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Showing papers on "Toxicity published in 1970"


Journal ArticleDOI
01 Feb 1970-Cancer
TL;DR: During therapeutic trials with E. coli L‐asparaginase in 131 children and 143 adults with neoplastic disease the following signs of toxicity have been observed: fever, nausea and vomiting, weight loss, somnolence, lethargy, confusion, hypolipidemia, hyperlipidemia and hypoproteinemia.
Abstract: During therapeutic trials with E. coli L-asparaginase in 131 children and 143 adults with neoplastic disease the following signs of toxicity have been observed: fever, nausea and vomiting, weight loss, somnolence, lethargy, confusion, hypolipidemia, hyperlipidemia, hypoproteinemia, abnormal liver function tests, fatty metamorphosis of the liver, pancreatitis (in rare instances), azotemia, granulocytopenia, lymphopenia, thrombocytopenia, and hypersensitivity reactions. While these effects have been moderately severe and reversible in most instances, some patients have shown dangerous degrees of toxicity. This has been the case most frequently in adult patients receiving a dose of 5000 IU/kg/day.

284 citations


Journal ArticleDOI
TL;DR: It is suggested that at least one dietary factor, low Ca ingestion, influences the pathologic effects of exposure to a specific dose of Pb, and this finding may be particularly relevant to the incidence of toxic manifestations of P b exposure among marginally nourished urban inhabitants.

262 citations


Journal ArticleDOI
TL;DR: A significant difference in toxicity was found between the compounds: compounds I and II showed the highest, compound III the lowest, toxicity.

167 citations


Journal ArticleDOI
TL;DR: Mithramycin, an inhibitor of the synthesis of ribonucleic acid (RNA), was administered to fifty-eight patients with a variety of advanced carcinomas, and striking objective improvement occurred in embryonal cell cancer of the testis.

147 citations


Journal Article
TL;DR: The exposure of L1210 leukemia cells to a temperature of 42° for a short time sensitizes them to the action of lower temperatures, and a 3-hr exposure at 40° has a highly lethal effect when applied after an initial treatment at 42°.
Abstract: Summary The lethal action of elevated temperatures on neoplastic cells has been determined quantitatively by means of an in vitro-in vivo system of L1210 leukemia cells Temperatures from 37° to 40° have little effect on these cells Prolonged exposure at 41° impairs their viability Between 41° and 42° the lethal effect increases markedly; in Fischer medium, a 4-log kill is achieved at 42° in 3 hr The exposure of L1210 leukemia cells to a temperature of 42° for a short time sensitizes them to the action of lower temperatures A 3-hr exposure at 40° has a highly lethal effect when applied after an initial treatment at 42° If the sequence of heating is reversed, no such effect is observed Many drugs have been tested for combined therapy l-erythro-α,β-Dihydroxybutyraldehyde has been found to act synergistically with heat dl-Glyceraldehyde, l-phenylalanine mustard, actinomycin D, and sodium oxamate are also active in combination with heat However, if toxicity to humans is considered, only dl-erythro-α,β-dihydroxybutyraldehyde, dl-glyceraldehyde, and phenylalanine mustard can be considered as suitable for clinical trial in combination with heat

115 citations


Journal ArticleDOI
TL;DR: During a period of 15 days following induction of adjuvant arthritis in rats, the liver microsomal N -demethylase and NADPH 2 -oxidase enzyme activity and levels of cytochrome P-450 are greatly reduced, implying a reduced capacity for the oxidative metabolism of steroids and foreign compounds in adjuant arthritic rats which should influence the toxicity and half-life of any administered compound.

72 citations


Journal Article
TL;DR: Mice given a single sublethal intraperitoneal injection of methylnitrosourea underwent cell depletion of the thymolymphoid and myeloid systems, followed by recovery, which may represent steps in the genesis of lymphomas induced by methylnitroso- p -tolylsulfonamide.
Abstract: The toxic and carcinogenic actions of four methylnitrosamine or -amide compounds, given as a single intraperitoneal injection to newborn and adult inbred Swiss mice, were examined. Toxicity was approximately directly proportional to the stability of the three compounds capable of methylating macromolecules in vitro . Methylnitrosourea induced a high incidence of thymic lymphomas in adults and newborns of either sex. Dimethylnitrosamine induced a high incidence of hepatomas in newborns only. These two drugs, as well as methylnitrosourethan and methylnitroso- p -tolylsulfonamide, induced a high incidence of pulmonary adenomas. Mice given a single sublethal intraperitoneal injection of methylnitrosourea underwent cell depletion of the thymolymphoid and myeloid systems, followed by recovery. These events occurred more rapidly in the myeloid systems than in the thymolymphoid system. These events may represent steps in the genesis of lymphomas induced by methylnitrosourea.

