High LD50 Value Research Articles

Identification of Virulence Factors in Vibrio vulnificus by Comparative Transcriptomic Analyses between Clinical and Environmental Isolates Using cDNA Microarray

We compared the gene expression among four clinical and five environmental V. vulnificus isolates, using a cDNA microarray containing 131 genes possibly associated with pathogenicity, transport, signal transduction, and gene regulations in the pathogen. cDNAs from total RNAs of these isolates were hybridized into the cDNA microarray using the cDNA of the wild-type strain MO6/24-O as a reference. We focused on selecting differentially expressed (DE) genes between clinical and environmental isolates using a modified t-statistic. We could detect two statistically significant DE genes between virulent isolates and less-virulent isolates with a marginal statistical significance (pvalue of 0.008). These were genes putatively encoding pilin and adenlyate cylase. Real time-PCR confirmed that these two selected genes transcribed in significantly higher levels in virulent isolates than in less-virulent isolates. Mutants with lesions in the gene encoding pilin showed significantly higher LD50 values than that of wild type.

An Evaluation of Acute and Subchronic Toxicities of a Nigerian Polyherbal Tea Remedy

5 Abstract: The evaluation of the acute and subchronc toxicities of a Nigerian polyherbal tea remedy, prepared with Anthocleista vogelii, Ficus exasperata leaves and Viscum album (mistletoe), was carried out in Swiss albino mice and Wistar rats of both sexes. The lyophilized extract in the dose ranges of 1.0 g to 20.0 g/kg body weight was administered orally to the mice and observed continuously for the first 4 h and hourly for the next 12 h, then 6 hourly for 56 h (72 h, acute toxicity). Wistar rats were also fed with different doses of the lyophilized formulation for 30 days and the effects on some tissues - heart, liver and testes - wer e histologically evaluated. Also the effects on the biochemical and haematological parameters were evaluated (subchronic toxicity model). The median acute toxicity value (LD50) of the polyherbal tea was determined to be 8.970 g/kg body weight. The tea significantly reduced (p<0.05) plasma glucose and Low Density Lipoprotein (LDL)-cholesterol levels, but increased High Density Lipoprotein (HDL)-cholesterol in the treated groups compared to the control. No significant increase in the body weight was observed in the treated groups. Aspartate Aminotransferases (AST) and creatinine levels were not significantly increased while significant decrease in Alanine Aminotransferases (ALT) levels were observed in all the treated groups. The high LD50 value of the drug implies that the drug could be safe in one dose treatment. The study also revealed that the polyherbal tea may have good hypoglycemic effects and favourable reducing effects on the cardiovascular risk factors.

Efficacy of essential oils of Lippia alba (Mill.) N.E. Brown and Callistemon lanceolatus (Sm.) Sweet and their major constituents on mortality, oviposition and feeding behaviour of pulse beetle, Callosobruchus chinensis L.

Pulse beetle, Callosobruchus chinensis L., is the most destructive insect pest of pulses under storage in Asia and Africa. Keeping in view the negative impacts of synthetic insecticides and the demands of botanical pesticides, the present investigation explores the repellents, antifeedants, ovicidal, larvicidal and pupaecidal activity of two plant essential oils (EOs) and their major components, geranial and 1,8-cineole, when applied as fumigants for the management of the pulse beetle. EO of Callistemon lanceolatus (Sm.) Sweet caused 100% repellency of pulse beetle in a Y-shaped olfactometer at a dose of 150 µL, while Lippia alba (Mill.) N.E. Brown EO and 1,8-cineole showed 76 and 74.7% repellency at the same dose. At 0.1 µL mL(-1) , both the oils and 1,8-cineole provided 100% insect mortality. The EO of C. lanceolatus was recorded as the most effective fumigant, showing 96.03% oviposition deterrency and 100% antifeedant activity at 0.1 µL mL(-1) . The LD(50) of L. alba (11049.2 µL kg(-1) ) and C. lanceolatus (14 626.3 µL kg(-1) ) exhibited their favourable safety profiles when recorded on mice. EOs of L. alba and C. lanceolatus exhibited significant biological activity on the mortality and reproductive behaviour of pulse beetle. Based on their high LD(50) values, the oils could be safely recommended as non-mammalian toxic fumigants in management strategies for pulse beetle.

