Chronic Toxicity Study of Neosaxitoxin in Rats
Abstract
:1. Introduction
2. Results and Discussion
2.1. Acute Toxicity, Physical and Clinical Observations
Intravenous | Intramuscular | Subcutaneous | Intraperitoneal | |
---|---|---|---|---|
LD50 (μg/kg) | 6.06 | 11.4 | 12.41 | 30.35 |
Upper 95% CL | 8.14 | 13.69 | 16.15 | 46.51 |
Lower 95% CL | 4.51 | 9.49 | 9.55 | 19.81 |
2.2. Plasmatic Concentration of NeoSTX
2.3. Effect of NeoSTX on Body Weight, Food and Water Intake
2.4. Effect on Weight of Vital Organs
Heart | Spleen | Stomach | Liver | Lung | Kidney | |
---|---|---|---|---|---|---|
Control | 0.28 ± 0.02 | 0.26 ± 0.07 | 0.44 ± 0.04 | 3.04 ± 0.08 | 0.47 ± 0.08 | 0.69 ± 0.05 |
Solvent | 0.30 ± 0.02 | 0.21 ± 0.01 | 0.42 ± 0.05 | 3.27 ± 0.44 | 0.42 ± 0.05 | 0.70 ± 0.03 |
NeoSTX 1 μg/kg | 0.27 ± 0.01 | 0.21 ± 0.01 | 0.37 ± 0.02 | 2.97 ± 0.10 | 0.46 ± 0.02 | 0.64 ± 0.03 |
NeoSTX 3 μg/kg | 0.30 ± 0.02 | 0.22 ± 0.02 | 0.47 ± 0.03 | 2.84 ± 0.19 | 0.46 ± 0.01 | 0.65 ± 0.07 |
NeoSTX 6 μg/kg | 0.36 ± 0.04 | 0.24 ± 0.02 | 2.06 ± 0.11 | 3.47 ± 0.62 | 0.54 ± 0.07 | 0.75 ± 0.05 |
Heart | Spleen | Stomach | Liver | Lung | Kidney | |
---|---|---|---|---|---|---|
Control | 0.27 ± 0.02 | 0.23 ± 0.06 | 0.42 ± 0.06 | 2.89 ± 0.16 | 0.44 ± 0.07 | 0.65 ± 0.03 |
Solvent | 0.29 ± 0.04 | 0.20 ± 0.01 | 0.40 ± 0.07 | 3.13 ± 0.27 | 0.39 ± 0.05 | 0.66 ± 0.05 |
NeoSTX 1 μg/kg | 0.25 ± 0.04 | 0.19 ± 0.03 | 0.33 ± 0.05 | 2.68 ± 0.49 | 0.41 ± 0.06 | 0.58 ± 0.12 |
NeoSTX 3 μg/kg | 0.25 ± 0.03 | 0.18 ± 0.03 | 0.40 ± 0.08 | 2.40 ± 0.42 | 0.39 ± 0.05 | 0.57 ± 0.06 |
NeoSTX 6 μg/kg | 0.36 ± 0.07 | 0.23 ± 0.03 | 0.45 ± 0.14 | 3.48 ± 0.86 | 0.44 ± 0.07 | 0.64 ± 0.11 |
2.5. Effect of NeoSTX on Hematological Parameters
Control | Solvent | NSTX 1 μg/kg | NSTX 3 μg/kg | NSTX 6 μg/kg | |
---|---|---|---|---|---|
Hemoglobin (%) | 15.0 ± 2.3 | 15.4 ± 1.7 | 15.8 ± 3.4 | 16.4 ± 2.6 | 15.5 ± 1.9 |
RBC Count (106/μL) | 9.36 ± 0.30 | 9.40 ± 0.84 | 9.05 ± 0.22 | 9.23 ± 0.13 | 8.42 ± 1.30 |
Hemotocrite (%) | 52.0 ± 1.4 | 52.9 ± 1.8 | 52.2 ± 2.2 | 52.3 ± 0.6 | 53.1 ± 2.1 |
MCV (fL) | 55.5 ± 0.5 | 56.0 ± 4.3 | 57.6 ± 1.6 | 56.7 ± 0.6 | 55.1 ±2.3 |
MCH (pg) | 16.9 ± 0.2 | 17.8 ± 0.3 | 17.1 ± 0.2 | 17.5 ± 0.4 | 17.2 ± 0.5 |
MCHC (g/dL) | 30.4 ± 0.4 | 32.0 ± 2.6 | 31.4 ± 0.8 | 31.7 ± 0.2 | 32.4 ± 1.2 |
Platelet count (103/μL) | 1238 ± 360 | 1145 ± 407 | 995 ± 330 | 1050 ± 200 | 1090 ± 180 |
