The potential influence of 5-aminosalicylic acid on the induction of myelotoxicity during thiopurine therapy in inflammatory bowel disease patients.
OBJECTIVE
To investigate the potential influence of 5-aminosalicylic acid (5-ASA) on the induction of myelotoxicity during thiopurine therapy in inflammatory bowel disease patients.


METHODS
(a) The retrospective study included inflammatory bowel disease patients treated with azathioprine (AZA)/6-mercaptopurine (6-MP). Thiopurine methyltransferase (TPMT) activity and 6-thioguanine nucleotide (6-TGN) levels were detected at stable medication points. (b) The prospective study was performed in active disease patients: 4 weeks of AZA 50 mg/day followed by concomitant 5-ASA 3 g/day for another 4 weeks. 6-TGN was analyzed at weeks 4 and 8.


RESULTS
(a) Of the 139 retrospective study patients, 45 were on AZA/6-MP+5-ASA and 94 on AZA/6-MP alone. The myelotoxicity rates were 47 and 16%, respectively. Multivariates regression analysis indicated that the administration of concomitant 5-ASA was the only risk factor associated with myelotoxicity (odds ratio=3.45, 95% confidence interval 1.31-9.04, P=0.01). (b) Thiopurine methyltransferase activity was not significantly different between patients on AZA/6-MP+5-ASA and patients on AZA/6-MP alone (P=0.78). (c) 6-TGN levels were significantly higher in samples on AZA/6-MP+5-ASA than those on AZA/6-MP (P=0.003) alone. (d) Sixteen patients completed the prospective study. After 4 weeks on AZA 50 mg/day, 6-TGN levels of 13 patients were less than 230 pmol/8×10 RBC. After another 4 weeks' cotreatment with mesalazine 3 g/day, 12 patients had 6-TGN levels at least 230 pmol/8×10 RBC, five patients had 6-TGN levels at least 420 pmol/8×10 RBC, and two of these five patients developed myelotoxicity.


CONCLUSIONS
The risk of thiopurine-induced myelotoxicity markedly increases in patients treated with combined 5-ASA and 2 mg/kg/day AZA therapy, which may be correlated to the increase in 6-TGN. 50 mg daily AZA when concomitant 5-ASA might help maintain an effective 6-TGN level without increasing the risk of myelotoxicity.
Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, No. 58 Zhongshan Er Road, Guangzhou, People's Republic of China.
Xiang
X
Gao
Fang-bin
FB
Zhang
Liang
L
Ding
Hui
H
Liu
Xue-ding
XD
Wang
Bai-li
BL
Chen
Hui-chang
HC
Bi
Ying-lian
YL
Xiao
Li-zi
LZ
Zhao
Min-hu
MH
Chen
Min
M
Huang
Pin-jin
PJ
Hu
D000293:Adolescent; D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000009:adverse effects; D044466:Asian People; D001379:Azathioprine / Q000008:administration & dosage*; D001853:Bone Marrow / Q000187:drug effects*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004359:Drug Therapy, Combination; D005260:Female; D006150:Guanine Nucleotides / Q000097:blood*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D007223:Infant; D015212:Inflammatory Bowel Diseases / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage*; D019804:Mesalamine / Q000008:administration & dosage / Q000009:adverse effects*; D008780:Methyltransferases / Q000097:blood; D008875:Middle Aged; D011446:Prospective Studies; D012189:Retrospective Studies; D013873:Thionucleotides / Q000097:blood*; D055815:Young Adult
D000894:Anti-Inflammatory Agents, Non-Steroidal; D006150:Guanine Nucleotides; D007166:Immunosuppressive Agents; D013873:Thionucleotides; C003964:6-thioguanylic acid; D019804:Mesalamine; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine