kg (European egency 1). The dosage is 600-mg once a day or 300 mg twice a day regimen for adults how ever in children the dosage used depends on body weight (jadide 1 ph) . in children the administration changes, in those who weight more than 30 kg the dosage taken is the same as adults, children that weight between >21<30 should take half of the drug in day and a whole tablet at evening how ever in children which weight 14 to 21 kg this amount decreases to half a tablet, twice a day (European egency 1) . the administration rout is oral and are 83% bio available , the absorption is quick and reaches peak concentration of 0.6 3to 2.5 one hour after using .due to its good solubility in water and lipophilic solvents , it has a good distribution in body with a volume distribution of 0.86±0.15 L/kg (Achenbach et al., 2010) abacavir can be taken with or with out food and this has no effect on its exposure although it changes Tmax and Cmax (Achenbach et al., 2010) .for patients suffering of renal dysfunction no adjustment of drug is needed how ever in patients with mild hepatic problems , this drug is not recommended because the metabolisation of this drug occurs in liver . abacvir is also not recommended in pregnancy and in breast feeding of the infant although the effect of abacavir in this consumers is not yet been confirmed. (European egency 1)

No adverse reaction was absorbed, in a single dose up to 1200 mg and daily doses up to 1800 mg with Abacavir. (European egency 1)

Synthesis routs Process:

Ziagen , (1S,cis)-4-[2-amino-6-(cyclopropylamino)-9H-pu~-9-y1]-2-cyclopentene- 1-methanol, was synthesized from (IS,4R)-azabicyclo[2.2.l]hept-5-en-3 . The most important intermediate which makes it possible to get an efficient construction of the purine is 2-Amino-4, 6-dichloro-5-formamidopyrhidi .

Synthetic options:

There are two general approaches to making 2'3'-didehydro (i.e.,cyclopentenyl) carbocyclic nucleosides are coupling of the intact purine to a carbocycle and to use cyclopentenylamine to construct the purine .

FIG : Retrosynthetic analysis of routes to Ziagen .

Different have been experimented:

it is not feasible to use the route which converts the heterocyclic base to an activated allyalically cyclopntene since , in this rout , 2-aminopurine precursor in 2 amino-6-cyclopropylaminopurne , has a low solubility in the suitable solvent which is one of the reasons that makes the synthesis of 2 amino-6-cyclopropylaminopurne which is relatively toxic , not trivial in large scale , here the major problem is the lack of N9/N7 regioselectivity in purine coupling . During the deblocking of intermediates, 7-substitute isomer decays and produces glycone which is a contaminant more ever to purify the final drug separation of N7 and N9 isomers are also required and also the production of intermediates had not been developed in large scale.

cyclopentenylamine synthesis :

reaction between sulfonyl cyanide and cyclopentadiene produces rademic lactam 3b which is an intermediate used to produce carbocyclic nucleoside and is feasible in industrial production how ever its unstable especially in linear production construction of purine from amine 5a .

FIG : Amino alcohol intermediates to cyclopentenyl nucleosides .

Several problems occur when conversion of 3b to amide 7 , isomeric and saturated by products will be generate in the reduction step, during deprotonation of any α to the ester group which effect the purity of the drug.

FIG: consequences of impurities generated in ester reductions .

In large scales , the reduction of 6 with calcium borohydride often has a slow reaction another problem is that it is difficult to separate impurities like 11which is yield in calcium bromide reduction and has not activity against HIV-1 and non toxic and 12 which is synthesized by hydrogenation of 1 .

To save steps, they introduced lactam to amino acid and then reduced the amino acid with lithium aluminum hydride. Lactam will hydrolyze and generates highly crystalline salt in present of water and strong acid (4a-4d). The purity of crystalline depends on purity of lactam; if the impurity is high it will be washed with THF.

The aluminum salt produced because high chelating of amino alcohol, which is insoluble in a hydrous solvent, and unstable in light and air when concentrated from solution. To over come this problem they add thermodynamically strong ligand for aluminum .for reduction they introduce it to water followed by sodium fluoride this generates sodium aluminum fluoride which is insoluble and can be extract by polar solvent.