WBC (103/μL) | 3.9 ± 0.9 | 4.5 ± 2.3 | 5.3 ± 2.3 | 4.8 ± 0.7 | 4.0 ± 0.8 |
Reticulocyte (%) | 0 | 0 | 0 | 0 | 0 |
Neutrophils (%) | 12 ± 6 | 5 ± 2 | 7 ± 3 | 4 ± 2 | 7 ± 2 |
Lynphocytes (%) | 88 ± 6 | 92 ± 2 | 92 ± 3 | 93 ± 3 | 91 ± 4 |
Eosinophils (%) | 0 | 1 ± 1 | 1 ± 1 | 1 ± 1 | 2 ± 2 |
Monocytes (%) | 0 | 1 ± 1 | 0 | 2 ± 2 | 0 |
Basophils (%) | 0 | 0 | 0 | 0 | 0 |
Control | Solvent | NeoSTX 1 μg/kg | NeoSTX 3 μg/kg | NeoSTX 6 μg/kg | |
---|---|---|---|---|---|
Hemoglobin (%) | 15.4 ± 2.6 | 14.7 ± 1.5 | 15.2 ± 2.4 | 15.7 ± 2.4 | 15.9 ± 2.3 |
RBC Count (106/μL) | 8.78 ± 0.50 | 9.32 ± 0.94 | 9.35 ± 0.78 | 9.32 ± 1.03 | 8.82 ± 1.55 |
Hematocrit(%) | 51.9 ± 2.1 | 52.5 ± 1.2 | 52.7 ± 2.3 | 52.6 ± 1.1 | 53.2 ± 2.4 |
MCV (fL) | 56.5 ± 1.5 | 56.5 ± 2.3 | 56.4 ± 1.8 | 56.3 ± 0.9 | 55.7 ± 1.8 |
MCH (pg) | 17.5 ± 0.4 | 17.7 ± 0.6 | 17.0 ± 0.4 | 17.8 ± 0.4 | 17.1 ± 0.5 |
MCHC (g/dL) | 31.4 ± 0.6 | 32.3 ± 1.7 | 31.7 ± 0.8 | 32.4 ± 1.1 | 32.2 ± 1.4 |
Platelet count (103/μL) | 1145 ± 242 | 1275 ± 322 | 1035 ± 240 | 1100 ± 220 | 1140 ± 245 |
WBC (103/μL) | 4.9 ± 1.5 | 4.4 ± 1.3 | 4.8 ± 1.9 | 5.4 ± 1.2 | 4.3 ± 1.2 |
Reticulocyte (%) | 0 | 0 | 0 | 0 | 0 |
Neutrophils (%) | 8 ± 4 | 6 ± 3 | 6 ± 2 | 5 ± 3 | 6 ± 3 |
Lymphocytes (%) | 91 ± 7 | 92 ± 4 | 92 ± 3 | 92 ± 4 | 90 ± 3 |
Eosinophils (%) | 0 | 1 ± 1 | 1 ± 1 | 1 ± 1 | 1 ± 1 |
Monocytes (%) | 0 | 1 ± 1 | 1 ± 1 | 1 ± 1 | 1 ± 1 |
Basophils (%) | 0 | 0 | 0 | 0 | 0 |
2.6. Effect of NeoSTX on Serum Biochemical Parameters
Control | Solvent | NeoSTX 1 μg/kg | NeoSTX 3 μg/kg | NeoSTX 6 μg/kg | |
---|---|---|---|---|---|
Glucose (mg/dL) | 326.2 ± 82.4 | 367.8 ± 59.95 | 289.6 ± 45.23 | 303.8 ± 47.21 | 307.8 ± 117.78 |
Ureic Nitrogen (mg/dL) | 15.5 ± 2.1 | 18.8 ± 1.17 | 17.4 ± 1.85 | 15.6 ± 1.6 | 18.4 ± 1.4 |
Ureic acid (mg/dL) | 1.02 ± 0.25 | 1.12 ± 0.44 | 0.88 ± 0.44 | 1.04 ± 0.32 | 4.5 ± 4.00 |
Total Protein (g/dL) | 6.42 ± 0.12 | 6.26 ± 0.36 | 6.46 ± 0.28 | 6.44 ± 0.36 | 6.65 ± 0.37 |
Albumin (g/dL) | 3.28 ± 0.21 | 3.2 ± 0.16 | 3.28 ± 0.22 | 3.38 ± 0.15 | 3.59 ± 0.24 |
Total Cholesterol (mg/dL) | 58.2 ± 6.58 | 61.2 ± 5.71 | 72.4 ± 13.66 | 64.8 ± 7.76 | 68.6 ± 5.38 |
HDL (mg/dL) | 35.4 ± 5.78 | 39.2 ± 3.41 | 46.8 ± 6.23 | 41.2 ± 5.27 | 46.6 ± 8.69 |
LDL (mg/dL) | 7.72 ± 5.06 | 14.28 ± 16.98 | 9.42 ± 5.63 | 12.76 ± 4.59 | 10.08 ± 5.79 |
