Effects of chronic β-glycerophosphate administration on growth rate and serum,liver and bile lipid composition in the rat — A toxicity study

The possible toxic effects of a high dose of orally administered disodium β-glycerophosphate to the rat for a period of 33 weeks has been investigated. The studies revealed that β-glycerophosphate administration had no effect on either survival rate, body weight, hematological and liver function tests or on serum and liver lipids concentrations. All organ weights were similar in the control and experimental rats except for the kidneys which were significantly heavier in the β-glycerophosphate-fed rats. The biliary phospholipids concentrations was significantly increased in the treated group as observed previously during short-term treatments. Histological examination of liver and kidneys did not reveal any pathological findings. These results suggest that long-term administration of β-glycerophosphate did not induce any toxic manifestations. The observed hyperplasia of the kidneys was attribute to the effect of the sodium content of β-glycerophosphate.     

Toxicological effects of intravenous administration of pyridine in anaesthetized dogs.

In 17 anaesthetized dogs effects on blood pressure, respiration and biochemical changes in blood, i.e. serum glutamic oxaloacetic transaminase (SGOT), alkaline phosphatase (Alk.Pase), and urea, after intravenous administration of pyridine at various dose levels of 88 to 880 mg/kg body weight (LD5 to LD50) are reported. Commonly observed toxicity signs and symptoms are due to action of pyridine on the nervous system. There is no direct evidence of lowering of blood pressure. Lowering of blood pressure is noticed only at lethal doses and is accompanied by marked tachycardia. Death is due to respiratory failure. The significant biochemical changes are increase in SGOT and blood urea (p less than 0.01) and decrease in serum Alk,Pase (p less than 0.01).     

High-performance micellar liquid chromatography determination of sulphonamides in pharmaceuticals after azodye precolumn derivatization

A chromatographic procedure with precolumn derivatization to form the N-(1-naphthyl)ethylenediamine dihydrochloride azodyes is proposed for the analysis of several sulphonamides (sodium sulphacetamide, sulphadiazine, sulphaguanidine, sulphamerazine, sulphamethizole, sulphamethoxazole, sulphanilamide and sulphathiazole) in pharmaceutical preparations (tablets, pills, capsules, suspensions and drops). The separation is performed with a 0.05 M sodium dodecyl sulphate/2.4% pentanol eluent at pH 7. The precolumn derivatization improved the resolution in the chromatograms and increased the selectivity in the determination of mixtures of sulphonamides and in preparations where other drugs were present. The derivatization reaction was readily performed in a micellar medium of SDS at pH 1, leading to a rapid and simple procedure. The recoveries were in the 97–104% range with relative standard deviations usually below 3%.     

Potentiation of carbon tetrachloride hepatotoxicity in rats by pretreatment with polychlorinated biphenyls.

Pretreatment of male rats with Aroclor 1254 at a dose of 25 mg/kg i.p. for 6 days resulted in potentiation of the hepatotoxicity of inhaled carbon tetrachloride (CCl4) as evidenced by a decrease in liver glucose-6-phosphatase and elevations of serum glutamic oxalacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), isocitrate dehydrogenase, and sorbitol dehydrogenase. Aroclor 1254 alone did not demonstrate hepatotoxicity. Aroclor 1254 administration resulted in large increases in cytochrome c reductase, cytochrome P-450 (448) AND P-Nitroanisole demethylation. Subsequent exposure to CCl4 vapor resulted in over 70% decreases in the latter two parameters. The potentiation was dose-dependent with a dose of 5 mg/kg or higher being effective. Aroclor 1260 administration gave results similar to those of Aroclor 1254, but Aroclor 1221 enhanced CCl4 toxicity to a lesser extent.     

The effect of massive transplacental iron loading.

Intravenous injection of three doses of 50 mg Fe/kg (total dose 150 mg Fe/kg) as iron dextran into rabbits late in pregnancy (days 26, 28, and 30 of gestation) reduced the weight gain of the dams and increased fetal mortality. Three doses of 20 mg Fe/kg also increased fetal mortality, while three doses of 5 mg Fe/kg were without effect. Liver and kidney iron concentrations of the dams and offspring were markedly increased at the time of parturition by treatment with a total dose of 150 mg Fe/kg. At 6 weeks after birth the liver and kidney iron concentrations of offspring from treated dams were comparable to those from control dams. The liver and kidney iron concentrations of the treated dams were significantly reduced from the levels found immediately post-partum. In the rat, four i.v. doses of 200 mg Fe/kg as iron dextran on days 17, 18, 19, and 20 of gestation (total dose 800 mg Fe/kg) produced tremors, reduced body weight gain, and reduced food consumption in the dams. The growth and survival of the offspring were adversely influenced by these effects on the dam. The liver iron concentration in offspring of rats treated with 800 and 400 mg Fe/kg was increased at parturition, but had returned to normal at 4 weeks of age. No iron-induced pathology was evident in the offspring of either rabbits or rats after 14 and 18 weeks, respectively.     