This process has also done starting with racemic lactam 3b, with enzymatic differentiation of the monophosphate; it will produce small enantiopure samples of 1 and 1b enantiomer which is used for antiviral testing.

To purify the amino alcohol 5a the most direct way is the use of hydrolysis / LAH reduction of 3a. how ever an alternative way is the more efficient, to add THF solutions of BOC lacyam 8 which was generated by derivitization of lactam 3a with di-ter-butyl dicarbonate in presence of catalyc DMAP and is stable at 25 C in aqueous THF, to sodium borohydride will generate highly pure 9 on a 100 - gram scale although in larger scales result in slow, incomplete reactions. More ever sodium borohydride has a tendency to precipitate from THF/water mixture. For multi kilogram scales, adding of three equivalents of methanol with catalytic acetic acid is needed.

Chloropyrimidine intermediate:

Rout mention below may provide enantiopure amino alcohol . the original synthesis of carbocyclic 2-aminopurine nucleosides is to couple 2-amino-4, 6-dichloropyrimidine with cyclopentylamines, by phenyldiazo insertion adding Nitrogen at the 5-position of the resulting pyrimidine intermediates.

Problems of this rout:

risk of diazotizations in large scale

Properties of triaminopyrimidine intermediate which is generated with zinc reduction of the 5- diazopyrimidine (19 )

Chlorination of 13 might yield to 14 in presence of with phosphoryl chloride or to 15 if refluxed in methylene chloride or chloroform with 6-8 equivalents of "vilsmeier reagent".

To yield 2,5-diamino-4,6-dichloropyrimidin(e1 4) , chlorination of 2,5-diamino-4,6-dihydroxypyrimidine (13) with phosphoryl chloride in presence of quaternary ammonium chloride is required . here the draw backs are :

1. High degradation of starting pyrimidine chlorination .

2.To isolate 14 , chromatography is required .

To yield 15 refluxing in chloride or chloroform with 6-8 equivalents of "vilsmeier reagent is required; in mild condition this reagent allows efficient chlorination by protecting and stabilizing 13. 15 can be stored as stable solid or be converted to 16 by acidic hydrolysis . PH plays an important role when removing methylene groups from 15 or 16. in PH 1 in aqueous acid converts it to oxopyrimidines, how ever rising the PH to 3, will convert 16 to 17 in an ionic strength aqueous phosphate buffer, this buffer limit tats the solubility of reactant and product .by decreasing PH in steps, an over all of approximately 70% yield from 17 which can be isolate in a simple way .due to this in large scales they convert 13 to 17 which dose not required the isolation of 15or 16.

If the PH decreases to 1-2 by adding sulfuric acid, 17 will hydrolysis to 14. At PH 1 , 17 will hydrolysis effectively to 14 in contrast at the same PH ,15 and 16 will convert to oxopyrimdines . By refluxing 17 with catalytic hydrochloric acid in equeous ethanol ,because both 14 and 17 are not sensitive to hydrolysis ,a yield of 14 (77%) will occur .

FIG : Chloropyrimidine intermediates to 2-aminopurines .

Coupling and purin formation :

Vilsmeier chlorination chemistry and subsequent hydrolysis to provide 17 , is scalable due to , need of simple reagents and work up , simple the purification is and the stability and purity of solid intermediates generated in this process .17 is the most attractive intermediate in the synthesis of 1 and related 9-subsitituted 2-aminopurines and is useful reagent for synthesis of 2- aminopurins .it supplies 18 in > 85% after crystallization when condensation with amino alcohol 5a ( which is generated from 9 un refluxing ethanolic HCl ) .

Activation provided with formylation t of the 5 - amino group makes the conditions for formation of 18 is more easier than formation of trimopyrimidines (e.g 19 ) from 14 , more ever solid crystalline 18( which is a 5-formamdiointermediate) is more stable to light and air compared with trimopyrimidines .with 4 equivalents of concentrated aqueous hydrochloric acid the cyclization of 18 to 20 occurs smoothly in triethylorthoformate , by dissolving formamide 18 after adding acid the hydrochloride of 20 began to precipitate which will be used to prepare 1 (among a variety of other novel analogs ).

