Lethality In Rats Research Articles

Research on the embryotoxic effect and carcinogenicity of the drug “BTF plus” – a means for normalizing metabolic processes in animals and poul-try

Laboratory studies were conducted to determine the embryotoxic effect and carcinogenicity of the veterinary drug “BTF plus” on white rats and white mice. The drug “BTF plus” is a complex vitamin-mineral drug based on butophosphane, L-carnitine, and cyanocobalamin, which is used to normalize and correct metabolic processes in animals and poultry. The drug is used for various types of animals and poultry as a stimulating, tonic and general strengthening agent for obstetric pathologies (complicated childbirth, postpartum complications, paresis, eclampsia, sexual cycle disorders); metabolic disorders caused by irrational feeding, malnutrition, asthenic syndrome, etc.; anemia with helminthiasis; secondary anemias, as an additional means in the treatment of magnesium and calcium deficiency; to increase muscle activity, with significant loads, overstrain and exhaustion in animals; to increase the body's resistance to various pathogens; to stimulate growth, development and live weight gain in young animals and poultry; as an additional means in the treatment of diseases caused by various factors (infectious and non-infectious origin). The drug “BTF plus”, under the conditions of subcutaneous administration to pregnant female rats in doses (based on the absolute weight of the drug) of 200.0 and 2000.0 mg/kg of body weight, does not cause death and pathological changes in embryos do not have an embryotoxic and teratogenic effect since indicators of total, preimplantation, and postimplantation embryonic lethality in rats of the experimental groups had no significant differences compared to indicators in control and also did not show changes in the weight of the placenta, fetuses, and their cranio-caudal size. The drug “BTF plus”, under conditions of 5-day subcutaneous administration to white mice in doses (based on the absolute weight of the drug) of 200.0 and 2000.0 mg/kg of body weight, does not show a carcinogenic effect (during microscopic studies, the proportion of polychromatophilic erythrocytes was not probable deviations between themselves and was 0.117-0.133%, which is within the normal range of up to 0.2 %). Further studies will be the next stage of pre-registration tests aimed at studying the ecotoxicity of “BTF plus”, which is a mandatory material of the “Safety and residue studies” section of the dossier for this drug.

Refinement of the acute inhalation limit test for inert, nano-sized dusts by an in silico dosimetry-based evaluation: case study for the dissolution of a regulatory dilemma.

This case study aims to describe the dilemma faced when exposing rats to very high concentrations of fine, pulverulent materials for acute inhalation studies and to address the regulatory question of whether the effects seen here are relevant to humans and the subject of classification according to the Globally Harmonized System of Classification and Labeling of Chemicals (GHS). Many powders match the definition of nanomaterials in the EU; therefore, information on acute inhalation testing of powders up to the GHS cutoff of 5mg/L is required. However, testing rats at such a high aerosol concentration can cause physical obstruction of the airways and even mortality by suffocation. Therefore, to evaluate whether the physical effects on airway obstruction in rats exposed to 5mg/L for 4hours and alternative exposures to 1 and 2mg/L are relevant for humans, an in silico evaluation of aerosol deposition was conducted using the multiple-path particle dosimetry (MPPD) model. For this evaluation, actual exposure conditions for an organic, nano-sized pigment which produced 100% lethality in rats at 5mg/L, but not at 1mg/L, were used to assess the potential for airway obstruction in rats and accordingly in humans. As an indicator of the potential for airway obstruction, the ratio of the diameter of the deposited, aggregated aerosol to airway diameter was calculated for each exposure condition. For rats exposed to 5mg/L for 4h, approximately 75% of tracheobronchial and 22% of pulmonary/alveolar airways were considered vulnerable to significant or complete obstruction (ratios >0.5). In humans, an equivalent exposure resulted in just over 96% of human tracheobronchial airways that received deposited mass to airway diameter ratios between 0.3 and 0.4 (nasal) or 0.4 and 0.5 (oral), with no airways with ratios >0.5. For the pulmonary/alveolar region, ∼88% of the airways following nasal or oral breathing were predicted to have deposited aerosol diameter to airway diameter ratios <0.1, with no airways with ratios >0.5. Thus, the in silico results obtained for rats are in line with the pathological findings of the animal test. The predicted results in humans, however, affirm the hypothesis of a rat-specific high dose effect which does not justify a classification according to GHS.