The administration of monosodium L-glutamate to neonatal and pregnant rhesus monkeys

Monosodium L-glutamate (MSG) was administered, in 3 series of experiments, to infant rhesus monkeys of both sexes in single oral doses at the rate of 2 to 4 g/kg body weight: after observation for approx. 4 h, during which there was no evidence of vomiting or other malreaction, and subsequent perfusion, examination was made by light and electron microscopy for evidence of changes in the hypothalamic region. In a fourth experiment the new-born progeny of the mothers that had received 4 g/kg body weight/day MSG during the last one-third of pregnancy were similarly examined after having seen removed at birth and observed for 3 h. There was no evidence in any instance of any change that could be attributed to MSG as described by Olney and Sharpe, although there were artefacts in some inadequately fixed areas as recorded by Reynolds and her co-workers.It is concluded that the negative effect of high oral doses, taken into account with the results of investigation by Olney and others, is consistent with the safety-in-use of MSG as a food flavour enhancer.     

Antidiabetic effect of plumbagin isolated from Plumbago zeylanica L. root and its effect on GLUT4 translocation in streptozotocin-induced diabetic rats

Plumbago zeylanica L. root is widely used in Indian medicine to treat diabetes mellitus. The aim of the present investigation was to evaluate the antidiabetic effects of plumbagin isolated from P. zeylanica L. root and its effect on GLUT4 translocation in STZ-induced diabetic rats. Plumbagin (15 and 30 mg/kg b wt) was orally administered to STZ-induced diabetic rats for 28 days. An oral glucose tolerance test was performed on 21st day. The effect of plumbagin on body weight, blood glucose, plasma insulin, total protein, urea, creatinine, liver glycogen, plasma enzymes (SGOT, SGPT and ALP) and carbohydrate metabolism enzymes (glucose-6-phosphatase, fructose-1,6-bisphosphatase and hexokinase) were investigated. GLUT4 mRNA and protein expression in skeletal muscles were also studied. Plumbagin significantly reduced the blood glucose and significantly altered all other biochemical parameters to near normal. Further, plumbagin increased the activity of hexokinase and decreased the activities of glucose-6-phosphatase and fructose-1,6-bisphosphatase significantly in treated diabetic rats. Enhanced GLUT4 mRNA and protein expression were observed in diabetic rats after treatment with plumbagin. The results indicated that plumbagin enhanced GLUT4 translocation and contributed to glucose homeostasis. It could be further probed for use as a drug to treat diabetes.     

Effect of gossypol on liver metabolic enzymes in male rats

The effects of gossypol on liver metabolism were examined in male rats. Gossypol acetic acid was administered to Sprague-Dawley rats intraperitoneally (i.p.) at 5 mg/kg daily, 5 days/week for 2 weeks. The rats were killed 24 h after the last injection. The liver/body weight ratio (-42%), concentration of liver glutathione (-34%), activities of liver alpha-naphthtylacetate esterase (-30%) and DNase (-39%) were significantly decreased when compared to controls. Hepatic beta-glucuronidase (+37%), RNase (+35%) and serum alkaline RNase (+23%) activities were significantly increased. No changes were found in serum transaminases (SGPT, SGOT) or in hepatic RNA and DNA concentration. Elevation of liver and serum RNase activities suggest that gossypol treatment produces some catabolic effects. The depletion of hepatic glutathione and the elevation of beta-glucuronidase activity indicate that gossypol is hepatotoxic when given at this dose for 2 weeks.     

