Effectiveness of metyrapone in the treatment of acetaminophen toxicity in mice

Metyrapone tartrate, 400 mg/kg i.p. raised the LD₅₀ for acetaminophen from 340 mg/kg i.p. to 540 mg/kg i.p. in fasting male Swiss white mice. The minimum protective dose of metyrapone was 200 mg/kg. Metyrapone was effective in preventing death when given up to 2 h after acetaminophen administration. The LD₅₀ for metyrapone tartrate was 760 mg/kg i.p. Metyrapone decreased or prevented acetaminophen induced hepatic damage measured either by histology or plasma glutamate pyruvate transaminase activity. Metyrapone tartrate, 400 mg/kg i.p., inbibited the severe liver glutathione depletion seen with acetaminophen alone. It is proposed that metyrapone protects mice from acetaminophen induced liver toxicity and death by inhibiting the oxidation of acetaminophen to a toxic intermediate.     

A safety study on single intravenous dose of tetrachloro-diphenyl glycoluril [iodogen] dissolved in dimethyl sulphoxide (DMSO)

Abstract

1. Iodogen (tetrachloro-diphenyl glycoluril) dissolved in DMSO (dimethyl sulphoxide) appears indispensable in radioiodination of hypericin for a new anticancer strategy. We studied the safety of intravenously administered iodogen/DMSO in mice (n?=?132).

2. Median lethal dose (LD₅₀) of iodogen/DMSO was determined with doses of 40.0, 50.0, 55.0, 60.0, 65.0 and 70.0?mg/kg. Next, toxicity of iodogen/DMSO at 30.0?mg/kg was evaluated using saline and DMSO as controls. Changes in behaviour, body weight and serum biochemistry were evaluated. Histopathology of lungs, heart, liver and kidney was performed.

3. LD₅₀ values of iodogen/DMSO were 59.5?mg/kg (95% confidence limits (CI): 54.1–65.4?mg/kg) and 61.0?mg/kg (95%CI: 56.2–66.2?mg/kg) for female and male mice, respectively. Similar to that of control groups, no animal deaths were encountered after iodogen/DMSO administration at 30.0?mg/kg. Body weights over 24?h were not altered in all groups, but significantly higher in iodogen/DMSO and DMSO groups (p?<?0.05) 14?d post-injection. Blood urea nitrogen and alkaline phosphatase increased (p?<?0.05) in iodogen/DMSO group without clinical symptoms. No pathologies were found by gross and microscopic inspection.

4. A single dose of iodogen/DMSO up to 30.0?mg/kg, over 3000 times the dose in potential human applications, appears safe, with an LD₅₀ doubling that dose in mice.     

Comparative lethality of coca and cocaine

The 24 hour lethal effects of cocaine were compared to those of a crude ethanol extract of the coca leaf (Erthroxylon coca) in male, Swiss mice. Various doses of cocaine HCl and coca leaf extracts suspended in a Tween 60, Arlacel 83, and distilled water vehicle were injected IP into groups of 10 mice. The LD₅₀ for cocaine was 95.1 mg/kg. The LD₅₀ for the coca extract was 3450 mg/kg. The LD₅₀ of the extract based on its cocaine content was 31.4 mg/kg. The results clearly indicate that the coca leaf contains constituents other than cocaine that can contribute to a toxic effect of the plant.     

Role of biotransformation in the alterations of chloroform hepatotoxicity produced by Kepone and mirex

