Single and 90-day repeated oral dose toxicity studies of fermented Rhus verniciflua stem bark extract in Sprague–Dawley rats

Fermented Rhus verniciflua stem bark (FRVSB) extract, an urushiol-free extract of Rhus verniciflua Stokes (RVS) fermented with Fomitella fraxinea, has various biological activities. The present study was carried out to investigate the potential toxicity of the FRVSB extract following single and repeated oral administration to Sprague–Dawley rats. In the single dose toxicity study, the FRVSB extract was administered orally to male and female rats at single doses of 0, 2500, 5000, and 10,000 mg/kg. No animals died and no toxic changes were observed in clinical signs, body weight, and necropsy findings during the 15-day period following administration. In the repeated dose toxicity study, the FRVSB extract was administered orally to male and female rats for 90 days at doses of 0, 556, 1667, and 5000 mg/kg/day. There were no treatment-related adverse effects in clinical signs, body weight, food and water consumption, ophthalmic examination, urinalysis, hematology, serum biochemistry, necropsy findings, organ weight, and histopathology at any dose tested. The approximate lethal dose of the FRVSB extract was >10,000 mg/kg in both genders, the oral no-observed-adverse-effect level of the FRVSB extract was >5000 mg/kg/day in both genders, and no target organs were identified.     

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.     

Safety evaluation of a natural eggshell membrane-derived product

Natural Eggshell Membrane (NEM®) is a novel dietary ingredient that contains naturally occurring glycosaminoglycans and proteins essential for maintaining healthy joint and connective tissues. NEM® was evaluated for safety via in vitro and in vivo toxicological studies. This included testing for cytotoxicity, genotoxicity, acute oral toxicity, and 90-day repeated-dose oral toxicity. NEM® did not exhibit any cytotoxic effects at a dose of 100 μg in an in vitro human cell viability assay after incubation for up to 20 h. NEM® did not exhibit any genotoxic effects in an in vitro assay of four strains of histidine-dependent Salmonella typhimurium and one strain of tryptophan-dependent Escherichia coli at a dose of up to 5000 μg/plate. NEM® did not exhibit any signs of acute toxicity in rats at a single oral dose of up to 2000 mg/kg body weight, nor signs of toxicity (via urinalysis, hematology, clinical chemistry, or histopathological evaluation) in rats at a repeated oral dose of up to 2000 mg/kg body weight per day for 90 days. The results of these studies suggest that NEM® may be safe for human consumption.     

Tolerance liability of diazepam is dependent on the dose used for protracted treatment

BackgroundBehavioral effects of benzodiazepines following repeated exposure vary according to the intrinsic efficacy of the benzodiazepine studied, treatment schedule and the behavioral parameters evaluated.MethodsWe applied the behavioral paradigms of spontaneous locomotor activity, elevated plus maze and grip strength to investigate the sedative, anxiolytic and myorelaxant effect of acute challenge with 2 mg/kg diazepam administered after 14 days of protracted treatment with 0.5, 2 or 10 mg/kg of diazepam. In addition, we studied the effects of everyday handling and intraperito-neal (ip) administration on animal behavior.ResultsTolerance to the sedative effect of 2 mg/kg diazepam ensued after 14 days of protracted treatment with 2 and 10 mg/kg of diazepam. In contrast, treatment with the lowest dose (0.5 mg/kg) of diazepam resulted in potentiation of the sedative effect of acute challenge with 2 mg/kg diazepam thus confounding the detection of the anxiolytic effect of diazepam. A sensitization-like response to the anxiolytic action of 2 mg/kg diazepam was seen after protracted treatment with the intermediate dose (2 mg/kg); however, anxiolytic effect was absent after protracted administration of the highest dose. Partial tolerance to the muscle relaxant effect of 2 mg/kg diazepam ensued after protracted treatment with diazepam regardless of the dose. Daily handling or ip administration did not alter the behavioral response to acute challenge with 2 mg/kg diazepam in all the three behavioral paradigms studied.ConclusionThe presented results showed that behavioral effects of acute challenge with diazepam were differently affected by the dose administered during protracted treatment.     

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.     