Evaluation of the antiulcer and antimicrobial activities of methanol leaf extract of Helianthus annuus

Background: Medicinal plants are widely used in treating and preventing specific diseases and are known to play an important role in health care. Helianthus annuus is one of such plants whose therapeutic applications no doubt have numerous folkloric background. This study aimed at assessing Helianthus annuus methanol leaf extract for antiulcer and antimicrobial potentials Methods: The antiulcer activity was evaluated using aspirin, ethanol and histamine methods in Wistar rats, while the antimicrobial activity was carried out on selected microorganisms. The acute toxicity test and phytochemical screening of the extract were also conducted. Results: The methanol leaf extract exhibited significant (p&lt;0.05 and p&lt;0.01) antiulcer effect in both model. The ulcer protection effect of the extract is comparable to omeprazole. The extract also significantly inhibited the growth of test organisms. The acute toxicity test produced no lethality in rats, whereas the phytochemical analysis revealed the presence of alkaloids, saponins, tannins, flavonoids, terpenoids and steroids. Conclusions: The findings confirm the ethnomedicinal use of H. annuus leaf as a valuable natural agent for the treatment of ulcer and microbial infections.

Physical Obstruction of Nasal Cavities With Subsequent Asphyxia, Causes Lethality of Rats in an Acute Inhalation Study With Hydrophobic HMDZ Surface-Treated Synthetic Amorphous Silica (SAS).

The aim of the present study was to understand the mechanism of lethality associated with high dose inhalation of a low-density hydrophobic surface-treated SAS observed in some acute inhalation studies. It was demonstrated that physical obstruction of the upper respiratory tract (nasal cavities) caused the effects observed. Hydrophobic surface-treated SAS was inhaled (flow-past, nose-only) by six Wistar rats (three males and three females) in an acute toxicity study at a concentration of ~500 mg/m3 for an intended 4-hr exposure. Under the conditions of the test set-up, the concentration applied was found to be the highest that can be delivered to the test animal port without significant alteration of the aerosol size distribution over time. None of the test- material-exposed animals survived the planned observation time of 4 h; three animals died between 2 h after starting exposure and cessation of exposure at 3 h, two died after transfer to their cages and the remaining animal was sacrificed due to its poor condition and welfare considerations. Histology accomplished by energy dispersive X-ray (EDX) analysis demonstrated that test material particles agglomerated and formed a gel-like substrate that ultimately blocked the upper respiratory airways, which proved fatal for the rat as an obligatory nose breather. This observation is in line with the findings reported by Hofmann et al. showing a correlation between lethality and hydrophobicity determined by contact angle measurement. The aerosol characterizations associated with this study are provided in detail by Wessely et al.

EVALUATION OF ABCB1-PROTEIN INHIBITION PROSPECTIVENESS IN HEMATOENCEPHALIC BARRIER AS METHOD FOR INCREASING EFFICIENCY OF PHARMACOTHERAPY IN CEREBRAL ISCHEMIA