A previous report demonstrated that pretreatment of mice with Kepone resulted in marked potentiation of CHCl₃-induced hepatotoxicity whereas pretreatment with a structural analog, mirex, had no effect on the liver injury produced by a challenging dose of CHCl₃. To determine some of the possible mechanisms for this difference in potentiating ability, various parameters were studied. The hepatic content of mirex and Kepone was determined 42 hr after the oral administration of each agent to male Swiss-Webster mice. The concentration of mirex within the liver increased in a dose-related fashion. Following a single dose (50 mg/kg) of either mirex or Kepone, the hepatic content of each agent was approximately equal. Kepone (50 mg/kg, po) had no effect on mouse hepatic glutathione content at 18 hr. The relationship between the effects of mirex and Kepone on microsomal mixed function oxidase (MFO) activity and the in vivo and in vitro irreversible binding of ¹⁴CHCl₃ reactive metabolite(s) to hepatic constituents was assessed at 18 hr. Mirex pretreatment (10, 50, 250 mg/kg) resulted in a more profound effect on hepatic MFO activity than did pretreatment with Kepone (50 mg/kg). However, mirex pretreatment (50 mg/kg) did not alter either the in vivo or in vitro irreversible binding of ¹⁴CHCl₃-derived radioactivity to mouse hepatic constituents. In contrast, pretreatment of mice with Kepone (50 mg/kg) resulted in profound increases in both the in vivo and in vitro irreversible binding of ¹⁴CHCl₃ metabolites. Thus it appears that the disparate potentiating abilities of mirex and Kepone are related to a difference in the capacity of these agents to increase the activity of the CHCl₃ bioactivation system of the liver.     

Effect of pretreatment with sodium phenobarbital on the toxicity of soman in mice

Pretreatment with sodium phenobarbital induces hepatic microsomal enzymes which are responsible for the metabolic breakdown of a large number of endogenous and exogenous chemical compounds. A previous study [K. P. DuBois and F. K. Kinoshita, Proc. Soc. exp. Biol. Med.129, 699 (1968)]reported that phenobarbital pretreatment reduced the toxicity of various organophosphorus anticholinesterases; however, the exact mechanism for the increased detoxification was not investigated. In this study, the effect of phenobarbital pretreatment on the toxicity of soman was investigated. Male mice were injected daily for 4 days with sodium phenobarbital (100 mg/kg, i.p.) and used in the various experiments 24 hr after the last injection. Phenobarbital pretreatment produced a significant increase in liver weight and decreased the sodium pentobarbital (75 mg/kg, i.p.) induced sleep-time to 41 min compared to 141 min in controls. The lethality of soman was reduced following phenobarbital pretreatment. In control mice, the soman 24hr LD₅₀ values (μg/kg) were 130, 393 and 42 following s.c., i.p. and i.v. administration, respectively, whereas in phenobarbital-pretreated mice the soman 24 hr LD₅₀ values (μg/kg) were 261, 746 and 63 following s.c., i.p. and i.v. administration respectively. Acetylcholinesterase activity was increased in the plasma (90%) but not in brain or diaphragm following phenobarbital pretreatment. Liver somanase activity was not affected. Liver aliesterase and serum aliesterase were both increased significantly following phenobarbital pretreatment. An increase in the amount of nonspecific binding sites for soman (esterases in liver and plasma) and not an increase in the metabolism of soman in vivo probably accounts for the protection afforded by phenobarbital pretreatment in mice.     

Survivors of soman poisoning: recovery of the soman LD50 to control value in the presence of extensive acetylcholinesterase inhibition

Initially, mice were pretreated with atropine (17.4 mg/kg; IP) and the oxime reactivator HI-6 (50 mg/kg; IP) 5 min prior to an injection of soman (287 g/kg, SC); approximately 2.1 × LD₅₀ dose). More than 95% of the mice survived this dose of soman with atropine and HI-6 pretreatment. In these survivors of soman poisoning the return of the soman LD₅₀ value to control value (124 g/kg, SC) was determined at various times after the initial soman exposure. Mice which survived exposure to a lethal dose of soman by pretreatment with atropine and HI-6 were sensitized to the lethal effects of soman upon re-exposure. The SC soman LD₅₀ at 4 h, after surviving the initial soman exposure, was 20 g/kg. The normal soman LD₅₀ (as evidenced by a LD₅₀ value which was not significantly different from the control value) returned within 4 days, at which time there was still extensive acetylcholinesterase inhibition in all brain regions (striatum, pons-medulla, cerebellum, hypothalamus, hippocampus), diaphragm and erythrocytes. Serum carboxylesterase recovered to control levels within 48 h, whereas liver carboxylesterase activity was not inhibited following the initial soman exposure. The results demonstrate that there is an excess of acetylcholinesterase which is required for normal response in the toxicological sense.     

