Developmental toxicities of ethylbenzene, ortho-, meta-, para-xylene and technical xylene in rats following inhalation exposure.

The developmental toxicities of ethylbenzene, o-, m-, p-xylene and technical xylene were studied in Sprague-Dawley rats after inhalation exposure. Animals were exposed to either of these agents at 100, 500, 1000 or 2000 ppm, for 6 h/day, during days 6-20 of gestation. All the agents tested caused maternal toxicity expressed as a reduction in maternal body weight gain at 1000 and 2000 ppm. Decreased corrected weight gain and food consumption were observed at 1000 and 2000 ppm ethylbenzene, o-, m- or p-xylene, and at 2000 ppm technical xylene. No evidence of teratogenic effects was found after exposure to any of these agents up to 2000 ppm. Fetal toxicity evidenced by significant decreases in fetal body weights occurred at concentrations of 500 ppm or greater of o-xylene or technical xylene, and 1000 ppm or greater of ethylbenzene, m- or p-xylene. A significant increase in the mean percentage of fetuses per litter with skeletal variations was also noted at 2000 ppm ethylbenzene, o- and p-xylene. In summary, all tested agents produced developmental toxicity at 1000 and 2000 ppm, concentrations that also produced significant maternal toxicity. With o-xylene and technical xylene, developmental toxicity also occurred at 500 ppm, in the absence of maternal toxic effects. However, the only indication of a treatment-related effect was a slight decrease in fetal weight.     

Clinical activity of venlafaxine and topiramate against oxaliplatin-induced disabling permanent neuropathy

Venlafaxine (Effexor; Wyeth Lederle), a serotoninergic-like anti-depressant, and Topiramate (Epitomax; Jansen Cilag), a new anti-epileptic drug, share some evidence of clinical activity in the treatment of neuropathic pain. Several anti-cancer agents have neurosensory toxicity as limiting toxicity of their repeated administration. One of the most recent and the most widely used is oxaliplatin. No medication is presently known to be active against oxaliplatin permanent neurosensory toxicity. We observed that venlafaxine hydrochloride or low-dose topiramate could be active against the permanent neuropathy-related symptoms of oxaliplatin. Both agents allowed pain relief and a significant autonomy improvement. These preliminary results invite us to evaluate further venlafaxine hydrochloride and topiramate for the treatment of permanent anti-cancer chemotherapy-induced neuropathies.     

Development of safety profile evaluating pharmacokinetics, pharmacodynamics and toxicity of a combination of pioglitazone and olmesartan medoxomil in Wistar albino rats

Pioglitazone (PIO), an antidiabetic drug and olmesartan medoxomil (OLM), an antihypertensive drug were administered orally alone and in combination to Wistar albino rats for evaluation of pharmacokinetics, pharmacodynamics and repeated dose 28-day oral toxicity of individual drugs and their combination. Pharmacokinetic study was performed by orally administering PIO and OLM at single dose of 3 and 2mg/kg, respectively alone and in combination analyzing the plasma samples using LC-MS/MS. Antidiabetic activity evaluation was done in type-2 diabetes mellitus induced animals at same dose level as in pharmacokinetic study daily for 30 days. PIO and/or OLM were administered orally to animals at daily doses of 50, 100 and 150 mg/kg for 28 days for toxicity study. There was no significant alteration in the pharmacokinetic parameters of either drug indicating absence of any pharmacokinetic interaction when co-administered. Positive pharmacodynamic interaction between PIO and OLM was established in this study. Two drugs in combination showed no evidence of potentiation of 28-day repeated dose toxicity in animals. Again, drugs, alone and in combination, caused only minor changes in clinical-laboratory tests and histopathological change was not found in the experiment performed. In conclusion, PIO and OLM combination can primarily be stated as safe in terms of present toxicity and pharmacokinetics findings.     

Toxicological studies on aqueous extract of Gmelina arborea in rodents

Context:?Gmelina arborea Roxb. (Verbenaceae) is an important medicinal plant in the traditional system of medicine of India. The plant is used in the treatment of snake-bites, fever, piles, and diabetes. However, there is little toxicological information available regarding its safety after exposure. The present study was designed to evaluate acute and repeated dose toxicity of the aqueous extract of Gmelina arborea stem bark.

Materials and methods:?In the acute toxicity test, Swiss albino mice were treated with aqueous extract (300, 2000, and 5000?mg/kg), orally. Animals were observed periodically during the first 24?h after administration of the extract, and daily thereafter for 14 days. In the repeated dose toxicity study, the aqueous extract of Gmelina arborea (300, 1000, and 2000?mg/kg per day) was administered orally for a period of 28 days in Wistar rats. The effects on body weight, food and water consumption, organ weight, hematology, clinical biochemistry, as well as histology, were studied.

