Rats In Single Doses Research Articles

Pain Allaying Epalrestat-Loaded Lipid Nanoformulation for the Diabetic Neuropathic Pain Interventions: Design, Development, and Animal Study.

Diabetic peripheral neuropathy is the most common complication of diabetes mellitus. Epalrestat, an aldose reductase inhibitor, has been approved for clinical therapy for diabetic peripheral neuropathic pain. In the present study, solid lipid-based nanoparticles are used for oral administration of epalrestat (E-SLN) and evaluated against diabetic neuropathic pain in a rat model. Experimental diabetes in rats was induced by a single dose of streptozotocin (STZ) administration. The therapeutic efficiency of Epalrestat nanoparticles (0.25, 0.50, 1, and 5 mg/kg) in diabetic rats was studied. STZinduced diabetic rats were treated with different doses of E-SLN for 8 weeks. The nanoparticles were orally administered at a single dose in rats, and the various parameters related to peripheral neuropathy were evaluated and compared with the bare drug. The blood glucose level was estimated by standard glucometer, HbA1c, triglycerides, total cholesterol, and liver function test (ALT and AST) were analyzed by blood samples collected from retro-orbital plexus. Oxidative stress markers and Na+K+ATPase, TNF-α, and IL-1β levels were measured in the homogenate of sciatic nerves. Behavioral tests were also performed by the hot plate method and tail-flick method. E-SLN synthesized by the micro-emulsification method was 281 ± 60 nm in size, and encapsulation efficacy was found to be 88 ± 2%. Optimized E-SLN were characterized and found to be optimum in size, spherical shape, decent encapsulation efficiency, stable at acidic gastric pH, and suitable for oral delivery. E-SLNs did not significantly reverse the STZ-induced elevated blood glucose level (FBS and PPBS), HbA1c, triglycerides, and total cholesterol but significantly improved TNF-α, IL-1β, and increased Na+K+ATPase levels, oxidative stress marker and ALT, AST in the treated rat group as compared with the diabetic group. Doses of E-SLN, i.e. 0.5, 1.0, 2.5, and 5 mg/kg, significantly increased the tail-flick latency time and hot plate response time in a dose-dependent manner compared with the diabetic group. Thus, it is suggested that E-SLN were equally effective and less hepatotoxic compared with the standard treatment of epalrestat. To the best of our knowledge, we, for the first time, propose the orally deliverable E-SLN that ameliorates STZ-induced diabetes neuropathic pain effectively as compared with conventional epalrestat.

The in vivo toxicity evaluation of leaf and root methanolic extracts of Tephrosia vogelii Hook.f using animal model

BackgroundTraditionally, herbal medicines are commonly used to cure several diseases since immemorial of human life. Nevertheless, the safety of some traditionally used medicinal plants is uncertain. Since Tephrosia vogelii Hook.f is a traditionally used medicinal plant, the effects of its extracts were evaluated on lethality (LD50) and sub-acute toxicity in this study.MethodsPhytochemistry screening and an in vivo toxicity evaluation of leaf and root methanolic extracts of T. vogelii using laboratory albino rats were conducted. Methanolic extracts of doses 600, 1200, 2000 and 5000 mg/kg body weights were administered single dose in rats to observe deaths within 72 h in order to determine the LD50. Methanolic extracts doses of 600, 1200 and 2000 mg/kg body weights were consecutively administered for 14 days in order to evaluate sub-acute toxicity.ResultsTannins, steroids, terpenoids, flavonoids and saponins were identified in the phytochemical screening. The LD50 experiments revealed zero deaths of rats for the administered doses, 600 to 5000 mg/kg body weight. Histopathological examination of liver and kidney for sub-acute toxicity test showed safety at all doses except root methanolic extracts dose of 2000 mg/kg which exhibited necrosis and vacuolation of liver cells on the 14th day. Nonetheless, hepatic necrosis and hepatic vacuolation disappeared upon time elongation without dose administration to 28th day.ConclusionThe conducted toxicity evaluation of methanolic leaf and root extracts in albino rats revealed no deleterious effects, henceforth, suggesting that T. vogelii could be safe to users using it as a medicinal plant.