Triglycerides (mg/dL) | 75.8 ± 28.13 | 132.5 ± 107.88 | 107.4 ± 70.43 | 54.2 ± 20.88 | 91.2 ± 40.36 |
LDH (U/L) | 2383.8 ± 760.51 | 2356.6 ± 1024.64 | 2475.2 ± 528.45 | 2302.6 ± 727.33 | 4015.5 ± 2497.87 |
Creatinine (mg/dL) | 0.52 ± 0.04 | 0.54 ± 0.05 | 0.54 ± 0.05 | 0.46 ± 0.05 | 0.54 ± 0.08 |
Total Bilirubin (mg/dL) | 0.11 ± 0.02 | 0.13 ± 0.02 | 0.14 ± 0.02 | 0.13 ± 0.02 | 0.38 ± 0.03 * |
Direct Bilirubin (mg/dL) | 0.01 ± 0.02 | 0.02 ± 0.04 | 0.03 ± 0.04 | 0.02 ± 0.02 | 0.30 ± 0.07 * |
Alkaline Phosphatase (U/L) | 206.4 ± 56.57 | 238.2 ± 62.31 | 293.4 ± 30.72 | 292.2 ± 68.38 | 237.4 ± 67.93 |
GGT (U/L) | 7.2 ± 3.53 | 7.4 ± 0.84 | 7.5 ± 0.87 | 8.2 ± 4.17 | 12.5 ± 2.75 * |
SGOT (UI/dL) | 91.2 ± 8.45 | 88.6 ± 12.12 | 95.7 ± 10.92 | 81.2 ± 11.07 | 142.8 ± 15.42 * |
SGPT (UI/dL) | 67.8 ± 6.96 | 60.9 ± 6.93 | 61.0 ± 4 | 75.4 ± 12.81 | 80.2 ± 15.32 |
Control | Solvent | NeoSTX 1 μg/kg | NeoSTX 3 μg/kg | NeoSTX 6 μg/kg | |
---|---|---|---|---|---|
Glucose (mg/dL) | 334.7 ± 61.3 | 352.5 ± 45.67 | 297.5 ± 53.2323 | 335.8 ± 52.32 | 325.8 ± 52.46 |
Ureic Nitrogen (mg/dL) | 16.3 ± 1.73 | 17.6 ± 1.49 | 15.9 ± 1.57 | 18.4 ± 2.1 | 18.1 ± 1.6 |
Ureic acid (mg/dL) | 0.92 ± 0.42 | 1.22 ± 0.54 | 0.96 ± 0.51 | 1.10 ± 0.3 | 1.5 ± 0.57 |
Total Protein (g/dL) | 6.32 ± 0.24 | 6.36 ± 0.26 | 6.42 ± 0.26 | 6.46 ± 0.5 | 6.35 ± 0.47 |
Albumin (g/dL) | 3.30 ± 0.19 | 3.24 ± 0.17 | 3.28 ± 0.19 | 3.32 ± 0.22 | 3.29 ± 0.20 |
Total Cholesterol (mg/dL) | 59.3 ± 7.38 | 62.6 ± 6.52 | 64.4 ± 6.35 | 63.8 ± 5.8 | 62.8 ± 6.18 |
HDL (mg/dL) | 38.6 ± 4.52 | 43.1 ± 4.43 | 42.9 ± 5.36 | 43.5 ± 6.10 | 41.8 ± 6.12 |
LDL (mg/dL) | 10.53 ± 4.34 | 12.58 ± 6.33 | 10.5 ± 5.42 | 11.34 ± 4.87 | 10.54 ± 4.90 |
Triglycerides (mg/dL) | 93.5 ± 23.4 | 102.3 ± 36.4 | 90.6 ± 22.4 | 76.8 ± 25.66 | 105.2 ± 32.10 |
LDH (U/L) | 2525.4 ± 665.50 | 2248.6 ± 735.42 | 2160.8 ± 460.76 | 2650.2 ± 643.55 | 2540.9 ± 580.32 |
Creatinine (mg/dL) | 0.53 ± 0.05 | 0.54 ± 0.04 | 0.52 ± 0.04 | 0.51 ± 0.05 | 0.53 ± 0.05 |
Total Bilirubin (mg/dL) | 0.11 ± 0.02 | 0.12 ± 0.01 | 0.11 ± 0.01 | 0.10 ± 0.03 | 0.12 ± 0.03 |
Direct Bilirubin (mg/dL) | 0.02 ± 0.02 | 0.03 ± 0.02 | 0.02 ± 0.03 | 0.01 ± 0.02 | 0.03 ± 0.02 |
Alkaline Phosphatase (U/L) | 226.8 ± 48.37 | 242.9 ± 54.35 | 248.9 ± 42.52 | 225.2 ± 45.55 | 235.6 ± 49.76 |
GGT (U/L) | 7.2 ± 1.51 | 7.3 ± 1.22 | 7.4 ± 0.91 | 7.8 ± 2.45 | 7.4 ± 1.73 |
