Bioactive microconstituents and antioxidant properties of wild edible mushrooms from the island of Lesvos,Greece

Crude composition, fatty acids, sterols, total phenolic content (TPC), individual polyphenols and terpenic acids were determined in five wild edible mushrooms species (Lactarius deliciosus, Lactarius sanguifluus, Lactarius semisanguifluus, Russula delica, Suillus bellinii) from Lesvos Island, Greece. In addition, the DPPH scavenging capacity, the ferric ion reducing power (FRAP) and the ferrous ion chelating activity of mushroom methanolic extracts were assessed. Among sterols, ergosterol predominated at concentrations 9.2–18.0 mg/100 g fw. Total phenolic content of mushroom extracts ranged from 6.0 to 20.8 mg GAE/100 g fw. Up to 19 simple polyphenols were determined in mushrooms extracts, the more abundant being p-OH-benzoic acid, p-OH-phenylacetic acid, o-coumaric acid, ferulic acid and chrysin. In addition, the triterpenic acids oleanolic and ursolic were detected for the first time in mushrooms. All species exerted antioxidant activity and ferrous ion chelating capacity. Principal component analysis revealed good correlations between TPC, DPPH and FRAP but not with metal chelating activity. It seems that mushrooms polyphenols exert antiradical and reducing activities, but they are not strong metal chelators, the observed chelating ability being probably due to other classes of compounds.To our knowledge, this is the first report on the bioactive microconstituents and antioxidant activity of wild Greek edible mushrooms.     

Biomarkers of renal toxicity caused by exposure to arsenic in drinking water

This study is intended to explore effective and sensitive biomarkers for kidney damage after low level arsenic (As) exposure and to provide scientific evidence on cut-off values of arsenic concentrations in drinking water. The levels of α1-MG detected in urine samples were found to have statistically significant differences between high As group (As > 0.05 mg/L) and a combination of low and medium As exposure groups (As < 0.05 mg/L, p = 0.018), as well as between the patient and high As groups (As in two group were both higher than 0.05 mg/L, p < 0.001). After the logistic regression analysis the AUC values of α1-MG between two comparisons were 0.613 and 0.701, and p value was less than 0.05. The present data demonstrate the potential value of α1-MG excretion as a biomarker of renal toxicity, which could contribute to the enforcement of the maximum limit of 0.05 mg/L arsenic in drinking water for non-central water supply in rural areas.     

Possible involvement of nitric oxide mechanism in the neuroprotective effect of rutin against immobilization stress induced anxiety like behaviour,oxidative damage in mice

Dietary supplements are widely used to manage stress and related consequences. However, the exact pathological mechanism and cellular cascades involved in the action of these supplements are not properly understood so far. Therefore, the present study has been designed to explore the neuroprotective mechanism of rutin against immobilization stress-induced anxiety-like behavioural and oxidative damage in mice. Laboratory Animal Centre A-strain (laca) mice were used in the present study. Rutin (20, 40, and 80 mg/kg), l-arginine (100 mg/kg), l-nitroarginine methyl ester (l-NAME) (5 mg/kg) and vitamin-E (50 mg/kg) were administered for 5 days before 6 h immobilization stress on 6th day. Various behavioural parameters (mirror chamber test, locomotor activity) followed by biochemical parameters (lipid peroxidation, nitrite concentration, reduced glutathione and catalase) in brain and then serum corticosterone level were assessed. 6 h immobilization stress produced anxiety-like behavioural in mirror chamber test, raised corticosterone level and oxidative stress (as evidenced by rise in lipid peroxidation, nitrite concentration, depletion of reduced glutathione and catalase activity) significantly as compared to naive group. 5 days pre-treatment with rutin (40 and 80 mg/kg) causes a significant attenuation of locomotor activity, corticosterone level, oxidative stress as compared to control. Further, l-arginine (100 mg/kg) pre-treatment significantly reversed the protective effect of rutin (40 mg/kg) in 6 h immobilized animals. However, l-NAME (5 mg/kg) pre-treatment with rutin (40 mg/kg) potentiated their protective effect which was significant as compared to their effect per se. The present study suggests the involvement of nitric oxide mechanism in the neuroprotective effect of rutin against immobilization stress-induced anxiety-like behaviour and oxidative damage in mice.     

