Background
Methods
Preparation of α –Tocopheryloxyacetic acid lysine salt in capsules
Animal studies
Group | Number of animals (M/F) | Test article | Nominal dose level (mg/kg/day) | Actual dose levela
| Number of animals for necropsy (M/F) | |
---|---|---|---|---|---|---|
Terminal (Day 29) | Recovery (Day 57) | |||||
1 | 6/6 | Vehicle | 0 | 0 | 4/4 | 2/2 |
2 | 4/4 | α-TEA | 100 | 130 | 4/4 | - |
3 | 6/6 | α-TEA | 300 | 390 | 4/4 | 2/2 |
4 | 6/6 | α-TEA | 1500 | 1950 | 4/4 | 2/2 |
Toxicokinetics studies
Data collection
Sample preparation and High Performance Liquid Chromatography (HPLC) analysis
Statistical analysis
Results
Anti-tumor activity of α-TEA lysine salt
Test article | Dose level (mg/kg) | Tmax (hr) | T½ (hr) | Cmax (ug/mL) | AUC0-24 (hr*ug/mL) | AUC0-∞ (hr/*ug/mL) |
---|---|---|---|---|---|---|
α-TEA Free Acid | 100 | 8 | 54.6 | 20.4 | 1,180 | 1,670 |
α-TEA Lysine Acid | 200 | 4 | 54. | 29.4 | 1,680 | 2,470 |
α-TEA Free Acid | 200 | 24 | 50.2 | 14.7 | 1,020 | 1,400 |
Repeat daily dosing of α-TEA Lysine Salt did not cause gross toxicity
Clinical pathology (erythroid, leukocytes, coagulation parameters, serum chemistry and urinalysis) of α-TEA-treated animals
Vehicle | 100 mg/kg | 300 mg/kg | 1500 mg/kg | Unit | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Mean | SD | N | Mean | SD | N | Mean | SD | N | Mean | SD | N | |||
Males | Erythrocytes | |||||||||||||
Red blood cells | 6.315 | 0.485 | 6 | 6.418 | 0.316 | 4 | 6.523 | 0.211 | 6 | 6.74 | 0.416 | 6 | M/ul | |
Hemoglobin | 13.98 | 1.13 | 6 | 13.83 | 0.71 | 4 | 14.43 | 0.48 | 6 | 14.8 | 1.21 | 6 | g/L | |
Hematocrit | 43.18 | 3.51 | 6 | 43.08 | 1.54 | 4 | 44 | 1.5 | 6 | 45.23 | 3.2 | 6 | % | |
Mean corpuscular volume | 63.38 | 0.97 | 6 | 67.18 | 1.55 | 4 | 67.52 | 2.46 | 6 | 67.1 | 1.42 | 6 | fL | |
Mean corpuscular hemoglobin | 22.1 | 0.3 | 6 | 21.58 | 0.62 | 4 | 22.12 | 0.78 | 6 | 21.95 | 0.76 | pg | ||
Mean corpuscular hemoglobin concentration | 32.37 | 0.18 | 6 | 32.13 | 0.61 | 4 | 32.73 | 0.2 | 6 | 32.73 | 0.56 | 6 | g/dL | |
Reticulocytes | 24.63 | 13.54 | 6 | 29.25 | 7.68 | 4 | 22.28 | 5.7 | 6 | 21.75 | 10 | 6 | 109/L | |
Leukocytes | ||||||||||||||
White blood cells | 7.473 | 1.869 | 6 | 7.373 | 1.858 | 4 | 9.175 | 2.951 | 6 | 7.103 | 1.64 | 6 | K/uL | |
Neutrophils | 1.207 | 1.602 | 6 | 3.9 | 1.37 | 4 | 5.428 | 2.489 | 6 | 3.943 | 1.249 | 6 | K/uL | |
Lymphocytes | 2.473 | 0.55 | 6 | 2.69 | 0.506 | 4 | 2.638 | 0.788 | 6 | 2.445 | 0.445 | 6 | K/uL | |
Monocytes | 0.512 | 0.275 | 6 | 0.54 | 0.083 | 4 | 0.668 | 0.413 | 6 | 0.375 | 0.121 | 6 | K/uL | |
Eosinophils | 0.128 | 0.077 | 6 | 0.14 | 0.022 | 4 | 0.282 | 0.171 | 6 | 0.193 | 0.108 | 6 | K/uL | |
Basophils | 0.093 | 0.051 | 6 | 0.063 | 0.021 | 4 | 0.09 | 0.029 | 6 | 0.082 | 0.018 | 4 | K/uL | |
Thrombocytes | ||||||||||||||
Platelets | 381.7 | 39.4 | 6 | 330.8 | 80.1 | 4 | 427.8 | 82.2 | 6 | 360 | 57.4 | 6 | K/uL | |
Mean platelet volume | 12.38 | 1.52 | 6 | 14.28 | 2.15 | 4 | 12.62 | 1.17 | 6 | 13.53 | 0.9 | 6 | fL | |
Protrombin time | 6.63 | 0.24 | 6 | 6.88 | 0.17 | 4 | 6.8 | 0.3 | 6 | 6.85 | 0.19 | 6 | Seconds | |