The aim of the article is to evaluate the ABCB1 protein inhibition in the blood-brain barrier to increase the effectiveness of neuroprotective therapy for focal and global cerebral ischemia.Materials and methods. The work was performed on 103 male Wistar rats. In the 1st group (n=33), the neuroprotective activity of the ABCB1 protein substrate, nimodipine (0.4 mg/kg), was analyzed in terms of reducing the area of the brain necrosis after a 1-hour occlusion of the middle cerebral artery with a 24-hour reperfusion (focal ischemia). In the 2nd group (n=60), the effectiveness of nimodipine was analyzed by reducing the lethality of rats and the neurological deficit (ND) level against the background of the bilateral occlusion of the common carotid arteries (global ischemia). In both groups, nimodipine was used alone or in the combination with omeprazole, the ABCB1 protein inhibitor (17.6 mg/kg). The drugs were administered intravenously.Results. The nimodipine administration to the 1st group led to the reduction of the necrosis focus by 28% compared with the control series. Omeprazole did not cause a change in the area of the necrosis. The combination of drugs caused a decrease in the area of the necrosis in relation to the control by 29%; there were no differences in comparison with the nimodipine series. Nimodipine reduced the rats’ lethality in the 2nd group against the background of the pathology (a tendency). Omeprazole alone did not change the mortality. The drug combination reduced the mortality compared to the control and nimodipine series. The administration of omeprazole alone did not reduce the neurological deficit score relative to the control. In the nimodipine series, ND was 88% lower than the control, after 24 hours. With the administration of the drugs combination, this indicator decreased in relation to the control by 88%, 80%, 88%, 87% and 86% after 4, 12, 24, 48 and 72 hours, respectively, and in relation to the nimodipine series it decreased by 60% and 67% after 4 and 48 hours.Conclusion. The ABCB1 protein inhibition is promising for increasing the effectiveness of neuroprotective therapy for global ischemia, but not for focal cerebral ischemia.

Centrally administered butyrate improves gut barrier function, visceral sensation and septic lethality in rats

Short chain fatty acids readily crosses the gut-blood and blood–brain barrier and acts centrally to influence neuronal signaling. We hypothesized that butyrate, a short-chain fatty acid produced by bacterial fermentation, in the central nervous system may play a role in the regulation of intestinal functions. Colonic permeability and visceral sensation was evaluated in rats. Septic lethality was evaluated in a sepsis model induced by subcutaneous administration of both lipopolysaccharide and colchicine. Intracisternal butyrate dose-dependently improved colonic hyperpermeability and visceral nociception. In contrast, subcutaneous injection of butyrate failed to change it. Intracisternal orexin 1 receptor antagonist or surgical vagotomy blocked the central butyrate-induced improvement of colonic hyperpermeability. The improvement of intestinal hyperpermeability by central butyrate or intracisternal orexin-A was blocked by cannabinoid 1 or 2 receptor antagonist. Intracisternal butyrate significantly improved survival period in septic rats. These results suggest that butyrate acts in the central nervous system to improve gut permeability and visceral nociception through cannabinoid signaling. Endogenous orexin in the brain may mediate the reduction of intestinal hyperpermeability by central butyrate through the vagus nerve. We would suggest that improvement of leaky gut by central butyrate may induce visceral antinociception and protection from septic lethality.

Antidiarrhoael and antimicrobial effects of ethanol root bark extract from Salacia lehmbachii

Introduction: The roots of Salacia lehmbachii are used in Nigerian folklore medicine without scientific basis. The present study was aimed to investigate the antidiarrheal and antimicrobial activities of the ethanol extract of S. lehmbachii root bark. Methods: The antidiarrheal activity was examined using castor oil induced diarrhoea method. The ethanol root bark extract effects on intestinal transit time and enteropooling were also evaluated in rats, while antimicrobial activity was conducted on selected microorganisms. The acute toxicity test and phytochemical screening of the extract were also carried out. Results: The extract produced significant (P &lt; 0.05) dose dependent protection on rats against castor oil induced diarrhoea. The extract inhibited intestinal transit time and caused significant dose related inhibition of castor oil induced enteropooling in rats, comparable to the standard drug, atropine (P &lt; 0.05). The root bark extract significantly and dose dependently delayed the onset of castor oil induced diarrhoea, reduced the frequency of defecation and decreased the severity of diarrhoea in rats. S. lehmbachii ethanol root bark extract significantly and dose dependently decreased the volume of intestinal fluid accumulation in the castor oil induced enteropooling. The extract also significantly inhibited the growth of test organisms. The acute toxicity test produced no lethality in rats, whereas the phytochemical analysis revealed the presence of alkaloids, saponins, tannins, flavonoids, terpenoids, steroids, cardiac glycosides, resins and balsam. Conclusion: The results of this study confirm the ethnomedicinal use of S. lehmbachii root bark as a valuable natural agent for the treatment of diarrhoea and microbial infections.

