Systemic Toxicity In Rats Research Articles

Pulmonary evaluation of whole-body inhalation exposure of polycarbonate (PC) filament 3D printer emissions in rats

ABSTRACT During fused filament fabrication (FFF) 3D printing with polycarbonate (PC) filament, a release of ultrafine particles (UFPs) and volatile organic compounds (VOCs) occurs. This study aimed to determine PC filament printing emission-induced toxicity in rats via whole-body inhalation exposure. Male Sprague Dawley rats were exposed to a single concentration (0.529 mg/m3, 40 nm mean diameter) of the 3D PC filament emissions in a time-course via whole body inhalation for 1, 4, 8, 15, and 30 days (4 hr/day, 4 days/week), and sacrificed 24 hr after the last exposure. Following exposures, rats were assessed for pulmonary and systemic responses. To determine pulmonary injury, total protein and lactate dehydrogenase (LDH) activity, surfactant proteins A and D, total as well as lavage fluid differential cells in bronchoalveolar lavage fluid (BALF) were examined, as well as histopathological analysis of lung and nasal passages was performed. To determine systemic injury, hematological differentials, and blood biomarkers of muscle, metabolic, renal, and hepatic functions were also measured. Results showed that inhalation exposure induced no marked pulmonary or systemic toxicity in rats. In conclusion, inhalation exposure of rats to a low concentration of PC filament emissions produced no significant pulmonary or systemic toxicity.

The effects of KEM CON ONG and KEM TRI BONG creams on doxorubicin-induced skin ulcer in rats

The present study evaluated the effects of topical administration of KEM CON ONG and KEM TRI BONG creams on doxorubicin-induced skin ulcer, and their systemic toxicity in ulcerated rats. The skin lesions were induced by a single intradermal injection of 0.2ml doxorubicin 1 mg/0.5ml on the dorsal region. The ulcerated areas were covered topically with dimethyl sulfoxide, KEM CON ONG, or KEM TRI BONG twice a day for 28 days. The results indicated that KEM CON ONG and KEM TRI BONG significantly reduced the ulcer size, increased the hydroxyproline content in animals’ skin tissues, and improved the histopathological structure of skin tissues. No significant difference in the healing effect was observed between KEM CON ONG and KEM TRI BONG-treated ulcerated rats. Besides, our study demonstrated that topical administration of KEM CON ONG and KEM TRI BONG creams caused no significant change in the general status, hematological parameters, renal and hepatic functions. Additionally, they did not alter the histology of the liver and kidney in animals. In conclusion, the topical application of KEM CON ONG and KEM TRI BONG creams exerted healing effects on the ulcerated skin and did not cause systemic toxicity in a rat model.

The effects of KEM CON ONG and KEM TRI BONG creams on thermal burn in rats

The present study evaluated the healing effect of topical administration of KEM CON ONG and KEM TRI BONG creams on thermal burns in rats, and their systemic toxicity in burned rats. Thermal burns were induced on the dorsal region of rats using a standard burning technique. The burned areas were covered topically with silver sulfadiazine, KEM CON ONG, or KEM TRI BONG twice a day for 21 days. The results indicated that treatment with KEM CON ONG and KEM TRI BONG significantly reduced the size of the wounded area, increased the hydroxyproline content in animals’ skin tissues, and improved the histopathological structure of skin tissues. KEM TRI BONG exerted better effects than KEM CON ONG on thermal burns in rats. Besides, our study demonstrated that topical administration of KEM CON ONG and KEM TRI BONG creams caused no significant change in the general status, haematological parameters, renal and hepatic functions. Additionally, they did not alter the histology of liver and kidney in animals. In conclusion, the topical application of KEM CON ONG and KEM TRI BONG creams exerted healing effects on the burned skin, and did not cause systemic toxicity in a rat model.