Activated partial thromboplastin time | 13.12 | 0.82 | 6 | 12.9 | 0.66 | 4 | 13.83 | 0.81 | 6 | 13.33 | 0.83 | 6 | Seconds | |
Fibrinogen | 270.2 | 47.3 | 6 | 312.5 | 47.5 | 4 | 282 | 44.6 | 6 | 259.8 | 56.7 | 6 | Mg/dL | |
Females | Erythrocytes | |||||||||||||
Red blood cells | 6.562 | 0.322 | 6 | 6.788 | 0.297 | 4 | 6.49 | 0.417 | 6 | 6.59 | 0.344 | 6 | M/ul | |
Hemoglobin | 14.62 | 0.8 | 6 | 15.43 | 0.77 | 4 | 14.12 | 1.52 | 6 | 14.7 | 0.79 | 6 | g/L | |
Hematocrit | 45.15 | 2.42 | 6 | 46.98 | 2.33 | 4 | 43.78 | 3.88 | 6 | 45.22 | 2.26 | 6 | % | |
Mean corpuscular volume | 68.82 | 2.46 | 6 | 69.2 | 1.83 | 4 | 67.4 | 2.3 | 6 | 68.63 | 1.52 | 6 | fL | |
Mean corpuscular volume hemoglobin | 22.3 | 0.58 | 6 | 22.75 | 0.83 | 4 | 21.73 | 1.12 | 6 | 22.32 | 0.61 | 6 | Pg | |
Mean corpuscular hemoglobin concentration | 32.4 | 0.41 | 6 | 32.85 | 0.31 | 4 | 32.17 | 0.65 | 6 | 32.55 | 0.21 | 6 | g/dL | |
Reticulocytes | 32.4 | 15.63 | 6 | 41.9 | 19.22 | 4 | 34.42 | 14.98 | 6 | 25.3 | 11.84 | 6 | 109/L | |
Leukocytes | ||||||||||||||
White blood cells | 8.123 | 1.412 | 6 | 8.54 | 1.517 | 4 | 8.418 | 2.205 | 6 | 8.655 | 1.246 | 6 | K/uL | |
Neutrophils | 4.873 | 1.151 | 6 | 4.855 | 1.139 | 4 | 4.88 | 1.404 | 6 | 5.457 | 0.986 | 6 | K/uL | |
Lymphocytes | 2.482 | 0.62 | 6 | 2.793 | 0.381 | 4 | 2.578 | 0.459 | 6 | 2.482 | 0.213 | 6 | K/uL | |
Monocytes | 0.473 | 0.079 | 6 | 0.513 | 0.131 | 4 | 0.505 | 0.185 | 6 | 0.353 | 0.119 | 6 | K/uL | |
Eosinophils | 0.15 | 0.14 | 6 | 0.138 | 0.019 | 4 | 0.313 | 0.324 | 6 | 0.197 | 0.072 | 6 | K/uL | |
Basophils | 0.093 | 0.047 | 6 | 0.148 | 0.038 | 4 | 0.08 | 0.029 | 6 | 0.102 | 0.014 | 6 | K/uL | |
Thrombocytes | ||||||||||||||
platelets | 358.8 | 83 | 6 | 350.5 | 81.3 | 4 | 319.2 | 53.1 | 6 | 356.7 | 49.3 | 6 | K/uL | |
Mean platelet volume | 13.23 | 2.08 | 6 | 13.13 | 1.27 | 4 | 13.43 | 1.24 | 6 | 12.85 | 1.05 | 6 | fL | |
Prothrombin time | 6.9 | 0.32 | 6 | 7.03 | 0.25 | 4 | 6.73 | 0.36 | 6 | 6.97 | 0.34 | 6 | Seconds | |
Activated partial thromboplastin time | 13.42 | 0.65 | 6 | 13.4 | 0.41 | 4 | 13.37 | 0.44 | 6 | 13.12 | 0.37 | 6 | Seconds | |
Fibrinogen | 227 | 54.8 | 6 | 225.8 | 90.2 | 4 | 219.2 | 42.6 | 6 | 205.8 | 35.3 | 6 | mg/dL |
Vehicle | 100 mg/kg | 300 mg/kg | 1500 mg/kg | Unit | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Mean | SD | N | Mean | SD | N | Mean | SD | N | Mean | SD | N | |||
Males | Erythrocytes | |||||||||||||
Red blood cells | 6.238 | 0.841 | 4 | 6.438 | 0.598 | 4 | 6.21 | 0.143 | 4 | 6.418 | 0.437 | 4 | M/ul | |
Hemoglobin | 14.55 | 1.91 | 4 | 14.55 | 1.1 | 4 | 6.21 | 0.143 | 4 | 6.418 | 0.437 | 4 | g/L | |
Hematocrit | 42.1 | 6.09 | 4 | 42.18 | 3.27 | 4 | 41.05 | 1.04 | 4 | 41.7 | 2.79 | 4 | % | |
Mean corpuscular volume | 67.45 | 1.1 | 4 | 65.63 | 1.51 | 4 | 66.08 | 2.16 | 4 | 65 | 1.75 | 4 | fL | |
Mean corpuscular hemoglobin | 23.35 | 0.24 | 4 | 22.68 | 0.59 | 4 | 22.9 | 0.64 | 4 | 22.73 | 0.7 | 4 | pg | |
Mean corpuscular hemoglobin concentration | 34.6 | 0.47 | 4 | 34.6 | 0.37 | 4 | 34.63 | 0.33 | 4 | 34.9 | 0.51 | 4 | g/dL | |