Myricetin against myocardial injury in rat heat stroke model

BackgroundHeat stroke-induced mortality is rising across the globe. So, the design of prophylactic and/or therapeutic modalities for heat stroke is pressing need. The common plant derived flavonoid exhibits strong anti-oxidant and anti-inflammatory activities; however, its effects in heat stroke remain unknown. The study aimed to investigate the cardioprotective effects of myricetin on heat stroke induced acute myocardial injury as well as lethality in rats and to explore the underlying mechanisms. MethodsMyocardial injury was induced by subjecting the anesthetized rats to a high ambient temperature of 43 °C for 70 min. An intragastrical dose of myricetin (5−25 mg/kg body weight) was given to rats once per day for one week prior to the start of heat stress. Heat shock protein 72 antibodies was given intraperitoneally to rats 24 h before the start of heat stress. Myocardial injury severity was estimated by determing myocardial damage scores, myocardial injury indicators, myocardial oxidative and inflammatory factors. Western blot analysis was used for cardiac expression of heat shock protein (HSP)72. ResultsSignificant (P < 0.05) up-regulation of HSP-72 after chronic administration of myricetin coincided with significant (P < 0.05) reduction in hyperthermia, hypotension, cardiac inflammatory and oxidative damage and lethality. Inhibition of HSP-72 showed a significant (P < 0.05) reversal in the cardiaprotection as well as survival. ConclusionsOur results indicate that myricetin diminishes myocardial injury as well as lethality in heat stroke by up-regulating HSP-72 and show promise as a novel prevention therapeutic for heat stroke.

Evaluation of neuroprotective properties of Ademol with experimental traumatic brain injury conditions

The choice of drugs in traumatic injuries of the head is one of the most complex problems in the complex treatment of such patients. The aim was to estimate the cerebroprotective action of Ademol on the indicator of lethality of rats against the background of an experimental traumatic brain injury (TBI). The experimental model of the TBI of severe severity was caused by the action of the flow of carbon dioxide under pressure that was created using a gas cylinder pneumatic gun. The therapeutic effect of Ademol on the model TBI was evaluated at doses of 1, 2 and 4 mg/kg intravenously. Pseudo-operative animals and control group received a 0.9% NaCl solution at a dose of 2 ml/kg. The results were processed using the statistical program StatPlus 2009. Used Fisher angular transformation when accounting for results in an alternative form. In the course of the experiment, it was found that in the control group at the end of the experiment, 8 days after the TBI model, death of 90% of the rats was recorded p&lt;0.05. Ademol showed the highest protective effect on the brain at a dose of 2 mg/kg where the death of rats was 30% on the 8th day of the experiment. The obtained data indicate that among the studied doses 1; 2 and 4 mg/kg is conventionally effective at just 2 mg/kg, in which Ademol exhibited the highest neuroprotective activity (p&lt;0.05).

Exposure assessments in reproductive and developmental toxicity testing: An IQ-DruSafe industry survey on current practices and experiences in support of exposure-based high dose selection

The draft ICH S5(R3) guideline includes an exposure-based endpoint as an option for selecting the high dose in developmental and reproductive toxicity (DART) studies. In 2016, IQ DruSafe conducted an anonymous survey to identify industry practices and experiences related to pharmacokinetic assessments in DART studies in order to facilitate a pragmatic data-driven approach to development of an acceptable multiple of the clinical exposure to be proposed for dose selection in the guideline. Questions in the survey were designed to explore pharmacokinetic differences in pregnant versus non-pregnant animals, and to assess exposure levels attained in the absence of maternal toxicity as well as DART outcomes in animal studies associated with those exposures. Small molecule and therapeutic proteins were analyzed separately. The key findings for small molecules were: a) differences in exposures between pregnant and non-pregnant animals were generally ≤3-fold, b) Cmax or AUC exposures ≥25-fold the clinical exposure were achieved in the absence of maternal toxicity for 31% and 23% of rat and rabbit developmental toxicity studies, respectively, and c) only 3.3% (5/153) and 1.6% (2/128) of the developmental toxicity studies were positive for malformations or embryofetal lethality in rats and rabbits, respectively, that were not observed until exposure margins were ≥25-fold.