Interaction toxicity between ethanol and narcotics in mice with reference to alpha-l-acetylmethadol (LAAM)

Interactions between narcotics, especially alpha-l-acetylmethadol (LAAM) and ethanol were studied in mice. Co-administration of LAAM either at 18 or 36 mg/kg significantly potentiated ethanol lethality, the LD₅₀ due to ethanol was lowered by 21% and 36%, respectively. At low doses of ethanol (0.5 and 1.0 g/kg), toxicity due to LAAM was decreased; the LD₅₀ was increased significantly (p<0.006?0.05) to 76 and 64 mg/kg, respectively, compared with 56 mg/kg for LAAM alone. At 4 g/kg of ethanol, the LD₅₀ due to LAAM was decreased to 43.9 mg/kg, showing a significant (p<0.002) potentiation of interaction toxicity between the two compounds. Chronic pretreatment of LAAM for 7 days produced no significant alteration in ethanol lethality. Treatment with various narcotic agonists (morphine, LAAM, methadone, and levorphanol) and ethanol, the rate of disappearance of ethanol was decreased significantly in the blood and brain whereas naloxone and dextrorphan, an inactive stereoisomer of levorphanol, produced a small but significant increase. Ethanol pretreatment produced no significant alteration on the brain and blood levels of morphine with the exception of 4g/kg at 150 min after treatment. Increase in toxicity with the combined administration of LAAM and ethanol was attributed in part to the retention of ethanol.     

抗癌新药-乙双吗啉(AT-1727)的药理研究

乙双吗啉(AT-1727)是我国合成的一种抗癌新药。它是一种双内酰亚胺化合物,实验证明,乙双吗啉对小鼠肉瘤S₃₇、S₁₈₀有显著抗肿瘤作用,对ECS,HCS,脑瘤B₂₂及L₆₁₅等移植性肿瘤亦有明显抗肿瘤作用。它对S₃₇的50%抑制剂量(ID₅₀)为1.88 mg/kg(ip)及6.61 mg/kg(po)。其抗肿瘤作用与给药方案有一定关系。乙双吗啉对小白鼠毒性LD₅₀为372.8±27.mg/kg(ip)及243.8±26.1 mg/kg(po)。因此,乙双吗啉腹腔注射及口服时,对S₃₇的化疗指数分别为47.5及36.9。给健康犬肌肉注射乙双吗啉25及50 mg/kg/天,连用10天,除出现食量减少,白细胞轻度下降外,对红细胞,血小板、肝、肾功能均无明显影响。乙双吗啉对以溶血素反应为指标的体液免疫有抑制作用;对以移植物抗宿主反应为指标的细胞免疫则无抑制作用。     

The lethal effects of delta9-tetrahydrocannabinol in mice enhanced by pretreatment with SKF 525-A or chloramphenicol

The i.p. lethal activity of THC following single dose administration was significantly enhanced by pretreatment with SKF 523-A (30.0 mg/kg) or chloramphenicol (100.0 mg/kg) as evidenced by a significant reduction in the LD₅₀ value. Moreover, the onset to lethality was also sharply reduced. These results are discussed in light of the present knowledge concenring the metabolism of THC.     

关于抗肿瘤药物的研究 Ⅶ.N-甲酰溶肉瘤素的抗瘤谱及毒性

N-甲酰溶肉瘤素是一种有效的抗肿瘤药,抗瘤譜广,在12种动物肿瘤中,对9种具有明显的抑制作用。对大鼠吉田肉瘤腹水型及实体型,Walker癌-肉瘤256等抑制作用最明显,抑制率为96—100%。对小鼠网織細胞肉瘤L₂抑制率为60—70%;对腹水瘤L₁及Krebs-2腹水癌亦有明显抑制作用,分別延长寿命5天及7天;对Ehrlich癌腹水型小鼠,可延长寿命2.2—2.6天;对Ehrlich癌实体型及梭形細胞肉瘤B₂₂抑制率分別为30—41%及36—43%。在不致中毒的剂量下,对小鼠肉瘤180,肉瘤AK,黑色素瘤Me則无明显抑制作用。口服N-甲酰溶肉瘤素对小鼠及大鼠的半数致死量(LD₅₀±S.E.)分別为730±79毫克/公斤及700±79毫克/公斤;腹腔內給药則分別为152±7毫克/公斤及80±10毫克/公斤。靜脉注射对小鼠的半数致死量为155±10毫克/公斤。     