Reticulocytes | 42.73 | 11.31 | 4 | 58.65 | 15.92 | 4 | 46 | 11.97 | 4 | 24.55 | 3.67 | 4 | 109/L | |
Leukocytes | ||||||||||||||
White blood cells | 7.438 | 0.919 | 4 | 9.23 | 1.25 | 4 | 12.23 | 3.277 | 4 | 11.91 | 3.574 | 4 | K/uL | |
Neutrophils | 4.183 | 0.937 | 4 | 4.805 | 0.658 | 4 | 7.438 | 3.162 | 4 | 7.193 | 2.464 | 4 | K/uL | |
Lymphocytes | 2.593 | 0.442 | 4 | 3.438 | 0.597 | 4 | 3.56 | 0.326 | 4 | 3.655 | 0.792 | 4 | K/uL | |
Monocytes | 0.43 | 0.153 | 4 | 0.683 | 0.089 | 4 | 0.825 | 0.26 | 4 | 0.565 | 0.14 | 4 | K/uL | |
Eosinophils | 0.095 | 0.039 | 4 | 0.178 | 0.055 | 4 | 0.223 | 0.101 | 4 | 0.388 | 0.328 | 4 | K/uL | |
Basophils | 0.098 | 0.078 | 4 | 0.1 | 0.018 | 4 | 0.138 | 0.038 | 4 | 0.08 | 0.026 | 4 | K/uL | |
Thrombocytes | ||||||||||||||
platelets | 259.8 | 64 | 4 | 281.8 | 44.7 | 4 | 369.5 | 87.3 | 4 | 262.3 | 75.2 | 4 | K/uL | |
Mean platelet volume | 10.95 | 1.11 | 4 | 9.88 | 0.8 | 4 | 9 | 0.87 | 4 | 8.6 | 0.77 | 4 | fL | |
Protrombin time | 6.78 | 0.05 | 4 | 7.08 | 0.19 | 4 | 6.85 | 0.17 | 4 | 6.9 | 0.24 | 4 | Seconds | |
Activated partial thromboplastin time | 12.68 | 1.16 | 4 | 12.7 | 0.84 | 4 | 13.5 | 0.88 | 4 | 13.05 | 1.28 | 4 | Seconds | |
Fibrinogen | 254.5 | 42.7 | 4 | 288.5 | 18.9 | 4 | 289.5 | 85.4 | 4 | 414.5 | 89.9 | 4 | mg/dL | |
Females | Erythrocytes | |||||||||||||
Red blood cells | 6.33 | 0.241 | 4 | 6.895 | 0.563 | 4 | 6.72 | 0.306 | 4 | 6.773 | 0.383 | 4 | M/ul | |
Hemoglobin | 14.85 | 1 | 4 | 16.43 | 1.7 | 4 | 15.55 | 1.1 | 4 | 15.78 | 0.8 | 4 | g/L | |
Hematocrit | 43.33 | 3.14 | 4 | 47.68 | 4.73 | 4 | 45.48 | 3.24 | 4 | 45.98 | 2.05 | 4 | % | |
Mean corpuscular volume | 68.33 | 2.53 | 4 | 69.1 | 1.14 | 4 | 67.83 | 3.07 | 4 | 67.88 | 1.6 | 4 | fL | |
Mean corpuscular volume hemoglobin | 23.45 | 0.71 | 4 | 23.83 | 0.55 | 4 | 23.15 | 1 | 4 | 23.3 | 0.55 | 4 | pg | |
Mean corpuscular hemoglobin concentration | 34.25 | 0.47 | 4 | 69.3 | 23.65 | 4 | 72.85 | 24.88 | 4 | 45.75 | 23.65 | 4 | g/dL | |
Reticulocytes | 34.25 | 0.47 | 4 | 34.5 | 0.24 | 4 | 34.23 | 0.35 | 4 | 34.3 | 0.46 | 4 | 109/L | |
Leukocytes | ||||||||||||||
White blood cells | 8.81 | 3.586 | 4 | 9.75 | 2.4 | 4 | 9.743 | 1.237 | 4 | 13.31 | 1.721 | 4 | K/uL | |
Neutrophils | 5.293 | 3.009 | 4 | 4.928 | 1.273 | 4 | 5.32 | 1.312 | 4 | 8.193 | 1.654 | 4 | K/uL | |
Lymphocytes | 2.693 | 0.318 | 4 | 3.575 | 0.702 | 4 | 3.358 | 0.543 | 4 | 3.985 | 0.625 | 4 | K/uL | |
Monocytes | 0.548 | 0.218 | 4 | 0.495 | 0.071 | 4 | 0.648 | 0.083 | 4 | 0.665 | 0.281 | 4 | K/uL | |
Eosinophils | 0.163 | 0.111 | 4 | 0.505 | 0.467 | 4 | 0.273 | 0.1 | 4 | 0.3 | 0.124 | 4 | K/uL | |
Basophils | 0.078 | 0.022 | 4 | 0.175 | 0.027 | 4 | 0.105 | 0.019 | 4 | 0.123 | 0.051 | 4 | K/uL | |
Thrombocytes | ||||||||||||||
platelets | 275.8 | 62.7 | 4 | 301.3 | 31.9 | 4 | 294.3 | 79 | 4 | 340 | 72.2 | 4 | K/uL | |
Mean platelet volume | 13.03 | 2.23 | 4 | 10.45 | 0.79 | 4 | 10.85 | 0.97 | 4 | 9.75 | 0.71 | 4 | fL | |
Prothrombin time | 7.1 | 0.18 | 4 | 7.18 | 0.15 | 4 | 6.8 | 0.22 | 4 | 6.93 | 0.19 | 4 | Seconds | |