Acute and subchronic toxicological evaluation of Mequindox in Wistar rats

We studied an acute and subchronic oral toxicity of Mequindox (MEQ), a quinoxaline 1,4-dioxide antimicrobial promoter, in Wistar rats according to OECD guidelines. For acute toxicity study, single doses of MEQ at 175, 550 and 2000 mg/kg b.w. were administered to rats by oral gavage. The calculated LD₅₀ was 550 mg/kg b.w. In subchronic study, rats were fed diets containing 0, 55, 110 or 275 mg MEQ/kg. There was a reduction in body weight of rats fed 275 mg MEQ/kg diet. At 90 days autopsy, a significant decrease in the kidney weight was observed in males while an increase in relative liver and adrenal weights were observed in females fed 275 mg MEQ/kg diet. There was a significant increased in alanineaminotransferase (ALT) and malondialdehyde (MDA) concentrations in males, superoxide dismutase (SOD) activities in females, and aspartateaminotransferase (AST) levels in serum of both genders fed 275 mg MEQ/kg diet. Other toxic effects of 275 mg MEQ/kg diet included significant decrease in sodium and significant increase in potassium concentrations in serum in both genders. We may conclude that MEQ can induce hepatic and adrenal histological changes as well as leaking of different serum constituents in Wistar rats.     

Acute and sub-chronic toxicity studies of the extract of Thunberg Fritillary Bulb

The aim of this study was to investigate the acute and sub-chronic toxicity of extract of Thunberg Fritillary Bulb. For the acute toxicity tests, graded doses of the extract were administered orally to mice. The animals were observed for toxic symptoms and mortality daily for 14 days. In the sub-chronic toxicity study, rats were orally administered the extract at doses of 1 and 3 mg/kg body weight (BW) for 26 weeks. After 26 weeks, the rats were sacrificed for hematological, biochemical and histological examination. In the acute toxicity tests, the estimated median lethal dosage (LD₅₀) was 52.2 mg/kg body weight in the mice. In the sub-chronic toxicity tests, a dose of 1 mg/kg body weight presented no toxicity. Above the 1 mg/kg dose, the main adverse signs observed in male rats were body or head tremor and spontaneous motor activity reduction. There were no other significant changes observed in hematology, blood biochemistry, organ weight and organ histology. The overall findings of this study indicate that the extract of Thunberg Fritillary Bulb is non-toxic up to 1 mg/kg body weight, which can be considered a safe application dose.     

Combined treatment with low dose prednisone and escin improves the anti-arthritic effect in experimental arthritis

The present study was aimed at investigating whether low dose oral prednisone combined with escin could inhibit the progression of adjuvant-induced arthritis (AIA) in rats. Adjuvant arthritis was induced in SD rats began day 1 for 28 days. Prednisone at doses of 2, 10 mg/kg/day alone or escin at doses of 5, 10 mg/kg/day alone, or prednisone at dose of 2 mg/kg/day with escin at doses of 5 or 10 mg/kg/day were given to different groups of rats intragastrically from day 13 to 28 respectively. Paw swelling, arthritic index, histological and radiographic changes were assessed to evaluate the anti-arthritic effect. Weight growth, spleen and thymus indexes were also calculated. Serum samples were collected for estimation of pro-inflammatory cytokines. Rats developed erosive arthritis of the hind paw when immunized with adjuvant. Prednisone 2 mg/kg combined with escin 5 or 10 mg/kg significantly inhibited the paw swelling. Histopathological and radiographic analysis showed a marked decrease of synovial inflammatory infiltration, synovial hyperplasia and bone erosion by combination therapy, which also markedly suppressed the expression of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6). No significant changes were found in monotherapy group except prednisone 10 mg/kg group. Furthermore, combined treatment rescued some of GCs' adverse effects evidenced by increase in body weight and decrease in index of spleen compared with untreated AIA rats. In conclusion, the combination therapy possessed synergistic anti-arthritic efficacy and reduced adverse effect, which may play a role in the management of human RA.     

An antioxidant,N,N′-diphenyl-p-phenylenediamine (DPPD), affects labor and delivery in rats: A 28-day repeated dose test and reproduction/developmental toxicity test

A 28-day repeated dose toxicity test and reproduction/developmental toxicity test for N,N′-diphenyl-p-phenylenediamine (DPPD) were conducted in [Crl:CD(SD)] SPF rats. Male and female rats were dosed with DPPD by gavage for 28 days at 0, 100, 300, or 1000 mg/kg bw/day or for a total of 42–46 days at 0, 8, 50, or 300 mg/kg bw/day. No significant adverse effects were observed in the repeated dose toxicity study up to 1000 mg/kg bw/day in both sexes. In the reproduction/developmental toxicity study, two females showed piloerection, hypothermia, and pale skin; one died and the other showed dystocia on day 23 of pregnancy at 300 mg/kg bw/day. Another female delivered only three live pups at 300 mg/kg bw/day. A significantly prolonged gestation period was observed at 50 and 300 mg/kg bw/day. The NOAELs of repeated dose toxicity and reproduction/developmental toxicity were considered to be 1000 and 8 mg/kg bw/day, respectively.     