Denture Adhesive Containing Microparticles for Delivery of Miconazole: In Vivo Toxicity

The choice treatment for denture stomatitis are topical antifungals such as miconazole nitrate (MN). Targeting denture wearers, an experimental denture adhesive (EA) was developed containing polymeric microparticles (MPs) for the delivery of MN. Objectives: To investigate the systemic toxicity in rats of the EA added with MN MPs. Methods: Thirty-five Wistar rats received intraperitoneal injection of the materials: artificial saliva (AS) as solvent, Corega Cream® (CCDA), pure EA or EA added with MN MPs (sigla), and pure MN or MNMP. Animal behavior impairment (level 0-4) and weight (g) analyses were carried out at 0, 24, 48 and 72 h. Blood was collected to detect C-reactive protein. The intraperitoneal washing was analyzed through red blood cell and leukocyte counts and turbidity degree. Descriptive statistical analysis was performed for behavior and turbidity. Normality of red blood cells (thousand/L) and leukocytes (million/L) counts was verified (Shapiro-Wilk, p<0.0001). Statistical analysis was performed using Kruskall-Wallis and Mann-Whitney U tests with Bonferroni adjustment. Results: No significant difference between weights of groups was found for time (p=0,551). No behavior alterations level 2, 3 or 4 were observed. The C-Reactive protein was negative for all groups. The leukocyte and red blood cell counts showed significant difference between the groups AS and EA+MNMP (p=0.016 and p=0.009, respectively). No significant difference was found between EA+MNM and the CCA (p=0.917) group in the leukocyte count. Significance: The denture adhesive with antifungal presented similar results to those of the commercially available adhesive, and pure saliva was sufficient to cause peritoneum systemic toxicity.

Sustained delivery of MMP-9 siRNA via thermosensitive hydrogel accelerates diabetic wound healing

Excessive expression of matrix metalloproteinase 9 (MMP-9) impedes healing of diabetic chronic wounds, thus wound dressing that could effectively inhibit the expression of MMP-9 offers significant clinical translation for diabetic wound healing. Herein, a hybrid hydrogel dressing was developed for localized and sustained delivery of MMP-9 siRNA (siMMP-9). siMMP-9 was complexed with Gly-TETA (GT), the GT/siMMP9 complex was then loaded into a thermosensitive hydrogel based on Pluronic F-127 (PF) and methylcellulose (MC). In vitro, this hybrid hydrogel dressing exhibited negligible cytotoxicity, prolonged the release of GT/siMMP-9 for up to 7 days, and significantly reduced MMP-9 expression. In vivo assessment in diabetic rats demonstrated that hydrogel provided localized and sustained delivery via the thermosensitive controlled release of entrapped GT/siMMP-9 into wound tissues for 7 days, resulting in dramatic MMP-9 silencing which significantly improved diabetic wound closure. This hybrid hydrogel dressing exhibited excellent biocompatibility, with no observed systemic toxicity in rats. Taken together, the hybrid hydrogel dressing may constitute an effective and biocompatible means of enhancing diabetic wound healing through effective silencing of the MMP-9 gene, and this hydrogel delivery system also offers a platform for in vivo delivery of siRNA for the treatment of other diseases.

Systemic effects and impact on the gut microbiota upon subacute oral exposure to silver acetate in rats.

The addition of silver (Ag) to food items, and its migration from food packaging and appliances results in a dietary exposure in humans, estimated to 70-90µg Ag/day. In view of the well-known bactericidal activity of Ag ions, concerns arise about a possible impact of dietary Ag on the gut microbiota (GM), which is a master determinant of human health and diseases. Repeated oral administration of Ag acetate (AgAc) can also cause systemic toxicity in rats with reported NOAELs of 4mg AgAc/b.w./d for impaired fertility and 0.4mg AgAc/b.w./d for developmental toxicity. The objective of this study was to investigate whether oral exposure to AgAc can induce GM alterations at doses causing reproductive toxicity in rats. Male and female Wistar rats were exposed during 10weeks to AgAc incorporated into food (0, 0.4, 4 or 40mg/kg b.w./d), and we analyzed the composition of the GM (α- and β-diversity). We documented bacterial function by measuring short-chain fatty acid (SCFA) production in cecal content. Ferroxidase activity, a biomarker of systemic Ag toxicity, was measured in serum. From 4mg/kg b.w./d onwards, we recorded systemic toxicity, as indicated by the reduction of serum ferroxidase activity, as well as serum Cu and Se concentrations. This systemic toxic response to AgAc might contribute to explain reprotoxic manifestations. We observed a dose-dependent modification of the GM composition in male rats exposed to AgAc. No impact of AgAc exposure on the production of bacterial SCFA was recorded. The limited GM changes recorded in this study do not appear related to a reprotoxicity outcome.