Activated partial thromboplastin time | 12.23 | 0.72 | 4 | 12.68 | 0.92 | 4 | 13.48 | 0.4 | 4 | 12.45 | 0.47 | 4 | Seconds | |
Fibrinogen | 206 | 11.1 | 4 | 178.5 | 16.3 | 4 | 251.5 | 68.3 | 4 | 275.8 | 58.8 | 4 | mg/dL |
Vehicle | 300 mg/kg | 1500 mg/kg | Unit | |||||
---|---|---|---|---|---|---|---|---|
Mean | N | Mean | N | Mean | N | |||
Males | Erythrocytes | |||||||
Red blood cells | 5.975 | 2 | 6.13 | 2 | 6.115 | 2 | M/ul | |
Hemoglobin | 14 | 2 | 14.2 | 2 | 14.15 | 2 | g/L | |
Hematocrit | 40 | 2 | 40.7 | 2 | 40.65 | 2 | % | |
Mean corpuscular volume | 67 | 2 | 6.35 | 2 | 66.7 | 2 | fL | |
Mean corpuscular hemoglobin | 23.4 | 2 | 23.15 | 2 | 23.2 | 2 | pg | |
Mean corpuscular hemoglobin concentration | 34.9 | 2 | 34.85 | 2 | 34.8 | 2 | g/dL | |
Reticulocytes | 34.15 | 2 | 78.3 | 2 | 59.92 | 2 | 109/L | |
Leukocytes | ||||||||
White blood cells | 8.705 | 2 | 8.025 | 2 | 10.37 | 2 | K/uL | |
Neutrophils | 5.275 | 2 | 4.53 | 2 | 6.14 | 2 | K/uL | |
Lymphocytes | 2.7 | 2 | 2.645 | 2 | 3.055 | 2 | K/uL | |
Monocytes | 0.34 | 2 | 0.225 | 2 | 0.385 | 2 | K/uL | |
Eosinophils | 0.21 | 2 | 0.225 | 2 | 0.385 | 2 | K/uL | |
Basophils | 0.125 | 2 | 0.125 | 2 | 0.125 | 2 | K/uL | |
Thrombocytes | ||||||||
platelets | 229 | 2 | 290.5 | 2 | 310 | 2 | K/uL | |
Mean platelet volume | 11.7 | 2 | 9.65 | 2 | 9.55 | 2 | fL | |
Protrombin time | 7.05 | 2 | 7.15 | 2 | 7.15 | 2 | Seconds | |
Activated partial thromboplastin time | 13.05 | 2 | 13.75 | 2 | 12.65 | 2 | Seconds | |
Fibrinogen | mg/dL | |||||||
Females | Erythrocytes | |||||||
Red blood cells | 7.41 | 2 | 6.775 | 2 | 6.455 | 2 | M/ul | |
Hemoglobin | 17.25 | 2 | 15.7 | 2 | 15.05 | 2 | g/L | |
Hematocrit | 49.65 | 2 | 44.75 | 2 | 43.25 | 2 | % | |
Mean corpuscular volume | 66.95 | 2 | 66 | 2 | 66.8 | 2 | fL | |
Mean corpuscular volume hemoglobin | 23.3 | 2 | 23.15 | 2 | 23.3 | 2 | pg | |
Mean corpuscular hemoglobin concentration | 34.8 | 2 | 35.1 | 2 | 34.85 | 2 | g/dL | |
Reticulocytes | 69.4 | 2 | 68.25 | 2 | 52.3 | 2 | 109/L | |
Leukocytes | ||||||||
White blood cells | 8.79 | 2 | 7.2 | 2 | 8.01 | 2 | K/uL | |
Neutrophils | 4.925 | 2 | 3.895 | 2 | 4.915 | 2 | K/uL | |
Lymphocytes | 2.87 | 2 | 2.785 | 2 | 2.475 | 2 | K/uL | |
Monocytes | 0.34 | 2 | 0.215 | 2 | 0.275 | 2 | K/uL | |
Eosinophils | 0445 | 2 | 0.16 | 2 | 0.2 | 2 | K/uL | |
Basophils | 0.165 | 2 | 0.11 | 2 | 0.11 | 2 | K/uL | |
Thrombocytes | ||||||||
platelets | 239.5 | 2 | 273 | 2 | 274.5 | 2 | K/uL | |
Mean platelet volume | 11.3 | 2 | 11.2 | 2 | 10 | 2 | fL | |
Prothrombin time | 6.7 | 2 | 7.35 | 2 | 6.8 | 2 | Seconds | |
Activated partial thromboplastin time | 12.6 | 2 | 12.3 | 2 | 12.7 | 2 | Seconds | |
Fibrinogen | 291 | 2 | 151.5 | 2 | 201.5 | 2 | mg/dL |
Vehicle | 100 mg/kg | 300 mg/kg | 1500 mg/kg | Unit | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Mean | SD | N | Mean | SD | N | Mean | SD | N | Mean | SD | N | |||
Males | Alanine transaminase (ALT) | 58.2 | 47.5 | 6 | 55.8 | 42.2 | 4 | 37.7 | 5.4 | 6 | 36.8 | 15.2 | 6 | U/L |
