scholarly journals Toxicity and medical countermeasure studies on the organophosphorus nerve agents VM and VX

2015 ◽  
Vol 471 (2176) ◽  
pp. 20140891 ◽  
Author(s):  
Helen Rice ◽  
Christopher H. Dalton ◽  
Matthew E. Price ◽  
Stuart J. Graham ◽  
A. Christopher Green ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Penetration Rate ◽  
Lethal Dose ◽  
Scientific Advice ◽  
Complete Protection ◽  
Pig Skin ◽  
Syrian Arab Republic ◽  
Medical Countermeasures

To support the effort to eliminate the Syrian Arab Republic chemical weapons stockpile safely, there was a requirement to provide scientific advice based on experimentally derived information on both toxicity and medical countermeasures (MedCM) in the event of exposure to VM, VX or VM–VX mixtures. Complementary in vitro and in vivo studies were undertaken to inform that advice. The penetration rate of neat VM was not significantly different from that of neat VX, through either guinea pig or pig skin in vitro . The presence of VX did not affect the penetration rate of VM in mixtures of various proportions. A lethal dose of VM was approximately twice that of VX in guinea pigs poisoned via the percutaneous route. There was no interaction in mixed agent solutions which altered the in vivo toxicity of the agents. Percutaneous poisoning by VM responded to treatment with standard MedCM, although complete protection was not achieved.

Species differences in the reactivation of organophosphate-inhibited plasma esterases by diacetymonoxime

1976 ◽  
Vol 54 (2) ◽  
pp. 86-92 ◽  
Author(s):  
D. J. Ecobichon
Keyword(s):  
Guinea Pig ◽  
Species Differences ◽  
Marked Effect ◽  
Lethal Dose ◽  
Rat Plasma ◽  
In Vivo Studies ◽  
Rapid Rate ◽  
Plasma Enzymes

A study was conducted to assess whether the protection afforded to organophosphate-poisoned animals by diacetylmonoxime (DAM) was correlated with the reactivation of non-essential aliesterases (AliE). In vitro, the DAM-catalyzed reactivation of plasma AliE and cholinesterases (ΨChE) of rat, rabbit and guinea pig inhibited by 10−5 M diisopropylphosphorofluoridate (DFP) and O,O-dimethyl-2,2-dichlorovinyl phosphate (DDVP) was investigated. Marked reactivation of the rat plasma enzymes was achieved with 10 mM DAM. Higher concentrations (30 mM) were necessary for the slow reactivation of rabbit and guinea pig plasma AliE. Reactivation of the ΨChE of these species was comparatively slow. Reactivation of DDVP-inhibited esterases proceeded in all species at a more rapid rate than those inhibited by DFP. The dependence of ΨChE reactivation upon concomitant more rapid reactivation of AliE by DAM was demonstrated using Sephadex fractionated AliE and ΨChE but only a marked effect was observed with the rat, suggesting that the plasma AliE of this species is functionally different.The in vitro observations were confirmed by in vivo studies in rats and rabbits. DAM (50 or 150 mg/kg), administered to atropinized rats 15 min before a lethal dose of DFP, protected the animals. Few severe toxic signs were observed and reactivation of both plasma AliE and ΨChE occurred. In contrast, DAM protected the rabbit against a lethal dose of DFP but only reactivation of the erythrocyte acetylcholinesterase was observed.

scholarly journals Antidiarrhoeal potentials of methanol bark extract of Hymenocardia Acida Tul (Euphorbiaceae) in laboratory animals

2021 ◽  
Vol 45 (1) ◽  
Author(s):  
Abba Musab Usman ◽  
Nuhu Muhammad Danjuma ◽  
Jamilu Ya’u ◽  
Muslim Muhammad Ahmad ◽  
Zakariyya Alhassan ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Lethal Dose ◽  
Stem Bark ◽  
Laboratory Animals ◽  
Bark Extract ◽  
Intestinal Fluid ◽  
Guinea Pig Ileum ◽  
Rabbit Jejunum

