Organ Weight Changes Research Articles

Effects on the reproductive system of young male rats of subcutaneous exposure to n-butylparaben

This study was aimed at determining whether an in vivo subcutaneous exposure to n-butylparaben (n-ButP) during one complete spermatogenic cycle could be harmful to the reproductive system of young male rats. Animals were subcutaneously given 0, 150, 300 and 600 mg/kg/day of n-ButP with vehicle (peanut oil). Body and organ weights, n-ButP excretion, biochemical parameters, sperm and spermatid count, sperm motility, viability, maturity and morphology were examined. Results showed that after a completed spermatogenic cycle, although n-ButP did not induce dose-related changes in the different biochemical parameters, a significant decrease of triacylglicerides (TAG) –due to the vehicle-was found. Furthermore, no effects of n-ButP on body weight gain and relative organ weight changes were noted. Regarding sexual organs, prostate relative weight was significantly increased at the high dose of n-ButP. On the other hand, a significant increase of abnormal sperm morphology due to n-ButP exposure, accompanied by different alterations in sexual organs histopathology, was found. The current results indicate that subcutaneous exposure of n-ButP in young male rats induced toxic effects on the reproductive system, which could affect the capacity of fertilization of animals.

Effects of preweaning nutrient intake in the developing mammary parenchymal tissue

Historically, mammary gland growth has been considered isometric the first 2 mo of life and then allometric until peripuberty. However, recent work indicated that the mammary gland might be responsive to nutrient intake preweaning. The objectives of this study were to describe the effects of nutrient intake preweaning on mammary gland development and to investigate cell specific proliferation during this phase of development. Twelve dairy heifer calves were fed either a fixed amount of milk replacer (MR; control, n = 6) or an amount of MR adjusted for BW (enhanced, n = 6). Control calves received a constant amount of a 28% crude protein, 15% fat milk MR per day that was equivalent to 2.8 Mcal of metabolizable energy intake per day; enhanced calves received 0.3 Mcal of metabolizable energy intake per kilogram of metabolic body weight (from 4.2 to 8.4 Mcal of metabolizable energy intake per day). All calves had constant access to water and a 22% crude protein commercial calf starter. Calves were killed at 54 ± 2 d. Control calves consumed 32.6 ± 2.4 kg of MR and 6.7 ± 0.5 kg of calf starter per calf, whereas the enhanced calves consumed 69.5 ± 2.4 kg of MR and 1.9 ± 0.5 kg of calf starter per calf over the 54-d period. Further, to evaluate putative stem cell proliferation, BrdU (5-bromo-2'-deoxyuridine; 5 mg/kg) was injected intramuscularly once per day between 12 to 15 d and again once per day between 24 to 27 d of life. Initial and final body weight for the control and enhanced treatments were 39.2, 61.0, 39.7, and 83.2 kg, respectively. At euthanasia, weights of liver, kidneys, pancreas, whole skinned mammary gland, and mammary parenchyma were measured. The growth rate of each organ was calculated using the concept of allometry as the difference in the change in organ weight as a percentage of body weight. The mammary glands of calves fed the enhanced diet were significantly heavier at euthanasia; when mammary parenchymal weight was analyzed, enhanced calves had 5.9 times greater mammary parenchymal mass, indicating the mammary gland was responsive to nutrient intake before weaning. Allometric growth of the mammary gland was initiated preweaning in the calves fed the enhanced treatment. Further characterization of mammary cells that retained BrdU label revealed no significant differences among the tissue slices analyzed between treatments; however, as calves fed the enhanced diet had more mammary parenchymal mass, if the number of label-retaining cells per counted slide were similar between treatments then the enhanced calves had a larger total population of putative mammary stem cells present in the mammary gland.