Plasma Polyethylene Glycol (PEG) Levels Reach Steady State Following Repeated Treatment with N8-GP (Turoctocog Alfa Pegol; Esperoct®).

BackgroundExtended half-life (EHL) factor VIII (FVIII)-replacement therapies enable patients with haemophilia A to maintain higher activity levels with fewer injections. N8-GP (turoctocog alfa pegol; Esperoct®) is an EHL product derived from conjugation of polyethylene glycol (PEG) to a recombinant FVIII protein. Upon activation, PEG is released from the active protein and excreted in urine and faeces. While PEG levels are expected to reach steady state with repeated dosing, there has been some discussion regarding whether abnormal accumulation of PEG in plasma and tissues may occur.ObjectiveOur objective was to examine plasma PEG concentrations in rats and humans repeatedly treated with N8-GP for periods of up to 5 years.MethodsPEG levels were measured using liquid chromatography-tandem mass spectrometry in plasma samples from rats treated with N8-GP as part of a 52-week toxicity study. Human plasma samples from children, adolescents and adults treated with N8-GP as part of the pathfinder programme were also examined (NCT01731600; NCT01480180). These data were compared with steady-state PEG levels predicted by pharmacokinetic modelling of single-dose rat data.ResultsPEG levels reached steady state in plasma in both rats and humans after repeated dosing. The timing and degree of PEG increase to steady state were in line with or below model predictions, confirming the utility of the pharmacokinetic model and indicating that rat data can be used to estimate human plasma PEG levels.ConclusionSteady-state PEG levels were reached in plasma from rats and humans repeatedly treated with N8-GP. No unexpected increase in PEG was observed.

Oral Delivery of Curcumin Using Silk Nano- and Microparticles.

The paper presents a study using silk nano- and microparticles as carriers to deliver curcumin (CUR), a multifunctional and efficient, yet water-insoluble, antioxidant, with the primary goal of enhancing bioavailability. CUR-loaded silk nanoparticles were prepared by emulsification, resulting in particle sizes ranging from 229 to 2286 nm in diameter, with loading efficiencies from 22 to 41%. The encapsulation mechanism involved hydrophobic interaction between the β-sheet structure fabricated from the silk and the phenol groups of curcumin. In vitro studies revealed that curcumin was released more slowly from the larger particles than the smaller particles. An HPLC-MS/MS method was developed to determine the content of curcumin in rat plasma. The particles were orally administered at a single dose in rats, and the pharmacokinetic parameters were evaluated and compared with those of plain curcumin crystals. After 24 h, the larger silk particles (CSN-800, CUR-silk nanoparticles with sizes ∼800 nm) showed longer plasma circulation time for CUR (Tmax was 1.76 ± 0.10 h) when compared with that of the smaller silk particles (CSN-200 with sizes ∼200 nm, Tmax was 1.17 ± 0.07 h). The Cmax of CSN-200 was 3-fold greater than that of CSN-800. By contrast to the groups of plain CUR (without silk particles), CSN-200 and CSN-800 increased CUR bioavailability 17- and 5- fold, respectively. When mixtures of CSN-200 and CSN-800 at different ratios were orally administered to rats, medium bioavailability (>13 times) and exposure time (T1/2 > 1.68 h) were obtained. These results elucidated the effect of CUR-silk particle sizes on bioavailability after oral delivery, as a basis for future applications.

A single administration of fish oil inhibits the acute inflammatory response in rats.

To investigate the antiinflammatory effects of a single administration of fish oil (FO) on the acute inflammatory response. The paw edema and pleurisy models were used to evaluate the effects of FO dissolved in olive oil (FOP) orally administered in a single dose in rats. Nitric oxide (NO) concentrations in the pleural exudate were performed according to the Griess method and the cytokine concentrations were determined by Luminex bead-based multiplex assay. FOP treatment (30 and 300mg/kg) significantly reduced paw edema. FOP treatment at 18.75, 37.5, 75.0, 150.0, and 300mg/kg decreased both the volume of pleural exudate and cellular migration into the pleural cavity and each of these doses presented the same effectiveness. Treatment with FOP (300mg/kg) reduced NO, TNF-α, IL-1β, and IL-6 concentrations in the pleural exudate. The present data provide evidence that FO has inhibitory effects on the acute inflammatory response when administered in a single dose in rats. This effect might be attributable to a direct inhibitory effect of FO on the production or release of inflammatory mediators that are involved in the pathological processes evaluated herein.