Prunus armeniaca (apricot) and Mucuna pruriens (Konch) seeds improves the liver damage in albino rat exposed to nicotine

Prunus armeniaca (apricot) and Mucuna pruriens (Konch) both are the plant, which are extensively used as medicine in Indian traditional system from ancients, they are considered to increase the protective mechanism against ailments. Nicotine is the main copious components in smoking of cigarette and it is primarily metabolized inside the liver. The current study was performed to explore the role of ethanolic extract of Prunus armeniaca and Mucuna pruriens seed on nicotine induced lethality in rats. Animals are divided in to seven group of with each group (n=6) number of rats. Wistar rats (Group II, III, IV, VI and VIII) were administered with oral nicotine diluted with drinking water for 32 days, While (Group I) plain control was treated with drinking water concurrently, following 32 days Group III, IV were administered with two different concentration of ethanolic extract of Prunus armeniaca seed (200 mg/kg , 400 mg/kg) and Group V and VI received ethanoilc extract of Mucuna pruriens seed at different doses (400 mg/kg, 800 mg/kg). Group II served as toxicity group (5mg/kg body weight of nicotine). Rats were sacrificed 24 hrs after last day of administration (40th day), the biochemical and histopathological parameter were studies. A significance increase in the activity of SGOT, SGPT, CRT, Total bile acid, LDL, ALP, TC, TG, TBL, DBL and decreased the activity of Albumin, TP and HDL in nicotine control group was observed. Group IV and Group VI, the ethanolic extract of Prunus armeniaca seed (400 mg/kg) and ethanolic extract of Mucuna pruriens seed (800 mg/kg) make the defensive effects which were found more considerable in rats. Thus the consequence was recommended that the Prunus armeniaca and Mucuna pruriens both were exert the protecting effects during nicotine induced hepatoxicity in rats. Keywords Prunus armeniaca, Mucuna pruriens, nicotine, hepatotoxicity.

Relationship between exposure, body burden and target tissue concentration after oral administration of a low-dose mixture of pyrethroid insecticides in young adult rats

Pyrethroids (PYRs) are synthetic insecticides increasingly used in agricultural and household pest control. Little is known on how the toxicity of highly effective bolus doses of single compounds compares to more realistic scenarios of low-level exposure to PYR mixtures. In this study, we examined a quaternary mixture of two noncyano (tefluthrin, TEF; bifenthrin, BIF) and two cyano (α-cypermethrin, α-CPM; deltamethrin, DTM) PYRs in young adult rats. These compounds are mostly composed of PYR isomers ranking top ten in acute lethality in rats. Concurrently, we administered near-threshold levels of the four PYRs dissolved in corn oil by oral route. Six hours later blood was collected and the liver and cerebellum were dissected out to determine PYR concentrations in these tissues using Gas Chromatography with Electron Capture Detector (GC-ECD). The mixture caused mild-to-moderate changes in non-locomotor behaviors and subcutaneous body temperature (up to +1.2–1.5 °C increase at 2–4 h after dosing, respectively, compared to pre-dosing records). The most toxic PYRs BIF and TEF reached higher concentrations in the cerebellum than the cyano-compounds α-CPM and DTM. In addition, PYR concentrations in the cerebellum were correlated to single compound proportions in the dosing solution and changes in body temperature. Our results suggest that aggregate exposures resulting in a target tissue burden of ∼10−1 nmoles PYR/g may be toxicologically relevant, expanding the evidence on exposure-dose-effect relationships for PYRs, and serving to design convenient pharmacokinetic models for environmentally relevant exposures to PYR mixtures.

