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General Information about Pyrrolizidine Alkaloids (PAs)
Review of Comfrey and Related Research
| Table 5: In Vivo Studies | ||||||
| Test Animal | Test Substance | Dose | Frequency | Estimated equivalent dose of dry weight comfrey for 60kg human (a) | Results | Ref |
| Male Rats 1-1.5 months old | Symphytine (i.p.) | 13mg/kg | twice weekly for 4 weeks and then once a week for 52 weeks. (Experiment ran 21 months) | 7 - 1040kg leaf (b) or 0.35 - 52kg leaf (c) | liver cell adenoma: 1 rat out of 20 herangioendothelial sarcomas of the liver: 3 rats out of 20 megalocytosis and proliferation of oval cells and endothelium of the sinusoids | [81] |
| Male rats (n=3) | Echimidine | 20mg/kg | thrice weekly for 136 days | dose is about 3 to 4.5 times dose reported for symphytine study above (d) | limited megalocytosis of the midzone and periphery of the lobule | [85] |
| Male and Female rats 1-1.5 months old | Leaf | % of diet
33% 33% 16% 8% | for 480 days for 600 days for 600 days for 600days | 0.5kg (1lbs)(e) 0.24kg (0.5lb) 0.12kg (0.25lb) | incidence of liver tumors (f) 26% 58% 33% 4% | [89] |
| Male and Female rats 1-1.5 months old | Root | % of diet 8% 4%/2%/1% 4%/0.5%/0% 2%/0.5%/0% 1%/0.5%/0% | variable time courses, >179 days with first diet composition |
0.12kg (4oz) 0.06kg (2 oz) 0.03kg (1 oz) 0.02kg (0.5 oz) | incidence of liver tumors (f) 86% 43% 33% 43% 80% | [89] |
| Male Rats (140g) | Symphytum leaf | % of diet 5% 10% 30% | 21 days |
0.3kg (0.67 lbs) 0.6kg (1.3lbs) 1.8kg (4lbs) | at 30% comfrey there was a significant decrease in daily weight gain at 10% and 30% comfrey (and 30% alfalfa) significant increase in Aminopyrine-N-demethylase activity. No changes in Glutathione S-transferase or Epoxide hydrolase at any feeding levels. | [90] |
| Rats 2 weeks old | Total Symphytum PA (i.p.) | 284 mg/kg | once | 19kg -130g leaf (42lbs - 4.5oz) or 2.8kg - 34g root (6lbs - 1.2 oz) | peracute (non-hepatic) deaths | [65] |
| Rats 2 weeks old | Total Symphytum PA (i.p.) | 142 mg/kg | once | 9.5kg - 65g leaf (21 lbs - 2.2oz) or 1.4kg - 17g root (3lbs - 0.6oz) | Temporary distress, no histological liver damage evident when rats killed 4 weeks later. | [65] |
| Male and female rats 2 weeks old | Total Symphytum PA (i.p.) | 71 mg/kg | thrice weekly until death at 3-4 weeks | 4.7kg - 32g leaf (10lbs - 1oz) or 0.7kg- 8.5g root (1.6lbs - 0.3oz) | death due to severely impaired liver function but mild histological damage | [65] |
| Male and female rats 2 weeks old | Total Symphytum PA (i.p.) | 17.8 mg/kg | thrice weekly for 3 weeks | 1.2kg - 8g leaf (2.6lbs - 0.3oz) or 180g -2g root (6oz - 0.07 oz) | reduced liver function (liver histology not checked) | [65] |
| Male and female rats 2 weeks old | Total Symphytum PA (i.p.) | 17.8 mg/kg | thrice weekly for 9 weeks | 1.2kg - 8g leaf (2.6lbs - 0.3oz) or 180g -2g root (6oz - 0.07 oz) | megalocytosis | [65] |
| Male and female rats 2 weeks old | Total Symphytum PA (i.p.) | 8.9 mg/kg | thrice weekly for 3 weeks | (0.6 kg - 4g leaf) (1.3 lb - 0.1 oz) or 89g - 1g root (3oz - 0.04oz) | reduced liver function (liver histology not checked) | [65] |
| Rats young adults | Total Symphytum PA (oral) | 200mg/kg | Single dose | 13kg - 91 g leaf (29lbs -3 oz) or 2kg - 24g root (4.4 lbs - 0.9 oz) | All rats showed evidence of liver damage that was dose dependent. | [76] |
| Rats young adults | Total Symphytum PA (oral) | 100mg/kg | thrice weekly for 3 weeks | 6.7kg - 45g leaf (15 lbs - 1.6 oz or 1kg - 12 g root (2.2 lbs - 0.4oz) | All rats showed evidence of liver damage that was dose dependent. | [76] |
| Rats young adults | Total Symphytum PA (oral) | 50 mg/kg | thrice weekly for 3 weeks | 3.3kg - 23g leaf (7.3 lbs - 0.8oz) or 0.5kg - 6g root (1 lb - 0.2 oz) | All rats showed evidence of liver damage that was dose dependent. | [76] |
| Rats young adults | Total Symphytum PA (oral) | 50mg/kg | once a week for 6 weeks | 3.3kg - 23 g leaf (7.3 lbs - 0.8oz) or 0.5kg -6g root (1 lb -0.2 oz) | All rats showed evidence of liver damage that was dose dependent. | [101] |
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(a) Ranges calculated based on data from table 3: leaf contains between 15 and 2200µg total alkaloids./g and root contains between 100 and 83\230µg total alkaloids/g. (b) Given 5% of comfrey PA are symphytine [65] (C) Alternately if all alkaloids have equivalent toxicity to symphytine. (d) Assuming echimidine is one half to a third of the concentration of symphytine [82]. (e) Assuming rat eats 10g/day and weighs 100g (f) Proliferation of the intrahepatic bile duct, megalocytosis, hyperplastic nodule or liver cirrhosis was encountered frequently, even in rats without tumors. © 2004 Dorena Rode | ||||||