Brain Disposition of cis-para-Methyl-4-Methylaminorex (cis-4,4'-DMAR) and Its Potential Metabolites after Acute and Chronic Treatment in Rats: Correlation with Central Behavioral Effects.

para-Methyl-4-methylaminorex (4,4'-DMAR) is a phenethylamine derivative with psychostimulant activity whose abuse has been associated with several deaths and a wide range of adverse effects. We recently validated a high-performance liquid chromatography-tandem mass spectrometry method to measure the compound's concentrations in plasma, and we applied it to describe the pharmacokinetic properties of 4,4'-DMAR after a single dose in rats. In this study, we investigated the brain disposition and metabolism of cis-4,4'-DMAR after intraperitoneal injection as well as its central behavioral effects. Locomotor activity increased after a single injection of 10 mg/kg, peaking at 2 hours and disappearing at 5 hours; in these conditions, brain absorption was very rapid, (tmax = 30-60 minutes) and large (brain-to-plasma ratio = 24); the half-life was approximately 50 minutes. After 14 daily doses, the compound's effect on locomotor activity was greater (approximately 20% compared with the effect after the first dose), but not for pharmacokinetic reasons. Using high-resolution mass spectrometry, we also identified four metabolites of cis-4,4'-DMAR in the plasma and brain of treated rats. Semiquantitative analysis indicated low brain permeability and very low brain concentrations, suggesting that these metabolites do not contribute to central behavioral effects; however, the metabolite originating from oxidation of the para-methyl group (M2) persisted in the plasma longer and at higher concentrations than the parent molecule and could be used to evaluate drug intake in human consumers. Finally, we describe the rewarding effect of cis-4,4'-DMAR in the conditioning place preference test, suggesting a high risk of addiction in humans.

Development and Validation of a Sensitive LC-MS-MS Method for Quantification of Mogrol in Rat Plasma and Application to Pharmacokinetic Study.

Mogrol, the aglycone of mogrosides, is a potential pharmacologically active ingredient isolated from the fruits of Siraitia grosvenorii. The aim of this study was to develop and validate an LC-MS-MS method for the quantification of mogrol in rat plasma. Protein precipitation extraction procedure using methanol/water (1:1, v/v) was employed to extract mogrol from rat plasma. Chromatographic separation was performed on a reverse-phase Agilent Zorbax XDB C18 column (50 mm × 2.1 mm, 3.5 μm) with gradient elution using a mobile phase containing methanol and water, both of which contained 0.1% formic acid at a flow rate of 0.50 mL/min. The analyte was monitored by tandem-mass spectrometry with positive electrospray ionization mode. The precursor/product transitions (m/z) in the positive ion mode were 459.3→423.3 and 386.2→122.3 for mogrol and internal standard, respectively. The method was validated over the concentration range of 10.0-10,000 ng/mL with a lower limit of quantification of 10.0 ng/mL in rat plasma. Validation experiments included tests for specificity, precision, accuracy, matrix effect, and stability under different storage and handling conditions. This method was successfully utilized to pharmacokinetic evaluation of mogrol after intravenous and oral administration of a single dose in rats at 2.0 and 5.0 mg/kg, respectively. The oral absolute bioavailability (F) of mogrol was estimated to be 10.3 ± 2.15% with an elimination half-life (t1/2) value of 2.41 ± 0.11 h.