Protection against carbon tetrachloride-induced hepatotoxicity by pretreatment with methylmercury hydroxide

Pretreatment of rats with methylmercury hydroxide (MMH) (15 mg/kg s.c. for 2 days) protected against hepatotoxicity due to the inhalation of CCl4 vapor (4800–6100 ppm for 2 h). This was evidenced by lessening of the changes due to CCl₄ in liver glucose-6-phosphatase, serum glutamic oxal-acetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), serum isocitrate dehydrogenase and serum sorbitol dehydrogenase. Decreases in p-nitroanisole demethylation and cytochrome P-450 were also altered. Lipid peroxidation due to CCl₄ was decreased by MMH. These biochemical indices of protection were supported by histopathological observations.These results lend further support to the concept that metabolism of CCl₄ is necessary for its hepatoxicity.     

Short-term inhalation toxicity studies with peroxyacetyl nitrate in rats

The inhalation toxicity of peroxyacetyl nitrate (PAN) was examined in acute (single exposure), sub-acute (4-week repeated exposure) and subchronic (13-week repeated exposure) studies in rats. The 4-h LC₅₀ was found to be 95 ppm.In the 4-week study rats were exposed to 0, 0.9, 4.1 or 11.8 ppm PAN vapour for 6 h/day, 5 days/week. Exposure to 11.8 ppm caused abnormal behaviour, growth retardation, mortality, elevated haemoglobin contents, haematocrit values and erythrocyte counts, increased lung weights and severe inflammatory changes and epithelial hyper- and metaplasia in the respiratory tract. At 4.1 ppm minimal behavioral disturbance, transient growth depression, slightly increased lung weights and mild histopathological changes in the respiratory tract were found. At 0.9 ppm no treatment-related alterations were detected.In the 13-week study rats were exposed to 0, 0.2, 1.0 or 4.6 ppm PAN vapour for 6.5 h/day, 5 days.week. Exposure to 4.6 ppm resulted in changes similar to those found at 11.8 ppm in the 4-week experiment, but no mortality occurred. At 1.0 ppm minimal irritation of the mucous membranes in the nasal cavity was the only PAN-related effect observed. No treatment- related changes were seen at 0.2 ppm. It was concluded that the no-toxic- effect level is between 0.2 and 1.0 ppm, and very probably close to the upper value.     

Development of an animal model of solvent abuse for use in evaluation of extreme tricholoroethyylene inhalation

Self-intoxication by inhalation of vapors of trichloroethylene (TCE) and other solvents in widespread. In order to develop exposure protocols which typify episodes of TCE “sniffing”, male Wistar-Munich rats were exposed to TCE vapor levels ranging from 9000 to 16 000 ppm. TCE in concentrations of 14 000 ppm and greater quickly produced loss of righting reflex. Recovery from the narcosis was very rapid. Central nervous system (CNS) depression was found to be cumulative in rats subjected for 5 h to alternating periods of 5 min of 15 000 ppm TCE and 15 min of fresh air. Ethanol markedly potentiated depression in these subjects. No evidence of liver or kidney damage was seen in rats subjected to the repetitive 5-h TCE inhalation regimen, nor in rats fasted for 16 h before the TCE-exposure session. Oral admnistration of 5 ml/kg body wt of ethanol 1 h, 16 h, or once daily for 3 days before the TCE-exposure regimen had little if any potentiating effect on hepatorenal toxicity potential. Animals that received ethanol and were fasted before TCE exposure exhibited slight elevations in SGOT and SGPT levels.     

Mercuric chloride stress on serum transaminase activity in Notopterus notopterus

Mercuric intoxication at sublethal levels ($\text{1}\text{5}$, $\text{1}\text{10}$, $\text{1}\text{15}$, $\text{1}\text{20}$ or $\text{1}\text{25}$ fractions of 96 h LC₅₀) produced alterations in the activity of serum glutamic oxalacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) of Notopterus notopterus. The difference between control and treated fish was found to be significant at P < 0.05, P < 0.01 and P < 0.001 levels. Maximum (81.75%) significant (P < 0.001) effect was observed in SGOT: maximum (69.23%) significant (P < 0.001) effect was observed in SGPT in fish exposed for 60 days.     