65 citations


Journal ArticleDOI
TL;DR: Three daily oral doses of ethoxyquin given before CCl4 were highly effective in preventing mortality, liver necrosis and the rise in hepatic triglycerides, and intraperitoneal treatment with Ethoxyquin substantially reduced the toxicity of CC14.
Abstract: 1. The acute toxicity of orally administered CCl4 and its subacute toxicity (liver necrosis and hepatic fat accumulation) were studied in young adult male and female rats. CCl4 was more toxic in males than in females. The protective effects of vitamin E (D-α-tocopheryl acetate) and three synthetic antioxidants, DPPD (N,N'-diphenyl-p-phenylenediamine), ethoxyquin (6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline) and BHT (butylated hydroxytoluene) were studied.2. Three daily oral doses (450 mg/kg) of vitamin E given before CCl4 increased survival in male rats but not consistently in females. Single oral doses (450 mg/kg) given previously at times between 24 and 72 h were also protective in males, but slightly decreased survival in females. Single intraperitoneal doses (500 mg/kg) given to female rats 1–48 h before CCl4 had no effect on survival. None of these treatments with vitamin E significantly decreased CC14-induced hepatic triglyceride accumulation. A large oral dose (2000 mg/kg) 6 h before CCl4 not only significantly increased hepatic fat accumulation but also increased mortality.3. Three daily doses (600 mg/kg) of DPPD or a single oral dose given 72 h before CCl4 increased survival in male and female rats. When single doses of DPPD were given 6–48 h before CCl4 they had no effect on survival. In contrast, DPPD usually significantly decreased the CC14-induced hepatic triglyceride rise when given orally 6–72 h before CCl4. Single intra-peritoneal doses (100–1500 mg/kg) of DPPD, given 1–48 h before CCl4, decreased the hepatic triglyceride rise. Multiple doses of DPPD decreased CC14-induced liver necrosis, but single doses were generally less effective.4. Three daily oral doses (300–500 mg/kg) of ethoxyquin given before CCl4 were highly effective in preventing mortality, liver necrosis and the rise in hepatic triglycerides. Single oral doses (500 mg/kg) given 72 or 48 h before CCl4 produced the same effect, but these single doses 24 or 6 h before CCl4 were without effect. The effective treatments usually increased liver weight markedly. Intraperitoneal treatment with ethoxyquin also substantially reduced the toxicity of CC14. Ethoxyquin was the most effective of all four treatments studied, and livers from animals given this substance were often nearly normal in histological appearance.5. The activity of oral doses (400–600 mg/kg) of BHT, given 48 h or more before CCl4 was, in general, similar to that of ethoxyquin, but less marked. This substance also caused a large increase in liver weight after 48 h. Oral doses given 6–24 h before CC14 increased the CC14-induced triglyceride rise still further. Intraperitoneal doses of BHT were ineffective against acute toxicity, liver necrosis or the triglyceride rise.6. Concentrations of a-tocopherol and the three synthetic antioxidants were measured in liver in many of the experiments. Very high hepatic concentrations of a-tocopherol could be obtained without affecting either the acute or subacute toxicity of CCl4. Ethoxyquin and BHT were rapidly eliminated from the liver after oral dosage, and when maximum concentrations were reached (24 h or less after administration) they were without protective effect. In contrast, when ethoxyquin and BHT were most active (48–96 h after administration) they could not be found in appreciable concentration in the liver.

62 citations


Journal ArticleDOI
04 Sep 1970-Science
TL;DR: Dietary ascorbic acid supplements almost completely prevented the anemia and improved the growth rate but did not markedly alter concentrations of iron or cadmium in the liver.
Abstract: Feeding the environmental toxicant cadmium to young Japanese quail for 4 weeks produced growth retardation, severe anemia, low concentrations of iron in the liver, and high concentrations of cadmium in the liver. Dietary ascorbic acid supplements almost completely prevented the anemia and improved the growth rate but did not markedly alter concentrations of iron or cadmium in the liver.