Simultaneous Determination of Pinoresinol Di-glucopyranoside and Pinoresinol Glucoside in Rat Plasma by HPLC-tandem MS/MS for Pharmacokinetic Study

ObjectivePinoresinol di-glucopyranoside (PDG) is one of the main active lignans of Eucommiae Cortex considered to be a high-quality antihypertensive drug. In this study the pharmacokinetic process of PDG and its primary in vivo metabolite pinoresinol glucoside (PG) in the portal and jugular vein were surveyed and evaluated simultaneously. MethodsA sensitive high-performance liquid chromatography coupled with tandem quadruple mass spectrometry (HPLC-MS/MS) method and sample preparation protocol were developed and validated in method of selectivity, sensitivity, precision, stability, and extraction recovery for the simultaneous determination of PDG and its primary metabolite PG in rat plasma. The double intubation technique was used to simultaneously collect blood from common jugular vein and hepatic portal vein after single ig administration of PDG. ResultsUsing this method, the quantification linearity ranges of PDG and PG in rat plasma were both 0.05-100 ng/mL. This method was successfully applied to the evaluation of the absolute oral bioavailability of PDG and determination of the pharmacokinetic properties of PDG and PG after ig administration of single dose in rats. The bioavailability of PDG at common jugular vein was 51.3% compared to that of 91.6% at hepatic portal vein. ConclusionWe conclude that liver is the major conversion site of PDG to PG.

Ergosterol-loaded poly(lactide-co-glycolide) nanoparticles with enhanced in vitro antitumor activity and oral bioavailability.

Ergosterol is a plant sterol with anti-tumor and anti-angiogenic activities, but is poorly soluble. In this study, we attempted to enhance its anti-tumor action and oral bioavailability via poly(lactide-co-glycolide) (PLGA) nanoparticle encapsulation. Ergosterol-loaded PLGA nanoparticles (NPs/Erg) were prepared using the emulsion/solvent evaporation technique. Their physicochemical properties were characterized, and their cytotoxicity against human cancer cell lines was evaluated with MTT assay. The pharmacokinetics and tissue distribution of NPs/Erg were investigated in rats and mice, respectively. NPs/Erg were spherical in shape with a particle size of 156.9±4.8 nm and a Zeta potential of -19.27±1.13 mV, and had acceptable encapsulation efficiency and loading capacity. NPs/Erg exerted much stronger cytotoxicity against human cancer cells than the free ergosterol, and showed significantly reduced IC50 values (14.69±0.48 μg/mL in glioma U251 cells; 9.43±0.52 μg/mL in breast cancer MCF-7 cells; 4.70±0.41 μg/mL in hepatoma HepG2 cells). After oral administration of a single dose in rats, NPs/Erg displayed a prolonged plasma circulation with a 4.9-fold increase of oral bioavailability compared with the free ergosterol. After mice received NPs/Erg, the ergosterol in NPs/Erg was rapidly distributed in stomach, kidneys, liver, brain, spleen, and virtually non-existent in heart and lungs. The presence of NPs/Erg in brain was particularly improved compared with the free ergosterol. The PLGA nanoparticles serve as a promising carrier for the poorly soluble ergosterol and significantly improve its bioavailability, biodistribution and in vitro anti-tumor activities.

Pharmacokinetic evaluation of avicularin using a model-based development approach.

The aim of this study was to use the pharmacokinetic information of avicularin in rats to project a dose for humans using allometric scaling. A highly sensitive and specific bioanalytical assay to determine avicularin concentrations in the plasma was developed and validated for UPLC-MS/MS. The plasma protein binding of avicularin in rat plasma determined by the ultrafiltration method was 64%. The pharmacokinetics of avicularin in nine rats was studied following an intravenous bolus administration of 1 mg/kg and was found to be best described by a two-compartment model using a nonlinear mixed effects modeling approach. The pharmacokinetic parameters were allometrically scaled by body weight and centered to the median rat weight of 0.23 kg, with the power coefficient fixed at 0.75 for clearance and 1 for volume parameters. Avicularin was rapidly eliminated from the systemic circulation within 1 h post-dose, and the avicularin pharmacokinetic was linear up to 5 mg/kg based on exposure comparison to literature data for a 5-mg/kg single dose in rats. Using allometric scaling and Monte Carlo simulation approaches, the rat doses of 1 and 5 mg/kg correspond to the human equivalent doses of 30 and 150 mg, respectively, to achieve comparable plasma avicularin concentrations in humans.

