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First, its dosing is complex.<ref name="pmid17897242">{{cite journal |pages=391–5 |doi=10.1111/j.1525-139X.2007.00270.x |title=Allopurinol Dosing in Renal Impairment: Walking the Tightrope Between Adequate Urate Lowering and Adverse Events |year=2007 |last1=Dalbeth |first1=Nicola |last2=Stamp |first2=Lisa |journal=Seminars in Dialysis |volume=20 |issue=5 |pmid=17897242}}</ref> Second, some patients are hypersensitive to the drug,<ref name="pmid20509717">{{cite journal |author= Tsai TF, Yeh TY. |title= Allopurinol in dermatology |journal= Am J Clin Dermatol. |volume= 11 |issue=4 |pages=225–232 |year=2010 |pmid=20509717 |doi=10.2165/11533190-000000000-00000}}</ref> therefore its use requires careful monitoring. Allopurinol has rare but potentially fatal adverse effects involving the skin. The most serious adverse effect is a hypersensitivity syndrome consisting of fever, skin rash, [[eosinophilia]], [[hepatitis]], worsened renal function, and, in some cases, allopurinol hypersensitivity syndrome.<ref name="pmid20509717"/> Allopurinol is one of the drugs commonly known to cause [[Stevens–Johnson syndrome]] (SJS) and [[toxic epidermal necrolysis]] (TENS), two life-threatening [[dermatology|dermatological]] conditions.<ref name="pmid7477195">{{cite journal| author=Roujeau JC| title=Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis | journal=N Engl J Med | year= 1995 | volume= 333 | issue= 24 | pages= 1600–7 | pmid=7477195 | doi=10.1056/NEJM199512143332404 | pmc= | url=| author-separator=,| author2=Kelly JP| author3=Naldi L| author4=Rzany B| author5=Stern RS| author6=Anderson T| display-authors=6| last7=Auquier| first7=Ariane| last8=Bastuji-Garin| first8=Sylvie| last9=Correia| first9=Osvaldo| first10=Francesco| first11=Maja }}</ref> More common is a less-serious rash that leads to discontinuing this drug.
First, its dosing is complex.<ref name="pmid17897242">{{cite journal |pages=391–5 |doi=10.1111/j.1525-139X.2007.00270.x |title=Allopurinol Dosing in Renal Impairment: Walking the Tightrope Between Adequate Urate Lowering and Adverse Events |year=2007 |last1=Dalbeth |first1=Nicola |last2=Stamp |first2=Lisa |journal=Seminars in Dialysis |volume=20 |issue=5 |pmid=17897242}}</ref> Second, some patients are hypersensitive to the drug,<ref name="pmid20509717">{{cite journal |author= Tsai TF, Yeh TY. |title= Allopurinol in dermatology |journal= Am J Clin Dermatol. |volume= 11 |issue=4 |pages=225–232 |year=2010 |pmid=20509717 |doi=10.2165/11533190-000000000-00000}}</ref> therefore its use requires careful monitoring. Allopurinol has rare but potentially fatal adverse effects involving the skin. The most serious adverse effect is a hypersensitivity syndrome consisting of fever, skin rash, [[eosinophilia]], [[hepatitis]], worsened renal function, and, in some cases, allopurinol hypersensitivity syndrome.<ref name="pmid20509717"/> Allopurinol is one of the drugs commonly known to cause [[Stevens–Johnson syndrome]] (SJS) and [[toxic epidermal necrolysis]] (TENS), two life-threatening [[dermatology|dermatological]] conditions.<ref name="pmid7477195">{{cite journal| author=Roujeau JC| title=Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis | journal=N Engl J Med | year= 1995 | volume= 333 | issue= 24 | pages= 1600–7 | pmid=7477195 | doi=10.1056/NEJM199512143332404 | pmc= | url=| author-separator=,| author2=Kelly JP| author3=Naldi L| author4=Rzany B| author5=Stern RS| author6=Anderson T| display-authors=6| last7=Auquier| first7=Ariane| last8=Bastuji-Garin| first8=Sylvie| last9=Correia| first9=Osvaldo| first10=Francesco| first11=Maja }}</ref> More common is a less-serious rash that leads to discontinuing this drug.
Studies have found HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions that include Steven Johnson Syndrome and toxic epidermal necrosis caused by allopurinol.<ref>{{cite journal |pmid=15743917 |year=2005 |last1=Hung |first1=SI |last2=Chung |first2=WH |last3=Liou |first3=LB |last4=Chu |first4=CC |last5=Lin |first5=M |last6=Huang |first6=HP |last7=Lin |first7=YL |last8=Lan |first8=JL |last9=Yang |first9=LC |title=HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol |volume=102 |issue=11 |pages=4134–9 |doi=10.1073/pnas.0409500102 |pmc=554812 |journal=Proceedings of the National Academy of Sciences of the United States of America |last10=Hong |first10=H.-S. |last11=Chen |first11=M.-J. |last12=Lai |first12=P.-C. |last13=Wu |first13=M.-S. |last14=Chu |first14=C.-Y. |last15=Wang |first15=K.-H. |last16=Chen |first16=C.-H. |last17=Fann |first17=C. S. J. |last18=Wu |first18=J.-Y. |last19=Chen |first19=Y.-T.}}</ref>


