1 ABSTRACT 3 6 7 1 8 2 10 3 19 4 22 23 1 24 2 26 3 31 4 34 35 48 58 60 61
(As 4 S 4 ) APL 10 80% P NP (HGAAS) APL APL 7-9 10-12 13-15 51.7 18.7µg/L 61.7 22.7µg/L 62.8 29.1µg/L 2359.1 1910.6µg/L 2834.0 1958.3µg/L 2859.3 2298.2µg/L 5.1 4.06mg/ 6.3 4.98mg/ 6.82 5.58mg/ APL 7-9 13-15 20.7 10.1µg/L 16.1 10.9µg/L 525.5 337.1µg/L 207.1 164.5µg/L 1.76 1.3mg/ 0.42 0.27mg/ 1 2 3 56.6 24.6µg/L 63.2 23.8µg/L 65.8 28.1µg/L 10 9.74 7.97mg/ 0.045~0.45% 106 APL 84 22 ALT AST 2 16.7% 15.5% ALT AST GGT P 0.05 0.5 1 2 3 ALT AST GGT P 0.05 ALP LDH T P ALB A/G TBIL DBIL BUN CRE P 0.05 3 33 2 1 21 63.6% 16 P NP 1
APL 22 ALT AST 63.6% 59.1% 2 3 9 4 2 6 6 2 (As 4 S 4 ) (APL) (HGAAS) (ALT) (AST) 2
Arsenic Absorption Retention and chronic hepatic damage in APL Patients Treated with Tetra-arsenic Tetra-sulfide Abstract In past 10 years,we administered an oral preparation of highly purified crystalline As 4 S 4 to acute promyelocytic leukemia APL patients,we found that oral As 4 S 4 used alone is highly effective,hematologic complete remission rate was high, relapse rate was low,the rate of long-time survival were more than 80%. In order to investigate the absoption retention and chronic hepatic damage of arsenic in APL patients treated with As 4 S 4, we determined the arsenic concentration of the blood urine and hair of APL patients We collected and analysed the periodical liver biochemical examinations and ultrasonography(the size of liver and spleen the echo of liver and spleen parenchyma the breadth of the portal vein ) and hepatic fibrosis indicators P NP and type collagen Quantitative determinations of arsenic levels in samples from APL patients were made with Hydride generation Atomic absorption Spectrometry HGAAS. Blood arsenic level on the 7th-9th day 10th-12th day 13th-15th day after As 4 S 4 began was 51.7 18.7µg/L 61.7 22.7µg/L 62.8 29.1µg/L Urine arsenic level was 2359.1 1910.6µg/L 2834.0 1958.3µg/L 2859.3 2298.2µg/L the average daily urinary arsenic excretion was 5.1 4.06mg/d 6.3 4.98mg/d 6.82 5.58mg/d Blood arsenic level on the 7th-9th day 13th-15th day after therapy was discontinued was 20.7 10.1µg/L 16.1 10.9µg/L Urine arsenic level was 525.5 337.1µg/L 207.1 164.5µg/L the average daily urinary arsenic excretion was 1.76 1.3mg/d 0.42 0.27mg/d The blood arsenic levels of APL patients treated with As 4 S 4 at the first year the second year and the third year were 56.6 24.6µg/L 63.2 23.8µg/L 65.8 28.1µg/L separately The results show that Blood arsenic concentration urine arsenic concentration and daily urinary arsenic excretion reach a steady state after 10 days` treatment with As 4 S 4. we deduce that 9.74 7.97 mg arsenic was absorbed from the intestinal tract each day by each patient in our serious then we deduce that the arsenic 3