The rapid formation of 20 suggested that the conformation of the formamide of 18 may be unfavorable for cyclization and that the addition of water could disrupt internal H-bonds and facilitate cyclization . In order to improve the cyclization mechanism by establishing the origin of the C-8 carbon of 18, they synthesized 17 from Vilsmeier reagent , and converted it to [13c] cyclized this in triethylorthoformate / aqueous hydrochloric acid . after crystallization they have used they have add cyclopropylamin which is a suitable salt in refluxing ethanol to provide them an high yield of 1 , they have used solvents because the free base of 1 is glass or solid foam and in this way they can trap them in solvents . This route was also used to prepare the HIV-inactive enantiomer lb from 5d .

FIG : Synthesis of Ziagen

Analysis of process for prepration of abacavir :

In prepration of abacavir there are 3 steps that still need improvement . here the main steps advantages and disadvantages of different methods have been compared .

A major and important step in preparation of abacavir is to prepare the intermediate which will transform to abacavir . The synthesis mentioned in EP 434 450 for this purpose is time consuming and needs a protection and reprotection sequence , starting with di-halo aminopyrimidine and yields to abacavire as free base .

another approach has been introduced in pateant number US 6448 403 which uses diamino-dihydroxy as starting material and when it is treated with POCl3 to generate the key intermediate however the toxicity of POCl 3 and the complex salt generated by this reaction which is difficult to stair makes the isolation and purification difficult . An alternative way is to treat the dichloro diamino pyrimidine with mixture of formic and acetic anhydride in this way it becom formylated and fully protected, the problem of this kind of synthesizes is that it needs an additional step to remove the protecting group.

In abacavir synthesis one of the most important part is the cyclisation process of abacavir intermediates there are still problems with amount yielding and purification of this process , especially those which have an acyl group that is protecting the amino group at 2- and 5- position of the pyrimidine , due to that looking for a sufficient process is still an active field .For cyclisation of the {pyrmidine -5-yl} , In the synthesis of abacavir that is discussed above from (cf.S.M.Daluge et al 2000) they used tritheyl orthoformate and concentrated aqueous hydrochloric acid . they have implied that cyclisation had been eased by addition of water and this had distrupt internal H-bonds .in EP 434450-A which is published before this , cyclisation of the N-2-acylate abacavir intermediates which have protecting amino group at 2 and 5 position of pyrimidine by removing the amino group of the pyrimidine in the intermediate occurs in presence of a co solvent and strong anhydrous acid they have used formic acid or reactive formic acid derivatives which may take 2 days in room temperature , the use of corrosive mineral acids to remove the amino protective groups may harm the machines and producing several by products which have effect on purity and the final yield of the product and the amount of agent used is also high 1-25 mole of solution of agent , high dilution rate and complicate ,the long time that is needed to remove the amino protective group , need for isolation after evaporating of solvent by use of chromatography and triturating to purify the free Abacavir base indicates the need of more efficient way .an alternative way was introduced in patent number US2010/0041883 A1 the cyclisation here has high yield and purity , low by-products and the amount of agent used is also decreased (2-5 mole of cycisating agent per mole ) compare the patents above and this reaction dose takes place without presence of water , here the formyle group of 5-amino group will be removed when it is introduced to anhydrous hydrochloride acid [(C1-C4)-alcohol] / isopropoanol in the room temperature which the presence of alcohol prevents the draw backs of known methods , followed by refluxing and introducing to (C1-C4)alkyl orthoformate in temperature between 0 CÌŠ and 30CÌŠ , the compound resulting from here can be convert to abacavir in presence of a base and a suitable solvent by reaction with cyclopropylamine , followed by hydrolysis in acidic condition .

another approach has been introduced in patent number US2010/0004446 A1 which uses a an inorganic base like alkaline metal hydroxide ( as lithium , sodium , potassium hydroxide ) comprised between 1 and 5 mole of base per mole of starting material in a mixture of water and alcohol to hydrolyze the formula ( ) and remove the amino protective group , for this reaction they increased the temperature to 50 C which , reduces the time of reaction which makes an advantage compared to methods known .