Evaluation of the toxicological safety of erinacine A-enriched Hericium erinaceus in a 28-day oral feeding study in Sprague–Dawley rats

Natural products have attained great importance as they are believed to be the new alternative medicines for conventional therapy. As numerous studies have proved the tremendous medicinal values of Hericium erinaceus, it is necessary to take into account its safety as well as its risk for the recipient. However, mushroom mycelium has an identity distinct from mushrooms, as two specific classes of compounds, hericenones and erinacines, can only be extracted from both the fruit body and the cultured mycelium, respectively. Therefore, this is the first report on the evaluation of the toxicity of H. erinaceus mycelium, enriched with 5 mg/g erinacine A, by a 28-day repeated oral administration study in Sprague–Dawley rats. Three doses of 1 (Low), 2 (Mid) and 3 (High) g/kg body weight/day were selected for the study while distilled water served as control. All animals survived to the end of the study. No abnormal changes were observed in clinical signs. No adverse or test article-related differences were found in urinalysis, haematology and serum biochemistry parameters, between the treatment and control groups. No gross pathological findings and histopathological differences were seen. Therefore, the no-observed-adverse-effect level of erinacine A-enriched H. erinaceus is greater than 3 g/kg body weight/day.     

Safety profile of Hoodia gordonii extract: Rabbit prenatal developmental toxicity study

Hoodia gordonii extract was orally administered by gavage to groups of 22 female New Zealand white rabbits from day 3–28 after mating at doses of 0 (control), 3, 6 or 12 mg/kg bodyweight/day. These doses were reached by a dose escalation phase between days 3 and 7 after mating. As well as a vehicle control group, a control group pair-fed to the high dose was also included. On day 29 after mating the females were euthanized and examined. Treatment at 6 or 12 mg/kg/day was associated with a dose-related reduction in feed intake and bodyweight gain. Feed consumption and bodyweight gain was unaffected at 3 mg/kg/day. In spite of marked maternal effects at 12 mg/kg/day, reproductive indices were unaffected at all doses and there were no effects on fetal or placental weights and no morphological changes in the fetuses. The no-observed-effect level (NOEL) for developmental effects was therefore 12 mg/kg/day, and the maternal NOEL was 3 mg/kg/day. At doses that caused marked maternal effects, H. gordonii extract did not affect embryonic or fetal development in a species that is considered predictive of developmental toxicity in man.     

Chronic exposure to low levels of inorganic arsenic causes alterations in locomotor activity and in the expression of dopaminergic and antioxidant systems in the albino rat

Several studies have associated chronic arsenicism with decreases in IQ and sensory and motor alterations in humans. Likewise, studies of rodents exposed to inorganic arsenic (_iAs) have found changes in locomotor activity, brain neurochemistry, behavioral tasks, oxidative stress, and in sensory and motor nerves. In the current study, male Sprague–Dawley rats were exposed to environmentally relevant doses of _iAs (0.05, 0.5 mg _iAs/L) and to a high dose (50 mg _iAs/L) in drinking water for one year. Hypoactivity and increases in the striatal dopamine content were found in the group treated with 50 mg _iAs/L. Exposure to 0.5 and 50 mg _iAs/L increased the total brain content of As. Furthermore, _iAs exposure produced a dose-dependent up-regulation of mRNA for Mn-SOD and Trx-1 and a down-regulation of DAR-D₂ mRNA levels in the nucleus accumbens. DAR-D₁ and Nrf2 mRNA expression were down-regulated in nucleus accumbens in the group exposed to 50 mg _iAs/L. Trx-1 mRNA levels were up-regulated in the cortex in an _iAs dose-dependent manner, while DAR-D₁ mRNA expression was increased in striatum in the 0.5 mg _iAs/L group. These results show that chronic exposure to low levels of arsenic causes subtle but region-specific changes in the nervous system, especially in antioxidant systems and dopaminergic elements. These changes became behaviorally evident only in the group exposed to 50 mg _iAs/L.     

