TABLE 1.
Acute and subacute toxicity of STAMPa
| Laboratory parameterb | Acute toxicity
|
Subacute toxicity
|
||||||
|---|---|---|---|---|---|---|---|---|
| Vehicle (n = 50)
|
STAMP (n = 150)
|
Vehicle (n = 110)
|
STAMP (n = 330)
|
|||||
| Mean ± SE (range) | Median (geo mean) | Mean ± SE (range) | Median (geo mean) | Mean ± SE (range) | Median (geo mean) | Mean ± SE (range) | Median (geo mean) | |
| Hematology | ||||||||
| WBC (109/liter) | 4.9 ± 0.3 (1.8-12.3) | 4.7 (4.5) | 5.2 ± 0.2 (1.2-18.9) | 4.6 (4.6) | 6.6 ± 0.6 (2-66.8) | 5.8 (5.7) | 5.7 ± 0.1 (1-17.6) | 5.2 (5.3) |
| ANC (109/liter) | 0.9 ± 0.1 (0.3-2.7) | 0.8 (0.8) | 1 ± 0 (0.1-2.9) | 0.8 (0.8) | 1.5 ± 0.1 (0.2-8.7) | 1.2 (1.1) | 1.5 ± 0.1 (0-6.1) | 1.3 (1.2) |
| ALC (109/liter) | 3.9 ± 0.3 (1.4-11.6) | 3.8 (3.6) | 4.1 ± 0.2 (1-17.2) | 3.5 (3.6) | 4.9 ± 0.5 (0.4-54.1) | 4.1 (4.2) | 4 ± 0.1 (0.8-15.1) | 3.6 (3.7) |
| RBC (1012/liter) | 8.6 ± 0.3 (5.1-12.1) | 8.3 (8.3) | 8.5 ± 0.2 (0.9-16.1) | 8.4 (7.9) | 8.7 ± 0.3 (1.9-19.3) | 8.6 (8.1) | 8.5 ± 0.2 (1-18.4) | 8.5 (8) |
| Renal function or metabolism | ||||||||
| BUN (mg/dl) | 19.7 ± 0.5 (14.1-28) | 19.9 (19.5) | 21 ± 0.4 (13.5-42) | 20 (20.4) | 21.5 ± 0.4 (13.8-34.3) | 20.5 (21.1) | 22.4 ± 0.2 (12.3-46.4) | 21.9 (22.1) |
| Creatinine (mg/dl) | 0.4 ± 0 (0.1-1) | 0.3 (0.3) | 0.3 ± 0 (0-0.9) | 0.3 (0.3) | 0.4 ± 0.1 (0-5) | 0.3 (0.3) | 0.4 ± 0 (0-1.8) | 0.3 (0.3) |
| Albumin (g/dl) | 1.1 ± 0 (1-1.4) | 1.1 (1.1) | 1.1 ± 0 (0.9-1.3) | 1.1 (1.1) | 1.1 ± 0 (0.7-1.6) | 1.1 (1.1) | 1.1 ± 0 (0.8-1.5) | 1.1 (1.1) |
| Total protein (g/dl) | 3.4 ± 0.1 (2.8-4.2) | 3.3 (3.3) | 3.4 ± 0 (2.7-4.3) | 3.3 (3.4) | 3.5 ± 0 (2.7-5.5) | 3.5 (3.5) | 3.5 ± 0 (2.7-4.8) | 3.5 (3.5) |
| Triglycerides (mg/dl) | 94.1 ± 4.9 (49-244) | 88 (89.1) | 104.8 ± 3.6 (43-282) | 95 (97.1) | 91.7 ± 3.8 (38-244) | 87 (84.6) | 102.9 ± 3.1 (10-448) | 90 (91.2) |
| Calcium (mg/dl) | 5.7 ± 0.3 (2-8.2) | 7 (5) | 5.7 ± 0.2 (2-8.3) | 6.9 (5) | 6.6 ± 0.1 (2-8.3) | 6.8 (6.4) | 6.7 ± 0.1 (2-8.6) | 6.9 (6.5) |
| Phosphate (mg/dl) | 6.3 ± 0.1 (4.3-9.4) | 6.4 (6.2) | 6.5 ± 0.1 (3.7-9.3) | 6.5 (6.5) | 5.7 ± 0.1 (2.7-8.6) | 5.6 (5.5) | 5.8 ± 0.1 (1-9.2) | 5.8 (5.6) |
| Liver function | ||||||||
| ALT (IU/liter) | 12 ± 0.5 (4.6-21.9) | 11.3 (11.4) | 12.6 ± 0.4 (2.8-27) | 12.4 (11.8) | 11.4 ± 0.6 (1.5-55.5) | 10.4 (9.9) | 12.5 ± 0.4 (0.6-87.2) | 11 (11.1) |