After cyclisation the intermediate abacavir can be isolate , as a salt or as free base , according to patent number WO9852949 using free bases to generate abacavir generates amorphous solids that cannot be use in large scale and needs purification this has implied the need of a salt of abacavir . To generate the pharmaceutically salt from free base, the free base can be introduced to corresponding acid. Different kind of salts can be produced for this purpose however abacavir hemi sulfate is the most preferred one. for example patent number PCT/GB95/02014 , uses succinate salt of compound , having some advantages like easy formation of salt , and cristalization how ever disadvantages like having the tendency to agglomerates make it undesirable for tableting machines and having multiple crystallization forms with different properties , which indicate the need of supervision when producing so that undesired form is not produced . These have made it not feasible in use in pharmaceutical industry. in contrast abacavir hemi sulfate is preferred to use in industry due to characteristic like easy preparation and purification , having only one form of crystallization , has no tendency in hydration or solvation , this charachtesitic makes it suitable for storage , good solubility which makes suitable for preparation of liquid formulation , no tendency to aggregation which prevents generation of amorphous solids and eases the purification .( AU7660 (B2)

another major step which is important in preparation of abacavir , is the isolation of abacavir and had been investigated in different ways .in patent number EP 434450-A isolation of abacavir had been done by use of chromatography which produces solid fumes and triturating with acetonitrile that generates gummy solids , these methods are time consuming and expensive method and generates by products . an alternative ways was introduced in patent number US2010/0004446 A1 have used solvents like (C2-C8) aliphatic ethers or ( C6-C8)-aromatic hydrocarbons before separation of the aqueous phase followed by washing with aqueous to remove the organic phase before the addition of acceptable acid , here they have removed the water to get higher yield in anhydrous solvent , or alternatively to isolate the abcavir they have introduced crystallization the abacavir which is the most sufficient way , for this purpose inorganic phase can be washed before the crystallization , the advantage of this method is that purification and isolation is much easier , and the final yield is also high .

Manufacturing and engineering:

Raw materials:


(Chloromethylene)dimethylammonium chloride



Tartaric acid, dibenzoate,

(-)-Orthoformate or diethoxymethyl acetate



Manufacturing Process:

The reaction between 2,5-diamino-4,6-dihydroxypyrimidine (I) and (chloromethylene)

dimethylammonium chloride results to dichloropyrimidine , in which the both amino groups will derivate to amidines , with HCl in hot ethanol it will partially hydrolyse this yields to N-(2-amino-4,6-dichloro-pyrimidin-5-yl)-N,Ndimethylformamidene (II) following that they hydrolysis it with buffer at PH 3.2 that will result to(2-amino-4,6-dichloro-pyrimididin-5-ylamino)acetaldehyde (III). Condensation of chloropyrimidine (III) in the presence of triethylamine and NaOH Condensation with (1S,4R)-4-amino-2-cyclopentene-1-methanol (IV) results to [2-amino-4-chloro-6-(4-hydroxymethyl-cyclopent-2-enylamino)pyrimidin-5-ylamino]-acetaldehyde (V).to collect the right enantiomer (IV) of racemic aminocyclopentene they resolut of diastereomeric salts with D-dibenzoyltartaric acid . refluxing triethyl orthoformate or diethoxymethyl acetate has done to provide Cyclization of (V) to the corresponding purine , which has resulted to nucleoside analogue [4-(2-amino-6-chloro-purin-9-yl)-cyclopent-2-enyl]methanol (VI) .Abacavir will be produced by replacement of chloride with cyclopropyl amine in this purine nucleus with refluxing butanol . to confirm the structure of the Abacavir 1H NMR method and elemental analysis can be used . (manufactur)

Environmental impact:

The material contains a pharmaceutical active ingredient that that is soluble in the water and chemically stable in water. more ever, if it is directly into environment it is not likely to be absorbed in soil or sediment and sludge or biomass further more it is also unlikely to undergo the photo degradation in Visible Spectrum 285 nm at pH 7due to this reasons it may effect the Aquatic life, in the test they made for toxicity it shows that it is toxic for Alga how ever it did not show toxicity in Daphnides and Fishes, when released in the environment.