Results and conclusion:?Aqueous extract did not produce mortality, changes in behavior or any other physiological activities in mice, for any of the selected doses. There were no significant differences in the body weight, organ weights and feeding habits between control and treated animals. Hematological and biochemical analysis showed no marked differences in any of the parameters examined in either the control or treated groups. Pathologically, neither gross abnormalities nor histopathological changes were observed. The aqueous extract of Gmelina arborea was found safe in acute and repeated dose toxicity studies when tested in rodents.     

Evaluation of developmental toxicity of microbicide Nisin in rats.

In the present study, we have investigated the developmental toxicity of a naturally occurring peptide, Nisin in rats in order to determine its suitability as a safe vaginal microbicide. Our earlier studies indicated that, Nisin is a dual function microbicide having contraceptive and antibacterial activities. However, as part of the safety evaluation of any vaginal microbicide, it is essential to determine its teratogenic potential in a suitable animal model before it is found suitable to enter clinical trials. Sixty pregnant rats allocated into four groups were orally administered with 10, 25 and 50 mg Nisin/kg/day from day 6 to day 15 of gestation. Individual food/water consumption and body weight changes were measured daily. Nisin did not cause maternal mortality nor did the treated animals show any clinical signs of toxicity when compared to the control animals. There were no biologically significant differences in maternal liver, kidney, thymus, ovary, gravid and empty uterine weights. Mean number of corpora lutea and implantation sites also did not differ in the treated groups when compared to their respective controls. All the fetuses were weighed, sexed and examined carefully for externally visible malformations. No gross external fetal alterations were observed at any dose tested. When stained by the double staining method, no skeletal malformations and visceral defects were observed in the fetuses. The growth and reproductive performance of the F1 progeny was also unaffected. In conclusion, Nisin shows unique clinical potential as a safe prophylactic microbicide to curb the transmission of STIs/HIV and unintended pregnancies.     

Twenty-eight-day oral toxicity study of lycopene from recombinant Escherichia coli in rats

Lycopene produced by recombinant Escherichia coli was tested for subacute oral toxicity to determine its No-Observed-Adverse-Effect Level (NOAEL). Doses of 0, 200, 500 and 2000 mg/kg body weight/day were administered daily by gavage to 10 rats/sex/group for 28 days. No statistically significant, dose-related effect on body weight gain, clinical signs or ophthalmoscopic parameters was observed in any treatment group. Likewise, no treatment-related or dose-related toxic effect was found in hematology, clinical chemistry, urinalysis, blood coagulation, organ weight, gross observation or histopathology. Thus, the NOAEL for lycopene derived from recombinant Escherichia coli was at least 2000 mg/kg body weight/day.     

Effects of CKD-602, a new camptothecin anticancer agent, on pregnant does and embryo-fetal development in rabbits

CKD-602 is a newly developed camptothecin anticancer agent. Preclinical studies suggest that it may have greater antitumor activity and lower toxicity than other camptothecin anticancer agents. The potential of CKD-602 to induce developmental toxicity was investigated in the New Zealand White rabbit. Seventy-two artificially inseminated females (artificial insemination=day 0) were distributed among three treatment groups and a control group. CKD-602 was at dose levels of 0, 0.024, 0.048, or 0.096 mg x kg(-1) x day(-1) administered intravenously to pregnant does from days 6 to 18 of gestation. All does were subjected to caesarean section on day 28 of gestation. At 0.096 mg x kg(-1) x day(-1), 2 cases of abortion and 3 cases of death in pregnant rabbits were found in late gestation. In addition, an increase in the embryonic resorptions and a decrease in the litter size were found. At 0.048 mg x kg(-1) x day(-1), a single doe aborted on gestational day 26. An increase in the embryonic resorptions and fetal morphological alterations and a decrease in the litter size were also found. There were no signs of maternal toxicity or developmental toxicity at 0.024 mg x kg(-1) x day(-1). The results show that 13-day repeated intravenous dose of CKD-602 during the major organogenetic period in rabbits produces increased incidence of abortion and death, increased number of embryonic resorptions and fetal morphological alterations, and decreased litter size at dose levels of above 0.048 mg x kg(-1) x day(-1). In the current experimental conditions, the no-observed-adverse-effect levels (NOAELs) of CKD-602 are considered to be 0.048 mg x kg(-1) x day(-1) for does and 0.024 mg x kg(-1) x day(-1) for embryo-fetal development.     