More rarely, allopurinol can also result in the depression of bone marrow elements, leading to [[cytopenia]]s, as well as [[aplastic anemia]]. Moreover, allopurinol can also cause [[peripheral neuritis]] in some patients, although this is a rare side effect. Another side effect of allopurinol is [[interstitial nephritis]].<ref>{{cite book|last=Marc E. De Broe, William M. Bennett, George A. Porter |first=|title=Clinical Nephrotoxins: Renal Injury from Drugs and Chemicals |url=http://books.google.com/?id=sLM8F-IBgNcC&pg=PA317&dq=interstitial+nephritis+allopurinol#v=onepage&q=interstitial%20nephritis%20allopurinol&f=false|year=2003|publisher=[[Springer Science+Business Media]]|quote=Acute interstitial nephritis has also been reported associated with by the administration of allopurinol.|isbn=9781402012778}}</ref>
More rarely, allopurinol can also result in the depression of bone marrow elements, leading to [[cytopenia]]s, as well as [[aplastic anemia]]. Moreover, allopurinol can also cause [[peripheral neuritis]] in some patients, although this is a rare side effect. Another side effect of allopurinol is [[interstitial nephritis]].<ref>{{cite book|last=Marc E. De Broe, William M. Bennett, George A. Porter |first=|title=Clinical Nephrotoxins: Renal Injury from Drugs and Chemicals |url=http://books.google.com/?id=sLM8F-IBgNcC&pg=PA317&dq=interstitial+nephritis+allopurinol#v=onepage&q=interstitial%20nephritis%20allopurinol&f=false|year=2003|publisher=[[Springer Science+Business Media]]|quote=Acute interstitial nephritis has also been reported associated with by the administration of allopurinol.|isbn=9781402012778}}</ref>


It is suspected to cause congenital malformations in a newborn infant whose mother was on allopurinol treatment through the pregnancy, and should be avoided whenever possible by women trying to conceive or during pregnancy.<ref name="AJMG">{{cite journal |doi=10.1002/ajmg.a.34139 |title=Potential teratogenic effects of allopurinol: A case report |year=2011 |last1=Kozenko |first1=Mariya |last2=Grynspan |first2=David |last3=Oluyomi-Obi |first3=Titi |last4=Sitar |first4=Daniel |last5=Elliott |first5=Alison M. |last6=Chodirker |first6=Bernard N. |journal=American Journal of Medical Genetics Part A |volume=155 |issue=9 |pages=2247–52 |pmid=21815259}}</ref>
It is suspected to cause congenital malformations in a newborn infant whose mother was on allopurinol treatment through the pregnancy, and should be avoided whenever possible by women trying to conceive or during pregnancy.<ref name="AJMG">{{cite journal |doi=10.1002/ajmg.a.34139 |title=Potential teratogenic effects of allopurinol: A case report |year=2011 |last1=Kozenko |first1=Mariya |last2=Grynspan |first2=David |last3=Oluyomi-Obi |first3=Titi |last4=Sitar |first4=Daniel |last5=Elliott |first5=Alison M. |last6=Chodirker |first6=Bernard N. |journal=American Journal of Medical Genetics Part A |volume=155 |issue=9 |pages=2247–52 |pmid=21815259}}</ref>