Assessment of pulmonary toxicity of potential antioxidant drug PEGylated nanoceria after intratracheal instillation in rats.

Cerium oxide (CeO2 ) nanoparticles have unique redox properties and exert excellent antioxidant effects in the biological environment. In recent years, many researchers have focused on the CeO2 nanoparticles as an effective antioxidant drug in the prevention and treatment of various diseases. However, the toxicity of CeO2 nanoparticles in vivo remains controversial and still needs intensive research. Therefore, the objective of this study is to investigate the pulmonary and systemic toxicity in rats after 14 days of exposure to the PEGylated CeO2 nanoparticles (abbreviated as CNPs; exposure dose of 2, 10, or 20 mg/kg) through a single intratracheal instillation (IT). We assessed the indicators of lung injury and the pathological damage degree of lung tissue. The bronchoalveolar lavage fluid (BALF) analysis and lung histopathology revealed the occurrence of slight pulmonary inflammation in the 20-mg/kg experimental group rats. However, the inflammation factors in the lung tissue of every group rats did not significantly increase, and the levels of superoxide dismutase (SOD) and glutathione (GSH) in lung tissue homogenate rose considerably in the experimental groups. Collectively, these results indicated that pulmonary exposure by the high dose of CNPs could induce mild pulmonary inflammation but did not cause severe systemic toxicity. Moreover, we speculate that the mechanism of pulmonary toxicity of CNPs in rats was due to the autophagic death of healthy lung epithelial cells mediated by endoplasmic reticulum stress. Our results implicate that CNPs can be safely used as an antioxidant drug for the oxidative stress pulmonary diseases.

Pulmonary and systemic toxicity in rats following inhalation exposure of 3-D printer emissions from acrylonitrile butadiene styrene (ABS) filament

Background Fused filament fabrication 3-D printing with acrylonitrile butadiene styrene (ABS) filament emits ultrafine particulates (UFPs) and volatile organic compounds (VOCs). However, the toxicological implications of the emissions generated during 3-D printing have not been fully elucidated. Aim and methods The goal of this study was to investigate the in vivo toxicity of ABS-emissions from a commercial desktop 3-D printer. Male Sprague Dawley rats were exposed to a single concentration of ABS-emissions or air for 4 hours/day, 4 days/week for five exposure durations (1, 4, 8, 15, and 30 days). At 24 hours after the last exposure, rats were assessed for pulmonary injury, inflammation, and oxidative stress as well as systemic toxicity. Results and discussion 3-D printing generated particulate with average particle mass concentration of 240 ± 90 µg/m³, with an average geometric mean particle mobility diameter of 85 nm (geometric standard deviation = 1.6). The number of macrophages increased significantly at day 15. In bronchoalveolar lavage, IFN-γ and IL-10 were significantly higher at days 1 and 4, with IL-10 levels reaching a peak at day 15 in ABS-exposed rats. Neither pulmonary oxidative stress responses nor histopathological changes of the lungs and nasal passages were found among the treatments. There was an increase in platelets and monocytes in the circulation at day 15. Several serum biomarkers of hepatic and kidney functions were significantly higher at day 1. Conclusions At the current experimental conditions applied, it was concluded that the emissions from ABS filament caused minimal transient pulmonary and systemic toxicity.

Manifestation of Systemic Toxicity in Rats after a Short-Time Inhalation of Lead Oxide Nanoparticles.

Outbred female rats were exposed to inhalation of lead oxide nanoparticle aerosol produced right then and there at a concentration of 1.30 ± 0.10 mg/m3 during 5 days for 4 h a day in a nose-only setup. A control group of rats were sham-exposed in parallel under similar conditions. Even this short-time exposure of a relatively low level was associated with nanoparticles retention demonstrable by transmission electron microscopy in the lungs and the olfactory brain. Some impairments were found in the organism’s status in the exposed group, some of which might be considered lead-specific toxicological outcomes (in particular, increase in reticulocytes proportion, in δ-aminolevulinic acid (δ-ALA) urine excretion, and the arterial hypertension’s development).