Gemcitabine and urothelial tumours

Since 1985, standard chemotherapy of metastatic urothelial tumours has been based on a combination of methotrexate, vinblastine, doxorubicin and cisplatin (M-VAC protocol). Two major lessons have been learned from the use of M-VAC, namely, clear evidence of chemo-sensitivity, and an absence of chemo-curability associated with notable toxicity. Three phase II studies using gemcitabine monotherapy have demonstrated promising efficacy with an objective response rate of 22-28%, and a satisfactory toxicity profile. Three further phase II studies have confirmed the efficacy of gemcitabine in association with cisplatine (GC protocol), with a response rate of 42-66%, of which 18-28% were complete responses. The main adverse effects were haematological, including neutropenia, or grade 3 or 4 thrombocytopenia without any symptoms of fever or significant haemorrhage. Current research with gemcitabine in the treatment of urothelial tumours is aimed at optimising administration of the GC protocol, investigating the use of gemcitabine in association with other cytotoxic agents such as taxanes, or expanding the use of this drug as adjuvant therapy. The results of a phase III study to compare the efficacy and toxicity of the M-VAC and GC protocols are eagerly awaited.     

A PEGylated dendritic nanoparticulate carrier of fluorouracil

The present study was aimed at developing and exploring the use of uncoated and PEGylated newer PAMAM dendrimers for delivery of anti-cancer drug 5-fluorouracil. For this study, successive Michael addition and exhaustive amidation reactions were used to synthesize 4.0 G PAMAM dendrimers, using ethylenediamine as core and methylmethacrylate as propagating agent. The dendrimer was PEGylated using N-hydroxysuccinimide-activated carboxymethyl MPEG-5000. IR and NMR data proved the synthesis. Various physicochemical parameters, SEM, TEM, lambda(max) values, hemolytic toxicity, drug entrapment, drug release and blood-level studies of both PEGylated and non-PEGylated systems were determined and compared. The PEGylation of the systems was found to have increased their drug-loading capacity, reduced their drug release rate and hemolytic toxicity. TEM study revealed surface properties of the systems. Stability studies had shown its stability at room temperature in dark. The systems were found suitable for prolonged delivery of an anti-cancer drug by in vitro and blood-level studies in albino rats, without producing any significant hematological disturbances. PEGylation has been found to be suitable for modification of PAMAM dendrimers for reduction of drug leakage and hemolytic toxicity. This, in turn, could improve drug-loading capacity and stabilize such systems in body. The study suggests use of such PEGylated dendrimeric systems as nanoparticulate depot type of system for drug administration.     

Brief overview of nanoparticulate therapy in cancer

Nanoparticles govern an all-important role, in this day and age, in determining the tissue distribution of either hydrophobic or hydrophilic anti-cancer drugs by encapsulating them or by covalent attachment. The whole purpose is to systematically improve upon the existing anti-tumour efficacy of these drugs. Selective delivery of these chemotherapeutic agents to the compromised or diseased tissue is the key to avoid any potential toxicity problems. Certain types of nanoparticles, through various mechanisms such as active targeting or reversing multi-drug resistance, display immense potential in adding to the existing anti-tumour efficacy profile. Determining the optimal composition of the polymers or size of the nanoparticles or appropriately tailoring the surface of these nanoparticles with molecular ligands are the key components in governing the successful biological fate of these nanoparticles.     

Subacute toxicity assessment of carotenoids extracted from citrus peel (Nanfengmiju, Citrus reticulata Blanco) in rats

The mixture of carotenoids extracted from citrus peel (Nanfengmiju, Citrus reticulata Blanco) was tested for subacute oral toxicity. In this study, dose levels of 0, 200, 500 and 2000 mg/kg body weight/day were administered by gavage to 10 Wistar rats/sex/group for 28 days. No statistically significant, dose-related effect on food consumption, food efficiency, body weight gain, clinical signs or ophthalmoscopic parameters was observed in any treatment group. Urinalysis, hematological, blood coagulation and serum biochemical examination as well as necropsy or histopathology showed that no observed adverse effect was found. These findings suggested that the No-Observed-Adverse-Effect Level for the mixture of carotenoids extracted from citrus peel was at least 2000 mg/kg body weight/day.     