===Pharmacogenetics===

Studies have found the HLA-B*5801 allele to be a genetic marker for allopurinol-induced severe cutaneous adverse reactions, including [[Stevens-Johnson Syndrome]] and [[toxic epidermal necrolysis]].<ref>http://www.pharmgkb.org/haplotype/PA165956630#tabview=tab3&subtab=</ref><ref>http://www.pharmgkb.org/pathway/PA165980774</ref> The frequency of the HLA-B*5801 allele varies between ethnicities: Han Chinese and Thai populations have HLA-B*5801 [[allele frequency|allele frequencies]] of around 8%, as compared to European and Japanese populations, who have [[allele frequency|allele frequencies]] of around 1% and 0.5%, respectively<ref>http://www.allelefrequencies.net</ref>. The increase in risk for developing allopurinol-induced [[Stevens-Johnson Syndrome]] or [[toxic epidermal necrolysis]] in individuals with the HLA-B*5801 allele (as compared to those who do not have this allele) is very high, ranging from a 40-fold to a 580-fold increase in risk, depending on ethnicity.<ref>http://www.pharmgkb.org/haplotype/PA165956630#tabview=tab3&subtab=</ref><ref>http://www.pharmgkb.org/pathway/PA165980774</ref> Currently, the FDA-approved drug label for allopurinol does not contain any information regarding this increased risk, though FDA scientists did publish a study in 2011 which reported a strong, reproducible and consistent association between the allele and allopurinol-induced [[Stevens-Johnson Syndrome]] and [[toxic epidermal necrolysis]].<ref>{{cite journal|author= Zineh I, Mummaneni P, Lyndly J ''et al.''
|title=Allopurinol pharmacogenetics: assessment of potential clinical usefulness|journal=Pharmacogenomics|volume=12 |issue=12|pages=1741-9|date=December 2011|pmid= 22118056|pmc=|doi=10.2217/pgs.11.131|url=}}</ref> However, The American College of Rheumatology recommends screening for HLA-B*5801 in high risk populations (e.g. Koreans with stage 3 or worse chronic kidney disease and those of Han Chinese and Thai descent), and prescribing patients who are positive for the allele an alternative drug.<ref>{{cite journal|author= Khanna D, Fitzgerald JD, Khanna PP ''et al.'' |title=2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia|journal= Arthritis Care Res (Hoboken)|volume=64|issue=10|pages=1431-46|date=October 2012|pmid= 23024028 |pmc=3683400|doi=10.1002/acr.21772|url=}}</ref>. The [http://www.pharmgkb.org/page/cpic Clinical Pharmacogenetics Implementation Consortium] guidelines state that allopurinol is contraindicated in known carriers of the HLA-B*5801 allele <ref>http://www.pharmgkb.org/guideline/PA166105003</ref><ref>{{cite journal|author=Hershfield MS, Callaghan JT, Tassaneeyakul W ''et al.''|title=Clinical Pharmacogenetics Implementation Consortium guidelines for human leukocyte antigen-B genotype and allopurinol dosing|journal=Clin Pharmacol Ther|volume=93|issue=2|pages=153-8|date=February 2013|pmid=23232549|pmc=3564416|doi=10.1038/clpt.2012.209|url=}}</ref>.