Activity of aminocandin (IP960; HMR3270) compared with amphotericin B,itraconazole, caspofungin and micafungin in neutropenic murine models of disseminated infection caused by itraconazole-susceptible and -resistant strains of Aspergillus fumigatus

Aminocandin (IP960; HMR3270; NXL201) is a new echinocandin with broad-spectrum in vitro activity against Aspergillus and Candida spp. We compared the activity of aminocandin with that of amphotericin B (AmB), itraconazole (ITC) and caspofungin (CAS) in murine models of disseminated aspergillosis against three strains of A. fumigatus, two of which were fully susceptible (AF293 and A1163) and one was resistant to ITC (AF91). Mice were rendered temporarily neutropenic or persistently neutropenic with cyclophosphamide and were infected intravenously 3 days later. Temporarily neutropenic mice were treated with either intraperitoneal (i.p.) AmB (5 mg/kg/dose), oral (p.o.) ITC (25 mg/kg/dose), intravenous (i.v.) aminocandin (0.25–10 mg/kg/dose), i.p. aminocandin (1 mg/kg/dose) or solvent control for 9 days. Mice were euthanised 11 days post infection and the kidneys and liver were removed for quantitative culture. Following infection with AF293, only aminocandin 5 mg/kg i.v. yielded 100% survival. Aminocandin 1 mg/kg i.v., AmB 5 mg/kg i.p. or ITC 25 mg/kg p.o. were equivalent (P > 0.05). Aminocandin 5 mg/kg was superior to aminocandin 0.25 mg/kg (P < 0.0001) as well as all controls (P < 0.0001) in reducing mortality. Following infection with AF91, only aminocandin at 5 mg/kg and 1 mg/kg i.v. yielded 100% survival, which was superior to ITC, aminocandin 0.25 mg/kg and controls (all P < 0.0001). In the persistently neutropenic model with A1163, aminocandin, CAS and micafungin (2–10 mg/kg) were all effective at prolonging survival, with some impact on reducing culture burdens, even with alternate-day dosing (4 mg/kg). The only fungicidal regimen was aminocandin 5 mg/kg, which sterilised 40% and 50% of mice following infection with AF293 and AF91, respectively. Aminocandin at doses of ≥1 mg/kg is highly effective in reducing mortality and organ burden in disseminated infection caused by ITC-susceptible and -resistant A. fumigatus.     

Toxic effects and depuration after the dietary lead(II) exposure on the bioaccumulation and hematological parameters in starry flounder (Platichthys stellatus)

Platichthys stellatus (mean length 20 ± 2 cm, mean weight 160.15 ± 15 g) were exposed to the different levels of dietary lead(II) at the concentrations of 0, 30, 60, 120, 240 mg/kg for 4 weeks. Depuration was conducted for 2 weeks after exposure. The lead exposure over 60 mg Pb/kg induced the significant bioaccumulation in tissues of P. stellatus (5–30 μg/g tissue), except for brain and muscle where the exposure to 240 mg Pb/kg caused the bioaccumulation (2–4 μg/g tissue). The hematological parameters such as red blood cell (RBC) counts, hematocrit (Ht) value and hemoglobin (Hb) concentration were substantially decreased over 60 mg Pb/kg, and lasted even after the depuration period. For plasma components, calcium and magnesium levels in plasma were generally decreased over 60 mg Pb/kg, and glucose level was also mainly increased over 60 mg Pb/kg. Total protein was significantly decreased over 120 mg Pb/kg after 4 weeks exposure. Glucose and total protein showed the restoration after the depuration period in groups of fish exposed previously to over 60 and 120 mg Pb/kg, respectively. However, other parameters that changed during the exposure over 60 mg Pb/kg did not recovered. For enzymatic components in plasma, glutamic oxalate transminase (GOT), glutamic pyruvate transminase (GPT) and alkaline phosphatase (ALP) were significantly increased over 120 mg Pb/kg, and there was only restoration observed after the depuration for ALP over 120 mg Pb/kg.     