Reproductive and developmental toxicity screening test of 3-cyanopyridine in rats

Crl:CD(SD)rats were given 3-cyanopyridine by gavage at 0, 5, 30 or 180 mg/kg/day. Males were dosed for 42 days beginning 14 days before mating, and females for 40–53 days beginning 14 days before mating to day 3 of lactation, including throughout the mating and gestation periods. General toxicity, mainly liver damage, was observed in males at ≥30 mg/kg/day and in females at ≥5 mg/kg/day. Sertoli cell vacuolation was observed at 180 mg/kg/day, and spermatocyte damages were observed at ≥30 mg/kg/day. Effects on estrous cycles, corpora lutea and implantations, and unsuccessfully mated females, despite additional mating, were observed at 180 mg/kg/day. Delayed initiation of delivery, dystocia, and deaths or moribundities of pregnant females were observed at 180 mg/kg/day, and only two pregnant rats delivered live pups at that dose. The NOAEL for reproductive/developmental toxicity was concluded to be 30 mg/kg/day.     

Toxicokinetic study and absolute oral bioavailability of deoxynivalenol,T-2 toxin and zearalenone in broiler chickens

Mycotoxins lead to economic losses in animal production. A way to counteract mycotoxicosis is the use of detoxifiers. The European Food Safety Authority stated that the efficacy of detoxifiers should be investigated based on toxicokinetic studies. Little information is available on the absolute oral bioavailability and the toxicokinetic parameters of deoxynivalenol, T-2 and zearalenone in broilers. Toxins were administered intravenously and orally in a two-way cross-over design. For deoxynivalenol a bolus of 0.75 mg/kg BW was administered, for T-2 toxin 0.02 mg/kg BW and for zearalenone 0.3 mg/kg BW. Blood was collected at several time points. Plasma levels of the mycotoxins and their metabolite(s) were quantified using LC–MS/MS methods and toxicokinetic parameters were analyzed. Deoxynivalenol has a low absolute oral bioavailability (19.3%). For zearalenone and T-2 no plasma levels above the limit of quantification were observed after an oral bolus. Volumes of distribution were recorded, i.e. 4.99, 0.14 and 22.26 L/kg for deoxynivalenol, T-2 toxin and zearalenone, respectively. Total body clearance was 0.12, 0.03 and 0.48 L/min kg for deoxynivalenol, T-2 toxin and zearalenone, respectively. After IV administration, T-2 toxin had the shortest elimination half-life (3.9 min), followed by deoxynivalenol (27.9 min) and zearalenone (31.8 min).     

Critical period and minimum single oral dose of ochratoxin A for inducing developmental toxicity in pregnant Wistar rats

Ochratoxin A (OTA), a potent in vivo teratogen, has been tested in various laboratory animal species. Present investigation was conducted to determine critical dose and critical time for the developmental toxicity of OTA in pregnant Wistar rats after single oral dose administration. OTA at different graded dose levels (2–4 mg/kg body weight) and at different gestation days (6–15), caused variable developmental defects in developing fetuses. OTA at 2.75 mg/kg body weight, dissolved in 0.1 M sodium bicarbonate (vehicle) and administered by oral intubation as a single dose on one of the gestational days 6–15, caused significant maternal toxicity in the dams and various gross, visceral and skeletal anomalies in the fetuses. The major gross malformations were external hydrocephaly, incomplete closure of skull and omphalocele. Internal hydrocephaly, microphthalmia, enlarged renal pelvis and renal hypoplasia were the main internal soft tissue anomalies. Major skeletal defects were developmental defects in skull bones, sternebrae, vertebrae and ribs. The gestational days 6 and 7 were found to be the most critical for the induction of teratogenicity in rats. Single oral dose of 2.75 mg/kg body weight OTA was found to be the minimum effective teratogenic dose in pregnant Wistar rats.     

