| dc.description.abstract | The undesirable toxic effects of babesicidal agent quinuronium have been observed since its introduction in 1933. The main signs of salivation, defecation, lacrimation, muscular tremors and depression are thought to be associated with cholinesterase inhibition. The purpose of this project was to perform acute toxicity studies with quinuronium in laboratory animals and sheep, compare effects of quinuronium and diminazene in sheep, investigate quinuronium effects on liver function in rats and to monitor quinuronium levels in ovine plasma using an i_n vitro/in vivo system with Babesia rodhaini.
Quinuronium concentration in ovine plasma was determined by the jin vitro/in vivo model system with Babesia rodhaini. An in vitro ECcrk of 13.5ng/ml was
observed for quinuronium. Plasma collected from sheep receiving therapeutic dose of lmg/kg of quinuronium inhibited parasitemia. Quinuronium levels in ovine plasma increased to a maximum of 27ng/ml at 2 hr which remained fairly elevated up to 8 hr, thereafter the
concentration of the drug declined gradually until none was detected at 48 hr.
LD,-q (median lethal dose) in mice intraperitoneally (i.p.) and subcutaneously (s.c.) were 4.8 and 5.4mg/kg while corresponding values in rats were 6.3 and 6.5mg/kg respectively Clinical signs of salivation, defecation, anorexia, muscular tremors and depression were observed within 20 min in sheep following lmg/kg of quinuronium administration s.c. In rabbits only mild signs of anorexia and depression were observed following administration
of lmg/kg of quinuronium s.c. Normal cholinesterase activity was low in rabbits compared to sheep. Quinuronium
inhibited cholinesterase activity from 10 min to 24 hr in 5 sheep by 24% of the normal baseline values.
The activity of cholinesterase returned to normal at 48 hr. Atropinisation partially protected against
anticholinesterase activity in other 5 sheep and the activity was only inhibited by 14% of the normal baseline values.
Effects of quinuronium on hepatic function was investigated in rats. Quinuronium affected hepatic excretion of sulfobromophthalein (BSP) as measured by isolated perfused rat liver. Three groups of rats exposed to 0 (n=5), 1.5 (n=6) and 2.3 (n=6)mg/kg of quinuronium i.p. 30 min before perfusion had half life
(t^ + S.E.) in min of BSP elimination from perfusate of 12.5 + 1.8, 13.7 + 1.0 and 16.8 + 3.3 respectively. Groups of rats receiving 0 and 2.3mg/kg had a significant difference (p<0.05) in their t^. Bile volumes decreased in both quinuronium pre-exposed groups of rats compared to controls. In another experimental study rats received 0 (n=5), 2.3 (n=6) and 5.0 (n=6) mg/kg of quinuronium daily for 2 days. A dose dependent increase in liver weight/body weight ratios were observed. Fatty liver degeneration was observed in rats receiving 5mg/kg. There was no significant depletion of hepatic glutathione (GSH) in groups of rats exposed to quinuronium. This suggested that no reactive metabolites that are dependent on hepatic glutathione inactivation are involved in quinuronium metabolism.
In another experimental study 20 sheep were used to compare the effects of quinuronium and diminazene on lactic dehydrogenase (LDH) and creatine phosphokinase (CPK) activity and blood urea nitrogen (BUN) levels in plasma. Five sheep received therapeutic dose of lmg/kg and subsequent 5 received double (higher) dose of 2mg/kg of quinuronium. In diminazene treatments, 5 sheep received therapeutic dose of 3.5mg/kg and subsequent 5 received double (higher) dose of 7.Omg/kg respectively.
LDH activity expressed in B-B Units/ml in the two dosage levels of quinuronium increased above baseline values following administration of the drug. Activity of LDH was also elevated above baseline values in sheep receiving the two dosage levels of diminazene. CPK activity in Sigma Units/ml in the two dosage levels of quinuronium increased above baseline values following its administration with a maximum activity at 2 hr followed by a gradual decline to end of study. CPK levels in sheep receiving two dosage levels of diminazene had a similar trend compared to quinuronium treatments.
BUN levels in mg/lOOml increased above baseline values in both dosages of quinuronium treated animals and one animal receiving lmg/kg had levels above the upper normal limit of 20mg/100ml from 4 hr to end of the study at 48 hr. BUN levels in sheep receiving the two dosage levels of diminazene also increased above baseline
values. The increase, however, was not as high as in quinuronium treatments. Increase in BUN levels and LDH and CPK activities shows that quinuronium is more organo- toxic than diminazene at therapeutic and/or above therapeutic dosages.
This study has shown that the in vitro/in vivo model system with B. rodhaini is a simple method that can be used to determine quinuronium levels in ovine
plasma. Quinuronium can be classified as a highly toxic compound as shown by very low median lethal dose. The study also supports the view that depression of cholinesterase activity plays an important role as the cause of death in quinuronium toxicity. The study has shown that hepatoxicity may contribute to or potentiate the cause of death in quinuronium toxicity. | |