The immune responses in juvenile rockfish,Sebastes schlegelii for the stress by the exposure to the dietary lead (II)

The aim of this study was to evaluate the lead toxic effects on the stress parameters and immune responses of Sebastes schlegelii. Juvenile rockfish, S. schlegelii (mean length 14.2 ± 1.9 cm, and mean weight 57.3 ± 5.2 g) were exposed for 4 weeks with the different levels of dietary lead (Pb²⁺) at 0, 30, 60, 120 and 240 mg/L. The plasma cortisol and heat shock protein 70 was evaluated as stress indicators. The plasma cortisol of S. schlegelii was significantly increased in response to the dietary lead exposure over 60 mg/kg at 2 weeks. After 4 weeks, the significant increase in the plasma cortisol was observed at 30 and 60 mg/kg, but the level was decreased over 120 mg/kg. The heat shock protein 70 of S. schlegelii was also notably elevated over 60 mg/kg for 4 weeks. In the immune response, the immunoglobulin M of S. schlegelii was considerably increased over 120 mg/kg for 4 weeks. A significant increase was observed in lysozyme activity. The plasma lysozyme activity of S. schlegelii was elevated over 120 mg/kg after 2 weeks and 60 mg/kg after 4 weeks, and kidney lysozyme activity was also increased at 240 mg/kg after 2 weeks and over 120 mg/kg after 4 weeks. The results indicate that dietary Pb exposure can cause a significant stress and immune stimulation of S. schlegelii.     

Research on choleretic effect of menthol,menthone, pluegone,isomenthone, and limonene in DanShu capsule

Danshu capsule (DSC) is a medicinal compound in traditional Chinese medicine (TCM). It is commonly used for the treatment of acute & chronic cholecystitis as well as choleithiasis. To study its choleretic effect, healthy rats were randomly divided into DSC high (DSCH, 900 mg/kg), medium (DSCM, 450 mg/kg), and low (DSCL, 225 mg/kg) group, Xiaoyan Lidan tablet (XYLDT, 750 mg/kg), and saline group. The bile was collected for 1 h after 20-minute stabilization as the base level, and at 1 h, 2 h, 3 h, and 4 h after drug administration, respectively. Bile volume, total cholesterol, and total bile acid were measured at each time point. The results revealed that DSC significantly stimulated bile secretion, decreased total cholesterol level and increased total bile acid level. Therefore, it had choleretic effects. To identify the active components contributing to its choleretic effects, five major constituents which are menthol (39.33 mg/kg), menthone (18.02 mg/kg), isomenthone (8.18 mg/kg), pluegone (3.31 mg/kg), and limonene (4.39 mg/kg) were tested on our rat model. The results showed that menthol and limonene could promote bile secretion when compared to DSC treatment (p > 0.05); Menthol, menthol and limonene could significantly decrease total cholesterol level (p < 0.05 or p < 0.01) as well as increase total bile acid level (p < 0.05 or p < 0.01); Isomenthone, as a isomer of menthone, existed slightly choleretic effects; Pluegone had no obvious role in bile acid efflux. These findings indicated that the choleretic effects of DSC may be attributed mainly to its three major constituents: menthol, menthone and limonene.     

Influence of MRP1 G1666A and GSTP1 Ile105Val genetic variants on the urinary and blood arsenic levels of Turkish smelter workers

To understand the cellular mechanisms responsible for arsenic metabolism and transport pathways plays a fundamental role in order to prevent the arsenic-induced toxicity. The effect of MRP1 G1666A and GSTP1 Ile105Val polymorphisms on blood and urinary arsenic levels were determined in 95 Turkish smelter workers. Blood and urinary arsenic concentrations were measured by GF-AAS with Zeeman correction and gene polymorphisms were investigated by PCR-RFLP method. The mean blood and urinary arsenic levels were 21.60 ± 12.28 μg/L and 5.58 ± 4.37 μg/L, respectively. A significant association between MRP1 1666A allele and urinary arsenic levels was found (p = 0.001). GSTP1 Ile105Val polymorphism was detected not to be associated with either blood or urinary arsenic levels (p = 0.384, p = 0.440, respectively). Significant association was also detected between MRP1A^-/GSTP1Val⁻ genotypes and urinary arsenic levels (p = 0.001). This study suggested that MRP1 G1666A alone and, also, combined with GSTP1 Ile105Val were associated with inter-individual variations in urinary arsenic levels, but not with blood arsenic levels.     