Research of the toxicological profile of the new gel, which contains an extract of the oak bark and aloe extract

On these days periodontal diseases are widely distributed and diagnosed in more than 75 % of the world population and occurs in all age groups. Drugs based on medicinal plants should be considered as promising products, which have therapeutic effect with minimum adverse reactions. The aim of this work was to study the acute toxicity of new gel containing plant extract of oak bark and extract of aloe. Methods. Acute toxicity was studied in accordance with the guidelines on white nonlinear rats with 180–220 g in weight, by several steps: the study of acute toxicity of components of a new gel, the study of acute toxicity of a new gel under intragastric administration, intraperitoneal and skin administration. Results. It was established that it is not possible to determine LD 50 by intragastric administration of extract of oak bark and extract of aloe, since administration of a maximum dose of 15100 mg / kg did not cause lethality of rats. In order to confirm this assertion, in further studies the acute toxicity of extracts was studied only at a dose of 15100 mg / kg. In terms of intraperitoneally administration, LD 50 of extract of oak bark is 2580 (1930–3220) mg / kg, LD 50 of extract of aloe – 2180 (1460–2900) mg / kg. At the subsequent stages of the study during the observation for 14 days, there were no visible signs of the toxic effect of the new gel on the functional state of the animals at the maximum recommended doses: intragastric – 15100 mg / kg and skin application – 22600 mg / kg. Conclusions. The complex of the conducted studies allowed establishing that the new gel does not have a toxic effect on organs and systems of experimental animals and does not have a lethal action. Extract of oak bark and extract of aloe under conditions of intragastric administration are classified as VI class of toxicity Relatively harmless substances. In case of intraperitoneally administration, the studied extracts were classified as V class of toxicity Practically nontoxic substances. According to the study of acute toxicity, the new gel, in conditions of intragastric administration and skin application, belongs to the VI class of toxicity Relatively harmless substances

Influence of matrix nature on the functional efficacy of biomedical cell product for the regeneration of damaged liver (experimental model of acute liver failure)

Aim. A comparative analysis of the functional efficacy of biomedical cell products (BMCP) for the regeneration of damaged liver based on biopolymer scaffolded porous and hydrogel matrices was performed on the experimental model of acute liver failure. Materials and methods. Matrices allowed for clinical use were employed for BMCP in the form of a sponge made from biopolymer nanostructured composite material (BNCM) based on a highly purified bacterial copolymers of poly (β-hydroxybutyrate-co-β-oxyvalerate) and polyethylene glycol and a hydrogel matrix from biopolymer microheterogeneous collagen-containing hydrogel (BMCH). Cellular component of BMCP was represented by liver cells and multipotent mesenchymal bone marrow stem cells. The functional efficacy of BMCP for the regeneration of damaged liver was evaluated on the experimental model of acute liver failure in Wistar rats (n = 40) via biochemical, morphological, and immunohistochemical methods. Results. When BMCP was implanted to regenerate the damaged liver on the basis of the scaffolded BNCM or hydrogel BMCH matrices, the lethality in rats with acute liver failure was absent; while in control it was 66.6%. Restoration of the activity of cytolytic enzyme levels and protein-synthetic liver function began on day 9 after modeling acute liver failure, in contrast to the control group, where recovery occurred only by days 18–21. Both matrices maintained the viability and functional activity of liver cells up to 90 days with the formation of blood vessels in BMCP. The obtained data confirm that scaffolded BNCM matrix and hydrogel BMCH matrix retain for a long time (up to 90 days) the vital activity of the adherent cells in the BMCP composition, which allows using them to correct acute liver failure. At the same time, hydrogel matrix due to the presence of bioactive components contributes to the creation of the best conditions for adhesion and cell activity which accelerate the regeneration processes in the damaged liver compared to BMCP on scaffolded matrix. Conclusion. A statistically significant difference was found between the functional efficacy of the BMCP studied based on BNCM and BMCH matrices. BMCP based on hydrogel BMCH matrix was more effective for the regeneration of damaged liver.