Aspartate transaminase (AST) | 27.3 | 2.1 | 6 | 29.8 | 5.4 | 4 | 32.5 | 3.8 | 6 | 29.7 | 3.7 | 8 | U/L | |
Alkaline phosphatase (ALKP) | 91.2 | 20.5 | 6 | 109.8 | 39.9 | 4 | 93.8 | 21.7 | 6 | 128.7 | 40.1 | 6 | U/L | |
Lactate deshydrogenase (LDH) | 75.3 | 24.7 | 6 | 71.3 | 14.4 | 4 | 76 | 13.8 | 6 | 67.5 | 24.5 | 6 | U/L | |
Total bilirubin (TBILI) | 0 | 0 | 6 | 0 | 0 | 4 | 0 | 0 | 0 | 0 | 0 | 6 | mg/dL | |
Gamma-Glutamyl transferase (GGT) | 0 | 0 | 6 | 0 | 0 | 4 | 0 | 0 | 6 | 0 | 0 | 6 | U/L | |
Creatine phosphokinase (CK) | 0 | 0 | 6 | 0 | 0 | 4 | 0 | 0 | 4 | 0 | 0 | 6 | U/L | |
Sodium (Na) | 146 | 1.5 | 6 | 145.5 | 1 | 4 | 146.2 | 1.3 | 6 | 146.7 | 0.8 | 6 | mmol/L | |
Potassium (K) | 4.65 | 0.19 | 6 | 4.65 | 0.17 | 4 | 113.3 | 1 | 6 | 113 | 1.1 | 6 | mmol/L | |
Chloride (CL) | 113.5 | 1.5 | 6 | 113.3 | 1 | 4 | 113 | 1.1 | 6 | 113.5 | 2.4 | 6 | mmol/L | |
Calcium (CA) | 10.13 | 0.19 | 6 | 10.28 | 0.15 | 4 | 10.43 | 0.3 | 6 | 10.53 | 0.45 | 0 | mg/dL | |
Inorganic phosphorus (PHOS) | 5.43 | 0.77 | 6 | 5.98 | 0.7 | 4 | 5.23 | 0.38 | 6 | 5.3 | 0.45 | 6 | mg/dL | |
Blood urea nitrogen (BUN) | 14.2 | 0.8 | 6 | 14.5 | 0.6 | 4 | 17 | 2.7 | 6 | 16 | 2.1 | 6 | mg/dL | |
Creatinine (CREA) | 0.63 | 0.12 | 6 | 0.58 | 0.05 | 4 | 0.6 | 0 | 6 | 0.67 | 0.08 | 6 | mg/dL | |
Glucose (GLU) | 97.3 | 3.5 | 5 | 91.3 | 8.3 | 4 | 92.3 | 7.4 | 6 | 96 | 8.9 | 6 | mg/dL | |
Total protein (TPRO) | 4.75 | 0.24 | 6 | 4.98 | 0.29 | 4 | 4.9 | 0.14 | 6 | 4.87 | 0.26 | 6 | g/dL | |
Albumin (ALB) | 2.88 | 0.17 | 6 | 2.93 | 0.26 | 4 | 2.92 | 0.12 | 6 | 2.83 | 0.28 | 6 | g/dL | |
Globulin (GLOB) | 1.87 | 0.18 | 6 | 2.05 | 0.13 | 4 | 1.98 | 0.04 | 6 | 2.03 | 0.23 | 6 | g/dL | |
Albumin/Globulin ratio (A/G) | 1.555 | 0.165 | 6 | 1.431 | 0.155 | 4 | 1.471 | 0.051 | 6 | 1.415 | 0.249 | 6 | Ratio | |
Cholesterol (CHOL) | 168.3 | 48.5 | 6 | 160.8 | 9.3 | 4 | 150.5 | 31.5 | 6 | 163.8 | 24 | 6 | mg/dL | |
Triglycerides (TRIG) | 37.3 | 8.2 | 6 | 38.3 | 5.9 | 4 | 36 | 4 | 6 | 40.2 | 5 | 6 | mg/dL | |
Females | Alanine transaminase (ALT) | 31.8 | 6.6 | 6 | 32.8 | 7.4 | 4 | 30.3 | 4.1 | 6 | 37.5 | 16.3 | 6 | U/L |
Aspartate transaminase (AST) | 29.3 | 4.1 | 6 | 31.8 | 11.2 | 4 | 27.5 | 3.4 | 6 | 28.3 | 3.7 | 6 | U/L | |
Alkaline phosphatase (ALKP) | 100 | 32 | 6 | 83.8 | 18.3 | 4 | 95.7 | 25.5 | 6 | 75.3 | 13.7 | 6 | U/L | |
Lactate deshydrogenase (LDH) | 60.3 | 18.1 | 6 | 65.3 | 25.1 | 4 | 52.2 | 15.4 | 6 | 62.2 | 21.8 | 6 | U/L | |
Total bilirubin (TBILI) | 0.02 | 0.04 | 6 | 0 | 0 | 4 | 0 | 0 | 6 | 0 | 0 | 6 | mg/dL | |
Gamma-Glutamyl transferase (GGT) | 0 | 0 | 6 | 0 | 0 | 4 | 0 | 0 | 6 | 0 | 0 | 6 | U/L | |
Creatine phosphokinase (CK) | 165.7 | 37.4 | 6 | 161.5 | 73.7 | 4 | 141 | 30.1 | 6 | 142 | 43.6 | 6 | U/L | |
Sodium (Na) | 146.8 | 1.5 | 6 | 147.3 | 1.7 | 4 | 146.7 | 1 | 6 | 147.3 | 0.8 | 6 | mmol/L | |
Potassium (K) | 4.48 | 0.26 | 6 | 4.48 | 0.05 | 4 | 4.43 | 0.31 | 6 | 4.43 | 0.21 | 6 | mmol/L | |
Chloride (CL) | 114.2 | 2.1 | 6 | 116 | 2.2 | 4 | 114.7 | 2.9 | 6 | 115 | 1.3 | 6 | mmol/L | |
Calcium (CA) | 10.48 | 0.26 | 6 | 10.58 | 0.21 | 4 | 10.95 | 0.27 | 6 | 10.82 | 0.31 | 6 | mg/dL | |