Evaluation of Cinnamomum tamala Oil and Its Phenylpropanoid Eugenol for Their Antifungal and Antiaflatoxigenic Activity

During screening of 20 plant extracts against toxigenic strain of Aspergillus flavus (SK 3NSt), the extract of Cinnamomum tamala was found to exhibit absolute fungitoxic activity (100% growth inhibition). Hence, essential oil of C. tamala was extracted and selected for further investigations. The selected oil was subsequently standardised through physico-chemical and fungitoxic properties. Minimum inhibitory concentration (MIC) of the oil for absolute inhibition of growth of the toxigenic strain of A. flavus (SK 3NSt) was found to be 150 μl/l and oil showed fungicidal nature at its respective MIC. The oil had a broad fungitoxic spectrum. It was found to be absolutely inhibitory to almost all the 11 fungi tested when its fungitoxic spectrum was assayed. The antifungal potency of oil was found to be greater in comparison to some prevalent synthetic fungicides. The oils had the potency to withstand high inoculum density. The oil remained active up to 2 years and was thermostable. In addition, the oil showed significant efficacy in arresting aflatoxin B1 secretion by the toxigenic strain (SK 3NSt) of A. flavus at 750 μl/l. GC-MS analysis of the oil led to the identification of main components of oil viz. eugenol (45.58%), β-pinene (10.03%), β-myrcene (9.73%), β-ocimene (4.51%), β-costol (3.88%) and thujyl alcohol isomer (2.51%). The efficacy of C. tamala oil as aflatoxin B1 suppressor is being reported for the first time. Eugenol, the major component of oil showed absolute antiaflatoxigenic efficacy even at 250 μl/l. The high LD50 value (16.94 ml/kg body weight) of oil recorded on mice indicates its non-mammalian toxicity and suggests the recommendation of the oil as a novel and safe post-harvest biological preservative of food commodities for their preservation from contaminating fungi.

Final Report on the Safety Assessment of Glycyrrhetinic Acid, Potassium Glycyrrhetinate, Disodium Succinoyl Glycyrrhetinate, Glyceryl Glycyrrhetinate, Glycyrrhetinyl Stearate, Stearyl Glycyrrhetinate, Glycyrrhizic Acid, Ammonium Glycyrrhizate, Dipotassium Glycyrrhizate, Disodium Glycyrrhizate, Trisodium Glycyrrhizate, Methyl Glycyrrhizate, and Potassium Glycyrrhizinate1

Final Report on the Safety Assessment of Glycyrrhetinic Acid, Potassium Glycyrrhetinate, Disodium Succinoyl Glycyrrhetinate, Glyceryl Glycyrrhetinate, Glycyrrhetinyl Stearate, Stearyl Glycyrrhetinate, Glycyrrhizic Acid, Ammonium Glycyrrhizate, Dipotassium Glycyrrhizate, Disodium Glycyrrhizate, Trisodium Glycyrrhizate, Methyl Glycyrrhizate, and Potassium Glycyrrhizinate1

Hawthorn Evokes a Potent Anti-Hyperglycemic Capacity in Streptozotocin-Induced Diabetic Rats

The hypoglycaemic effect of an aqueous extract of hawthorn leaves (Crataegus oxyacantha) was investigated in normal and streptozotocin (STZ) diabetic rats. After a single dose or 9 daily doses, oral administration of the aqueous extract produced a significant and dose-dependent decrease on blood glucose levels in STZ diabetic rats (P < 0.001), but had no effect on blood glucose levels in normal rats. No changes were observed in basal plasma insulin concentrations after treatment in normal or STZ diabetic rats. In addition, the acute toxicity study of the extract was investigated in mice. The results obtained showed that the aqueous extract had a high LD50 value (13.5 g/kg) in mice. We conclude that an aqueous extract of hawthorn leaves exhibits a potent anti-hyperglycemic activity in STZ rats, but not in normal rats, without affecting basal plasma insulin concentrations.

Acute and chronic toxicity of Nigella sativa fixed oil.

We investigated the toxicity of the fixed oil of Nigella sativa L seeds in mice and rats through determination of LD50 values and examination of possible biochemical, hematological and histopathological changes. The acute toxicity of Nigella sativa fixed oil was investigated in mice. LD50 values, obtained by single doses, orally and intraperitoneally administered in mice, were 28.8 ml/kg body wt. p.o. [26.2-31.6] and 2.06 ml/kg body wt. i.p. [1.86-2.26], respectively. Chronic toxicity was studied in rats treated daily with an oral dose of 2 ml/kg body wt. for 12 weeks. Changes in key hepatic enzymes levels, including aspartate-aminotransferase, alanine-aminotranferase, and gamma-glutamyltransferase and histopathological modifications (heart, liver, kidneys and pancreas) were not observed in rats treated with Nigella sativa after 12 weeks of treatment. The serum cholesterol, triglyceride and glucose levels and the count of leukocytes and platelets decreased significantly, compared to control values, while hematocrit and hemoglobin levels increased significantly. A slowing of body weight gain was also observed in Nigella sativa treated rats, as compared to control animals. The low toxicity of Nigella sativa fixed oil, evidenced by high LD50 values, key hepatic enzyme stability and organ integrity, suggests a wide margin of safety for therapeutic doses of Nigella sativa fixed oil, but the changes in hemoglobin metabolism and the fall in leukocyte and platelet count must be taken into consideration.