62 citations


Journal ArticleDOI
TL;DR: Circadian variation in cyclopropane toxicity (apneic concentration) was not found, however, calculations of the anesthetic index showed a cyclic pattern similar to that observed for MAC.
Abstract: The effects of circadian rhythm on cyclopropane and halothane requirements (MAC) and cyclopropane toxicity have been investigated at four-hour intervals in rats synchronized to a standard 24-hour day. Longitudinal and transverse determinations in four groups of animals showed characteristic circadian patterns, with the highest values occurring in the early dark (active) period and lowest values occurring in the early light (inactive) period. Differences in MAC were significant (P < 0.05) for each agent, with maximal changes showing 10 to 14 per cent variation from mean values. Circadian variation in cyclopropane toxicity (apneic concentration) was not found. However, calculations of the anesthetic index showed a cyclic pattern similar to that observed for MAC.

54 citations


Journal ArticleDOI
TL;DR: It was found that phenobarbital pretreated mice exhibited an enhanced liver metabolism of nicotine both in vitro and in vivo, which caused a significant decrease of nicotine concentration in the brain only when nicotine was given intraperitoneally.
Abstract: Male albino mice were injected intraperitoneally or intravenously with 14C-labelled nicotine. Both untreated and phenobarbital pretreated mice were used. The concentrations of nicotine and metabolically formed cotinine were determined in the brain, liver and blood 1, 2.5, 5, 10, 20 and 60 min after injection. It was found that phenobarbital pretreated mice exhibited an enhanced liver metabolism of nicotine both in vitro and in vivo. The increased liver metabolism caused a significant decrease of nicotine concentration in the brain only when nicotine was given intraperitoneally. Phenobarbital pretreatment elevated the intraperitoneal LD50 value 2–3 times and also increased tolerance to repeated sublethal doses of nicotine. No change in the intravenous LD50 value was observed.



Journal Article
TL;DR: Tubercidin (NSC 56408), a cytotoxic antibiotic, was used in the treatment of 93 patients with various types of advanced neoplastic disease in a Phase I study to determine human toxicity.
Abstract: Summary Tubercidin (NSC 56408), a cytotoxic antibiotic, was used in the treatment of 93 patients with various types of advanced neoplastic disease in a Phase I study to determine human toxicity Significant toxicity was limited to the observation of nephrotoxicity in 18 cases and local irritation of veins in 12 Tumor response was suggested in only 3 cases, all of which were cases of primary carcinoma of the pancreas

Journal Article
TL;DR: Tubercidin with EDTA has been given a Phase I clinical trial in 45 patients and the biological effect was apparent between 4 and 12 weeks after onset of therapy and was transitory.
Abstract: Tubercidin with EDTA has been given a Phase I clinical trial in 45 patients. The drug was mixed with approximately 500 ml blood withdrawn from the patient, with EDTA as an anticoagulant, and after 1 hr incubation at 37°, given intravenously to the patient. The dose levels ranged from 200 to 1500 μg/kg given at weekly intervals for two doses. Toxicity to the drug was uncommon and usually not severe. Hematological toxicity was noted in six patients, renal toxicity in five patients, hepatic toxicity in two patients, and severe gastrointestinal toxicity in one patient. Objective regression of the tumor was noted in four patients. The biological effect was apparent between 4 and 12 weeks after onset of therapy and was transitory.

Journal ArticleDOI
TL;DR: Results suggest that an increased plasma binding after treatment with organochlorine insecticides may be an important mechanism of the protection against paraoxon toxicity.

Journal ArticleDOI
TL;DR: Studies of diethyl-1-(2,4-dichlorophenyl)-2-chlorovinyl phosphate were undertaken in several animal species to characterize toxicity and assess safety, and there was a significant and variable decrease in plasma and/or red blood cell cholinesterase activity, with reversal trends.

Journal ArticleDOI
01 Sep 1970-Toxicon
TL;DR: A decrease in toxicity and inactivation of all three enzymes studied was clearly shown and no difference could be detected in the immunological response of rabbits to untreated and irradiated venom.

Journal ArticleDOI
TL;DR: In experiments on mice acute toxicity of morphine did not differ in aggregated and non-aggregated animals and the development of tolerance to morphine affected differently the duration of the stereotypies produced by amphetamine and apomorphine.
Abstract: In experiments on mice acute toxicity of morphine did not differ in aggregated and non-aggregated animals. Morphine in doses of 5, 10, 20, 40, 80 mg/kg s.c. did not significantly influence the amphetamine group toxicity in mice.