Synthesis and hepatoprotector activity of water-soluble derivatives of aminoalkylphenols

A series of 2(4)-hydroxybenzyl-and 3-(4-hydroxyaryl)propylamines and their hydrochlorides were synthesized based on 2,4-and 2,6-alkylsubstituted phenols. The synthesized hydrophilic derivatives are characterized by average half-lethal doses (LD₅₀), which fall within 50–170 mg/kg for intraperitoneal administration in mice. Some of the synthesized compounds in a dose of 0.1LD₅₀ show pronounced hepatoprotector activity with respect to tetrachloromethane-induced model toxic hepatitis in mice. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 40, No. 5, pp. 10–13, May, 2006.     

Toxicity of Jatropha curcas phorbol esters in mice

Phorbol esters are the main toxins in Jatropha curcas seed and oil. The aim of this study was to assess the acute toxicity of phorbol esters given by intragastric administration and to determine the LD₅₀ for Swiss Hauschka mice. The LD₅₀ and 95% confidence limits for male mice were 27.34 mg/kg body mass and 24.90–29.89 mg/kg body mass; and the LD₅ and LD₉₅ were 18.87 and 39.62 mg/kg body mass, respectively. The regression equations between the probits of mortalities (Y) and the log of doses (D) was Y = −9.67 + 10.21 log (D). Histopathological studies on the organs from the dead mice showed: (1) no significant abnormal changes in the organs at the lowest dose (21.26 mg/kg body mass) studied, (2) prominent lesions mainly found in lung and kidney, with diffused haemorrhages in lung, and glomerular sclerosis and atrophy in kidney at doses ?32.40 mg/kg body mass, and (3) multiple abruption of cardiac muscle fibres and anachromasis of cortical neurons at the highest dose of 36.00 mg/kg body mass. The results obtained would aid in developing safety measures for the Jatropha based biofuel industry and in exploiting the pharmaceutical and agricultural applications of phorbol esters.     

Increased toxicity of methamphetamine in morphine-dependent mice

• 1.1. The effect of methamphetamine on morphine-dependent mice was investigated by calculating the LD₅₀ (IP), measuring motor activity, anorectic actions, and body temperature.
• 2.2. Methamphetamine was more toxic in morphine-dependent mice (LD₅₀=20.6 mg/kg) than in normal mice (LD₅₀=43.2 mg/kg).
• 3.3. Methamphetamine-induced locomotor activity was greater in morphinized than in nonmorphinized mice at doses of 2.5 and 5 mg/kg IP.
• 4.4. Methamphetamine also increased the body temperature of morphinized mice more than that of normal mice (P<0.05).
• 5.5. These findings suggest that methamphetamine is more toxic in morphine-dependent than in nondependent mice.

     

Acetylcholinesterase Inhibition by (+)Physostigmine and Efficacy against Lethality Induced by Soman

ABSTRACT

The optical isomer (+)Physostigmine [(+) Phy] is a very weak anticholinesterase. In a recent report, pretreatment with (+)Phy, at a dose which failed to inhibit acetylcholinesterase (AChE), and atropine provided efficacy against a lethal dose of sarin (SYNAPSE:2,139,1988). It was of interest to see whether (+)Phy could protect against soman at a dose which caused only marginal inhibition of the whole blood (WB) AChE in guinea pigs (GPs). (-)Phy (0.15 rog/kg, im) and (+)Phy (10.0 mg/kg, im) produced nearly 70% inhibition of WB AChE at 30 min whereas (+)Phy (0.15 rog/kg, im) caused only marginal inhibition. Groups of guinea pigs (20/group) were dosed, im, with (-)Phy (0.15 mg/kg), (+)Phy (0.15 rog/kg), (+)Phy (10.0 mg/kg) or vehicle (0.5 ml/kg) respectively in one thigh while the mild anticholinergic trihexyphenidyl (THP), 2.0 mg/kg, was injected into the other thigh of 10 animals from each of the respective groups. Thirty min after pretreatment, all animals were challenged with soman (60 ug/kg, sc; 2 LD₅₀S); this dose of soman is lethal in unprotected animals. (-)Phy or (+)Phy (10 rog/kg) alone protected nearly 50% from soman lethality, and in combination with THP, all animals survived. In contrast, (+)Phy (0.15 mq/kq; alone or together with THP) was completely ineffective against a 2 LD₅₀ challenge of soman. These data support the hypothesis that protection against soman-induced lethality is related to the degree of carbamylation of the AChE just prior to challenge.     