Toxicity assessment of molindone hydrochloride, a dopamine D2/D5 receptor antagonist in juvenile and adult rats

Neuroleptic drug molindone hydrochloride is a dopamine D2/D5 receptor antagonist and it is in late stage development for the treatment of impulsive aggression in children and adolescents who have attention deficient/hyperactivity disorder (ADHD). This new indication for this drug would expand the target population to include younger patients, and therefore, toxicity assessments in juvenile animals were undertaken in order to determine susceptibility differences, if any, between this age group and the adult rats. Adult rats were administered molindone by oral gavage for 13 weeks at dose levels of 0, 5, 20, or 60 mg/kg-bw/day. Juvenile rats were dosed for 8 weeks by oral gavage at dose levels of 0, 5, 25, 50, or 75 mg/kg-bw/day. Standard toxicological assessments were made using relevant study designs in consultation with FDA. Treatment-related elevation in serum cholesterol and triglycerides and decreases in glucose levels were observed in both the age groups. Organ weight changes included increases in liver, adrenal gland and seminal vesicles/prostate weights. Decreases in uterine weights were also observed in adult females exposed to the top two doses with sufficient exposure. In juveniles, sexual maturity parameters secondary to decreased body weights were observed, but, were reversed. In conclusion, the adverse effects noted in reproductive tissues of adults were attributed to hyperprolactinemia and these changes were not considered to be relevant to humans due to species differences in hormonal regulation of reproduction. On the whole, there were no remarkable differences in the toxicity profile of the drug between the two age groups.

Toxicological evaluation of alpha-galacto-oligosaccharides shows no adverse effects over a 90-day study in rats

AlphaGOS®, an alpha-galacto-oligosaccharides product, is a mixture of bi-, tri- and tetrasaccharides derived from oligosaccharides in the raffinose family of oligosaccharides (RFOs), naturally occurring plant-derived sugars. RFOs are alpha α-1,6-linked chains of D-galactose attached to the 6-position of D-glucose and differ from the currently commercially available beta-galacto-oligosaccharides products in the chirality and glyosidic bonds. In order to determine the safety of AlphaGOS, rats were given 2000 mg AlphaGOS/kg/day daily via gavage over 90 days. Daily assessments of the animals showed no adverse clinical signs. No adverse treatment-related changes in feed consumption, body weight, clinical chemistry or hematology were noted. There were no adverse treatment-related changes in organ weights, gross or histopathology. Given these findings, it can be concluded that the no observed adverse effect level for AlphaGOS is greater than 2000 mg/kg/day.

Assessment of Toxicity and Beneficiary Effects of Garcinia pedunculata on the Hematological, Biochemical, and Histological Homeostasis in Rats.

This study was undertaken to investigate the toxicological profile of a methanolic extract of Garcinia pedunculata fruit in rats by conducting hematological, biochemical, and histopathological examinations. Long Evans rats were divided into four groups, each with 6 animals, and were treated with three oral doses (250, 500, and 1000 mg/kg) once daily for 21 days. The extract did not cause significant changes in body and relative organ weight, percent water content, or hematological parameters at any administered doses. However, a significant dose-dependent positive effect in serum lipid profile and all atherogenic indices including the cardiac risk ratio, Castelli's risk index-2, and the atherogenic coefficient were observed. Significant increases in the levels of iron and decreases in serum alkaline phosphatase, alanine transaminase, and lactate dehydrogenase activities and the levels of serum glucose were noted when the extract was administered at the highest dose (1000 mg/kg). Histopathological examination of the target tissues further confirmed that the extract was safe and had no observed toxicological features. Our study indicates that G. pedunculata fruit is nontoxic, has the potential to be effective against atherosclerosis, and may be used as a hepatoprotectant. The fruit extract is also beneficial to those with iron deficiency and hyperglycemia.

Safety Evaluation of Honey from Jatropha Curcas Nectar and its Implication for Honey Production in Ghana

Jatropha curcas L. (Euphorbiaceae) is a plant documented to have an interesting toxicity profile however; bees produce honey from the nectar of its flowers in a Jatropha curcas plantation in the Yeji municipality of the Brong- Ahafo Region of Ghana. This study therefore is aimed at ascertaining the safety for consumption of honey produced from the J. curcas plant. Grouped Sprague-Dawley rats administered orally with single doses of this honey (300-1500 mg/kg) were observed critically for 24 h in an acute toxicity study. Cage-side observation, hematological profile, liver and kidney function tests, and body and organ weight monitoring were also carried out on grouped rats given 300-800 mg/kg of honey daily for 30 days in a sub-chronic toxicity test. Results indicated no physical, clinical signs and symptoms of toxicity, morbidity, and mortality after acute and prolonged administration of the honey. Subchronic toxicity studies revealed no significant changes (p>0.05) in body weight and organ weight (stomach, heart, and kidney), hematological parameters, liver and kidney function. There was however a dose-dependent increase (p ≤ 0.05-0.01) in aspartate transaminase, and significant increments in liver weight at all treatment doses. Histopathological studies of stomach, heart, kidney and liver showed normal architecture with no pathologies. Honey produced from Jatropha curcas flower nectar would be deemed safe for consumption as it did not show significant toxicity symptoms in Sprague-Dawley rats.