absoption efficiency was 0.045~0.45% There was no obvious arsenic retention in blood after long-term As 4 S 4 treatment A total of 106 APL patients maintenance treatment with As 4 S 4 were entered into this study all 106 APL patients were not infected with hepatitis B virus(hbv),they were divided into two groups,the HCV - group includes 84 APL patients without hepatitis C virus infections,the HCV + group includes 22 APL patients with HCV infection. In the HCV - group during the first course the abnomal rate of the ALT and AST was16.7% and 14.5% higher than the two times of the nomal value the ALT AST GGT levels during the first course were statistically elevated compared with As 4 S 4 treatment before P 0.05, there were no statistically differences between the ALT AST GGT levels in half a year one year two year more than three years and treated with As 4 S 4 before P 0.05,other biochemical indicators such as ALP LDH TP ALB A/G TBIL DBIL BUN CRE,there were no siganificantly differences before and after As 4 S 4 treatment P 0.05.In the HCV - group 33 APL patients were examined with ultrosonography two APL patients had splenomegaly one APL patient`s breadth of the portal vein was wider than 1.4cm,21 APL patients had fatty liver 63.6% the hepatic fibrosis indicators P NP and type collagen of the16 APL patients treated with As 4 S 4 more than 3 years were nomal In the HCV + group during the first course the abnomal rate of the ALT AST were 63.6% and 59.1% but at the 2 year more than 3 years there were no siganificantly differences compared with As 4 S 4 treatment before P 0.05 In the HCV + group 9 APL patients were examined with ultrosonography, 4 APL patients had splenomegaly,two APL patients`breadth of portal vein were wider than 1.4cm,6 APL patients had fatty liver 6 patients were examined the hepatic fibrosis indicators 2 patients were higher than the nomal value The above results show that long-term As 4 S 4 treatment had no obvious effects on hepatic function of APL patients there were no obvious hepatic fibrosis and portal hypertention signs in APL patients treated with As 4 S 4 more than 3 years, but the rate of fatty liver was high in APL patients with As 4 S 4 treatment more than 3 years,we need do 4
more work to observe the long-term effects of the As 4 S 4 treatment. Key words Tetra-arsenic tetra-sulfide(as 4 S 4 ) Acute promyelocytic leukemia APL Hydride generation Atomic absorption Spectrometry HGAAS Blood arsenic level Urine arsenic level Daily urinary arsenic excretion Alanine aminotransferase (ALT) Asparate aminotransferase (AST) Fatty liver Noncirrhotic portal hypertention 5
APL 10% 1-3 APL 20 ATRA APL 85~95% 3,5-7 ATRA / APL As 2 O 3 / APL 52~92% 57~88% 8-16 1994 As 4 S 4 APL 19 7 103 1 6 96.7% 87.4% 17-18 APL 87 Fowler`s (1% ) 72-86 APL 106 3 APL P NP, 6