| AST (IU/liter) | 110.1 ± 8.9 (25-270) | 104 (94.1) | 112.8 ± 5.7 (43-399) | 93 (98.2) | 131.1 ± 10 (19-646) | 91 (105.6) | 138.2 ± 6.3 (5-952) | 104 (110.9) |
| Alkaline phosphatase (IU/liter) | 84.3 ± 2.4 (31.8-115.8) | 84.4 (82.4) | 85.6 ± 1.2 (41.7-121.8) | 85.5 (84.3) | 66 ± 1.8 (5-120.3) | 67.1 (62.5) | 64.8 ± 1 (5-107) | 65.5 (61.6) |
| Total bilirubin (mg/dl) | 0.5 ± 0 (0-1.2) | 0.4 (0.4) | 0.4 ± 0 (0-1.7) | 0.4 (0.4) | 0.4 ± 0 (0.2-1.7) | 0.4 (0.3) | 0.4 ± 0 (0-1.9) | 0.4 (0.3) |
| Pancreas function: amylase (U/liter) | 777.2 ± 15.6 (558.8-1,049.9) | 787.1 (769.3) | 799.4 ± 9.4 (487-1,332.7) | 791 (791.3) | 829.3 ± 31.5 (459-3,058) | 782.6 (792.5) | 811.5 ± 12.9 (462.1-2,442.9) | 764 (787) |
In acute-toxicity experiments, BALB/c mice were treated with a single p.o. bolus of STAMP administered via gavage or an i.p. bolus injection of STAMP at multiple dose levels as detailed in the text. Five mice from each dose group were sacrificed on days 3, 7, and 14, and the remaining 10 mice from each group were sacrificed on day 30. Combined laboratory results from all time points and data points for the 150 STAMP-treated test mice and 50 vehicle-treated control mice are presented as the values for mean ± standard error geometric mean, median, and range (minimum to maximum) of laboratory parameters. Tissues from 133 STAMP-treated and 44 vehicle-treated mice in these experiments were subjected to histopathologic examinations and did not reveal any lesions. In subacute-toxicity experiments, BALB/c mice were treated daily with p.o.-administered STAMP added to their food or with i.p. bolus injections of STAMP at multiple dose levels, for 8 consecutive weeks, as detailed in the text. Five to ten mice per dose group were sacrificed weekly while on therapy. Combined laboratory results from all time points and data points for the 330 STAMP-treated test mice and 110 vehicle-treated control mice are presented as the values for mean ± standard error, geometric mean, median, and range (minimum to maximum) of laboratory parameters. Tissues from 270 STAMP-treated and 90 vehicle-treated mice in these experiments were subjected to histopathologic examinations and did not reveal any lesions.
Abbreviations: WBC, white blood count; ANC, absolute neutrophil count; ALC, absolute lymphocyte count; RBC, red blood count; BUN, blood urea nitrogen; ALT, alanine aminotransferase (glutamic pyruvic transaminase); AST, aspartate aminotransferase (glutamic oxaloacetic transaminase).