Safety evaluation of galacto-oligosaccharides

Galacto-oligosaccharides (GOS) have been added to infant formulas and conventional foods as prebiotics all over the world. The present study was conducted to assess the subchronic toxicity of a GOS syrup (VITAGOS™) when administered orally by gavage daily at 0, 1020, 2041, and 4082 mg GOS syrup/kg/day to male and female Sprague-Dawley rats to deliver doses of 0, 500, 1000, and 2000 mg GOS/kg/day for 90 days. Throughout the entire treatment period, no abnormal clinical signs or mortalities were observed. Similarly, no test article-related toxicologically adverse findings were seen in body weight, feed consumption, ophthalmological findings, hematology, coagulation, clinical chemistry, urinalysis, organ weights, and gross pathology or histopathology. Significant increases in the cecum weight of males and females treated with 2000 mg GOS/kg/day were associated with mucosal hypertrophy/hyperplasia; no changes in the cecum were noted at lower doses. The organ weight and histopathological changes noted in the cecum are consistent with findings in rats administered other poorly digestible and fermentable substances; thus, this is considered to be an adaptive rather than toxic response. The No-Observed-Adverse-Effect-Levels for VITAGOS™ is 4082 mg GOS syrup/kg body weight/day or 2000 mg GOS/kg body weight/day.

Suppressive effects of the expectorant drug ambroxol hydrochloride on quartz-induced lung inflammation in F344 rats.

Surfactant proteins (SPs) are essential to respiratory structure and function. The expectorant drug ambroxol hydrochloride is clinically prescribed to stimulate pulmonary surfactant and airway serous secretion. Therefore, ambroxol hydrochloride may affect SP production and pulmonary inflammation. Lung toxicity of fine particles of various materials has been examined previously in our in vivo bioassay using the intratracheal (i.t.) instillation approach. In the present study, we evaluated modulatory effects of ambroxol hydrochloride on quartz-induced lung inflammation in F344 rats. Male 6-week-old F344 rats were exposed by i.t. instillation to 2 mg of quartz particles suspended in 0.2 mL of saline. Ambroxol hydrochloride was administered at 0, 12, and 120 ppm in rat basal diet for 28 days, and then formalin-fixed paraffin-embedded lung, liver, and kidney samples were prepared. No changes in general condition, body and organ weights, or food consumption upon exposure to quartz were noted. The mean ambroxol intake in rats of the 12 ppm group was comparable to the human conventional dose. Histopathology of lung lesions was evaluated, and the degree of inflammation was scored. At 120 ppm, ambroxol hydrochloride significantly decreased individual lung inflammation scores for pulmonary edema and lymph follicle proliferation around the bronchiole, as well as the total inflammation score, in quartz-treated rats. Expression of SP-C in the type II alveolar cells and macrophages was greater in inflammatory lesions than in non-inflamed areas. Ambroxol treatment did not affect expression of SP-B and SP-C. In conclusion, we demonstrated that ambroxol hydrochloride relieves quartz-induced lung inflammation.

Environmentally Relevant Chronic Low-Dose Tritium and Gamma Exposures do not Increase Somatic Intrachromosomal Recombination in pKZ1 Mouse Spleen.

The toxicity of tritium is a public health concern given its presence and mobility in the environment. For risk predictions using radiological protection models, it is essential to allocate an appropriate radiation weighting factor (WR). This in turn should be consistent with the observed relative biological effectiveness (RBE) of tritium beta radiation. Although the International Commission on Radiological Protection (ICRP) currently recommends a WR of 1 for the calculation of committed effective dose for X rays, gamma rays and electrons of all energies, including tritium energies, there are concerns that tritium health risks are underestimated and that current regulatory tritium drinking water standards need revision. In this study, we investigated potential cytotoxic and genotoxic effects in mouse spleen after one month and eight months of chronic exposure to low-dose tritiated water (HTO). The dose regimes studied were designed to mimic human chronic consumption of HTO at levels of 10 kBq/l, 1 MBq/l and 20 MBq/l. The total doses from these radiation exposures ranged from 0.01 to 180 mGy. We also compared the biological effects of exposure to HTO with equivalent exposure to external whole-body 60Co gamma rays. Changes in spleen weight and somatic intrachromosomal recombination (DNA inversions) in spleen tissue of pKZ1Tg/+ mice were monitored. Our results showed no overall changes in either spleen organ weights and no increase mouse splenic intrachromosomal recombination frequencies, indicating that current drinking water standards for tritium exposure in the form of HTO are likely to be adequately protective against cytotoxic and genotoxic damage in spleen. These results demonstrate no evidence for cytotoxicity or genotoxicity in mouse spleen following chronic exposures to HTO activities (or equivalent gamma doses) up to 20 MBq/L.