Inorganic phosphorus (PHOS) | 5.3 | 0.23 | 6 | 4.83 | 0.31 | 4 | 5.35 | 0.55 | 6 | 5.17 | 0.5 | 6 | mg/dL | |
Blood urea nitrogen (BUN) | 15.2 | 2.3 | 6 | 13.3 | 1 | 4 | 14.2 | 2.6 | 6 | 14 | 3 | 6 | mg/dL | |
Creatinine (CREA) | 0.57 | 0.05 | 6 | 0.6 | 0 | 4 | 0.58 | 0.08 | 6 | 0.65 | 0.08 | 6 | mg/dL | |
Glucose (GLU) | 99.3 | 5 | 6 | 99.3 | 7.5 | 4 | 99.7 | 7.4 | 6 | 94.5 | 7 | 6 | mg/dL | |
Total protein (TPRO) | 4.85 | 0.27 | 6 | 5 | 0.28 | 4 | 4.8 | 0.14 | 6 | 5.13 | 0.16 | 6 | g/dL | |
Albumin (ALB) | 2.95 | 0.26 | 6 | 3.1 | 0.14 | 4 | 2.95 | 0.18 | 6 | 3.13 | 0.16 | 4 | g/dL | |
Globulin (GLOB) | 1.9 | 0.09 | 6 | 1.9 | 0.18 | 4 | 1.85 | 0.14 | 6 | 2 | 0 | 6 | g/dL | |
Albumin/Globulin ratio (A/G) | 1.556 | 0.157 | 6 | 162.3 | 10.5 | 4 | 1.607 | 0.21 | 6 | 1.567 | 0.082 | 6 | Ratio | |
Cholesterol (CHOL) | 160 | 20.2 | 6 | 162.3 | 10.5 | 4 | 142.3 | 11.3 | 6 | 158.2 | 33 | 6 | mg/dL | |
Triglycerides (TRIG) | 37.3 | 3.8 | 6 | 36 | 14.1 | 4 | 34 | 4.8 | 6 | 46.3 | 10.4 | 6 | mg/dL |
Vehicle | 100 mg/kg | 300 mg/kg | 1500 mg/kg | Unit | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Mean | SD | N | Mean | SD | N | Mean | SD | N | Mean | SD | N | |||
Males | Alanine transaminase (ALT) | 33.5 | 9.9 | 4 | 32 | 8.6 | 4 | 37.3 | 6.8 | 4 | 51 | 25.9 | 4 | U/L |
Aspartate transaminase (AST) | 34.8 | 3.2 | 4 | 36.5 | 5.7 | 4 | 46 | 8.8 | 4 | 49.8 | 5.9 | 4 | U/L | |
Alkaline phosphatase (ALKP) | 96 | 24.4 | 4 | 104.3 | 37.1 | 4 | 116 | 71.9 | 4 | 227 | 315.9 | 4 | U/L | |
Lactate deshydrogenase (LDH) | 57.8 | 6.4 | 4 | 61 | 18.7 | 4 | 70 | 21.8 | 4 | 55 | 18.9 | 4 | U/L | |
Total bilirubin (TBILI) | 0.03 | 0.05 | 4 | 0.03 | 0.05 | 4 | 0.03 | 0.05 | 4 | 0 | 0 | 4 | mg/dL | |
Gamma-Glutamyl transferase (GGT) | 0 | 0 | 4 | 0 | 0 | 4 | 0 | 0 | 4 | 0 | 0 | 4 | U/L | |
Creatine phosphokinase (CK) | 246.3 | 79.8 | 4 | 185.3 | 61.2 | 4 | 272.3 | 145.6 | 4 | 133 | 29.1 | 4 | U/L | |
Sodium (Na) | 148.5 | 1.3 | 4 | 148 | 0.8 | 4 | 147.8 | 0.5 | 4 | 148 | 1.4 | 4 | mmol/L | |
Potassium (K) | 4.35 | 0.31 | 4 | 4.5 | 0.26 | 4 | 4.08 | 0.32 | 4 | 4.48 | 0.21 | 4 | mmol/L | |
Chloride (CL) | 115.8 | 1 | 4 | 115 | 0.8 | 4 | 115 | 1.3 | 4 | 118.8 | 0.5 | 4 | mmol/L | |
Calcium (CA) | 10.83 | 0.25 | 4 | 10.88 | 0.33 | 4 | 11.05 | 0.13 | 4 | 10.35 | 0.29 | 4 | mg/dL | |
Inorganic phosphorus (PHOS) | 5.13 | 0.75 | 4 | 5.45 | 0.29 | 4 | 4.68 | 0.26 | 4 | 3.98 | 0.32 | 4 | mg/dL | |
Blood urea nitrogen (BUN) | 18.3 | 2.1 | 4 | 18.8 | 3.3 | 4 | 19.3 | 1.9 | 4 | 24.3 | 1.7 | 4 | mg/dL | |
Creatinine (CREA) | 0.6 | 0.14 | 4 | 0.6 | 0 | 4 | 0.58 | 0.1 | 4 | 0.55 | 0.08 | 4 | mg/dL | |
Glucose (GLU) | 102.5 | 4 | 4 | 96.3 | 9 | 4 | 96.8 | 11.2 | 4 | 80.8 | 8.4 | 4 | mg/dL | |
Total protein (TPRO) | 5.25 | 0.3 | 4 | 5.38 | 0.28 | 4 | 5.38 | 0.24 | 4 | 4.45 | 0.42 | 4 | g/dL | |
Albumin (ALB) | 3.33 | 0.26 | 4 | 3.23 | 0.29 | 4 | 3.18 | 0.21 | 4 | 2.45 | 0.1 | 4 | g/dL | |
Globulin (GLOB) | 1.93 | 0.1 | 4 | 2.15 | 0.06 | 4 | 2.2 | 0.14 | 4 | 2 | 0.34 | 4 | g/dL | |