AAS AFS ICP-AES ICP-MS (HGAAS) 114 HGAAS APL 7
1 1.1 1998-10 2002-7 (APL) MIC 112 As 4 S 4 60mg/kg/d 3 14 14 As 4 S 4 X 100% As 2 O 3 As 4 S 4 As 4 S 4 250mg 1.2 4 20 24 24 100 4 2 3 1.3 ( 100 g/ml) GBW09103 ( 360 40 g/l) 1:1 PE-MHS10 PE Aanalyst 100 197.3nm 0.7nm 48 1:5 1. 4 2 0.2 50 5 : : 10:3:2 100 1 130 1 160 1 180 1 250 8
3 4 1.5 25 5 5 1.5 3 3 (1 ) 4 GBW08572 Norin H Vahter M 28 GBW09103 10 150 1.5 10 3 3 (1 ) 4 1. 5 2ml 1 g/ml w/v 0 50 100 200 300 l 0 25 50 100 150 g/l 1.4 GBW09103 0 25 50 100 200µl 0 90 180 360 720µg/L 1.4 1.6 150µg/L 100µg/L 25µg/L 5 1.4 150µg/L 100µg/L 25µg/L 5 1.4 10 3 1. 7 150µg/L 100µg/L 25µg/L 5 1.4 GBW08572 GBW09101 9
1.8 SPSS12.0 t P<0.05 2 2.1 1 2 3 APL APL 1 2 10
2.2 3 APL 1 4 2 5 1 µg/l 0 25 50 100 150 1 0.000 0.043 0.075 0.164 0.253 0.9990 2 0.000 0.039 0.079 0.146 0.220 0.9996 3 0.000 0.046 0.093 0.183 0.249 0.9977 4 0.000 0.044 0.075 0.162 0.255 0.9988 5 0.000 0.040 0.080 0.160 0.239 0.99998 1 2 3 4 5 0.3 0.25 0.2 0.15 0.1 0.05 0 0 50 100 150 200 ug/l) 4 11
2 µg/l 0 90 180 360 720 1 0.000 0.033 0.065 0.13 0.253 0.9999 2 0.000 0.030 0.068 0.128 0.258 0.9998 3 0.000 0.034 0.064 0.127 0.249 0.9999 4 0.000 0.032 0.062 0.125 0.255 0.99994 5 0.000 0.031 0.063 0.12 0.245 0.9998 0.3 1 2 3 4 5 0.25 0.2 0.15 0.1 0.05 0 0 100 200 300 400 500 600 700 800 ug/l 2.3 5 1.3~3.9% 2.9~5.6% 10% 3 4 2ng 5µg/L 20µg/L 3 n=5 X SD µg/l RSD% 25 0.168±0.007 3.6 100 0.288±0.004 1.3 150 0.378±0.015 3.9 12
4 n=5 X SD µg/l RSD% 25 0.170±0.005 2.9 100 0.290±0.013 4.6 150 0.372±0.021 5.6 2. 4 97.3~105.6% 5 GBW08572 GBW09101 6 5 n=5 X±SD µg/l µg/l % 25 25.6± 2.39 102.4±9.6 100 97.3 ±7.67 97.3±7.7 150 146.8 ±15.4 105.6±10.3 6 X SD GBW08572 1.42 0.06 g/g 1.46 0.10 g/g n=28 GBW09101 570 90ng/g 571.6 55.2ng/g n=14 2.5 APL As 4 S 4 APL 7-9 51.7 18.7µg/L n=41 10-12 61.7 22.7µg/L n=30 13-15 62.8 29.1µg/L n=34 7-9 20.7 10.1µg/L n=31 13-15 16.1 10.9µg/L n=34 7 6 t 10-12 7-9 P=0.043 0.05 13-15 10-12 13
P=0.803 0.05 P=0.000 7 (APL) As 4S 4 g/l µg/l 7-9 10-12 13-15 7-9 13-15 µg/l 51.7 61.7 62.8 20.7 16.1 n 41 30 34 31 34 18.7 22.7 29.1 10.1 10.9 µg/l 24.7 31.7 31.7 7.2 5 µg/l 110.4 128.3 145.9 52 41.7 ( g/l) 100 90 80 70 60 50 40 30 20 10 0 0 2 4 6 8 10 12 14-2 -4-6 -8-10 -12-14 6 (APL) As 4S 4 g/l 2 14 2-14 -2-14 2-14 2.6 APL As 4 S 4 APL 7-9 2359.1 1910.6µg/L n=36 10-12 2834.0 1958.3µg/L n=27 13-15 2859.3 2298.2µg/L n=32 7-10 525.5 337.1µg/L n=28 13-15 207.1 164.5µg/L n=28 8 7 14
t 7-9 10-12 P=0.192 0.05 10-12 13-15 P=0.773 0.05 P=0.000 8 (APL) As 4S 4 g/l µg/l 7-9 10-12 13-15 7-9 13-15 µg/l 2359.1 2834.0 2859.3 525.5 207.1 n 36 27 32 28 28 1910.6 1958.3 2298.2 337.1 164.5 µg/l 520.6 591.5 392.6 53.1 20 µg/l 8670.0 8390.7 9330.9 1160.7 709.1 ( g/l) 6000 5000 4000 3000 2000 1000 0 0 2 4 6 8 10 12 14-2 -4-6 -8-10 -12-14 7 (APL) As 4S 4 g/l 2 14 2-14 -2-14 2-14 15