1. The anticonvulsant effects of n-3 PUFA: Animal studies

The omega-3 polyunsaturated acids (n-3 PUFA) show great promise as a therapy for epileptic seizures. There has been considerable confusion, however, in the animal data related to the n-3 PUFAs’ anticonvulsant effects. Our own recent work has clarified this confusion, and led to a simple, reproducible animal preparation in which to study the n-3 PUFAs’ mechanism(s) of action. We first attempted to replicate the studies of Yehuda et al. (1994), who had reported dramatic seizure suppression after 21 days of 40 mg/kg injections of the “SR 3” formula i.p in rats. In our replication, we found no effect at all at this dose (Taha et al., 2006). We therefore tested the higher dose of 200 mg/kg of the SR-3 mixture. At 200 mg/kg, we found a significant increase in PTZ seizure latency, although no change in severity (Taha et al., 2009). We subsequently tried acute administration of a single dose in rats, switching from SR 3 to docosahexaenoic acid (DHA). Injecting subcutaneously (s.c.), we found a significant elevation in PTZ-seizure latency following after a single injection (Taha et al., 2010). Our dose–response curves in this study, however, were “inverted U” shaped. In parallel studies, we tested dietary (p.o.) administration. Working in rats with chronically implanted electrodes, we found that dietary PUFAs elevated thresholds in both the cortex and the amygdala of rats. These effects, however, took several months to occur (Taha et al., in preparation). To simplify the kinetics, we have moved to intravenous (i.v.) injections of DHA (tail vein in rats). Our i.v. experiments have now shown anticonvulsant effects 5 min after injection and plasma concentrations that rise rapidly, plateau at 5 min, and drop to baseline a minute after infusion (Trepanier et al., in preparation). We have therefore finally evolved a preparation in which anticonvulsant effects and plasma concentrations parallel the known kinetics of DHA. This preparation will now allow a meaningful study of DHA’s mechanisms of anticonvulsant action.

Concentration-dependent inhibitory effects of baicalin on the metabolism of dextromethorphan, a dual probe of CYP2D and CYP3A, in rats

Baicalin has been shown to possess many pharmacological effects, including antiviral, antioxidant, anti-cancer and anti-inflammatory properties. In the current study, we reveal the inhibitory effects of baicalin on the metabolism of dextromethorphan (DXM), a dual probe substrate of CYP2D and CYP3A, in rats. Lineweaver–Burk plots demonstrated that baicalin inhibited the activities of CYP2D and CYP3A in a non-competitive manner in rat liver microsomes (RLMs). Concomitant administration of baicalin (0.90g/kg, i.v.) and DXM (10mg/kg, i.v.) increased the maximum drug concentration (Cmax) (37%) and the area under concentration–time curve (AUC) (42%) and decreased the clearance (CL) (27%) of DXM in a randomised, crossover study in rats (P<0.01). The change in the AUC of DXM was significantly correlated with the Cmax and AUC of baicalin (P<0.05). The inhibitory effects of multiple doses of baicalin (0.90g/kg, i.v., 12days) on the metabolism of DXM were similar to those observed following a single dose in rats. The activity of CYP3A in excised liver samples from rats following multiple baicalin treatment was significantly decreased compared to that of the control group (P<0.05), whereas multiple doses of baicalin had no obvious effect on the activity of CYP2D. Taken together, these data demonstrate that baicalin inhibits the metabolism of DXM in a concentration-dependent manner in rats, possibly through inhibiting hepatic CYP2D and CYP3A activities.

Pharmacokinetics of curcumin-loaded PLGA and PLGA–PEG blend nanoparticles after oral administration in rats