β-Diethylaminoethyl-diphenylpropylacetate (SKF 525-A) enhancement of tissue accumulation of aldrin in mice

Pretreatment of male Swiss-Webster mice given acutely toxic doses of [¹⁴C]aldrin (150 mg/kg ip) with SKF 525-A (50 mg/kg ip) resulted in significant increases in the accumulation of radioactivity in blood, brain, kidney, and liver. Elevated levels of radioactivity were seen whether aldrin was injected in dimethylsulfoxide or methoxytriglycol. This effect was not seen at 5 mg/kg SKF 525-A but was dose-related in blood, kidney, and liver at 50 and 100 mg/kg. Whole body measurements of the extent of aldrin biotransformation in mice pretreated with 50 mg/kg SKF 525-A indicate that the effect is probably not related to differences in metabolite formation or excretion. Both the alteration of tissue accumulation and metabolism may be dependent on the route of administration, dose, and pretreatment interval of SKF 525-A, as well as the route of administration and dose of the compound being tested.     

Studies on the role of protein synthesis in cell injury by toxic agents: I. Effect of cycloheximide administration on several factors modulating carbon tetrachloride-induced liver necrosis

Cycloheximide pretreatment (1 mg/kg, ip) slightly attenuated the hepatic necrosis 24 hr after CCl₄ administration and this attenuation was more obvious at 72 hr. A dose of cycloheximide, 2 mg/kg, evoked a marked protective effect even at 24 hr. Cycloheximide administration (1 mg/kg) significantly reduced the body temperature in CCl₄-treated rats but did not change the CCl₄ concentrations in the liver. Prior treatment of the rats with cycloheximide decreased the amount of binding of ¹⁴CCl₄ to liver microsomal lipids and reduced CCl₄-induced lipid peroxidation at 1 hr but not at 6 hr after administration of the hepatotoxin. Cycloheximide did not alter the pentobarbital sleeping time of the rats nor did it interact with microsomes to give spectral changes. Cycloheximide did not alter microsomal cytochrome P-450 reductase activity. Administration of cycloheximide prior to CCl₄ did not prevent the CCl₄-induced decrease in cytochrome P-450 or glucose 6-phosphatase activity caused by the hepatotoxin. However it did prevent the CCl₄-induced polysome breakdown and it did attenuate the severity of the lesions caused by CCl₄ at the ultrastructural level.     

Effect of buthionine sulfoximine on orthophenylphenol-induced hepato- and nephrotoxic potential in male rats

A single oral administration of orthophenylphenol (OPP, 1400 mg/kg; about half the LD₅₀) to male Fischer 344 rats produced an elevation of serum transaminase activity 24 h later. Pretreatment with l-buthionine-S,R-sulfoximine (BSO, 900 mg/kg) in the OPP-treated rats potentiated the hepatic and renal damage which was accompanied by necrosis. Six hours after the administration of OPP (700 or 1400 mg/kg), hepatic and renal glutathione (GSH) levels decreased with increasing dosage. Hepatic GSH depletion with OPP was enhanced with BSO pretreatment and the recovery of GSH in both organs was slow in the high-dose OPP group. These results suggest that hepatic and renal damage is associated with a serious and prolonged GSH depletion. When either phenyl-p-benzoquinone (PBQ) or phenylhydroquinone (PHQ), which are intermediates of OPP, was administered orally to rats at 700 or 1400 mg/kg, the mortality with the high dose of PBQ was 75% at 24 h. The serum transaminase activity and UN level increased with the low dose of PBQ, accompanied by necrotic hepatocytes. The toxic effects of PHQ on kidney or liver were less than those on PBQ. These observations suggest that the liver and kidney may be target organs for toxic actions of a large dose of OPP and its intermediate, PBQ.Part of this work was presented at IInd International ISSX Meeting Xenobiotic Metabolism and Disposition, May 16–20, 1988, Kobe, Japan     