The investigation of the drug “Decasan” acute and chronic toxicity

The intestinal diseases of bacterial aetiology are characterized by high prevalence and a severe course, especially at a young age, concomitant immunity suppression or chronic diseases of the gastrointestinal system. Therefore, it is expedient to search for the new antimicrobial drugs, and it seems promising to use known antimicrobial agent decamethoxinum for the development of peroral medicinal forms, such as “Decasan” that is 0.02% decamethoxinum solution for peroral use worked out by “Yuria Pharm.” This study aimed to determine the parameters of acute toxicity of decamethoxinum substance and “Decasan,” as well as to study the possible toxic effects of the latter in chronic administration. The experiments on rats have shown that “Decasan” at the maximal allowable dose of 20 ml/kg does not cause lethality in rats. For decamethoxinum substance LD50 equals 586 (484:588) mg/kg in intragastric administration, corresponding to the IV class of low toxic substances (500 mg/kg<LD50<5000 mg/kg). The single intragastric administration of decamethoxinum substance at a dose of 400 mg/kg after 2 days causes moderate reversible changes in the gastrointestinal system, in the thymus and adrenal glands. “Decasan” intragastric administration at doses of 3 ml/kg and 30 ml/kg for a period of 30 days to male and female rats does not causes pathological changes in biochemical parameters of the blood (only the decrease in content of albumins is seen in male rats receiving the drug at both doses) as well as in histological structure of the internal organs and functions of the kidney, heart, and CNS.

Hormone-dependence of sarin lethality in rats: Sex differences and stage of the estrous cycle

Chemical warfare nerve agents (CWNAs) are highly toxic compounds that cause a cascade of symptoms and death, if exposed casualties are left untreated. Numerous rodent models have investigated the toxicity and mechanisms of toxicity of CWNAs, but most are limited to male subjects. Given the profound physiological effects of circulating gonadal hormones in female rodents, it is possible that the daily cyclical fluctuations of these hormones affect females' sensitivity to the lethal effects of CWNAs, and previous reports that included female subjects did not control for the stage of the hormonal cycle. The aim of the current study was to determine the 24-hour median lethal dose (LD50) of the CWNA sarin in male, ovariectomized (OVEX) female, and female rats during different stages of the estrous cycle (diestrus, proestrus, and estrus). Additionally, baseline activity levels of plasma acetylcholinesterase, butyrylcholinesterase, and carboxylesterase were measured to determine differences among the groups. Results indicated that females in proestrus had a significantly higher LD50 of sarin compared to OVEX and estrous females. Although some sex differences were observed in the activity levels of plasma esterases, they were not consistent and likely not large enough to significantly affect the LD50s. These results suggest that hormonal cyclicity can influence the outcome of CWNA-related studies using female rodents, and that this variability can be minimized by controlling for the stage of the cycle. Additional research is necessary to determine the precise mechanism of the observed differences because it is unlikely to be solely explained by plasma esterase activity.

Combined Blockade of NMDA and AMPA Receptors Prevents Acute Kainate Seizures and Chronic Kainate Lethality in Rats

Single intramuscular injection of selective of NMDA receptor blocker memantine in the maximum dose of 20 mg/kg prevented the development of acute generalized tonic-clonic kainate seizures in 60% rats, but did not alleviate clonic kainate seizures and prevented chronic kainate lethality in only 30% rats. Intramuscular injection of NBQX, a selective blocker of AMPA receptors (10 mg/kg), produced more pronounced anticonvulsant and neuroprotective effects: it prevented generalized kainate seizures and chronic kainate lethality in 100 and 80% rats, respectively. However, even the high dose of NBQX prevented the clonic kainate seizures only in 30% rats. The intramuscular injection of novel agent IEM-2121 (0.03-1.00 mg/kg) known to block both AMPA and NMDA receptors, prevented the clonic kainate seizures only in 50-70%, although it precluded the chronic kainate lethality in 100%.