Abstract Background The plant Hymenocardia acida (Euphorbiaceae) is utilized as herbal preparation against diarrhoea, dysentery and other diseases. We aimed to determine the antidiarrhoeal potentials of Hymenocardia acida (MEHA) stem bark in vivo and in vitro. Preliminary phytochemical contents, as well as the acute toxicity effect of the extract, were investigated based on standard experimental methods. The antidiarrhoeal properties of the MEHA at 150, 300 and 600 mg/kg were studied against diarrhoea induced by castor oil, intestinal fluid accumulation, as well as intestinal movement tests using distilled water (10 ml/kg) and loperamide/atropine sulphate as the control groups. Besides, the in vitro effects of the extract (8 × 10−2–640 × 10−2 mg/ml) on the rabbit jejunum and guinea-pig ileum were evaluated. Results Phytochemical screening showed alkaloids, glycoside, saponins, tannins, triterpenes, flavonoids and steroids in the MEHA. The median lethal dose (LD50) of the MEHA after oral administration was approximately greater than 2000 mg/kg. The MEHA declined the diarrhoea onset and remarkably decreased the number of watery stools in the group that received 300 and 600 mg/kg. It also elicited a remarkable and non-dose-dependent reduction in the intestinal fluid volume. At 1000 mg/kg, the MEHA significantly inhibited the charcoal movement. In addition, the MEHA (8 × 10−2–640 × 10−2 mg/ml) elicited a remarkable decrease in the contractility of the rabbit jejunum over time and relaxed the guinea pig ileum. Besides, it showed concentration-dependent attenuation of the acetylcholine and histamine-induced contraction. Conclusion The extract under investigation revealed promising antidiarrhoeal properties that justified its traditional claim for use against diarrhoea.

Inhibition of Human and Animal Platelet Adhesiveness to Glass Bead Columns by Adenosine, Dipyridamole, Chlorpromazine and Acetylsalicylic Acid

1976 ◽  
Vol 36 (02) ◽  
pp. 401-410 ◽  
Author(s):  
Buichi Fujttani ◽  
Toshimichi Tsuboi ◽  
Kazuko Takeno ◽  
Kouichi Yoshida ◽  
Masanao Shimizu
Keyword(s):  
Guinea Pig ◽  
Acetylsalicylic Acid ◽  
Guinea Pigs ◽  
Glass Bead ◽  
Animal Species ◽  
Inhibitory Effect ◽  
Rabbit Platelet ◽  
Platelet Adhesiveness

SummaryThe differences among human, rabbit and guinea-pig platelet adhesiveness as for inhibitions by adenosine, dipyridamole, chlorpromazine and acetylsalicylic acid are described, and the influence of measurement conditions on platelet adhesiveness is also reported. Platelet adhesiveness of human and animal species decreased with an increase of heparin concentrations and an increase of flow rate of blood passing through a glass bead column. Human and rabbit platelet adhesiveness was inhibited in vitro by adenosine, dipyridamole and chlorpromazine, but not by acetylsalicylic acid. On the other hand, guinea-pig platelet adhesiveness was inhibited by the four drugs including acetylsalicylic acid. In in vivo study, adenosine, dipyridamole and chlorpromazine inhibited platelet adhesiveness in rabbits and guinea-pigs. Acetylsalicylic acid showed the inhibitory effect in guinea-pigs, but not in rabbits.

Hepato- and Nephroprotective Effects of the Polyphenol Concentrate From Cabernet Sauvignon Grape Varieties Cultivated in Kazakhstan in the Experimental Model Of CCL4-Induced Toxicity

2017 ◽  
Vol 9 (03) ◽  
Author(s):  
Nurgozhin T. ◽  
Sergazy S. H. ◽  
Adilgozhina G. ◽  
Gulyayev A. ◽  
Shulgau Z. ◽  
...  
Keyword(s):  
Carbon Tetrachloride ◽  
Experimental Model ◽  
Lethal Dose ◽  
Radical Scavenging ◽  
Cabernet Sauvignon ◽  
Intragastric Administration ◽  
Liver And Kidney ◽  
Antioxidant Stress

Objective:This study investigates the hepatoprotective effect and the antioxidant role of polyphenol concentrate in the experimental model of carbon tetrachloride (CCl4) induced toxicity. Methods: Antioxidant activity of Cabernet Sauvignon grape polyphenol were evaluated by radical scavenging of 1,1-diphenyl-2-picryl hydrazyl radical (DPPH), 2,2’-azinobis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS.+). In addition, the effects of polyphenol concentrate on the survival of Wistar rats in the toxicity model, was also investigated. The polyphenol concentrate was administered for 5 five days prior to injection of carbon tetrachloride in a sub-lethal dose of 300 mg/kg of animal body weight in order to perform histological examinations of the liver and kidney, and detect the levels of AST, ALT and bilirubin. Results: Administration of polyphenol concentrate increased animal survival in the experimental model. Moreover, the intragastric administration of polyphenol concentrate prior to the initiation of the experimental model of toxicity, which was caused by a sub-lethal CCl4 dose, reduced morphological injuries in the liver and kidney, decreased the AST and ALT levels of the blood serum. Discussion and conclusion: Our data demonstrate that polyphenol concentrate possesses an antioxidant potential both in vitro and in vivo by reducing antioxidant stress that was caused by CCl4 administration into rats.