Acute and subacute oral toxicity assessment of the oil extracted from Attalea phalerata Mart ex Spreng. pulp fruit in rats

Attalea phalerata Mart. ex Spreng., popularly known as “bacuri”, is a native plant from the brazilian Cerrado and used in folk medicine as a pulmonary decongestant, an anti-inflammatory for joints and antipyretic. There is an expectation about the use in chronic disease of the Attalea phalerata oil since its composition is high in carotenoids and beneficial fatty acids. The aim of the study was to evaluate the toxicological profile of the oil extracted from Attalea phalerata Mart. ex Spreng. pulp (APO). Acute and subacute toxicity studies were performed in male and female Wistar rats according to the OECD - Guidelines 425 and 407. For the acute toxicity, one single dose of the APO (2000mg/kg) was administered by gavage to five female rats. In the subacute toxicity, four different doses (125, 250, 500 and 1000mg/kg) of the APO were administered to male and female rats for 28 consecutive days. No deaths or behavioral changes were observed during both experiments as well as no changes in organ weights, hematological, histopathological parameters. The biochemical parameters showed changes in phosphatase alkaline and albumin levels, however these values are within the normal range for the species. A significant reduction in cholesterol and triglycerides was also observed in some of the animals treated with the APO. Therefore, the LD50 is higher than 2000mg/kg and the APO oil can be considered safe at the doses tested in rats. However, further assessments are required in order to proceed to clinical studies in humans.

The acute and sub-acute toxicity of C60/PVP complex in vivo

The detailed study of acute and sub-acute toxicity of the complex polyvinylpyrrolidon (PVP 20 kDa)-wrapped fullerene <TEX>$C_{60}$</TEX> after intraperitoneal (ip) administration was carried out on adult male Wistar rats. The <TEX>$LD_{50}$</TEX> value of <TEX>$C_{60}/PVP$</TEX> complex was found to be 7, 8 g/kg. In sub-acute study which lasted for 30 days the rats were exposed to daily administration of the complex in the doses of 350 or 700 mg/kg. All animals survived during the study and had no significant changes in clinical signs, organ weight, hematological and biochemical parameters of blood. The electrophysiological properties of myocardium and the excretory function of kidneys remained normal. Histological analysis of liver, kidney and spleen at the end of the study also did not demonstrate toxic alterations. It was thus established that intraperitoneal administration of complex <TEX>$C_{60}/PVP$</TEX> has no toxic effect. These results suggest that <TEX>$C_{60}/PVP$</TEX> has no acute and sub-acute toxicity and is a perspective substance for potential application in biology and medicine.

Subchronic Treatment of Combination Extract Detam 1 Soybean and Jati Belanda Leaves has No Toxic Effect on Function, Weight, and Histopathological of Wistar Rat Kidney

The combination of Detam 1 soybean and Jati Belanda leaves proved to have effect of weight loss. Since it will become longterm using, toxicity effectvresearch is needed. This study was conducted to determine the effect of subchronic combination of ethanol extract of soybean Detam 1 (EEDS) and Jati belanda (EEJB) on kidney function, with parameters: urea and creatinine, macroscopic and histopathological of kidney. This study were conducted on 120 Wistar rats (60 males, 60 females), 90 days (treatment group) and 120 days (satellite group). Rats were divided into six treatment groups. Test results of urea and creatinine levels of all treatment groups was lower than control group (p &lt;0.05). The treatment turned out to have a good effect on kidney function. Kidney weight of all groups showed no significant difference with the control group (p&gt; 0.05). Histopathological score interpretation’s result of low dose group male and female kidney rats were not disturbed. In conclusion, the combination of EEDS and EEJB have a good effect on kidney function, did not lead to changes in organ weight and at low doses did not cause disturbance of renal histopathology. Key words: combination of soybean jati Belanda, subchronic treatment, kidney function, kidney’s weight, kidney’s histopathology