Final Report on the Safety Assessment of Peg-30,-33,-35,-36, ANd-40 Castor Oil and Peg-30 and-40 Hydrogenated Castor Oil

PEG Castor Oils and PEG Hydrogenated Castor Oils are a family of polyethylene glycol derivatives of castor oil and hydrogenated castor oil that are used in over 500 formulations representing a wide variety of cosmetic products. They are used as skin conditioning agents and as surfactants (emulsifying and or solubilizing agents). The PEG Castor Oils and PEG Hydrogenated Castor Oils include various chain lengths, depending on the quantity of ethylene oxide used in synthesis. Although not all polymer lengths have been studied, it is considered acceptable to extrapolate the results of the few that have been studied to allingredients in the family. Because a principal noncosmetic use of PEG Castor Oils is as solvents for intravenous drugs, clinical data are available that indicate intravenous exposure can result in cardiovascular changes. Results from animal studies indicate very high LD50 values, with some evidence of acute nephrotoxicity in rats but not in rabbits. Short-term studies with intravenous exposure produced some evidence of toxicity in dogs but not in rabbits. Intramusuclar injection produced no toxicity in several species, including dogs. Subchronic oral studies also were negative. No dermal or ocular irritation was observed in studies in rabbits. Irritation was seen during induction, but no sen-sitization was found on challenge in guinea-pig studies using up to 50% PEG-35 Castor Oil; however, thisingredient was found to be a potent adjuvant in guinea pigs and mice. No evidence of developmental toxicity was seen in mice and rat feeding studies. Theseingredients, tested as vehicle controls, produced no mutagenic or carcinogenic effect. Clinical data are generally negative for irritation and sensitization, although some anaphylactoid reactions have been seen in studies of intravenous drugs in which PEG-35 Castor Oil was used as the vehicle. Because the maximum concentration used in animal sensitization studies was 50% for PEG Castor Oils and 100% for PEG Hydrogenated Castor Oils, it was concluded that PEG Castor Oils are safe for use in cosmetic formulations up to a concentration of 50% and that PEG Hydrogenated Castor Oils are safe as used in cosmetic formulations.

Preparation and pharmacological evaluation of 4-(1,4-benzoquinon-2-yl)-4-phenylbutanamides as potential cerebral protective agents.

A new series of 4-(1,4-benzoquinon-2-yl)-4-phenylbutanamides (2) were synthesized for evaluation of their pharmacological activities. All these compounds synthesized showed significant antilipidperoxidation (ALP) activities with brain homogenate in rats and some of them possessed a protective effect against hypobaric hypoxia in mice. Especially, a thiomorpholine derivative (2l, SUN-4757) showed a wide efficacy spectrum to a variety of experimental screening assays designed for cerebral protective agents, and it had a high LD50 value.

Germination et croissance pollinique in vitro du pollen de melon ( Cucumis melo L.) apres irradiations gamma

The effects of several factors (dose-intensity) of gamma irradiation on the germination ability and pollen growth in vitro of the Cucumis melo L. type Cantaloup Charentais cv. “védrantais” pollen are quantified. The level of germination is determined by a manual count using a binocular microscope. The morphometric characteristics of the pollen tube are evaluated by image analysis. The automated nature of the evaluation method permits a rapid processing of a large number of samples and, therefore, good reliability in the established comparisons. Relatively high doses of irradiation (1.6 kGy) are needed to reduce the level of germination. Nevertheless, doses greater than 0.5 kGy are sufficient to reduce pollen tube growth rates. The maximum length of pollen tubes is affected only by doses greater than 2.5 kGy. The lethal dose is around 4 kGy. The high radioresistance of this pollen is confirmed by the high LD50 (3 kGy) value.