== Mechanism of action ==
== Mechanism of action ==

Revision as of 21:59, 1 August 2014

Not to be confused with Enalapril.
Allopurinol
Clinical data
Trade namesZyloprim
AHFS/Drugs.comMonograph
MedlinePlusa682673
Pregnancy
category
  • C(USA)
Routes of
administration		tablet (100, 300 mg)
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability78±20%
Protein bindingNegligible
Metabolismhepatic (80% oxypurinol, 10% allopurinol ribosides)
Elimination half-life2 h (oxypurinol 18-30 h)
Identifiers
  • 1H-pyrazolo[3,4-d]pyrimidin-4(2H)-one
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.005.684 Edit this at Wikidata
Chemical and physical data
FormulaC5H4N4O
Molar mass136.112 g/mol g·mol−1
3D model (JSmol)
  • c1c2c([nH]n1)ncnc2O
  • InChI=1S/C5H4N4O/c10-5-3-1-8-9-4(3)6-2-7-5/h1-2H,(H2,6,7,8,9,10) checkY
  • Key:OFCNXPDARWKPPY-UHFFFAOYSA-N checkY
  (verify)

Allopurinol (Zyloprim, and generics) is a drug used primarily to treat hyperuricemia (excess uric acid in blood plasma) and its complications, including chronic gout.[1] It is a xanthine oxidase inhibitor which is administered orally.

It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.[2]

Medical uses

Gout and hyperuricemia

Subsequently the uric acid lowering capacity of allopurinol was noted and the drug went on to be developed for its more famous use: to treat hyperuricemia (excess uric acid in blood plasma) and its complications.[3] Allopurinol does not alleviate acute attacks of gout,[4] and there is currently controversy over the issue of whether it can actually make acute gout attacks worse initially, but is useful in chronic gout to prevent future attacks.

Tumor lysis syndrome

Allopurinol was also commonly used to treat tumor lysis syndrome in chemotherapeutic treatments as these regimes can rapidly produce severe acute hyperuricemia, although it has gradually been replaced by urate oxidase therapy.[5]

Thiopurine co-therapy

Allopurinol can cause severe pancytopenia if given with full-dose mercaptopurine or its pro-drug azathioprine, due to the inhibition of xanthine oxidase that metabolizes mercaptopurine.[6] For this reason, allopurinol has been strongly contraindicated during thiopurine therapy in the past. However, in recent years the use of allopurinol in combination with azathioprine or mercaptopurine has been revived. First, it was shown that an azathioprine/allopurinol combination significantly improved renal transplant graft survival.[7] More recently, it was discovered that this co-therapy greatly improves the outcome for patients that do not respond to thiopurine monotherapy when treating inflammatory bowel disease (IBD), specifically Crohn's disease.[8] Co-therapy has also been shown to greatly improve hepatoxicity side effects in treatment of IBD.[9] Co-therapy invariably requires dose reduction of the thiopurine, usually to 1/3 of the standard dose depending upon the patient's genetic status for thiopurine methyltransferase (TPMT).[10]

Reperfusion injury

Other established indications for allopurinol therapy include ischemic reperfusion injury, kidney stones with a uric acid component (uric acid nephrolithiasis), and protozoal infections (Leishmaniasis).

Renal disease, Heart failure and Angina

Allopurinol can be used in patients with poor kidney function, but it may also help them. A study of allopurinol use in patients with chronic kidney disease suggested that "Allopurinol decreases C-reactive protein and slows down the progression of renal disease in patients with chronic kidney disease. In addition, allopurinol reduces cardiovascular and hospitalization risk in these subjects."[11]

A mechanistic study in patients with chronic heart failure has shown that the actions of allopurinol may be due to its inhibition of xanthine oxidase rather than a urate-lowering effect. This study also showed for the first time that a high dose (600 mg) is significantly better at improving endothelial function compared to standard doses.[12]

A recent study has suggested that allopurinol may help reduce the effects of angina in ischaemic heart disease by reducing the workload on the heart.[13]

Epilepsy

Allopurinol is used as an add-on drug for refractory epilepsy, because it is an adenosine agonist, which inhibits glutamine release from excitatory neurons, but does not change the plasma concentration of other epilepsy drugs.[14]

Blood pressure

Allopurinol can decrease blood pressure reducing hypertension.[15]

Side-effects

Because allopurinol is not a uricosuric, it can be used in patients with poor kidney function. However, allopurinol has two important disadvantages.

