Acute and sub-acute toxicological studies of Rapanea Melanophloeos (L.) Mez. in laboratory rats
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Rapanea melanophloeos is a tropical tree that is extensively utilized in African traditional medicine to treat helminthoses, tuberculosis and heart-water. It is also used as an expectorant, emetic, astringent, as an anti-inflammatory agent; and it bears anthelmintic, molluscicidal, fungicidal, anticancer and antimalarial activity. Despite its wide medicinal utilization, data and documentation of its adverse effects or toxicity to humans and animals are scanty. The present study examined the in vitro toxicity of the chlorofonnic and aqueous extracts of R. melanophloeos bark to brine shrimp tArtemia salina), and the acute and sub-acute in vivo toxicity to Sprague Dawley rats that were orally dosed, once daily with the aqueous and chloroformic extracts for 56 and 28 days respectively. The aqueous extract was found to have significant in vitro toxicity to brine shrimp with a median lethal concentration (LCso) of 59.37 ug/ml, The chlorofonnic extract had no significant toxicity to brine shrimp (LCso of 1250 ug/ml) at 24 hours post-exposure. Both the aqueous and chlorofonnic extracts of R. melanophloeos were practically non toxic to rats (oral median lethal dose after single dosing was above 7500 mg/kg). The aqueous extract demonstrated a no-observed-adverse-effect-level (NOAEL)of 300 mg/kg and lowest-observed-adverse-effect-level(LOAEL) of 500 mg/kg; and the chlorofonnic extract had a NOAEL of 500 mg/kg and a LOAEL of 1000 mg/kg. Transient clinical signs of acute toxicity that included depression, inactivity, somnolence, delayed reaction to stimuli, lethargy and piloerection were less prolonged in rats dosed with the chloroformic extract. All the animals recovered in 24 hours. Necropsy of the rats that died of the aqueous extract at 7500 mg/kg revealed mucoid content in the lower gastrointestinal tract, modest congestion of the kidneys, general congestion and modest enlargement of the liver and spleen. Histopathology revealed congestion of the liver, lungs and kidneys. Repeated doses of the aqueous extract at 1000 mg/kg for 56 days caused a significant increase in organ weight indices of kidneys (p=0.008) and testis (p=O.015) compared to the controls. In contrast, the chloroformic extract significantly reduced weight gain of the rats at the same dosage (p<0. 000 1), after administration for 28 days. TIle results indicate that a dose of 1000mg/kg of the aqueous and chlorofonnic extracts of R. melanophloeos caused a significant reduction in the WBC count from day 14 and remained so up to day 56 and day 28 for the aqueous and chlorofonnic extract. The chlorofonnic extract caused a significant increase in the red blood cell count and the hematocrit (p<O.OOOl)at the same dosage. In comparison with the pre-treatment values, the red blood cell count, hematocrit, hemoglobin and thrombocytes increased significantly in all dose groups at day 28 and day 56 (p<O.OOOl),while the mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration decreased in animals dosed with each extract (p<O.OOOl). The aqueous extract caused a non dose-related significant increase in alkaline phosphatase activity at all the dose levels (p=O.0034). Over time, and at all dose levels, there were elevations in alkaline phosphatase and creatine kinase activity, and decreases in creatinine and aspartate aminotransferase in rats dosed with each extract in comparison with pre-treatment readings. Increases in alanine aminotransferase activity and blood urea nitrogen levels were particular to animals dosed with the aqueous extract, while alanine aminotransferase activity decreased in animals dosed with the chloroformic extract. No pathological lesions were observed at histopathology after prolonged oral administration of the two extracts. The extracts are slightly toxic to the liver and kidneys since they moderately altered the biochemical parameters but did not induce detectable damage in these organs. The time-related changes in parameters are largely due to changes in age over the experimental periods. These results demonstrate that the polar and non polar extracts of R. melanophloeos have a wide margin of safety, and R. melanophloeos can be safely utilized in traditional medicine.