Albumin/Globulin ratio (A/G) | 1.729 | 0.141 | 4 | 1.502 | 0.152 | 4 | 1.448 | 0.14 | 4 | 1.247 | 0.184 | 4 | Ratio | |
Cholesterol (CHOL) | 168.8 | 35.4 | 4 | 176 | 28 | 4 | 152.3 | 19.4 | 4 | 104.5 | 183.4 | 4 | mg/dL | |
Triglycerides (TRIG) | 34 | 8.1 | 4 | 41.3 | 9.7 | 4 | 33.3 | 5.6 | 4 | 45.5 | 14.3 | 4 | mg/dL | |
Females | Alanine transaminase (ALT) | 27.3 | 5.1 | 4 | 26.3 | 1.9 | 4 | 35.8 | 10.2 | 4 | 45.5 | 20.9 | 4 | U/L |
Aspartate transaminase (AST) | 29 | 4.7 | 4 | 36.3 | 5.3 | 4 | 31.5 | 3.1 | 4 | 45.8 | 19.5 | 4 | U/L | |
Alkaline phosphatase (ALKP) | 98.8 | 12.4 | 4 | 78.8 | 22.5 | 4 | 178 | 131.5 | 4 | 251.3 | 211.2 | 4 | U/L | |
Lactate deshydrogenase (LDH) | 82.3 | 25.8 | 4 | 74 | 19.8 | 4 | 69.5 | 5.9 | 4 | 73 | 19.5 | 4 | U/L | |
Total bilirubin (TBILI) | 0.03 | 0.05 | 4 | 0.05 | 0.06 | 4 | 0.03 | 0.05 | 4 | 0.03 | 0.05 | 4 | mg/dL | |
Gamma-Glutamyl transferase (GGT) | 0 | 0 | 4 | 0.3 | 0.5 | 4 | 0 | 0 | 4 | 0 | 0 | 4 | U/L | |
Creatine phosphokinase (CK) | 162.8 | 54.3 | 4 | 198.8 | 44.1 | 4 | 162.3 | 40.6 | 4 | 147.3 | 47.6 | 4 | U/L | |
Sodium (Na) | 147.8 | 1 | 4 | 148.5 | 1.9 | 4 | 148.5 | 0.6 | 4 | 148.3 | 1 | 4 | mmol/L | |
Potassium (K) | 4.4 | 0.34 | 4 | 4.53 | 0.17 | 4 | 4.38 | 0.31 | 4 | 4.65 | 0.34 | 4 | mmol/L | |
Chloride (CL) | 114.5 | 1.7 | 4 | 115.5 | 1 | 4 | 115.5 | 1 | 4 | 117.8 | 2.8 | 4 | mmol/L | |
Calcium (CA) | 10.7 | 0.35 | 4 | 11.05 | 0.38 | 4 | 11.05 | 0.37 | 4 | 10.25 | 0.84 | 4 | mg/dL | |
Inorganic phosphorus (PHOS) | 5.03 | 0.54 | 4 | 4.25 | 0.9 | 4 | 4.4 | 0.47 | 4 | 4.35 | 0.58 | 4 | mg/dL | |
Blood urea nitrogen (BUN) | 17.5 | 2.4 | 4 | 14.5 | 1.3 | 4 | 18.5 | 1.3 | 4 | 23.5 | 7.9 | 4 | mg/dL | |
Creatinine (CREA) | 0.5 | 0.08 | 4 | 0.58 | 0.1 | 4 | 0.53 | 0.1 | 4 | 0.63 | 0.05 | 4 | mg/dL | |
Glucose (GLU) | 103.3 | 4.8 | 4 | 102.8 | 11.5 | 4 | 108.8 | 7.8 | 4 | 84.8 | 2.1 | 4 | mg/dL | |
Total protein (TPRO) | 5.28 | 0.17 | 4 | 5.35 | 0.31 | 4 | 5.3 | 0.22 | 4 | 4.65 | 0.3 | 4 | g/dL | |
Albumin (ALB) | 3.35 | 0.17 | 4 | 3.38 | 0.25 | 4 | 3.35 | 0.19 | 4 | 2.8 | 0.22 | 4 | g/dL | |
Globulin (GLOB) | 1.93 | 0.1 | 4 | 1.98 | 0.1 | 4 | 1.95 | 0.17 | 4 | 1.85 | 0.13 | 4 | g/dL | |
Albumin/Globulin ration (A/G) | 1.745 | 0.142 | 4 | 1.71 | 0.109 | 4 | 1.729 | 0.191 | 4 | 1.516 | 0.118 | 4 | Ratio | |
Cholesterol (CHOL) | 167.5 | 24.6 | 4 | 179 | 22.4 | 4 | 147.3 | 10.6 | 4 | 98.3 | 13 | 4 | mg/dL | |
Triglycerides (TRIG) | 40 | 9.8 | 4 | 42 | 8.8 | 4 | 43.5 | 5.8 | 4 | 50 | 8.3 | 4 | mg/dL |
Vehicle | 300 mg/kg | 1500 mg/kg | Unit | |||||
---|---|---|---|---|---|---|---|---|
Mean | N | Mean | N | Mean | N | |||
Males | Alanine transaminase (ALT) | 33 | 2 | 36.5 | 2 | 33 | 2 | U/L |
Aspartate transaminase (AST) | 31 | 2 | 30.5 | 2 | 33 | 2 | U/L | |
Alkaline phosphatase (ALKP) | 81.5 | 2 | 66 | 2 | 95 | 2 | U/L | |
Lactate deshydrogenase (LDH) | 36 | 2 | 50 | 2 | 45.5 | 2 | U/L | |
Total bilirubin (TBILI) | 0.05 | 2 | 0.05 | 2 | 0.1 | 2 | mg/dl | |
Gamma-Glutamyl transferase (GGT) | 0 | 2 | 1 | 2 | 0 | 2 | U/L | |
Creatine phosphokinase (CK) | 119 | 2 | 142.5 | 2 | 169 | 2 | U/L | |