Mercury affects uterine myogenic activity even without producing any apparent toxicity in rats: Involvement of calcium-signaling cascades

BackgroundMercury is an established environmental toxicant reported to cause reproductive disorders in women, however, its direct action on myometrial activity is yet to be understood. Earlier we have reported the underlying mechanism of mercury-induced myometrial contractions following in vitro exposure; however, no such information on the effect of mercury on myometrial activity following in vivo exposure is available, therefore, the present study was undertaken. ObjectivePresent study was designed to evaluate the effect of mercury on myometrial activity following in vivo exposure of rats and unravel the possible underlying mechanism. MethodsFemale Wistar rats were orally exposed to mercury (5, 50 and 500 μg/L in drinking water) for 28 days to investigate the toxicodynamics of mercuric chloride (HgCl2)-induced alterations in myometrial activity. Response of the isolated myometrial strips to different spasmogens was recorded using polyphysiograph. Blood and uterine calcium, mercury, iron and zinc levels were estimated by atomic absorption spectrophotometry. Blood biochemicals and serum hormonal profiles (estradiol, progesterone) were also determined. ResultsNo systemic toxicity of mercury was observed in any of the treatment groups (5, 50 and 500 μg/L) in terms of alterations in body weight, organ weights, blood biochemical parameters including hormonal profile. Interestingly, mercury at 5 μg/L concentration significantly increased the receptor-dependent (PGF2α-induced) and receptor-independent (CaCl2-induced and high K+-depolarizing solution-induced) myometrial contractions and it was coupled with corresponding increase in the uterine calcium levels. However, mercury at higher dose levels (50 and 500 μg/L) did not significantly alter the myometrial response. ConclusionOur results evidently suggest that mercury at low level (5 μg/L) produced detrimental effect on myometrial activity by altering calcium entry into the smooth muscle and/or the release of calcium from intracellular stores without causing any apparent systemic toxicity in rats.

A Fixed-Dose Combination, QXOH/Levobupivacaine, Produces Long-Acting Local Anesthesia in Rats Without Additional Toxicity.

QXOH, a QX314 derivative with longer duration and lesser local toxicity, is a novel local anesthetic in preclinical drug development. Previous studies demonstrated that bupivacaine can prolong the effects of QX314. So, we attempted to combine QXOH with levobupivacaine to shorten the onset time and lengthen the duration. In this study, we investigated the efficacy, local and systemic toxicity in rats. In subcutaneous infiltration anesthesia, the inhibition of cutaneous trunci muscle reflex for QXOH-LB was greater than QXOH and levobupivacaine in the first 8 h (QXOH-LB vs. QXOH, P = 0.004; QXOH-LB vs. LB, P = 0.004). The completely recovery time for QXOH-LB (17.5 ± 2.5 h) was significantly longer than levobupivacaine (9.0 ± 1.3 h, P = 0.034) and QXOH (9.8 ± 0.9 h, P = 0.049). In sciatic nerve block, QXOH-LB produced a rapid onset time, which was obviously shorter than QXOH. For sensory, the time to recovery for QXOH-LB was 17.3 ± 2.6 h, which was statistically longer than 6.0 ± 1.8 h for QXOH (P = 0.027), and 4 h for levobupivacaine (P = 0.001). Meanwhile, the time to motor recovery for QXOH-LB was 7.9 ± 2.8 h, significantly longer than 4 h for levobupivacaine (P = 0.003) but similar to 6.0 ± 1.7 h for QXOH (P = 0.061). In local toxicity, there was no significant difference of histological score regarding muscle and sciatic nerve in QXOH-LB, QXOH, levobupivacaine and saline (P < 0.01). In the combination, the interaction index of LD50 was 1.39, indicating antagonistic interaction between QXOH and levobupivacaine in terms of systemic toxicity. In this study, we demonstrated that QXOH-LB produced cutaneous anesthesia which was 2-fold greater than that produced by QXOH or LB alone, and elicited sciatic nerve block with a potency that was 5- and 3-fold that of LB and QXOH, respectively. Local tissue inflammation by QXOH-LB was mild, similar to that induced by LB. This fixed-dose combination led to an antagonistic interaction between QXOH and LB in terms of systemic toxicity. These results suggested that QXOH-LB induced a long-lasting local anesthesia, likely, avoiding clinically important local and systemic toxicities.