Journal ArticleDOI
TL;DR: In this article, it was shown that wheat and barley contain in the endosperm a toxic substance to brewing yeast, and the substance is easily extracted with a dilute sulfuric acid solution.
Abstract: It is shown that among various grains, wheat and barley contain in the endosperm a toxic substance to brewing yeast, and the substance is easily extracted with a dilute sulfuric acid solution. One unit of the toxicity is defined as the lowest amount of the extract which inhibits the yeast growth in 10 ml of wort medium. Two or more units of the toxicity not only inhibited the yeast growth, but also caused the death of yeast cells. Although the toxic effect was not observed when divalent metallic ions such as Ca2+, Zn2+ or Fe2+ were present at a concentration of 5 × l0−3 mole or more, the toxicity could be recovered by the addition of ethylene-diamine-tetra-acetate (EDTA). Genetic relationships on the content of the toxicity in wheat and barley and sensitivity of yeast strains to the toxicity are also presented.



Journal Article
TL;DR: Results indicate that the optimal doses of 5-azacytidine were more active against rapidly proliferating leukemic cells than nonleukemic Cells, and completely reversed the toxicity of the drug to nonleukesmic mice.
Abstract: Summary Investigations were carried out to examine the antileukemic effect of 5-azacytidine, a synthetic analog of cytidine. The effect of cytidine and deoxycytidine upon the antileukemic activity and toxicity of 5-azacytidine was also investigated. Treatment from Days 3 to 7 and 3 to 11 with optimal doses of 5-azacytidine increased the life-span of the leukemic mice by 85 to 100% over that of the untreated leukemic controls. Mice treated with doses above the optimum succumbed from the toxic effects of the drug. Simultaneous treatment with cytidine (600 or 360 mg/kg) reversed the antileukemic activity of optimal doses of 5-azacytidine. This treatment also reduced the toxicity of higher doses of 5-azacytidine (12 to 33 mg/kg) to leukemic mice, permitting the observations of increased survival time of these mice, and completely reversed the toxicity of the drug to nonleukemic mice. Spleen and bone marrow cells of leukemic and non-leukemic mice treated with 5-azacytidine were significantly reduced below the levels of untreated controls. However, the results indicate that the optimal doses of 5-azacytidine (2.6 and 4.3 mg/kg) were more active against rapidly proliferating leukemic cells than nonleukemic cells. Concurrent treatment with cytidine restored the spleen and bone marrow cells of leukemic and nonleukemic mice and also the colony-forming capability of nonleukemic cells. With deoxycytidine instead of cytidine in combination treatment with 5-azacytidine, only minor effects were observed in lowering antileukemic activity and host toxicity of the drug.

Journal ArticleDOI
TL;DR: Dieldrin has a more pronounced effect than DDT on the toxicity of the organophosphorus compounds used, although the toxicities of Bidrin and malathion were slightly decreased, and theoxicity of dimethoate was slightly increased.

Journal ArticleDOI
TL;DR: Strain differences of rats and mice used commonly in Japan concerning the activity of microsomal drug-metabolizing enzymes were studied in relation to the effect and toxicity of drugs.

Journal Article
TL;DR: The toxicity to rats could not be altered by castration, administration of testosterone to females and estradiol to males, and Pretreatment with phenobarbital decreased the toxicity to adult males and increased theoxicity to adult females.
Abstract: A study was made of the acute and subacute toxicity of 6-methyl-2,3-quinoxalinedithiol cyclic carbonate (Morestan) and a possible metabolite, 6-methyl-2,3-quinoxalinedithiol. and their effects on various enzyme systems. The dithiol derivative was twice as toxic as Morestan to rats and mice. Male adult rats were twice as susceptible as females to both of the compounds. Weanling rats exhibited no sex difference in susceptibility and were more resistant than adults. Mice were less susceptible than rats and showed no sex difference. The toxicity to rats could not be altered by castration, administration of testosterone to females and estradiol to males. Pretreatment with phenobarbital decreased the toxicity to adult males and increased the toxicity to adult females. Morestan had a high cumulative toxicity when administered daily. Acutely toxic doses caused decreased activity, diarrhea, increased hematocrit values, decreased urination and a fall in blood pressure. Both compounds inhibited sulfhydryl enzymes including pyruvic dehydrogenase, succinic dehydrogenase, malate dehydrogenase and α-ketoglutarate oxidase. Reduced glutathione levels were lowered in the liver. Nitroreductase activity was reduced. Feeding Morestan in the diet for 90 days at 500 ppm resulted in decreased body weight, enlarged livers, inhibition of acetoacetate synthesis and inhibition of microsomal enzymes.



Journal ArticleDOI
TL;DR: These selective inhibitors of the toxicity and carcinogenicity of N-2-fluorenylacetamide provide new methods for the study of the underlying mechanisms.

Journal ArticleDOI