The material is inherently biodegradable and is not expected to be persisting in environment and the percentage of degradation is 96 % in 2 days. Further more this material dose not enters the food chain. (environment )

The direct release of the materials might be harm full due to the pharmaceutical active ingredients that it has. To limit the release of the materials to environment appropriate precautions must be taken into account. (environment ) unfortunately no detoxification procedures had been identified for this product. .

Transportation of the drug:

According to UN Classification and Labeling, there is no limitation in Transportation and shipping of this drug. In transportation it dose not need any special packaging or labeling for air. (environment )

Marketing and approval of the drug:

Abacavir was first developed by GlaxoSmithKline (GSK) which is the largest manufacturer of HIV medications (manbah GSK)and has been approved for marketing by FDA on 1988 in America (Hughes et al., 2004) and in Europe it received the full approval in 1999 . To understand the ABC HSR, (GSK) had agreed to conduct a post-approval research. In this cost reduction Ziagen oral solution (abacavir) had the most significant reduction in price. Factors that made it possible for GSK to reduce its prices are:

manufacture improvement and supply

reduction in cost of raw materials to produce these medicines

Drug name

Date of approval

FDA Application No


Marketing status

ZIAGEN (Brand Name Drug)

December 17, 1998

(NDA) 020977



ZIAGEN (Brand Name Drug)

December 17, 1998

(NDA) 020978



Cost :

Since 1997 GSK company had reduced it prices for HIV medicines 5 times as part of pioneering preferential, in the last reduction which was in February 2008 GSK had decreased the price of the HIV drugs. (Price)

Drug name

GSK current $ per pack

New price

Percentage change

New Price per day $*

Ziagen 300mg tablet



- 31.3%


Ziagen Syrup 20mg/ml



- 39.7%


GSK is the only producer of Abacavir and has not given any licenses to generic

Manufacturers to produce it. (TAC) in 2002 a law suit was held against the company by AIDS Healthcare Foundation (AHF) , they claimed that the company had monopolization the manufacturing of Abacvir in this way it exclude competition in the market and the high rate of the prices of the drug . (law suit)


Abacavir with the brand name of Ziagen , the inventor of the drug are researchers from University of Minnesota with the financial support from the US government . Burroughs Wellcome holds the key use patent, the company marketing it is GSK . The approval of this drug from US FDA was at 17-Dec-98, the Exclusivity of it expired in Dec 17, 2003 to Jun 17, 2004. The patent number was EP 0434450 (A2) inventor DALUGE SUSAN MARY [US] and had expired at Jun 26, 2009 to Dec 26, 2009. (Patent).

Conclusion :

ACHENBACH, C., SCARSI, K. & MURPHY, R. 2010. Abacavir/lamivudine fixed-dose combination antiretroviral therapy for the treatment of HIV. Advances in Therapy, 27, 1-16.

CLAY, P. G. 2002. The abacavir hypersensitivity reaction: A review. Clinical Therapeutics, 24, 1502-1514.

DE CLERCQ, E. 2009. The history of antiretrovirals: key discoveries over the past 25 years. Reviews in Medical Virology, 19, 287-299.

FRANCIS, T. 2002. drug design and discovery In: POVL KROGSGAARD-LARSEN, T. L., ULF MADSEN (ed.) 3rd ed ed. London.

HUGHES, D. A., VILAR, F. J., WARD, C. C., ALFIREVIC, A., PARK, B. K. & PIRMOHAMED, M. 2004. Cost-effectiveness analysis of HLA B*5701 genotyping in preventing abacavir hypersensitivity. Pharmacogenetics and Genomics, 14, 335-342.

KOHLER, J., HOSSEINI, S., GREEN, E., FIELDS, E., ABUIN, A., LUDAWAY, T., RUSS, R. & LEWIS, W. 2010. Absence of Mitochondrial Toxicity in Hearts of Transgenic Mice Treated with Abacavir. Cardiovascular Toxicology, 10, 146-151.