In Vitro and In Vivo Neutralizing Activity of Uvaria chamae Leaves Fractions on the Venom of Naja nigricollis in Albino Rat and Bovine Blood

2020 ◽  
Vol 14 (4) ◽  
pp. 295-311
Author(s):  
Ada Gabriel ◽  
Mamman Mohammed ◽  
Mohammed G. Magaji ◽  
Yusuf P. Ofemile ◽  
Ameh P. Matthew ◽  
...  
Keyword(s):  
Ethyl Acetate ◽  
Neglected Tropical Diseases ◽  
Lethal Dose ◽  
Positive Control ◽  
Haemolytic Activity ◽  
Cytotoxic Activities ◽  
Albino Rat ◽  
Aqueous Residue

Background: Snakebite envenomation is a global priority ranked top among other neglected tropical diseases. There is a folkloric claim that Uvaria chamae is beneficial for the management of snakebite and wounds in African ethnobotanical surveys. Besides, there are many registered patents asserting the health benefits of U. chamae. Objective: This study aimed to investigate U. chamae’s potentials and identify candidates for the development of tools for the treatment and management of N. nigricollis envenomation. Methods: Freshly collected U. chamae leaves were air-dried, powdered, and extracted in methanol. The median lethal dose of the extract was determined and further fractionated with n-hexane, n-butanol and ethyl acetate. Each fraction was tested for neutralizing effect against venom-induced haemolytic, fibrinolytic, hemorrhagic, and cytotoxic activities. Results: U. chamae fractions significantly (p<0.05) neutralized the haemolytic activity of N. nigricollis venom in n-butanol; 31.40%, n-hexane; 33%, aqueous residue; 39.60% and ethyl acetate; 40.70% at the concentration of 100mg/ml of each fraction against 10mg/ml of the snake venom when compared to the positive control. The fibrinolytic activity of N. nigricollis venom was significantly (p<0.05) neutralized in n-hexane at 73.88%, n-butanol; 72.22% and aqueous residue; 72.22% by the fractions of U. chamae. In addition, haemorrhagic activity of N. nigricollis venom was significantly (p<0.05) neutralized by U. chamae fractions at the concentrations of 100mg/ml, 200mg/ml and 400mg/ml except for n-butanol and aqueous residues at 400 mg/ml. Conclusion: U. chamae leaves fractions possess a high level of protection against N. nigricollis venoms-induced lethality and thus validate the pharmacological rationale for its usage in the management of N. nigricollis envenomation.

scholarly journals Catalytic activity and stereoselectivity of engineered phosphotriesterases towards structurally different nerve agents in vitro

2021 ◽  
Author(s):  
Anja Köhler ◽  
Benjamin Escher ◽  
Laura Job ◽  
Marianne Koller ◽  
Horst Thiermann ◽  
...  
Keyword(s):  
Plasma Clearance ◽  
Nerve Agents ◽  
Inhibition Assay ◽  
Ache Inhibition ◽  
Catalytic Activities ◽  
Chiral Lc ◽  
Hydrolysis Of ◽  
Medical Countermeasures

AbstractHighly toxic organophosphorus nerve agents, especially the extremely stable and persistent V-type agents such as VX, still pose a threat to the human population and require effective medical countermeasures. Engineered mutants of the Brevundimonas diminuta phosphotriesterase (BdPTE) exhibit enhanced catalytic activities and have demonstrated detoxification in animal models, however, substrate specificity and fast plasma clearance limit their medical applicability. To allow better assessment of their substrate profiles, we have thoroughly investigated the catalytic efficacies of five BdPTE mutants with 17 different nerve agents using an AChE inhibition assay. In addition, we studied one BdPTE version that was fused with structurally disordered PAS polypeptides to enable delayed plasma clearance and one bispecific BdPTE with broadened substrate spectrum composed of two functionally distinct subunits connected by a PAS linker. Measured kcat/KM values were as high as 6.5 and 1.5 × 108 M−1 min−1 with G- and V-agents, respectively. Furthermore, the stereoselective degradation of VX enantiomers by the PASylated BdPTE-4 and the bispecific BdPTE-7 were investigated by chiral LC–MS/MS, resulting in a several fold faster hydrolysis of the more toxic P(−) VX stereoisomer compared to P(+) VX. In conclusion, the newly developed enzymes BdPTE-4 and BdPTE-7 have shown high catalytic efficacy towards structurally different nerve agents and stereoselectivity towards the toxic P(−) VX enantiomer in vitro and offer promise for use as bioscavengers in vivo.

scholarly journals A SPECIFIC POISON IN THE LIVER EXTRACTS OF RABBITS INOCULATED WITH TYPHOID AND PRODIGIOSUS BACILLI INTRAVENOUSLY