Optimization of formulation for enhanced intranasal delivery of insulin with translationally controlled tumor protein-derived protein transduction domain

Intranasal delivery of insulin is an alternative approach to treat diabetes, as it enables higher patient compliance than conventional therapy with subcutaneously injected insulin. However, the use of intranasal delivery of insulin is limited for insulin’s hydrophilicity and vulnerability to enzymatic degradation. This limitation makes optimization of formulation intranasal insulin for commercial purpose indispensable. This study evaluated bioavailability (BA) of various formulations of insulin intranasally delivered with protein transduction domain (PTD) derived from translationally controlled tumor protein. The therapeutic efficacy of newly formulated intranasal insulin + PTD was compared in vivo studies with normal and alloxan-induced diabetic rats, to those of free insulin and subcutaneously injected insulin. BA of insulin in two new formulations was, respectively, 60.71% and 45.81% of subcutaneously injected insulin, while the BA of free insulin was only 3.34%. Histological analysis of tissues, lactate dehydrogenase activity in nasal fluid, and biochemical analysis of sera revealed no detectable topical or systemic toxicity in rats and mice. Furthermore, stability analysis of newly formulated insulin + PTD to determine the optimal conditions for storage revealed that when stored at 4 °C, the delivery capacity of insulin was maintained up to 7 d. These results suggest that the new formulations of intranasal insulin are suitable for use in diabetes therapy and are easier to administer.

Di (2-ethylhexyl) adipate (DEHA): systemic toxicity in rats following 28-day intravenous exposure

Video monitoring the nearshore can provide high-frequency remotely-sensed optical information from which morphological changes and hydrodynamic data can be derived. Although overlooked in most of the studies, it is acknowledged that camera viewing angles can substantially vary in time for a variety of reasons, reducing consistently data accuracy. This paper aims to identify the primary environmental parameters controlling camera shifts at the video monitoring station of Sète (SE France) and develops an empirical model to routinely reduce these deviations. Our model simulates camera movements with an excellent skill (BSS = 0.87) and shows that camera viewing angles’ deviation is primarily controlled by the position of the sun during sunny days, making it predictable. This study opens new perspective to routinely improve camera geometry of video monitoring systems.

P-253 - Effects of methanol extract of Moringa oleifera leaves on indomethacin-induced free radical systemic toxicity in rats

We investigated the effects of methanol extract of Moringa oleifera leaves (MEMO) against indomethacin (Indo) induced systemic toxicity. Indo is known to cause free radicals-induced blood and tissue pathology. Sixty male Wistar rats, aged 14–16 weeks were randomly divided into 8 groups. Group 1, distilled water; Group 2, MEMO 250 mg/kg; Group 3, MEMO 500 mg/kg; Group 4, Indo 125 mg/kg; Group 5, MEMO 250 mg/ kg+Indo 125 mg/kg; Group 6, MEMO 500 mg/kg+Indo 125 mg/kg; Group 7, Indo 125 mg/kg+MEMO 250 mg/kg; Group 8, Indo 125 mg/kg+MEMO 500 mg/kg. After 24 hours, Indo-treated rats showed moderately severe anaemia, neutrophilia, elevated serum levels of ALT, AST, ALP, malondialdehyde, nitric oxide, myeloperoxidase, and decreased serum levels of superoxide dismutase and total glutathione. Histologic lesions in various organs of all Indo-treated rats were those of congestion, haemorrhage, thrombosis, degeneration and necrosis of parenchymal cells. The results of this study show that MEMO is protective against free radical-induced cytotoxic actions of Indo. Follow-up dosing of MEMO however seems to be necessary to sustain the anti-oxidative stress activity.

The hypolipidemic action of a diet supplemented with p,p'-methoxyl-diphenyl diselenide is not directly related to its antioxidant property.