Circadian Rhythm Changes in Toxicity of the Insecticide Dieldrin on Larvae of the Migratory Locust Locusta migratoria migratorioides

Circadian changes in toxicity of the insecticide dieldrin were documented in the larvae (fifth stage) of the migratory locust, Locusta migratoria migratorioides. Insects were housed under light (L): dark (D) = 12:12, with L from 0800 to 2000 h. Topical applications of dieldrin at fixed clock hours, with doses ranging from 0.1 to 8 micrograms/gm body weight, were carried out in a series of experiments on male and female larvae. Twenty-four h after dosing, mortality was recorded to quantify the median lethal dose (LD50) values with reference to time of treatment. Experiments were performed during February, early and late June, and August. Larvae were more susceptible to dieldrin when dosed during the night rather than during the day [analysis of variance (ANOVA); p less than 0.05]. Moreover, female larvae were less susceptible to dieldrin than were male larvae (ANOVA; p less than 0.05). Cosinor analysis revealed circadian rhythms in susceptibility-resistance to the insecticide in all experiments except no. 2. Toxicity was found to be greatest during the nighttime. Cosinor analysis of pooled data of the four experiments documented circadian rhythmicity to toxicity of dieldrin in female but not in male larvae. Regardless of sex, the timing of least susceptibility (greatest resistance and highest LD50 value) to the insecticide, dieldrin, was around 1500.

Anti-inflammatory activity of substituted 1,3,4-oxadiazoles.

Various 2-(4-biphenoxymethyl)-5-arylamino-1,3,4-oxadiazoles were synthesized by cyclization of the corresponding 1-(4-biphenoxyacetyl)-4-substituted thiosemicarbazides. These compounds were characterized by their elemental analyses and infrared, mass, and nuclear magnetic resonance spectral data. All substituted thiosemicarbazides (100 mg/kg, ip) and cyclized substituted oxadiazoles (100 mg/kg, ip) possessed anti-inflammatory activity, as reflected by their ability to provide protection against carrageenin-induced edema in the rat paw which ranged from 28 to 68% and 36 to 76%, respectively. Cyclization of the substituted thiosemicarbazides, in general, resulted in an increase in the anti-inflammatory activity of their corresponding substituted oxadiazoles, with the exception of those containing 2,4-dimethyl and 3,4-dimethyl substituents in their molecular structure. Hydrocortisone (10 mg/kg, ip) and oxyphenbutazone (40 mg/kg, ip) were used as the standard reference drugs and these provided 45 and 53% protection, respectively. All compounds (1 mM) possessed antiproteolytic activity and the in vitro inhibition of trypsin-induced hydrolysis of bovine serum albumin ranged from 13 to 75% for substituted thiosemicarbazides and 39 to 70% for substituted oxadiazoles. There was no relationship between the anti-inflammatory activity of substituted thiosemicarbazides and substituted oxadiazoles and their antiproteolytic effectiveness. The low toxicity of these compounds was reflected by their high approximate LD50 values, ranging from 500 to 1000 mg/kg.

Cobra cardiotoxins. Purification, effects on skeletal muscle and structure/activity relationships [published errtum appears in Eur J Biochem 1988 Feb 1;171(3):727

A new preparative method for isolating homogeneous cardiotoxins from cobra venoms is described. The technique, based on reverse-phase high-pressure liquid chromatography, was used to isolate eight cardiotoxins of known sequence from four different venoms. In each case the method was found to be particularly efficient at removing trace quantities of contaminating phospholipase. Cardiotoxins isolated in this manner were found to retain their full biological activity. Without exception the purified cardiotoxins lacked powerful haemolytic activity at concentrations up to 0.01 mM (about 100 micrograms ml-1), although some lysis of human erythrocytes was induced at higher concentrations. The cardiotoxins displayed a wide range of depolarizing activity on cultured skeletal muscle, the lowest activity being associated with the highest LD50 value. Correlating variations in amino acid sequence and variations in depolarization potency revealed the importance of residues in the second and third loops, especially lysine-46, serine-48 and lysine-52, together with a number of hydrophobic residues. Further modifications of pharmacological activity were associated with the presence of additional basic residues in the first and second loops and to minor differences in secondary structure.

ChemInform Abstract: SYNTHESIS OF SOME SUBSTITUTED BENZODIAZEPINES AS POSSIBLE CNS DEPRESSANT DRUGS

A new series of 2,3-cyclopentano-3,4-dihydro-4-spirocyclopentano-1,5-benzodi azepine which are substituted in 5-position with beta-N-heterocycloethyl or gamma-N-heterocyclo-n-propyl groups have been synthesized and evaluated for their CNS depressant activity including anticonvulsant, analgesic and pentobarbital induced hypnosis. These compounds were also investigated for their ability to inhibit in vitro succinate dehydrogenase (SDH). In most of the compounds an appreciable CNS depressant activity has been found to be associated with the compounds possessing good SDH inhibitory activity. Low toxicity of these compounds was reflected by their high approximate LD50 values.