English

Arsenic and di-(2-ethylhexyl) phthalate (DEHP) are environmentally ubiquitous and epidemiologically important toxic agents that millions of people are currently exposed to, worldwide. Although the adverse impact due to exposure to either arsenic or DEHP are documented, the toxicological effects of co-exposure to these agents are largely unknown. In this study, exposure to these chemicals was investigated for their effects on ATPase activities in the brain, liver and kidney of rats. Male Wistar rats were exposed daily to 100 mg L-1 arsenic via drinking water and to 100 mg DEHP kg-1 body weight in corn oil either individually or concurrently for 30 days. Toxicity was assessed by evaluating changes in body and organ weights, as well as, Na+/K+-, Ca2+-, Mg2+- and total ATPase activities in the brain, liver and kidney. Exposure to either arsenic or DEHP resulted in drastic reduction in activities of the enzymes in the compartments investigated, except in the brain where Na+/K+- and Mg2+- ATPases had their activities significantly increased. Also, DEHP displayed no effect on the total ATPase and Ca2+ ATPase in the kidney and brain, respectively. Interestingly, co-exposure to these toxicants significantly stimulated the activities of all these enzymes in the brain. In this compartment, combined treatment resulted in an additive interaction between the toxicants and a potentiation effect of arsenic on DEHP with regards to the Na+/K+- ATPase activity and Ca2+- ATPase activity, respectively. Our findings demonstrate tissue specific response to combined arsenic and DEHP exposure in rats with the effect on the brain significantly different from other compartments. Key words: Arsenic, di-(2-ethylhexyl) phthalate, Na+/K+-ATPase, Ca2+-ATPase, co-exposure.

Acute Oral Toxicity ofSalicornia herbaceaL. Extract in Mice

Salicornia herbacea L. (S. herbacea) is an annual herbaceous plant of Chenopodiaceae. It grows in groups on the coast or mud flat of Korea is known to be rich in minerals. S. herbacea has potent anti-cancer, antioxidant, anti-obesity, bowel function improvement. However, pharmacological mechanisms of S. herbacea extract (SHE) remain poorly understood. The aim of this study was to investigate the potential acute toxicity of SHE in ICR mice administered a single oral dose of 0, 500, 1,000, and 2,000 mg/kg by gavage. After administration of the extract, signs of toxicity were observed every day for 14 days. No mortality, abnormal clinical signs, body weight, organ weight or pathological changes were observed compared to a control group, and there were no differences in the body weights of the control and treatment groups. Biological serum activities and histological tests were not significantly changed in the treatment group compared to the control group. Especially, treatment of SHE was significantly decreased of total cholesterol and triglyceride levels. These results indicated that a single oral administration of SHE does not exerts any toxic effects at a dose of 2,000 mg/kg and that the LD50 of SHE is greater than 2,000 mg/kg. Accordingly, SHE appears to have potential in various functional agents of foods, without toxicity.

Hypolipidemic and Anti-oxidant Effects of Chunghyl Plus in Type II Diabetic Mice Model

This study was perfomed to investigate the effects of Chunghyul-plus(CHP) on oxidative damage and hyperlipidemia in db/db mouse. After treatment with CHP, safety in cytotoxicity, heavy metal toxicity, production of reactive oxygen species(ROS), nitric oxide (N0) and proinflammatory cytokine IL-Ib, TNF-a, IL-6 in RAW 264.7 cells. Serum total cholesterol, LDL cholesterol, HDL cholesterol, triglyceride, insulin, GLP-1, glucose, food intake, body weight, organ weight, AST, ALT, ALP, BUN, creatine and histologic change of liver and aorta were measured in db/db mouse after oral administration of CHP. CHP showed safety in cytotoxicity and toxicity of liver and kidney for logn time administration. CHP increased the DPPH and ABTS radical scavenging activity. CHP showed significant inhibitory effect on reactive oxygen species (ROS), and showed inhibitory effect on nitiric oxide(NO) compared to control group. CHP decreased cytokine IL-6 production significantly, and decreased IL-1β and TNF-α compared to control group. CHP decreased body and organ weitht, intake food, and glucose levels compared to control group. CHP decreased total cholesterol and triglyceride significantly, and decreased LDL-cholesterol levels and increased HDL-cholesterol levels compared to control group. CHP decreased atherogenic index and cardiac risk factor significantly. CHP increased serum insulin and GLP-1 compared to control group. In histologic examination, lipophagy in the liver and aorta decreased in CHP treated mice and the cell was regular and boundary of vessel wall was clear compared to control group. These results suggest that CHP is effective in antioxidation activity and treatment and prevention of hyperlipidemia, atherosclerosis, diabetes, ischemic heart disease, stroke and other cardiocerebrovascular disease.