The present study investigated whether a p,p'-methoxyl-diphenyl diselenide (MeOPhSe)2-supplemented diet causes toxicity in rats. A second aim of this study was to determine whether a 10 ppm (MeOPhSe)2-supplemented diet has hypolipidemic effect on Triton WR-1339-induced hyperlipidemia in rats. To rule out the antioxidant property of (MeOPhSe)2 in its hypolipidemic action, parameters of oxidative stress were carried out. Wistar rats were fed with 3, 10, or 30 ppm of (MeOPhSe)2-supplemented diet for 30 days. None of (MeOPhSe)2-supplemented diets caused alteration in general parameters of toxicity and lipid profile of rats. The hypolipidemic effect of 10 ppm of (MeOPhSe)2-supplemented diet on rats treated with Triton WR-1339 (400 mg/kg, intraperitoneal) was investigated. The (MeOPhSe)2-supplemented diet partially protected against the levels of total cholesterol (TC) and non-HDL-C and reduced the atherogenic index (AI) increased by Triton WR-1339 in rats. A positive correlation between TC and triglyceride levels (r = 0.679) and non-HDL-C levels (r = 0.929) and AI (r = 0.889) was demonstrated. Triton WR-1339 altered parameters of oxidative stress in livers of rats but (MeOPhSe)2-supplemented diet did not protect against these alterations. The results demonstrated that the hypolipidemic action of (MeOPhSe)2-supplemented diet is not directly related to its antioxidant property and devoid of systemic toxicity in rats at the parameters analyzed.

The genotoxicity and systemic toxicity of a pharmaceutical effluent in Wistar rats may involve oxidative stress induction.

There is scarcity of information on the possible mechanisms of pharmaceutical effluent induced genotoxicity and systemic toxicity. This study investigated the genotoxicity and systemic toxicity of a pharmaceutical effluent in Wistar rats. Rats were orally treated with 5–50% concentrations of the effluent for 28 days. At post-exposure, blood, liver, kidney and bone marrow cells were examined for alterations in serum biochemical parameters and hematological indices, histopathological lesions and micronucleated polychromatic erythrocytes formation (MNPCE). The effluent caused concentration independent significant (p < 0.05) alterations in aspartate (AST) and alanine (ALT) aminotransferases, superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), total and direct bilirubin and creatinine. There was reduction in red blood count (RBC), hemoglobin concentration (HGB), platelets, percentage hematocrit (HCT), white blood count (WBC) and mean corpuscle hemoglobin (MCH) except mean corpuscle hemoglobin concentration (MCHC), which increased in the treated rats. Histopathological lesions observed in the liver and kidney of the effluent treated rats were thinning of the hepatic cord, kuffer cell hyperplasia, vacuolation of the hepatocytes and renal cells, multifocal inflammatory changes, necrosis and congestion of the renal blood vessels and central vein. MNPCE significantly increase in the bone marrow of the treated rats compared to the negative control. The concentration of some toxic metals and anions in the effluent were above standard permissible limits. These findings showed that the pharmaceutical effluent caused somatic DNA damage and systemic toxicity in rats may involve induction of oxidative stress, suggesting environmental contamination and health risks in wildlife and humans.

Assessment of localized therapeutic effect for prolonged release biodegradable implants loaded with 5-Fluorouracil on rats with induced liver cancer

The objective of this research was to assess ability of biodegradable implantable 5-Fluorouracil dosage forms, to maximize the regional exposure of the drug while limiting its systemic toxicity in rats with induced liver cancer. Liver cancer was successfully induced in male Wistar rats using a selected protocol followed by surgical implantation of prepared 5-FU biodegradable implant. Rats were sacrificed at time intervals and the pooled blood used to perform the different tests and the implant was retrieved, and analyzed to calculate the amount of drug left in implant. The amount of 5-FU in blood was quantified using high pressure liquid chromatography (HPLC). Gross examination of rat liver, calculation of liver to body weight percentage, and complete blood picture analysis were also performed. Liver biopsies were examined to assess signs of liver necrosis. Localized necrotic areas were noted in rat liver biopsies after 5 days with a perimeter of 0.3 to 0.6 cm around the implants indicating the localized 5-FU therapeutic effect. Sustained drug release was detected in rats for about 2 months and the amount of 5-FU released from implant into the systemic circulation was found to represent less than 13%. PLA coated injection molded implants loaded with 5-FU could present a promising dosage form for liver cancer treatment.