1918 ◽  
Vol 28 (5) ◽  
pp. 571-583
Author(s):  
Julia T. Parker
Keyword(s):  
Anaphylactic Shock ◽  
Liver Extract ◽  
Lethal Dose ◽  
Toxic Substance ◽  
Normal Liver ◽  
Immune Serum ◽  
Minimum Lethal Dose ◽  
Lethal Doses

1. The livers of rabbits inoculated with cultures of Bacillus typhosus or Bacillus prodigiosus under certain conditions contain a toxic substance extractable with salt solution. When the toxic extracts are injected intravenously into normal rabbits the latter animals develop symptoms resembling those of anaphylactic shock and succumb. The lethal doses of the toxic extracts are far smaller than those of normal liver extract. 2. The livers of rabbits injected with typhoid antigen also yield a toxic extract. 3. Boiling as well as filtration through a Berkefeld filter only partially detoxicates the extract. 4. Tolerance to one to two lethal doses of the poisonous extracts can be induced by cautious immunization. 5. Rabbits actively immunized to Bacillus typhosus or Bacillus prodigiosus usually resist one lethal dose of the homologous liver poison; and animals tolerant to the typhoid liver poison resist one minimum lethal dose at least of Bacillus typhosus. 6. Typhoid immune serum is not detoxicating either in vivo or in vitro for the typhoid liver poison. 7. The liver poisons are specific, since rabbits actively immunized to either Bacillus typhosus or Bacillus prodigiosus withstand at least one minimum lethal dose of the homologous but not of the heterologous-liver poisons.

The control of trophoblastic growth in the guinea pig

Development ◽  
1980 ◽  
Vol 60 (1) ◽  
pp. 405-418
Author(s):  
E. B. Ilgren
Keyword(s):  
Guinea Pig ◽  
Inner Cell Mass ◽  
Cell Mass ◽  
The Other ◽  
In Vivo Analysis

The growth of mouse trophectoderm depends upon the presence of the inner cell mass. Whether this applies to other species of mammals is not known. To investigate this problem, the guinea pig was selected for two reasons. Firstly, the growth of guinea-pig trophoblast resembles that of man. Secondly, earlier studies suggest that the proliferation of guinea-pig trophectoderm may not be under ICM control. Therefore, in the present study, the guinea-pig blastocyst was cut microsurgically to yield two tissue fragments. These contained roughly equal numbers of trophectodermal cells, one fragment being composed only of trophectoderm and the other containing ICM tissue as well. Subsequently, the growth of these mural and polar fragments was followed in vitro since numerous technical difficulties make an in vivo analysis of this problem impracticable. In a manner similar to the mouse, the isolated mural trophectoderm of the guinea pig stopped dividing and became giant. In contrast, guinea-pig polar fragments formed egg-cylinder-like structures. The latter contained regions structurally similar to two presumptive polar trophectodermal derivatives namely the ectoplacental and extraembryonic ectodermal tissues. These findings suggest that guinea-pig trophectodermal growth may occur in a manner similar to the mouse and thus be under ICM control.

scholarly journals Human Recombinant Fab Fragment Neutralizes Shiga Toxin Type 2 Cytotoxic Effects in vitro and in vivo

Toxins ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 508 ◽  
Author(s):  
Daniela Luz ◽  
Maria Amaral ◽  
Flavia Sacerdoti ◽  
Alan Bernal ◽  
Wagner Quintilio ◽  
...  
Keyword(s):  
Shiga Toxin ◽  
Lethal Dose ◽  
Dependent Manner ◽  
Fab Fragment ◽  
Cell Viability Assay ◽  
Cytotoxic Effects ◽  
Morphological Alterations ◽  
Viability Assay

Shiga toxin (Stx) producing Escherichia coli (STEC) is responsible for causing hemolytic uremic syndrome (HUS), a life-threatening thrombotic microangiopathy characterized by thrombocytopenia, hemolytic anemia, and acute renal failure after bacterially induced hemorrhagic diarrhea. Until now, there has been neither an effective treatment nor method of prevention for the deleterious effects caused by Stx intoxication. Antibodies are well recognized as affinity components of therapeutic drugs; thus, a previously obtained recombinant human FabC11:Stx2 fragment was used to neutralize Stx2 in vitro in a Vero cell viability assay. Herein, we demonstrated that this fragment neutralized, in a dose-dependent manner, the cytotoxic effects of Stx2 on human glomerular endothelial cells, on human proximal tubular epithelial cells, and prevented the morphological alterations induced by Stx2. FabC11:Stx2 protected mice from a lethal dose of Stx2 by toxin-antibody pre-incubation. Altogether, our results show the ability of a new encouraging molecule to prevent Stx-intoxication symptoms during STEC infection.

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