Antidiabetic Activity of the Ethanol Extract of Capparis sepiaria L Leaves

Capparis sepiaria L, a profusely branched hedge plant, is used in Indian traditional medicine. Capparis sepiaria leaves were extracted with ethanol and concentrated to dryness. The LD₅₀ value was determined as 894.43 mg/kg body weight by acute toxicity study. The ethanol extract was investigated for possible hypoglycemic effect produced by single oral administration at various dose levels 100, 200 and 300 mg/kg in the streptozotocin induced diabetic rats and compared against normal saline control and the standard glibenclamide. A maximum fall of plasma glucose level 9.40%; 13.57%; 15.25% and 18.80% was observed after 12 h of treatment when administered with ethanol extract of Capparis sepiaria at 100, 200 and 300 mg/kg, and glibenclamide 10 mg/kg dose, respectively. The findings from the study suggest that the Capparis sepiaria leaves may be prescribed as an adjunct to traditional formulation and drug treatment for controlling diabetes mellitus.     

Acute toxicity evaluation of a thiazolo arene ruthenium (II) complex in rats

Recently, a series of thiazolo arene ruthenium complexes were found to be highly cytotoxic in vitro, on both cisplatin-sensitive and cisplatin-resistant ovarian cancer cells. The most active compound of the series, [(η⁶-p-cymene)Ru(L)Cl]Cl (L = 1-(2-(2-(3-chlorobenzylidene)hydrazinyl)-4-methylthiazol-5-yl)ethanone), was selected for an in vivo study in order to assess its safety profile.The ruthenium complex was administered to female Crl:WI rats orally, by gastric intubation and intraperitoneal injection. The hematological parameters and the histopathological changes in liver, kidneys, spleen and brain were investigated after a 14-days treatment. The substance was very well tolerated orally, with a LD₅₀ value of over 2000 mg/kg body weight. Symptoms were observed only in the first day after intraperitoneal administration of the highest dose, with a LD₅₀ value between 300 and 2000 mg/kg bw. The hematological profile was not modified at any of the tested doses, after both oral and intraperitoneal acute administration. Structural modifications (moderate lymphocytolysis) were identified only in the spleen at the highest tested dose. In conclusion, the thiazolo arene ruthenium complex was very well tolerated orally and had a low acute toxicity after intraperitoneal administration in Crl:WI rats The results justify further investigation to determine the in vivo therapeutic potential of this promising ruthenium complex.     

The role of hepatic microsomal enzymes in the modulation of phencyclidine-induced toxicity

The LD₅₀ of phencyclidine (PCP, 234 μmol/kg, i.p.) in male Swiss mice decreased by 62% in animals pretreated with 2-diethylamino-2,2-diphenylvalerate hydrochloride (SKF-525A, 40 mg/kg), and increased by 74% and 20% in animals pretreated with sodium phenobarbital (75 mg/kg), and 3-methylcholanthrene (70 mg/kg), respectively. No significant change in the LD₅₀ was observed with cysteine or diethylmaleate pretreatment. The treatment with PCP at 179 μmol/kg/day i.p. for 7 days resulted in body weight decrement in the first 2 days and gradual increment thereafter. The increase was only 33% of the control group. The food intake was also lower in the PCP treated group of animals. PCP withdrawal led to an increase in food intake as well as body weight at a normal rate. The ratio of liver weight to body weight was not significantly higher than that of control during the treatment period. The administration of PCP for 7 days did not alter the activities of liver function enzyme markers. However, within 12 h of the initial PCP treatment a 85% increase in activity of serum glutamicoxalacetic transaminase was observed. Later the enzyme activity reached close to normal levels. No liver lesions at the light microscopic level were observed. Treatment of mice for 4 days with PCP (179 μmol/kg) caused no significant change in pentobarbital sleeping time.