Safety evaluation of a thermolysin enzyme produced from Geobacillus stearothermophilus

Thermolysin is a zinc metalloprotease that has potential uses in the food industry. The safety of thermolysin has not been demonstrated before, and therefore a series of standard toxicological tests to assess its potential toxicity was undertaken. The thermolysin used in this study was derived from the thermophilic bacterium Geobacillus stearothermophilus, which had undergone chemical mutagenesis to generate strains with increased thermolysin production. Acute toxicity studies in rats and mice showed that thermolysin powder is not acutely toxic with an oral LD₅₀ of more than 18,000 mg/kg (2520 mg/kg thermolysin protein) in rats and more than 24,000 mg/kg (3360 mg/kg protein) in mice. Subchronic feeding studies in rats for 91 days at doses up to 1000 mg/kg (390 mg/kg protein) revealed no significant differences between treated and non-treated groups and a No Observed Effect Level (NOEL) of 1000 mg/kg (390 mg/kg protein) per day was established. Results from genotoxicity tests such as in vitro chromosomal aberration assay and in vivo mouse micronucleus were negative. Allergenicity sequence analysis revealed no evidence suggesting that thermolysin is an allergen. The data presented in this study support the conclusion that thermolysin is safe for use in food production.     

Evaluation of the anticonvulsant activity of 6-(4-chlorophenyoxy)-tetrazolo[5,1-a]phthalazine in various experimental seizure models in mice

This study investigated the anticonvulsant activity of a new phthalazine tetrazole derivative, QUAN-0808 (6-(4-chlorophenoxy)-tetrazolo[5,1-a]phthalazine), in the mouse maximal electroshock (MES) seizure model. The neurotoxicity of QUAN-0808 was investigated using the rotarod neurotoxicity test in mice. QUAN-0808 exhibited higher activity (median effective dose, ED₅₀ = 6.8 mg/ kg) and lower neurotoxicity (median toxic dose, TD₅₀ = 456.4 mg/kg), resulting in a higher protective index (PI = 67.1) compared with carbamazepine (PI = 6.4). In addition, QUAN-0808 exhibited significant oral anticonvulsant activity (ED₅₀ = 24 mg/kg) against MES-induced seizure with low neurotoxicity (TD₅₀ > 4500 mg/kg) in mice, resulting in a PI value of more than 187.5. QUAN-0808 was also tested in chemically induced animal models of seizure (pentylenetetrazole [PTZ], isoniazid [ISO], thiosemicarbazide [THIO] and 3-mercaptopropionic acid [3-MP]) to further investigate the anticonvulsant activity; QUAN-0808 produced significant anticonvulsant activity against seizures induced by ISO, THIO and 3-MP.     

Anxiolytic profile of fluoxetine as monitored following repeated administration in animal rat model of chronic mild stress

Background: Fluoxetine, a selective serotonin re-uptake inhibitor (SSRI), has been proposed to be more effective as an antidepressive drug as compared to other SSRIs. After chronic SSRI administration, the increase in synaptic levels of 5-HT leads to desensitization of somatodentritic 5-HT autoreceptors in the raphe nuclei. Chronic stress may alter behavioral, neurochemical and physiological responses to drug challenges and novel stressors. Methods: Twenty four male rats were used in this study. Animals of CMS group were exposed to CMS. Animals of stressed and unstressed group were administrated with fluoxetine at dose of 1.0 mg/kg s well as 5.0 mg/kg repeatedly for 07 days 1 h before exposed to CMS. The objective of the present study was to evaluate that repeated treatment with fluoxetine could attenuate CMS-induced behavioral deficits. Results: Treatment with fluoxetine attenuated CMS-induced behavioral deficits. Fluoxetine administration induced hypophagia in unstressed as well as CMS rats. Acute and repeated administration of fluoxetine increased motor activity in familiar environment but only repeated administration increased exploratory activity in open field. Anxiolytic effects of fluoxetine were greater in unstressed rats. These anxiolytic effects were produced as result of repeated administration not on acute administration of fluoxetine at 1.0 mg/kg as well as 5.0 mg/kg. Conclusion: The present study demonstrated that CMS exposure resulted into behavioral deficits and produced depressive-like symptoms. Fluoxetine, an SSRI, administration attenuated behavioral deficits induced by CMS. Anxiolytic effects of repeated fluoxetine administration were greater in unstressed than CMS animals.     

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.     

Does nebivolol influence serum concentrations of proinflammatory cytokines in hypertensive (SHR) and normotensive (WKY) rats?