Polymethylmethacrylate dermal fillers: evaluation of the systemic toxicity in rats

This study evaluated local and systemic reactions after an intravascular injection of polymethylmethacrylate (PMMA) at two concentrations in a murine model. Thirty rats were divided equally into three groups: 2% PMMA, 30% PMMA, and a control group (normal saline only injection). The filler was injected into the ranine vein. The rats were sedated at 7 and 90 days and a clinical evaluation performed. After euthanasia, the right lung, liver, and right kidney were removed, weighed, and microscopically analyzed. The submandibular lymph nodes and tongue were removed and examined microscopically. Serum was subjected to liver and kidney function tests. No groups showed clinical alterations. Microspheres were not observed at any distant organ. Two samples from the 2% PMMA group showed a local inflammatory response at day 7 and another two samples from the 30% PMMA group at day 90. The group injected with 30% PMMA presented higher levels of alanine aminotransferase (P=0.047) after 90 days when compared with the other groups. The data obtained in this study demonstrate that intravascular injections of PMMA fillers show potential health risks such as chronic inflammation at the implantation site.

Ninety-Day Toxicity Study of Alpha-Iso-Methylionone in Rats

Alpha-iso-methylionone (AIM), a fragrance ingredient, was evaluated for systemic toxicity in rats. Male and female Sprague Dawley rats were administered 0, 5, 30, or 500 mg/kg/d AIM via gavage for 90 days. Statistically significant changes in blood chemistry parameters (reduced aspartate aminotransferase [AST], and increased cholesterol, creatinine, and total protein) were observed in both sexes at 500 mg/kg/d. There were statistically significant increases in liver and kidney weights in both sexes and in spleen weights in males at 500 mg/kg/d. Adaptive hepatocyte enlargement was observed in both sexes at 500 mg/kg/d. Globular accumulations of eosinophilic material were observed in the renal tubular epithelium in males at ≥30 mg/kg/d. Thyroid and bone marrow histopathological changes were observed in males at 500 mg/kg/d. The no-observed-effect level was 5 mg/kg/d for males and 30 mg/kg/d for females. Based on histopathological changes in the kidney in males, the no-observed-adverse-effect level was 30 mg/kg/d.

Cutaneous analgesia after subcutaneous injection of memantine and amantadine and their systemic toxicity in rats

The purpose of the study is to find subcutaneous equianalgesic doses of memantine, amantadine and bupivacaine and use these doses to quantify the cardiovascular and central nervous system toxicity of these agents after intravenous administration. Memantine, amantadine and bupivacaine, a local anesthetic, in a dose-related fashion were determined for cutaneous analgesia by a block of the cutaneous trunci muscle reflex in rats, and equipotent doses were calculated. Following rapid intravenous infusion of equianalgesic bupivacaine, memantine, amantadine and saline (vehicle) in rats, we observed the onset time of seizure, apnea and impending death, and monitored mean arterial blood pressure and heart rate. Memantine and amantadine elicited dose-dependent cutaneous analgesia. At the 50% effective dose (ED50), the rank of potencies was bupivacaine [1.8 (1.7–2.0)]>memantine [19.1 (17.6–21.8)]>amantadine [36.1 (32.0–40.3)] (P<0.05). On ED25, ED50 and ED75 basis, the duration caused by bupivacaine was similar to that caused by memantine or amantadine. At equianalgesic doses, the infusion time of memantine or amantadine required to induce seizure, impending death, and apnea was longer than that of bupivacaine during rapid intravenous infusion (P<0.01). The decreasing slope in mean arterial blood pressure and heart rate was slower with memantine and amantadine when compared with bupivacaine at equivalent doses (P<0.01). Our data showed that memantine and amantadine (i) were equal to bupivacaine at producing durations of cutaneous analgesia but (ii) were less likely than bupivacaine to cause cardiovascular and central nervous system toxicity.