Subchronic and genetic safety evaluation of a calcium fructoborate in rats

A branded calcium fructoborate product, a nature-identical calcium salt of bis (fructose) ester of boric acid found in plants and a natural source of boron in the human diet and sold under the trade name FruiteX-B® Brand Calcium Fructoborate (“FrxB”), was evaluated in a 90-day dietary toxicity study and two genotoxicity studies. In the 90-day study, four groups of 10 male and 10 female Crl:SD CD® IGS rats were fed diets with FrxB admixtures of 0.56, 1.12, and 1.68% dietary concentration, providing mean overall daily intakes of FrxB in male rats of 385.8, 774.9, and 1161.3 mg/kg bw/day, and 392.1, 784.4, and 1171.1 mg/kg bw/day in female rats. There were no mortalities, no clinical or ophthalmologic signs, body weight, body weight gain, food consumption, food efficiency, Functional Observational Battery (FOB), or Motor Activity (MA) findings associated with the administration of FrxB. There were no adverse changes in hematology, coagulation, clinical chemistry, or urinalysis parameters in male or female rats considered the result of test substance administration. At necropsy, there were no macroscopic, histopathological findings, or organ weight changes deemed related to administration of the test substance. Under the conditions of this study, based on the toxicological endpoints evaluated, the no-observed-adverse-effect level (NOAEL) for FrxB in the diet was 1161.3 and 1171.1 mg/kg bw/day in male and female rats, respectively. Bacterial mutagenicity studies and a micronucleus test using Chinese hamster V79 cells demonstrated no mutagenic or genotoxic potential of the tested brand of calcium fructoborate.

Sub-acute toxicity study on the aqueous extract of &lt;i&gt;Albizia zygia&lt;/i&gt; stem bark

Albizia zygia DC (Fabaceae) is widely used in herbal medicine for the treatment of bronchial diseases, fever (including malaria), diarrhea, sores, wounds and toothache. This study was aimed at determining the sub-acute toxicity of the aqueous extract of Albizia zygia stem bark. The sub-acute toxicity was evaluated after administering daily oral doses of 100, 200 and 500 mg/kg of extract for 42 days to rats. Morphological (body weight and organ weight indices), haematological {white blood cell (WBC), red blood cell (RBC), haemoglobin, haematocrit, and platelet counts}, biochemical {alanine aminotransferase (ALT), aspartate amino transferase (AST), alkaline phosphatase (ALP), total protein, total bilirubin (TB), creatinine, urea} and histopathological parameters were assessed using standard procedures. There was no mortality up to the highest dose of 5000 mg/kg in both mice and rats on oral acute administration of A. zygia . Administration of A. zygia (500 mg/kg/day) for 42 days caused a significant (p<0.05) increase in WBC count, decrease in creatinine and no significant changes in relative organ weights or serum concentrations of ALT, ALP, TB, albumin and urea in the treated rats compared to the control. Histologic analysis of the various organs showed mild activation of the lymphocytes of the lungs and the liver, sinus histiocytes of the spleen and mild interstitial congestion in the kidneys, indicating activation of the local immune system of the lungs, liver, kidney and spleen. The results of the study suggest that the aqueous extract of Albizia zygia stem bark can be considered relatively safe on sub-acute exposure. Keywords: Albizia zygia ; Acute toxicity; Histopathology; Spleen

Antitumor activity of doxorubicine-loaded nanoemulsion against Ehrlich ascites carcinoma-bearing mice