The toxicity of brominated sesame oil and brominated soybean oil in miniature swine

Miniature swine were fed brominated sesame oil at dietary levels of 0, 5, 25, 50 or 500 mg/kg of body weight for 17 weeks and brominated soybean oil at levels of 0, 5, 50 or 500 mg/kg of body weight for 28 weeks. Growth rate and food intake were decreased only at the high dose level in the brominated sesame oil study. In both studies, signs of lethargy and ataxia occurred in pigs fed the highest dose, and were probably due to a dose-related increase in serum bromine concentrations. Marked elevations in lactic dehydrogenase (LDH), serum glutamic-oxalacetic transaminase (SGOT) and serum glutamic-pyruvic transaminase (SGPT) values were seen at the highest dose level with both substances and these enzyme activities were increased at the 50 mg/kg dose level in the brominated sesame oil study. Histopathologic lesions were confined to animals given the highest dose level of either oil. Marked fatty degeneration of the hepatic plate cells and renal tubular epithelial cells were seen in both studies. In the brominated sesame oil study, neutral fat was moderately increased in the myocardium of the pigs fed 500 mg/kg. However, marked diffuse accumulation of LDH, marked diffuse fatty degeneration and focal degeneration, and/or necrosis of individual or small groups of cardiac muscle fibers were seen in the group fed brominated soybean oil at 500 mg/kg. A moderate to marked testicular atrophy was also observed in this group.A dose-related accumulation of total and hexane-soluble bromine was observed in all tissues examined in both studies; the highest concentrations occurred in adipose tissue of the pigs given the highest dose level. Kidneys, livers, hearts and thyroids of these groups also contained large amounts of bromine. In pigs given the 50 mg/kg dose level, total and hexane-soluble bromine concentrations were higher in the brominated sesame oil study than in the longer brominated soybean oil study and may be responsible for the elevations in LDH, SGPT and SGOT activities in this group.     

Protective effect of zinc in the hepatotoxicity of bromobenzene and acetaminophen

Mice of the Balb'c strain were administered bromobenzene (BB) or acetaminophen (AA) i.p., in single doses of 400 and 300 mg/kg, respectively. In the blood activity of SGOT and SGPT as well as SDH was determined. In the liver the level of metallothionein (MT), malondialdehyde (MDA) and glutathione (GSH) was measured. The level of MT as well as GSH (determined as non-protein SH groups) showed a significant increase following administration of zinc alone. Joint action of zinc and either BB or AA resulted in a decrease of GSH which was less pronounced than expected for each of the xenobiotics alone. The protective effect of zinc reflected in the reduction of the increase of SGPT and SGOT activity was apparent shortly (4 h) after administration of AA. A day after injection of AA alone the activity of enzymes was lower and the rate of decline followed the sequence SGPT greater than SGOT greater than SDH. For BB, both the toxic effect and the protective influence of zinc were apparent 24 h following administration. At 4 h in a group receiving BB alone no changes of the indicatory enzymes in blood were noted.     

Disposition Kinetics and Urinary Excretion of Sulphadimidine in Normal and Alloxan Diabetic Dogs

Abstract: Disposition kinetics and urinary excretion of sulphadimidine were investigated in 16 dogs following a single intravenous injection (100 mg/kg body weight). Biochemical parameters including blood pH, blood glucose, plasma triglycerides and total plasma proteins of these animals were determined. The animals were injected alloxan (125 mg/kg) intravenously and when blood glucose level exceeded 300 mg%, the biochemical parameters, disposition kinetics and urinary excretion of sulphadimidine were determined again. After alloxan treatment of the dogs, there was a highly significant (P < 0.01) decrease in blood pH, increase in blood glucose and plasma triglycerides levels when compared with the pretreatment values. The alloxan diabetic dogs showed a highly significant (P < 0.01) reduction in elimination half-life (t1/2β) and apparent volume of distribution (Vd_(area) and increase in overall elimination rate constant (k_el), total body clearance (Cl_B) and percentage of sulphadimidine dose excreted in urine. In normal dogs, one-half of the intravenous dose and after alloxan treatment two-third of the dose was eliminated through urinary excretion during 48 hours after injection. This study shows that the metabolic alterations of alloxan induced diabetes in dogs, influence the drug disposition and urinary excretion which indicate the need for the adjustment of dosage regimen in such metabolic disorders.     

Antihyperglycemic and antihyperlipidemic activities of methanol:water (4:1) fraction isolated from aqueous extract of Syzygium alternifolium seeds in streptozotocin induced diabetic rats

The present study was taken up to identify potent antihyperglycemic fraction from the aqueous extract of Syzygium alternifolium (SA) seeds, using bioassay guided fractionation. The isolated fraction C at a dose of 50 mg/kg.b.w produced the maximum fall of 83% in the blood glucose level in the diabetic rats after 6 h of the treatment. The administration of fraction C (50 mg/kg.b.w) once daily for 30 days in STZ diabetic rats resulted in a significant decrease in blood glucose, glycosylated haemoglobin with a significant rise in plasma insulin level. Further fraction C showed antihyperlipidemic activity as evidenced by significant decrease in serum TC, TG, LDL-C, VLDL-C levels coupled together with elevation of HDL-C level in diabetic rats. A significant decrease in the activities of SGOT, SGPT, ALP and decreased levels of serum urea and creatinine in diabetic treated rats when compared to diabetic untreated rats, indicate the protective role against liver and kidney damage and non-toxic property of the fraction C. A comparison was made between the action of fraction C and antidiabetic drug glibenclamide (20 mg/kg.b.w). The effect of fraction C was more prominent when compared to that of glibenclamide.     