The aim of this study was to assess the potential of nanoparticles to improve the pharmacokinetics of curcumin, with a primary goal of enhancing its bioavailability. Polylactic-co-glycolic acid (PLGA) and PLGA–polyethylene glycol (PEG) (PLGA–PEG) blend nanoparticles containing curcumin were obtained by a single-emulsion solvent-evaporation technique, resulting in particles size smaller than 200nm. The encapsulation efficiency was over 70% for both formulations. The in vitro release study showed that curcumin was released more slowly from the PLGA nanoparticles than from the PLGA–PEG nanoparticles. A LC–MS/MS method was developed and validated to quantify curcumin in rat plasma. The nanoparticles were orally administered at a single dose in rats, and the pharmacokinetic parameters were evaluated and compared with the curcumin aqueous suspension. It was observed that both nanoparticles formulations were able to sustain the curcumin delivery over time, but greater efficiency was obtained with the PLGA–PEG nanoparticles, which showed better results in all of the pharmacokinetic parameters analyzed. The PLGA and PLGA–PEG nanoparticles increased the curcumin mean half-life in approximately 4 and 6h, respectively, and the Cmax of curcumin increased 2.9- and 7.4-fold, respectively. The distribution and metabolism of curcumin decreased when it was carried by nanoparticles, particularly PLGA–PEG nanoparticles. The bioavailability of curcumin-loaded PLGA–PEG nanoparticles was 3.5-fold greater than the curcumin from PLGA nanoparticles. Compared to the curcumin aqueous suspension, the PLGA and PLGA–PEG nanoparticles increased the curcumin bioavailability by 15.6- and 55.4-fold, respectively. These results suggest that PLGA and, in particular, PLGA–PEG blend nanoparticles are potential carriers for the oral delivery of curcumin.

Highly potent PDE4 inhibitors with therapeutic potential

The hypothesis that the dose-limiting side effects of PDE4 inhibitors could be mediated via the central nervous system prompted us to design and synthesize a hydrophilic piperidine analog to improve the side effect profile of Ariflo™ 1, which is an orally active second-generation PDE4 inhibitor. During evaluation of various water-soluble piperidine analogs, 2a– b, 11b– 14b, and 17a showed therapeutic potential in cross-species comparison studies. The following three findings were obtained: (1) The hydroxamic acid group, a well known metal chelator, caused a marked increase of inhibitory activity. (2) Water-soluble piperidine analogs lacked the configurational isomerism of Ariflo 1 without loss of inhibitory activity. (3) Replacement of the 4-methoxy residue with a difluoromethoxy residue led to an increase of in vivo potency. Structure–activity relationships are presented. Single-dose rat pharmacokinetic data for 11b, 12b, and 17a are also presented.

Pharmacokinetics of a new nitroderivative of acetylsalicylic acid after a single dose in rats.

The pharmacokinetics of a new ASA-nitroderivative compound, NCX 4016 (ASA-NO2), was evaluated using an HPLC method. After single equimolar doses of ASA (35 mg kg(-1)) or ASA-NO2 (65 mg kg(-1)), no detectable levels of these compounds have been observed in rat plasma samples. SA peak levels were obtained at 3 h and 6 h after ASA and ASA-NO2 administration respectively. The elimination rate constants of SA were similar after ASA and ASA-NO2, suggesting a similar elimination phase of this metabolite in rats. From these data it is evident that ASA-NO2 is slowly metabolized in ASA, which is rapidly converted to SA.

The relative hypolipidaemic activity and hepatic effects of ciprofibrate enantiomers in the rat

The aim of this study was to establish whether the individual enantiomers of racemic ciprofibrate, a potent hypolipidaemic agent and peroxisome proliferator, differ significantly in either pharmacological potency or toxic potential. After a single oral dose to male Fischer F344 rats at dosages below 10 mg/kg, S(−) ciprofibrate produced slightly, but statistically significantly, greater reductions in plasma concentrations of cholesterol than R(+) ciprofibrate. Similarly, at low concentrations in F344 rat hepatocyte cultures, S(−) ciprofibrate produced slightly, but statistically significantly, greater inductions of peroxisomal β-oxidation activity than R(+) ciprofibrate. However, after seven daily doses, the differences in pharmacological effects of the two enantiomers were no longer apparent. Furthermore, in contrast to its effects in vitro, R(+) ciprofibrate produced slightly, but statistically significantly, greater inductions of peroxisomal β-oxidation activity in vivo than S(−) ciprofibrate. These observations may be possibly explained on the basis that following multiple dosing, plasma concentrations of R(+) ciprofibrate 24 hr post-dose were greater than those of its optical antipode. Thus the slightly greater potency of the S(−) enantiomer after a single dose may have been overcome by the greater plasma concentrations of the less potent enantiomer. Both enantiomers produced similar reductions in plasma concentrations of thyroxine. The data indicate that at low dosages S(−) ciprofibrate is a slightly more potent hypolipidaemic agent after a single dose in rats and a slightly more potent peroxisome proliferator at low concentrations in vitro. However, following multiple dosing, both enantiomers produced changes in plasma concentrations of lipids, hepatic enzyme activities and plasma concentrations of thyroxine which were of comparable magnitude to those produced by the racemate. Since these early changes have been linked mechanistically to the chronic toxicity of the racemate in the rat, it could be predicted that the individual enantiomers of ciprofibrate under conditions employed in chronic safety studies, would produced the same spectrum of rodent toxicity as the racemate.