SGOT (UI/dL) | 89.5 ± 11.55 | 91.6 ± 11.83 | 96.4 ± 10.65 | 88.9 ± 10.88 | 95.8 ± 12.45 |
SGPT (UI/dL) | 65.4 ± 5.87 | 65.2 ± 4.22 | 62.3 ± 4.55 | 68.2 ± 5.28 | 70.1 ± 8.77 |
2.7. Effect of NeoSTX on Serum Electrolyte
Control | Solvent | NeoSTX 1 μg/kg | NeoSTX 3 μg/kg | NeoSTX 6 μg/kg | |
---|---|---|---|---|---|
Calcium (mg/dL) | 9.90 ± 0.41 | 9.88 ± 0.28 | 9.92 ± 0.14 | 9.84 ± 0.17 | 10.26 ± 0.81 |
Phosphorus (mg/dL) | 7.33 ± 0.94 | 7.66 ± 0.69 | 7.59 ± 0.59 | 7.45 ± 0.72 | 9.71 ± 3.72 |
Sodium (mEq/L) | 142.1 ± 1.41 | 140.8 ± 2.56 | 141.2 ± 2.13 | 142.4 ± 0.84 | 143.4 ± 4.84 |
Potassium (mEq/L) | 5.32 ± 1.11 | 5.32 ± 0.25 | 5.35 ± 0.36 | 4.96 ± 0.57 | 7.66 ± 2.81 |
Chloride (mEq/L) | 108.6 ± 1.28 | 106.2 ± 2.99 | 106.4 ± 1.59 | 107.8 ± 0.98 | 87.6 ± 37.90 |
Control | Solvent | NeoSTX 1 μg/kg | NeoSTX 3 μg/kg | NeoSTX 6 μg/kg | |
---|---|---|---|---|---|
Calcium (mg/dL) | 9.85 ± 0.43 | 9.78 ± 0.38 | 9.9 ± 0.24 | 9.82 ± 0.17 | 9.82 ± 0.31 |
Phosphorus (mg/dL) | 7.44 ± 0.62 | 7.45 ± 0.59 | 7.60 ± 0.67 | 7.52 ± 0.62 | 7.7 ± 0.72 |
Sodium (mEq/L) | 142.3 ± 1.75 | 141.5 ± 1.86 | 142.1 ± 2.05 | 141.8 ± 1.71 | 141.4 ± 2.10 |
Potassium (mEq/L) | 5.29 ± 0.65 | 5.31 ± 0.42 | 5.32 ± 0.47 | 5.33 ± 0.66 | 5.35 ± 0.93 |
Chloride (mEq/L) | 107.5 ± 1.45 | 106.8 ± 1.95 | 107.1 ± 1.7 | 106.2± 1.11 | 106.6 ± 1.90 |
2.8. Effect of NeoSTX on Histopathological Presentations and Macro Anatomical Features
2.9. Mortality
3. Discussion
4. Experimental Section
4.1. Animals
4.2. Acute Toxicity Study
4.3. Chronic Toxicity Study
4.4. Hematological Analysis
4.5. Biochemical Analysis
4.6. Histopathological Assessment
4.7. Pharmacokinetic Study
4.8. Statistical Analysis
5. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Zepeda, R.J.; Candiracci, M.; Lobos, N.; Lux, S.; Miranda, H.F. Chronic Toxicity Study of Neosaxitoxin in Rats. Mar. Drugs 2014, 12, 5055-5071. https://doi.org/10.3390/md12095055
Zepeda RJ, Candiracci M, Lobos N, Lux S, Miranda HF. Chronic Toxicity Study of Neosaxitoxin in Rats. Marine Drugs. 2014; 12(9):5055-5071. https://doi.org/10.3390/md12095055
Chicago/Turabian StyleZepeda, Ramiro J., Manila Candiracci, Nicolas Lobos, Sebastian Lux, and Hugo F. Miranda. 2014. "Chronic Toxicity Study of Neosaxitoxin in Rats" Marine Drugs 12, no. 9: 5055-5071. https://doi.org/10.3390/md12095055