A growing body of evidence suggests that some drugs used in cardiovascular diseases may modulate the level of proinflammatory cytokines. In the present study we examined whether nebivolol, a third generation P-adrenergic blocker, influences lipopolysaccha-ride (LPS)-induced serum concentrations of TNF-α, IL-1P, and IL-6 in normotensive (WKY) and spontaneously hypertensive rats (SHR). Nebivolol (5 mg/kg and 10 mg/kg) or vehicle were administered by gavage once a day for 21 days. The drug (5 mg/kg and 10 mg/kg) did not modify LPS-stimulated serum concentrations of TNF-α, IL-1P and IL-6 in normotensive or hypertensive rats and did not affect the total cholesterol and HDL cholesterol level. Nebivolol, at the dose of 10 mg/kg, significantly increased the triglyceride concentration in SHR only. The results were accompanied by a statistically significant decrease in systolic, diastolic and mean blood pressure after 21 days of both of the drug doses. In hypertensive and normotensive rats, nebivolol had a hypotensive activity and neutral effect on lipid profile. In our in vivo model, the immunomodulating effect of the drug was not significant and probably did not depend on hemodynamic action.     

Evaluation of acute and subacute toxicity and mutagenic activity of the aqueous extract of pecan shells [Carya illinoinensis (Wangenh.) K. Koch]

The infusion of pecan shells has been used to prevent and control hypercholesterolemia, diabetes and toxicological diseases. The aim of the present study was to evaluate toxicity and mutagenic effects of pecan shells aqueous extract (PSAE). Wistar rats were treated with a single dose of 300 or 2000 mg/kg of PSAE in the acute toxicity test. For the subacute test, the animals received 10 or 100 mg/kg of PSAE for 28 days. The mutagenicity was evaluated using Salmonella/microsome assay in TA1535, TA1537, TA98, TA100 and TA102 S. typhimurium strains in the presence and absence of metabolic activation (S9 mix) and micronucleus test in bone marrow. HPLC analyses indicated the presence of tannins, flavonoids, gallic and ellagic acids. Except for triglycerides, all treated groups presented normal hematological and biochemical parameters. Lower levels of triglycerides and weight loss were observed in the 100 mg/kg group. Mutagenic activities were not detected in S. typhimurium strains and by the micronucleus test. Based on these results, PSAE was not able to induce chromosomal or point mutations, under the conditions tested. The 100 mg/kg dose showed significant antihyperlipidemic action, with no severe toxic effects.     

Acute and 13 weeks subchronic toxicological evaluation of naringin in Sprague-Dawley rats

Naringin is widely distributed in plant foods and has not previously been evaluated for safety through standard in vivo toxicological studies. In the present study, acute and subchronic oral toxicity studies of naringin were designed and conducted in Sprague-Dawley (SD) rats. Acute oral administration of naringin was done as a single bolus dose up to 16 g/kg and subchronic toxicity study for 13 weeks was done by oral administration at doses of 0 (control), 50, 250 and 1250 mg/kg in SD rats. There were no mortality, adverse clinical signs, abnormal changes in body weights or food consumption, toxicologically relevant changes in hematology, clinical biochemistry and macroscopic findings during 14 days of the acute toxicity study. During the subchronic oral toxicity study, no mortality and toxicologically significant changes in clinical signs, food consumption, opthalmoscopic examination, hematology, clinical biochemistry, serum sex hormone, macroscopic findings, organ weights and histopathological examination except for slight body weight decrease were noted and attributed to naringin administration. These observations suggest that naringin is practically non-toxic for SD rats in oral acute toxicity study and the no-observed-adverse-effect-level (NOAEL) of naringin in rats is greater than 1250 mg/kg/day when administered orally for 13 consecutive weeks.     

Phenolic acid protects of renal damage induced by ochratoxin A in a 28-days-oral treatment in rats

The present study aimed to characterize the chlorogenic acid (ChlA) capacity to reverse the toxic effects induced by ochratoxin A (OTA) in a subacute toxicity test in rats. Male Wistar rats were fed orally by gavage for 28 days with OTA (0.4 mg/kg bw/day), ChlA (5 mg/kg bw/day) or the combination OTA (0.4 mg/kg bw/day) + ChlA (5 mg/kg bw/day). No deaths, no decrease in feed intake or body weight in any experimental group were recorded. The negative control group and the animals treated with ChlA alone showed no changes in any parameters evaluated. In OTA-treated group significant changes such as decrease in urine volume, proteinuria, occult blood, increase in serum creatinine values; decrease in absolute and relative kidney weight and characteristics histopathological lesions that indicated kidney damage were observed. However, limited effect on oxidative stress parameters were detected in kidneys of OTA-treated group. Animals treated with the combination OTA + ChlA were showed as negative control group in the evaluation of several parameters of toxicity. In conclusion, ChlA, at given concentration, improved biochemical parameters altered in urine and serum and pathological damages in kidneys induced by OTA exposure, showing a good protective activity, but not by an apparent antioxidant mechanism.