First, its dosing is complex.[16] Second, some patients are hypersensitive to the drug,[17] therefore its use requires careful monitoring. Allopurinol has rare but potentially fatal adverse effects involving the skin. The most serious adverse effect is a hypersensitivity syndrome consisting of fever, skin rash, eosinophilia, hepatitis, worsened renal function, and, in some cases, allopurinol hypersensitivity syndrome.[17] Allopurinol is one of the drugs commonly known to cause Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TENS), two life-threatening dermatological conditions.[18] More common is a less-serious rash that leads to discontinuing this drug.

More rarely, allopurinol can also result in the depression of bone marrow elements, leading to cytopenias, as well as aplastic anemia. Moreover, allopurinol can also cause peripheral neuritis in some patients, although this is a rare side effect. Another side effect of allopurinol is interstitial nephritis.[19]

It is suspected to cause congenital malformations in a newborn infant whose mother was on allopurinol treatment through the pregnancy, and should be avoided whenever possible by women trying to conceive or during pregnancy.[20]

Pharmacogenetics

Studies have found the HLA-B*5801 allele to be a genetic marker for allopurinol-induced severe cutaneous adverse reactions, including Stevens-Johnson Syndrome and toxic epidermal necrolysis.[21][22] The frequency of the HLA-B*5801 allele varies between ethnicities: Han Chinese and Thai populations have HLA-B*5801 allele frequencies of around 8%, as compared to European and Japanese populations, who have allele frequencies of around 1% and 0.5%, respectively[23]. The increase in risk for developing allopurinol-induced Stevens-Johnson Syndrome or toxic epidermal necrolysis in individuals with the HLA-B*5801 allele (as compared to those who do not have this allele) is very high, ranging from a 40-fold to a 580-fold increase in risk, depending on ethnicity.[24][25] Currently, the FDA-approved drug label for allopurinol does not contain any information regarding this increased risk, though FDA scientists did publish a study in 2011 which reported a strong, reproducible and consistent association between the allele and allopurinol-induced Stevens-Johnson Syndrome and toxic epidermal necrolysis.[26] However, The American College of Rheumatology recommends screening for HLA-B*5801 in high risk populations (e.g. Koreans with stage 3 or worse chronic kidney disease and those of Han Chinese and Thai descent), and prescribing patients who are positive for the allele an alternative drug.[27]. The Clinical Pharmacogenetics Implementation Consortium guidelines state that allopurinol is contraindicated in known carriers of the HLA-B*5801 allele [28][29].

Mechanism of action

Allopurinol is a purine analog; it is a structural isomer of hypoxanthine (a naturally occurring purine in the body) and is an inhibitor of the enzyme xanthine oxidase.[1] Xanthine oxidase is responsible for the successive oxidation of hypoxanthine and xanthine, resulting in the production of uric acid, the product of human purine metabolism.[1] In addition to blocking uric acid production, inhibition of xanthine oxidase causes an increase in hypoxanthine and xanthine. While xanthine cannot be converted to purine ribotides, hypoxanthine can be salvaged to the purine ribotides adenosine and guanosine monophosphates. Increased levels of these ribotides may cause feedback inhibition of amidophosphoribosyl transferase, the first and rate-limiting enzyme of purine biosynthesis. Allopurinol, therefore, decreases uric acid formation and may also inhibit purine synthesis.[30]

History

Allopurinol was first synthesized and reported in 1956 by Roland K. Robins (1926-1992), in a search for antineoplasitic agents.[31]

Allopurinol inhibits the breakdown (catabolism) of the thiopurine drug mercaptopurine, and it was later employed by Gertrude Elion to enhance the action of mercaptopurine in the treatment of acute lymphoblastic leukemia.[3] However, no improvement in leukemia response was noted with mercaptopurine-allopurinol co-therapy, and this use of the drug was abandoned.