Dosage-Mortality Studies with Pyrethroids and Other Insecticides on the Tobacco Budworm (Lepidoptera: Noctuidae) from the Imperial Valley, California

Dosage-mortality studies were conducted on populations of the tobacco budworm, Heliothis virescens (F.), from the Imperial Valley of California in 1979, 1980, and 1981. Progeny of field-collected budworms showed a steady increase in resistance over this period. Levels of resistance to permeethrin, fenvalerate, and methyl parathion increased to 51-, 29-, and 18-fold, respectively, compared with data from a susceptible laboratory colony. The LD50 for methomyl was greater than 2,000 µg/g of body weight, whereas the LD50 for this compound in the susceptible strain was 3.25 µg/g. Values obtained in the first generation decreased in the second generation of laboratory rearing and remained at this lower level in subsequent generations. This indicates that evaluation of insecticide resistance in this insect should be performed on the first generation. Response to permethrin was not different using field-collected larvae or adults to initiate the colony. However, higher LD50 values were obtained during October as compared with September collections.

Anticonvulsant activity and succinate dehydrogenase inhibitory property of new substituted thiobarbiturates

AbstractEight 1‐aryl‐3‐(2‐pyridyl)thiobarbiturates were synthesized and evaluated for their anticonvulsant property and their ability to inhibit succinate dehydrogenase activity of rat brain homogenates. These substituted thiobarbiturates (100 mg./kg., i.p.) provided 20–60% protection against pentylenetetrazol‐induced convulsions in albino mice. Low toxicity of these compounds was reflected by their high approximate LD50 values which were found to range from 500–1000 mg./kg. All substituted thiobarbiturates (ImM) inhibited in vitro succinate dehydrogenase activity and the degree of inhibition ranged from 10–72%.

Syntheses and Pharmacological Activity of N-Acyl-substituted Imidazolidinethiones and Thioimidazolines

A series of imidazolidinethiones and thioimidazolines was synthesized and tested for their effects on both forced and spontaneous motor activities as well as their ability to raise the convulsion threshold. The N-acyl-substituted 2-p-fluorobenzylthioimidazolines were the most active compounds, producing protection against maximal electroshock seizures and tonic convulsions induced by pentylenetetrazol. Both compounds had high LD50 values and safety indexes.

ChemInform Abstract: SYNTHESES AND PHARMACOLOGICAL ACTIVITY OF SUBSTITUTED IMIDAZOLIDINETHIONES AND THIOIMIDAZOLINES

AbstractDas Imidazolinthion (I) und das N‐Methylimidazolinthion (V) geben bei der Umsetzung mit Chlorameisensäureester und Acetylchlorid die Derivate (III) und (VI).

Influence of pH and route of injection on acute toxicity of tetracycline in mice

AbstractSome LD50 determinations for tetracycline hydrochloride in mice were carried out over a range of pH values, using both the intraperitoneal and the subcutaneous routes of injection. Depending on the pH of the formulation, either water or a solvent system of water and 60% (v/v) propylene glycol was employed thus ensuring complete solution of the drug at all pH values tested. Higher LD50 values were obtained with the subcutaneous route than with the intraperitoneal route. With either route of administration, there was a trend toward lowest LD50 value occurrence at the isoelectric pH of tetracycline. Actual statistical significance was achieved for the intraperitoneal route only when LD50 values obtained at the isoelectric pH were compared with either of the more acidic pH values.

THE RESISTANT LEVEL OF THE HOUSEFLIES TO SEVERAL SYNTHETIC INSECTICIDES IN INDONESIA

The resistant level of the houseflies to the several kinds of insecticides, pyrethrins, allethrin, Sumithion (fenitrothion), diazinon, DDVP, Baytex, γ-BHC and DDT, were examined on the sixteen strains collected in Indonesia. It was found that many housefly colonies in Indonesia showed higher susceptibility to these insecticides than the Takatsuki strain, especially the flies collected in Ambon, Celebes, Flores, Bali, Timor and Lombok Islands were found to be high susceptible for 9 insecticides. A few samples of flies from Indonesia showed tolerant to Sumithion, especially high LD50 values were obtained in the flies from 3 places of Jakarta city (0.615, 0.560 and 0.407 μg, respectively) and from Kabanjahe, Sumatra (0.435 μg). These LD50 values were much higher than the value of Takatsuki strain (0.088 μg).