Sodium (Na) | 147.5 | 2 | 146.5 | 2 | 148.5 | 2 | mmol/L | |
Potassium (K) | 4.3 | 2 | 4.6 | 2 | 4.4 | 2 | mmol/L | |
Chloride (CL) | 116 | 2 | 115 | 2 | 116.5 | 2 | mmol/L | |
Calcium (CA) | 10.65 | 2 | 10.45 | 2 | 10.55 | 2 | mg/dL | |
Inorganic phosphorus (PHOS) | 5.15 | 2 | 5.1 | 2 | 5.3 | 2 | mg/dL | |
Blood urea nitrogen (BUN) | 13.5 | 2 | 15.5 | 2 | 21 | 2 | mg/dL | |
Creatinine (CREA) | 0.65 | 2 | 0.6 | 2 | 0.7 | 2 | mg/dL | |
Glucose (GLU) | 99 | 2 | 99.5 | 2 | 96 | 2 | mg/dL | |
Total protein (TPRO) | 5.3 | 2 | 5.15 | 2 | 5.4 | 2 | g/dL | |
Albumin (ALB) | 3 | 2 | 2.9 | 2 | 2.95 | 2 | g/dL | |
Globulin (GLOB) | 2.3 | 2 | 2.25 | 2 | 2.45 | 2 | g/dL | |
Albumin/Globulin ratio (A/G) | 1.314 | 2 | 1.289 | 2 | 1.219 | 2 | Ratio | |
Cholesterol (CHOL) | 149 | 2 | 154 | 2 | 163.5 | 2 | mg/dL | |
Triglycerides (TRIG) | 24 | 2 | 24 | 2 | 41 | 2 | mg/dL | |
Females | Alanine transaminase (ALT) | 22.5 | 2 | 31 | 2 | 27.5 | 2 | U/L |
Aspartate transaminase (AST) | 33 | 2 | 29 | 2 | 26.5 | 2 | U/L | |
Alkaline phosphatase (ALKP) | 73 | 2 | 63.5 | 2 | 50 | 2 | U/L | |
Lactate deshydrogenase (LDH) | 52 | 2 | 49.5 | 2 | 47 | 2 | U/L | |
Total bilirubin (TBILI) | 0.1 | 2 | 0.1 | 2 | 0.1 | 2 | mg/dL | |
Gamma-Glutamyl transferase (GGT) | 0 | 2 | 0 | 2 | 0 | 0 | U/L | |
Creatine phosphokinase (CK) | 154.5 | 2 | 146 | 2 | 120 | 2 | U/L | |
Sodium (Na) | 146.5 | 2 | 146.5 | 2 | 147 | 2 | mmol/L | |
Potassium (K) | 4.5 | 2 | 4.5 | 2 | 4.1 | 2 | mmol/L | |
Chloride (CL) | 115.5 | 2 | 115.5 | 2 | 116.5 | 2 | mmol/L | |
Calcium (CA) | 10.95 | 2 | 10.65 | 2 | 10.5 | 2 | mg/dL | |
Inorganic phosphorus (PHOS) | 5.15 | 2 | 4.95 | 2 | 4.5 | 2 | mg/dL | |
Blood urea nitrogen (BUN) | 15.5 | 2 | 13.5 | 2 | 14.5 | 2 | mg/dL | |
Creatinine (CREA) | 0.65 | 2 | 0.7 | 2 | 0.65 | 2 | mg/dL | |
Glucose (GLU) | 103.5 | 2 | 101.5 | 2 | 100 | 2 | mg/dL | |
Total protein (TPRO) | 5.7 | 2 | 5.15 | 2 | 5.25 | 2 | g/dL | |
Albumin (ALB) | 3.3 | 2 | 3 | 2 | 3.1 | 2 | g/dL | |
Globulin (GLOB) | 2.4 | 2 | 2.15 | 2 | 2.15 | 2 | g/dL | |
Albumin/Globulin ratio (A/G) | 1.377 | 2 | 1.395 | 2 | 1.444 | 2 | Ratio | |
Cholesterol (CHOL) | 190.5 | 2 | 152 | 2 | 161 | 2 | mg/dL | |
Triglycerides (TRIG) | 29.5 | 2 | 30.5 | 2 | 32 | 2 | mg/dL |
Histology of major organs
Toxicokinetics parameters
Day | Group | α-TEA Dose (mg/kg) | Sex | Tmax (hr) | T1/2 (hr) | Cmax (ng/mL) | AUC0-24 (hr*ng/ml) |
---|---|---|---|---|---|---|---|
1 | 2 | 100 | Male | 24 | NC | 20200 | 335000 |
1 | 2 | 100 | Female | 20 | NC | 23900 | 35100 |
1 | 3 | 300 | Male | 16 | NC | 41000 | 718000 |
1 | 3 | 300 | Female | 18.7 | NC | 48600 | 72900 |
1 | 4 | 1500 | Male | 24 | NC | 69100 | 1170000 |
1 | 4 | 1500 | Female | 16 | NC | 76900 | 1240000 |
28 | 2 | 100 | Male | 6.3 | NC | 148000 | 3290000 |
28 | 2 | 100 | Female | 7 | NC | 16000 | 3620000 |
28 | 3 | 300 | Male | 7.3 | NC | 211000 | 4740000 |
28 | 3 | 300 | Female | 8 | NC | 212000 | 4670000 |
29 | 4 | 1500 | Male | 8 | NC | 206000 | 4580000 |
28 | 4 | 1500 | Female | 10.7 | NC | 192000 | 4210000 |