Metabolism

A common misconception is that allopurinol is metabolized by its target, xanthine oxidase, but this action is principally carried out by Aldehyde oxidase.[32] The active metabolite of allopurinol is oxypurinol, which is also an inhibitor of xanthine oxidase. Allopurinol is almost completely metabolized to oxypurinol within two hours of oral administration, whereas oxypurinol is slowly excreted by the kidneys over 18–30 hours. For this reason, oxypurinol is believed responsible for the majority of allopurinol's effect.[33]

Brand names

Pure Allopurinol is a white powder

Allopurinol has been marketed in the United States since August 19, 1966, when it was first approved by FDA under the trade name of Zyloprim.[34] Allopurinol was marketed at the time by Burroughs-Wellcome. Allopurinol is now a generic drug sold under a variety of brand names including Allohexal, Allosig, Milurit, Alloril, Progout, Zyloprim, Zyloric, Zyrik and Aluron.[35]

Synthesis

Allopurinol synthesis.[36]

References

  1. ^ a b c Pacher, P.; Nivorozhkin, A; Szabó, C (2006). "Therapeutic Effects of Xanthine Oxidase Inhibitors: Renaissance Half a Century after the Discovery of Allopurinol". Pharmacological Reviews. 58 (1): 87–114. doi:10.1124/pr.58.1.6. PMC 2233605. PMID 16507884.
  2. ^ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
  3. ^ a b Elion GB. (1989). "The purine path to chemotherapy (Nobel lecture in physiology or medicine - 1988)". Science. 244 (4900): 41–47. doi:10.1126/science.2649979. PMID 2649979.
  4. ^ Taylor, MD, TH; Mecchella JN; Larson RJ; Kerin KD; Mackenzie TA (November 2012). "Initiation of allopurinol at first medical contact for acute attacks of gout: a randomized clinical trial". JAMA. 125 (11): 1126–1134. doi:10.1016/j.amjmed.2012.05.025. PMID 23098865.
  5. ^ Jeha S. (2001). "Tumor lysis syndrome". Semin Hematol. 38 (4 Suppl 10): 4–8. doi:10.1016/S0037-1963(01)90037-X. PMID 11694945.
  6. ^ Evans WE. (2004). "Pharmacogenetics of thiopurine S-methyltransferase and thiopurine therapy". Ther Drug Monit. 26 (2): 186–91. doi:10.1097/00007691-200404000-00018. PMID 15228163. {{cite journal}}: |first10= missing |last10= (help); |first11= missing |last11= (help); |first2= missing |last2= (help); |first3= missing |last3= (help); |first4= missing |last4= (help); |first5= missing |last5= (help); |first6= missing |last6= (help); |first7= missing |last7= (help); |first8= missing |last8= (help); |first9= missing |last9= (help)
  7. ^ Chocair PR, Duley JA, Simmonds HA; et al. (1993). "Low dose allopurinol, plus azathioprine/ cyclosporin/ prednisolone, a novel immunosuppressive regimen". Lancet. 342 (8863): 83–84. doi:10.1016/0140-6736(93)91287-V. PMID 8100914. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  8. ^ Sparrow MP, Hande SA, Friedman S; et al. (2007). "Effect of allopurinol on clinical outcomes in inflammatory bowel disease nonresponders to azathioprine or 6-mercaptopurine". Clin Gastroenterol Hepatol. 5 (2): 209–214. doi:10.1016/j.cgh.2006.11.020. PMID 17296529. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  9. ^ Ansari AR, Patel N, Sanderson J; et al. (2010). "Low dose azathioprine or 6-mercaptopurine in combination with allopurinol can bypass many adverse drug reactions in patients with inflammatory bowel disease". Aliment Pharmacol Ther. 31 (6): 640–647. doi:10.1111/j.1365-2036.2009.04221.x. PMID 20015102. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  10. ^ Ansari AR, Duley JA. (March 2012). "Azathioprine co-therapy with allopurinol for inflammatory bowel disease: trials and tribulations". Rev Assoc Med Bras. 58 (Suppl.1): S28–33.