Combination of peramivir and rimantadine demonstrate synergistic antiviral effects in sub-lethal influenza A (H3N2) virus mouse model

Efficacy of combination of the intramuscularly administered neuraminidase (NA) inhibitor, peramivir, and the orally administered M2 ion channel blocker, rimantadine was evaluated in mouse influenza A/Victoria/3/75 (H3N2) model. Mice were challenged with a sub-lethal virus dose (0–40% mortality in placebo group) and changes in body weights were analyzed by three-dimensional effect analysis to assess mode of drug interactions.Compounds were administered in a 5-day treatment course starting 1 h before viral inoculation. The peramivir and rimantadine doses ranged from 0.3–3 mg/kg/d and 5–30 mg/kg/d, respectively. The maximum mean weight loss of 5.19 g was observed in the vehicle-infected group on day 10. In the 1 and 3 mg/kg/d peramivir monotherapy groups, the weight losses were 4.3 and 3.55 g, respectively. In the rimantadine monotherapy group, the weight losses were 3.43, 2.1, and 1.64 g for the 5, 10, and 30 mg/kg/d groups, respectively. Combination of 1 mg/kg/d peramivir with 5 and 10 mg/kg/d rimantadine produced weight losses of 1.69 and 0.69 (p < 0.05 vs. vehicle and individual agent), respectively, whereas the combination of 3.0 mg/kg/d peramivir with 10 and 30 mg/kg/d rimantadine did not show any weight loss (p < 0.05 vs. vehicle and individual agent). The three-dimensional analysis of the weight loss for the majority of the drug combinations of peramivir and rimantadine tested demonstrated synergistic antiviral effects.     

Combined effects of oxytetracycline and Pb on earthworm Eisenia fetida

Combined effects of oxytetracycline (OTC) and Pb on lysosomal membrane stability and coelomocyte apoptosis of earthworm were studied in the paper. Compared with control, the lysosomal membrane stability decreased and coelomocyte apoptosis increased in the treatments of single OTC and Pb contamination. As for compound pollution, combined effect of (5 mg/kg OTC + 50 mg/kg Pb) treatment on earthworm lysosomal was synergistic (except 28 d). However, it was antagonistic at higher concentration of (10 mg/kg OTC + 50 mg/kg Pb) and (20 mg/kg OTC + 50 mg/kg Pb) treatment. In addition, coelomocyte apoptosis of earthworm decreased significantly compared with single OTC, indicating an antagonistic reaction. And joint toxicity of OTC and Pb decreased significantly with the increasing OTC concentration.     

Comparative efficacy of novobiocin and amoxicillin in experimental sepsis caused by β-lactam-susceptible and highly resistant pneumococci

Therapeutic alternatives are needed against infections caused by highly multidrug-resistant Streptococcus pneumoniae. Novobiocin, an old antibiotic, was tested in vitro and in a murine sepsis model against one amoxicillin-susceptible and three amoxicillin-resistant strains [minimum inhibitory concentrations (MICs) 8–64 mg/L]. Novobiocin MICs for all strains were 0.25–0.5 mg/L. In sepsis, novobiocin and amoxicillin were evaluated at 25, 50, 100 and 200 mg/kg given at 1, 5, 24 and 48 h post bacterial challenge. The most effective regimens in animals infected with the amoxicillin-susceptible strain were 200 mg/kg novobiocin and 25 mg/kg amoxicillin, achieving 100% survival and undetectable organisms in the peritoneum. Among mice infected with amoxicillin-resistant S. pneumoniae, 200 mg/kg novobiocin gave the highest protection (90–100% survivors), followed by 200 mg/kg amoxicillin (60–100%), 100 mg/kg novobiocin (50–87.5%) and 50 mg/kg amoxicillin (14.3–25%). The killing effect of antibiotics in the peritoneum (mean Δlog₁₀ colony-forming units/mL between treated and control mice) was as follows: 200 mg/kg novobiocin (?6.6) > 200 mg/kg amoxicillin (?5.6) > 100 mg/kg novobiocin (?3.7) > 50 mg/kg amoxicillin (?0.7). Total plasma and ultrafiltrate pharmacokinetics of novobiocin (200 mg/kg, single dose) in non-infected mice showed, respectively, half-lives of 151 min and 215 min, area under the concentration–time curves (AUCs) of 945.0 mg h/L and 136.6 mg h/L and maximal concentrations of 147 mg/L and 18 mg/L. Novobiocin may be a promising agent for therapy of highly β-lactam-resistant pneumococcal infections.     

