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The development of Chloroquine as an antimalarial drug and the subsequent evolution of drug-resistant Plasmodium strains
had major imparts on global public health in the 20th century. In vivo curative anti-plasmodial activity of ethanol extract
and fraction of T. diversifolia leaves alone and in combination with Chloroquine were evaluated using albino mice infected
with Chloroquine resistant P. yoelii (P. yoeliiR) intraperitoneally. Possible effects on the hematological indices and mechanisms
of anti-plasmodial action were monitored using standard protocols. Oral administration of the ethanol extract of Tithonia
diversifolia leaves to mice caused no death at doses ranging from 10-5000 mg/kg. The presence of the phytochemical content of
the extract in the order: Reducing sugar>alkaloids>steroids>phenol>terpenoids>tannins>soluble carbohydrate were obtained.
The result of the percentage parasitemia of mice infected with P. yoeliiR treated with 5 mg/kg b. w of artemeter, different doses
of crude extract and C70:M30 fraction co-administered with 10 mg/kg b. w of Chloroquine from day 7 to day 28 revealed
significant (p<0.05) reduction compared with infected mice administered 0.2 ml of distilled water. The mice infected with P.
yoeliiR treated with 5 mg/kg b. w of artemeter, 200 mg/kg b. w of crude extract and C70:M30 fraction co-administered with
10 mg/kg b. w of Chloroquine showed significant (p<0.05) reduction in hemozoin level compared with the infected mice
administered 0.2 ml of distilled water. The mice infected with P. yoeliiR treated with 5 mg/kg b. w of artemeter, crude extract
and C70:M30 fraction showed dose dependent significant (p<0.05) increase in the PCV and RBC compared with the infected
control mice. The plasma calcium ion (Ca2+) and free fatty acid concentration revealed significant (P<0.05) decrease in the P.
yoeliiR infected mice treated with varying doses of the extract in combination with Chloroquine compared with the parasitized
untreated mice. The respective antimalarial drugs and the extract increase the percentage inhibition of phospholipase A2. The
effect of the crude extract, active fraction and antimalarial drugs causes inhibition of hypotonicity-induced hemolysis. This
indicates that T. diversifolia leaf extract dose-dependently restores the efficacy of Chloroquine against P. yoeliiR malaria in mice
due to rapid rate of recovery from plasmodial infections with the co-administration.