  11. ^ Goicoechea, M.; De Vinuesa, S. G.; Verdalles, U.; Ruiz-Caro, C.; Ampuero, J.; Rincón, A.; Arroyo, D.; Luño, J. (2010). "Effect of Allopurinol in Chronic Kidney Disease Progression and Cardiovascular Risk". Clinical Journal of the American Society of Nephrology. 5 (8): 1388–93. doi:10.2215/CJN.01580210. PMC 2924417. PMID 20538833..
  12. ^ George, J; Carr, E; Davies, J; Belch, JJ; Struthers, A (2006). "High-dose allopurinol improves endothelial function by profoundly reducing vascular oxidative stress and not by lowering uric acid". Circulation. 114 (23): 2508–16. doi:10.1161/CIRCULATIONAHA.106.651117. PMID 17130343.
  13. ^ "Gout drug 'can prevent angina pain of heart disease'". BBC News. 8 June 2010.
  14. ^ Drug-Resistant Epilepsy N Engl J Med 2011; 365:2238-2240December 8, 2011
  15. ^ Feig, D. I.; Soletsky, B.; Johnson, R. J. (2008). "Effect of Allopurinol on Blood Pressure of Adolescents with Newly Diagnosed Essential Hypertension: A Randomized Trial". JAMA: the Journal of the American Medical Association. 300 (8): 924–32. doi:10.1001/jama.300.8.924. {{cite journal}}: Unknown parameter |laydate= ignored (help); Unknown parameter |laysource= ignored (help); Unknown parameter |laysummary= ignored (help)
  16. ^ Dalbeth, Nicola; Stamp, Lisa (2007). "Allopurinol Dosing in Renal Impairment: Walking the Tightrope Between Adequate Urate Lowering and Adverse Events". Seminars in Dialysis. 20 (5): 391–5. doi:10.1111/j.1525-139X.2007.00270.x. PMID 17897242.
  17. ^ a b Tsai TF, Yeh TY. (2010). "Allopurinol in dermatology". Am J Clin Dermatol. 11 (4): 225–232. doi:10.2165/11533190-000000000-00000. PMID 20509717.
  18. ^ Roujeau JC; Kelly JP; Naldi L; Rzany B; Stern RS; Anderson T; et al. (1995). "Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis". N Engl J Med. 333 (24): 1600–7. doi:10.1056/NEJM199512143332404. PMID 7477195. {{cite journal}}: |first10= missing |last10= (help); |first11= missing |last11= (help); Unknown parameter |author-separator= ignored (help)
  19. ^ Marc E. De Broe, William M. Bennett, George A. Porter (2003). Clinical Nephrotoxins: Renal Injury from Drugs and Chemicals. Springer Science+Business Media. ISBN 9781402012778. Acute interstitial nephritis has also been reported associated with by the administration of allopurinol.{{cite book}}: CS1 maint: multiple names: authors list (link)
  20. ^ Kozenko, Mariya; Grynspan, David; Oluyomi-Obi, Titi; Sitar, Daniel; Elliott, Alison M.; Chodirker, Bernard N. (2011). "Potential teratogenic effects of allopurinol: A case report". American Journal of Medical Genetics Part A. 155 (9): 2247–52. doi:10.1002/ajmg.a.34139. PMID 21815259.
  21. ^ http://www.pharmgkb.org/haplotype/PA165956630#tabview=tab3&subtab=
  22. ^ http://www.pharmgkb.org/pathway/PA165980774
  23. ^ http://www.allelefrequencies.net
  24. ^ http://www.pharmgkb.org/haplotype/PA165956630#tabview=tab3&subtab=
  25. ^ http://www.pharmgkb.org/pathway/PA165980774
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Further reading

  • The Third International Thiopurine Symposium 2010, published in RAMB, for information on Allopurinol co-therapy: [1]

External links

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