Purpose: To evaluate the antitumor activity of doxorubicine (DOX) loaded nanoemulsion (NE) on Ehrlich ascites carcinoma (EAC)-bearing Swiss albino mice. Methods: The mice were divided into five groups ( n = 20) according to the administered drug. Groups I - V were labeled as negative control (normal), positive control of the untreated EAC bearing mice (EAC control), blank nanoemulsion (BI-NE), DOX-loaded-NE (DOX/LNE) and free DOX (DOX-Sol), respectively. Cardiotoxicity was assessed by measuring changes in body and organ weight, analyzing serum enzymes and lipids, and examining histological changes in heart tissues by light microscopy. In addition, mean survival time (MST), increase in life span (ILS) and survival (S) of the mice were determined. Results: DOX/LNE group reduced levels of serum enzymes and lowered damage to heart tissues relative to DOX-Sol group. The MST of the DOX/LNE group (80 ± 0.0 days) was significantly greater than that for DOX-Sol group (34.6 ± 8.9 days), while ILS of DOX/LNE (265.30 days) was higher than that of DOX-Sol (57.99 days) by 4.6-fold. Conclusion: Administration of DOX/LNE to EAC-bearing mice improves the efficacy of DOX and reduce its side effects on the heart. Keywords: Doxorubicine, Anti-tumor activity, Mean survival time, Heart histology, Nanoemulsion, Lipid profile

In vitro and in vivo antineoplastic and immunological effects of pterocarpanquinone LQB-118.

Cancer is a malignancy of worldwide prevalence, and although new therapeutic strategies are under investigation, patients still resort to reductive or palliative chemotherapy. Side effects are a great concern, since treatment can render patients susceptible to infections or secondary cancers. Thus, design of safer chemotherapeutic drugs must consider the risk of immunotoxicity. Pterocarpans are natural isoflavones that possess immunomodulatory and antineoplastic properties. Ubiquitous in nature, quinones are present in chemotherapeutic drugs such as doxorubicin and mitoxantrone. Our group has patented a hybrid molecule, the pterocarpanquinone LQB-118, and demonstrated its antineoplastic effect in vitro. In this report we describe its antineoplastic effect in vivo and assess its toxicity toward the immune system. Treated mice presented no changes in weight of primary and secondary organs of the immune system nor their cellular composition. Immunophenotyping showed that treatment increased CD4(+) thymocytes and proportionally reduced the CD4(+)CD8(+) subpopulation in the thymus. No significant changes were observed in T CD8(+) peripheral lymphocytes nor was the activation of fresh T cells affected after treatment. LQB-118 induced apoptosis in murine tumor cells in vitro, being synergistic with the autophagy promoter rapamycin. Furthermore, treatment significantly reduced ascites or solid Ehrlich and B16F10 melanoma growth in vivo, and ameliorated side effects such as cachexia. Based on its favorable preclinical profile and considering previous results obtained in vitro, this drug emerges as a promising candidate for further development.

Safety assessment of non-animal chondroitin sulfate sodium: Subchronic study in rats, genotoxicity tests and human bioavailability

Chondroitin sulfate, an amino sugar polymer made of glucuronic acid and N-acetyl-galactosamine, is used in dietary supplements to promote joint health. Commonly used chondroitin sulfate is of animal origin and can pose potential safety problems including bovine spongiform encephalopathy (BSE). The objective of the present study was to investigate potential adverse effects, if any, of microbial derived chondroitin sulfate sodium (CSS) in subchronic toxicity, genotoxicity and bioavailability studies. In the toxicity study, Sprague Dawley rats (10/sex/group) were gavaged with CSS at dose levels of 0, 250, 500 and 1000 mg/kg body weight (bw)/day for 90-days. No mortality or significant changes in clinical signs, body weights, body weight gain or feed consumption were noted. Similarly, no toxicologically relevant treatment-related changes in hematological, clinical chemistry, urinalysis and organ weights were noted. Macroscopic and microscopic examinations did not reveal treatment-related abnormalities. In vitro mutagenic and clastogenic potentials as evaluated by Ames assay, chromosomal aberration test and micronucleus assay did not reveal genotoxicity of CSS. In pharmacokinetic study in human, CSS showed higher absorption as compared to chondroitin sulfate of animal origin. The results of subchronic toxicity study supports the no-observed-adverse-effect level (NOAEL) for CSS as 1000 mg/kg bw/day, the highest dose tested.