Acute toxic and teratogenic effects of cyclic imides in rodents.

Four structurally different cyclic imides or related derivatives (o-(N-phthalimido)acetophenone (1), 2,3-dihydrophthalazine-1,4-dione (2), N-(4-methylphenyl)diphenamide (3), and 4,6-dihydro-5H-dibenz[c,e]azepine (4) were examined for acute toxicity in mice at multiple doses, for long term toxicity at a single dose in rats, and for deleterious effects on fertility and pup development in rodents. No deleterious effects were observed when mice were administered agents at 20, 50, and 100 mg/kg/day for seven days. All other measured characteristics and values were normal for the four compounds. The principle effect of the compounds was to reduce the percent pregnancies in treated mice compared to the controls. Compound 2 afforded the greatest reduction of pregnancy (54%) at 100 mg/kg/day. Compounds 3 and 4 caused a minor reduction in pregnancy (12-20%). The compounds did not appear to cause measureable teratogenic effects; pups of treated rodents thrived and survived as well as controls. There were no effects on murine male fertility when compounds were administered at 20, 50, and 100 mg/kg/day for six weeks.

Testicular toxicity induced by single dosing of diand mono-(2-ethylhexyl) phthalate in the rat

The testicular toxicity of di-(2-ethylhexyl) phthalate (DEHP), a widely used plasticizer, and of its major metabolite, mono-(2-ethylhexyl) phthalate (MEHP), was assessed after a single dose in rats. Treatment with a single dose of 2.8 g/kg DEHP or 0.8 g/kg MEHP was sufficient to induce testicular atrophy as observed 7 days after dosing. Such a treatment had no effect on plasma FSH levels, and had varying effects on testicular zinc concentrations. After a single dose of 0.8 g/kg MEHP the testicular toxicity was age-dependent, in that only prepubertal rats were susceptible.

The mammalian toxicity of fluomine dust.

Fluomine is a cobalt chelate compound which complexes molecular oxygen and releases it on heating. This property has led to its use a a regenerable oxygen source in high-altitude aircraft. Investigations into the acute effects of exposure to fluomine by various routes were undertaken as first steps in the toxicological characterization of the material. Single-dose rat and mouse oral administration led to LD50 values of 123 mg/kg for male CF1 mice and 187 mg/kg for male Sprague-Dawley rats. The LC50 values for single four-hour inhalation periods varied from 112 mg/m3 for male rats to 416 mg/m3 for male mice. Fluomine proved to be highly irritating when instilled in the eyes of rabbits and to the lungs of rats on inhalation. Exposure of rabbit skin to the compound demonstrated moderate irritancy particularly in areas of abrasion. Positive reactions to intradermal challenge were demonstrated after both intradermal and inhalation sensitization of guinea pigs.

Acute toxicity of N-(2,3-epoxy-propyl)-phthalimide

N-(2,3-Epoxy-propyl)-phthalimide (EPP) was tested for its oral LD50, its ability to cause ocular and dermal irritation in rabbits, and its ability to sensitize guinea pigs. The single-dose rat oral LD50 was found to be 4.7 g/kg. This chemical was slightly irritating to the rabbit skin, moderately irritating to the rabbit eye without a washout, and mildly, transiently irritating to the rabbit eye with a washout 4 sec after instillation. It did not induce a sensitization reaction in guinea pigs after 10 intracutaneous injections, although this regimen did induce a very mild irritation evident after the eighth injection. These data were interpreted to indicate that EPP did not represent a substantial acute toxic risk.