Behavioral side effects of prophylactic therapies against soman-induced seizures and lethality in rats

Four medical therapies previously shown to exert varying degrees of protection against a convulsant dose of soman were assessed for potential behavioral side effects in a novelty test. In Experiment 1, HI-6 (1-[([4-(aminocarbonyl)pyridino] methoxy)methyl]-2-[(hydroxyimino)methyl]pyridinium) (125 mg/kg), scopolamine (1 mg/kg), physostigmine (0.1 mg/kg), levetiracetam (50 mg/kg), and procyclidine (20 mg/kg) were tested separately. In Experiment 2, the combination of HI-6, scopolamine, and physostigmine (termed the physostigmine regimen) or HI-6, levetiracetam, and procyclidine (termed the procyclidine regimen) were tested. In Experiment 3, the metabotropic glutamate modulators DCG-IV ((2S,2′R,3′R)-2-(2′,3′-dicarboxycyclopropyl)glycine) (4 mg/kg) and MPEP (2-Methyl-6-(phenylethynyl)pyridine hydrochloride) (30 mg/kg) were tested separately or each drug in combination with HI-6 and procyclidine (termed the DCG-IV regimen and the MPEP regimen, respectively). The results showed that the physostigmine and procyclidine regimens both produced severe cognitive impairment (lack of preference for novelty) and reduced locomotor and rearing activities. The DCG-IV and MPEP regimens caused milder deficits on the same behavioral measures. Some relations were seen between prophylactic capacity and degree of behavioral side effects. Only HI-6 or levetiracetam had no adverse effects on behavior. DCG-IV or MPEP produced some impairment, whereas the detrimental effects of scopolamine or procyclidine were pronounced. The relatively high dose of procyclidine (anticholinergic and antiglutamatergic) needed for prophylactic efficacy may have played a major role for the side effects of the regimens in which the drug was used. It was concluded that behavioral side effects are inevitable for potent prophylactic therapies against soman intoxication.

Potassium nitrate effect on the development of neurological disorders in experimental brain ischemia

Effect of potassium nitrate (KNO3) on the dynamics of neurological disorders and lethality in rats as sequelae of brain ischemia induced by a single-step bilateral common carotid artery occlusion were investigated in Wistar rats. KNO3 at a dose of 5 mg/1000 g administered 60 min prior to the occlusion of the two carotid arteries reliably reduced the severity of neurological disorders and lethality in rats.

Antiarrhythmic effect of flax lignan concentrate alone and concomitantly with omega 3 fatty acid mediated through inhibition of cardiomyocyte apoptosis in digoxin induced ventricular arrhythmia and lethality in rats

The objective of the present study was to investigate antiarrhythmic effect of flax lignan concentrate (FLC) and omega 3 fatty acid (omega) in digoxin induced ventricular arrhythmia and lethality in rats. Male wistar rats (250–300g) were divided into four groups: control (received saline 1mL/kg/day p.o. for 28days); omega (received omega 1mL/kg for 28days); FLC (Animals received FLC 400mg/kg/day p.o. for 28days); FLC+omega (received concomitant treatment of FLC and omega for 28days). On last day, digoxin was infused by jugular vein until the cardiac arrest. Concomitant treatment of FLC and omega significantly increased the concentration of digoxin required to produce ectopic beats (P<0.05), ventricular fibrillation (P<0.05) and cardiac arrest (P<0.01), reduced the serum levels of CKMB (P<0.05), LDH (P<0.01) and restored the activities of endogenous antioxidant enzymes. FLC+Omega treatment showed antiapoptotic effect as evidenced by reduction in myocardial apoptosis. Transmission electron microscopy and histology of heart confirmed cardioprotective effect of concomitant treatment. The mechanism of this protective effect appears to be mediated through conservation of endogenous myocardial antioxidant enzymes and inhibition of apoptotic death of myocardial cells.