Herb–drug interaction of Fucus vesiculosus extract and amiodarone in rats: A potential risk for reduced bioavailability of amiodarone in clinical practice

Fucus vesiculosus is a seaweed claimed to be useful for obesity management. Therefore, considering the relationship between obesity and cardiovascular diseases, this work aimed to assess the potential for an herb–drug interaction among a standardized F. vesiculosus extract (GMP certificate) and amiodarone (a narrow therapeutic index drug) in rats. In a first pharmacokinetic study, rats were simultaneously co-administered with a single-dose of F. vesiculosus (575 mg/kg, p.o.) and amiodarone (50 mg/kg, p.o.); in a second study, rats were pre-treated during 14 days with F. vesiculosus (575 mg/kg/day, p.o.) and received amiodarone (50 mg/kg, p.o.) on the 15th day. Rats of the control groups received the corresponding volume of vehicle. After analysis of the pharmacokinetic data it deserves to be highlighted the significant decrease in the peak plasma concentration of amiodarone (55.4%) as well as the reduction of systemic exposure to the parent drug (∼30%) following the simultaneous co-administration of F. vesiculosus extract and amiodarone. This paper reports, for the first time, the herb–drug interaction between F. vesiculosus and amiodarone, which determined a considerable decrease on amiodarone bioavailability in rats. Therefore, the therapeutic efficacy of amiodarone may be compromised by the concurrent administration of herbal slimming medicines/dietary supplements containing F. vesiculosus.     

Assessment of propofol,midazolam and ziprasidone,or the combinations for the prevention of acute cocaine toxicity in a mouse model

Study objectiveTo evaluate the effects of pretreatment, midazolam (M), propofol (P), ziprasidone (Z), and two combinations of [(midazolam plus propofol (MP); midazolam plus ziprasidone (MZ)] in mice models in the prevention of seizures, and death due to acute cocaine toxicity.Methods180 male CF-1 mice were randomized to 6 groups (30/group) in this experimental study. The animals were administered intraperitoneal injections of M (2 mg/kg), P (25 mg/kg), Z (4 mg/kg), MP (2 mg/kg and 25 mg/kg) and MZ (2 mg/kg and 4 mg/kg) or saline (S) as a pretreatment. 10 min later, the mice were administered intraperitoneal injections of 105 mg/kg cocaine. The groups were observed for cocaine-induced seizure and lethality.ResultsThe MP and MZ combinations showed the highest protective effect in terms of seizure and lethality relative to P and S (p < 0.001). M and Z were found effective compared to P and S (p < 0.001). There were no significant differences among MP and MZ, however there were significant differences between MP and Z in terms of lethality (p = 0.05). There were no significant differences among MP, MZ, M and Z groups in terms of seizure (p > 0.05). No death was observed in the MP combination group. Seizure rate was observed o be least in the MZ group with respect to the other groups.ConclusionAccording to our particular mouse model, this study suggests that MP and MZ combinations may be more effective than M or Z only for the prevention of cocaine-induced seizure and lethality. However, P alone does not prevent cocaine-induced seizure and lethality.     