Pharmacokinetic studies in volunteers of intravenous and oral cis (Z)-flupentixol and intramuscular cis (Z)-flupentixol decanoate in viscoleo®

Summary Serum concentrations of cis (Z)-flupentixol have been estimated in three male human volunteers who received cis (Z)-flupentixol by intravenous infusion, flupentixol (cis (Z)/trans (E) mixture, 1:1) orally as single and repeated doses, and i. m. cis (Z)-flupentixol decanoate in Viscoleo^®. The intravenous data show that cis (Z)-flupentixol followed a multicompartment model, but it was not possible to fit the data to a two or three compartment model. The concentration curves after oral administration indicated relatively slow absorption with a peak concentration at 3–6 h, except for one case with peak at 1 h. The variation in the dosage interval after one daily oral administration was relatively limited (1.7–3.0 times), which indicates that 24 h is a reasonable dosage interval. Biological half-lives were estimated in different ways and showed some intra-individual variation; the half-life was of medium length (19–39 h). The serum concentrations after intramuscular injection of cis (Z)-flupentixol decanoate clearly demonstrated a depot effect, with a maximal concentration at 3–5 days after injection. The descending part of the serum curves allowed an approximate estimation of half-life of 3–8 days. This was not the elimination half-life, but in all probability the half-life of release of drug from the oil depot which was the rate-limiting step. From the areas under the serum concentration curves the fraction of orally administered cis (Z)-flupentixol available to the organism was calculated to be 55% (range 48–60%). The loss of drug might have been due to imcomplete absorption, but it is more likely that cis (Z)-flupentixol underwent first-pass metabolism in the gut wall and the liver. As the tablets contained about 50% cis (Z)-flupentixol, while the depot preparation contained 74% cis (Z)-flupentixol, the pharmacokinetically equivalent doses are: 10 mg tablet daily corresponds to 25 mg depot weekly. Calculation of systemic clearance gave values of 0.44–0.49 l/min, and an apparent volume of distribution was 12.5–17.2 l/kg.     

注射用加替沙星与注射用多索茶碱的配伍稳定性考察

目的:考察注射用加替沙星与注射用多索茶碱分别在0·9%氯化钠注射液和5%葡萄糖注射液中配伍的稳定性。方法:在室温((20±1)℃)条件下,分别观察及测定8h内配伍液的外观、pH值及紫外吸收光谱的变化,并用紫外双波长分光光度法测定加替沙星与多索茶碱的含量。结果:2药配伍后8h内,除在5%葡萄糖注射液中配伍后,6h时多索茶碱的含量降低外,其外观、pH值、含量和紫外吸收峰形均无明显变化。结论:注射用加替沙星与注射用多索茶碱可在0·9%氯化钠注射液或5%葡萄糖注射液中配伍使用,但在5%葡萄糖注射液中宜4h内滴注完毕。     

Toxicity of methyl testosterone in the beagle dog

When methyl testosterone was administered orally to beagle dogs at dosage levels of 2, 4 and 6 mg/kg per day for 27 weeks, hepatotixicty was induced. The change induced was characterized by enlargement of periportal hepatocytes and the presence of haemosiderin within macrophages. There was some evidence of recovery over a 13-week period.     

尾静脉注射不同剂量链脲佐菌素对大鼠血糖的影响

目的：探讨不同剂量链脲佐菌素（STZ）对大鼠血糖的影响。方法：尾静脉分别注射65mg/kg、25mg/kgSTZ,在48h、2周测血糖,观察血糖的变化。结果：大鼠尾静脉注射65mg/kg STZ,48h后引起血糖升高;大鼠尾静脉注射25mg/kg,2周后形成糖耐量异常。结论：65mg/kgSTZ给大鼠尾静脉注射,造成类似I型糖尿病模型：25mg/kg STZ形成糖耐量异常大鼠。