Subchronic and reproductive toxicity of whole dried Hoodia parviflora aerial parts in the rat

Hoodia parviflora is being developed commercially for use in weight loss food and dietary supplement products. As part of the safety assessment process for H. parviflora, a freeze dried powder preparation was tested in a 90-day oral toxicity study with reproductive/recovery component in rats. Groups of 10 male and female Sprague–Dawley rats were administered H. parviflora dried powder at doses of 0, 100, 250, and 350 mg/kg body weight/day by gavage for an 11-week pre-mating period and a 14-day co-habitation period, and for females, through lactation day 4. An additional 5 rats/sex/group received 0 or 350 mg/kg bw/day for 90 days and were sacrificed 28 days after cessation of treatment. Statistically significant, non-adverse reductions in body weight, body weight gain, food consumption and food efficiency were observed at 250 and 350 mg/kg/day in females. Food consumption was reduced in high-dose males. There were no adverse effects on hematological, blood biochemical, coagulation or urinalysis parameters or on the results of the functional observational battery and histopathological examinations. No evidence of any effect was noted on reproductive or developmental parameters. The NOAEL for dried H. parviflora powder was 350 mg/kg bw/day, the highest permissible dose tested, for both male and female rats.     

In vivo preliminary investigations of the effects of the benzimidazole anthelmintic drug flubendazole on rat embryos and fetuses

Flubendazole, in a new formulation with high systemic bioavailability, has been proposed as a macrofilaricide against filarial diseases.To investigate embryotoxic activity, the new flubendazole formulation was administered orally to Sprague Dawley rats at 2, 3.46, 6.32 mg/kg/day on gestation day (GD) 9.5 and 10.5. Embryos/fetuses were evaluated on GD 11.5, 12.5 or 20.At 6.32 mg/kg/day (C_max = 0.801 μg/mL after single administration), flubendazole initially induced an arrest of embryonic development followed by a generalized cell death that led to 100% embryolethality by GD 12.5.At 3.46 mg/kg/day (C_max = 0.539 μg/mL after single administration), flubendazole markedly reduced embryonic development by GD 12.5 without causing cell death. On GD 20, 80% of fetuses showed malformations.At 2 mg/kg/day (C_max = 0.389 μg/mL after single administration), it did not interfere with rat embryofetal development.     

Role of N-acetylcysteine in protecting against 2,5-hexanedione neurotoxicity in a rat model: Changes in urinary pyrroles levels and motor activity performance

The interference of N-acetylcysteine (NAC) on 2,5-hexanedione (2,5-HD) neurotoxicity was evaluated through behavioral assays and the analysis of urinary 2,5-HD, dimethylpyrrole norleucine (DMPN), and cysteine-pyrrole conjugate (DMPN NAC), by ESI-LC–MS/MS, in rats exposed to 2,5-HD and co-exposed to 2,5-HD and NAC.Wistar rats were treated with 4 doses of: 400 mg 2,5-HD/kg bw (group I), 400 mg 2,5-HD/kg bw + 200 mg NAC/kg bw (group II), 200 mg NAC/kg bw (group III) and with saline (group IV). The results show a significant decrease (p < 0.01) in urinary DMPN and free 2,5-HD, a significant increase (p < 0.01) in DMPN NAC excretion, and a significant recovery (p < 0.01) on motor activity in rats co-exposed to 2,5-HD + NAC, as compared with rats exposed to 2,5-HD alone. Taken together, our findings suggest that at the studied conditions NAC protects against 2,5-HD neurotoxicity and DMPN may be proposed as a new sensitive and specific biomarker of 2,5-HD neurotoxicity in animals treated with a toxic amount of 2,5-hexanedione.     

Safety profile of Hoodia gordonii extract: Mouse prenatal developmental toxicity study

Hoodia gordonii extract (0, 5, 15 or 50 mg/kg body weight/day, n = 24 mice/group) was orally administered by gavage to female CD-1 mice from gestation days 5–17. On gestation day 18 the females were euthanized and examined. Treatment at 50 mg/kg/day caused a marked reduction in feed intake and body weight gain. Feed consumption was sporadically reduced at 15 mg/kg/day. At 50 or 15 mg/kg/day fetal weights, ossification of some bones and full and empty uterus weights were reduced. There were no clear maternal or fetal effects at 5 mg/kg/day. Reproductive indices were unaffected at all doses and there were no treatment-related malformations, anomalies or variations. The overall study no-observed-adverse-effect level was set at 5 mg/kg/day.In summary, at doses that reduced maternal feed consumption, H. gordonii extract delayed fetal development. The fetal effects seen could be consequent to reduced maternal feed consumption, the desired biological activity of the test item.