Prenatal developmental toxicity study of ethyl tertiary-butyl ether in rabbits

Ethyl tertiary-butyl ether (ETBE) is commonly used as an oxygenated gasoline additive. In this study, the prenatal developmental toxicity of ETBE was determined in rabbits. New Zealand white rabbits were given ETBE by gavage at 100, 300, or 1,000 mg/kg/day on gestational days (GDs) 6-27, and the pregnancy outcome was determined on GD 28. Neither death nor abortion occurred in the pregnant rabbits at any dose. Slightly and significantly suppressed maternal body-weight gain and transiently decreased maternal food consumption were found at 1,000 mg/kg/day during the administration period. At this dose, no changes in clinical or macroscopic finding were noted in dams. No treatment-related changes were observed in any dam treated at 300 mg/kg/day or less. There was no significant effect of ETBE on the numbers of corpora lutea, implantations, live fetuses, resorptions and dead fetuses, incidences of pre- and postimplantation loss, viability of fetuses, fetal body weight, sex ratio of fetuses, or weights of gravid uteri. No significant difference was detected in the incidences of fetuses with malformations or variations between the ETBE-treated and control groups. Also, no adverse effects on the progress of ossification were noted in fetuses of dams given ETBE. Based on these findings, it is concluded that the no observed adverse effect levels of ETBE were 300 mg/kg/day for dams and 1,000 mg/kg/day for fetuses in rabbits.     

Toxicological and toxicokinetic analysis of angiotensin (1-7) in two species

The objectives of this study were to determine the potential systemic and local toxicity, as well as evaluate the toxicokinetic (TK) profile of angiotensin (1-7) [A(1-7)] when administered daily via subcutaneous injection for 28 days to Sprague-Dawley rats and Beagle dogs. A(1-7) is a member of the renin-angiotensin system and has undergone clinical evaluation for the treatment of chemotherapy-induced myelosuppression. In this present study, A(1-7) was given at 10 mg/(kg day) for 28 days to rats and canines. At day 27, blood was harvested to evaluate the TK parameters. On day 28, systemic toxicology was evaluated. Following A(1-7) administration for 27 days, no plasma A(1-7) accumulation was detected in canines; however, increased A(1-7) plasma concentrations were detected in rats. Despite the accumulation observed in rats, no detectable toxicity was found following A(1-7) administration for 28 days. The TK analysis of A(1-7) revealed a plasma half-life of 20-30 min in both rats and canines. The time to maximum plasma concentration was found to be 15 and 26.25 min in rats and canines, respectively. This study shows that subcutaneous administration of A(1-7) at 10 mg/(kg day) for 28 days did not lead to any detectable toxicities in either rats or canines.     

Assessment of chromosomal aberrations, micronuclei and proliferation rate index in peripheral lymphocytes from Tunisian nurses handling cytotoxic drugs

Anti-neoplastic agents are widely used in the treatment of cancer and some non-neoplastic diseases. These drugs have been proved to be mutagens, carcinogens and teratogens. To check the eventual effects of anti-cancer drugs on occupationally exposed Tunisian nurses, we used chromosomal aberration assay and micronucleus assay. Both parameters have been used to evaluate cellular DNA damage in the biological monitoring of occupationally exposed workers and each assay has its own aim .We used the proliferation rate index to evaluate the cytotoxic effect of antineoplastic drugs in exposed nurses. The frequency of binucleated micronucleated cells was significantly higher in nurses handling cytostatic drugs than in control. We detected also a significant increase of structural chromosomal aberrations. Control subjects generally had significantly higher values of proliferation rate index compared to expose ones. Our results confirm the genotoxic and the cytotoxic effects of antineoplastic drugs in blood lymphocytes circulation. This study points to the necessity to work under more safe and controlled conditions during the preparation and the administration of anti-cancer drugs.     

Emodin: A metabolite that exhibits anti-neoplastic activities by modulating multiple oncogenic targets

Oncogenic transformation has been the major cause of global mortality since decades. Despite established therapeutic regimes, majority of cancer patients either present with tumor relapse, refractory disease or therapeutic resistance. Numerous drug candidates are being explored to tap the key reason being poor tumor remission rates, from novel chemotherapy agents to immunotherapy to exploring natural compound derivatives with effective anti-cancer potential. One of these natural product metabolites, emodin has present with significant potential to target tumor oncogenic processes: induction of apoptosis and cell cycle arrest, tumor angiogenesis, and metastasis to chemoresistance in malignant cells. Based on the present scientific excerpts on safety and effectiveness of emodin in targeting hallmarks of tumor progression, emodin is being promisingly explored using nanotechnology platforms for long-term sustained treatment and management of cancer patients. In this review, we summarize the up-to-date scientific literature supporting the anti-neoplastic potential of emodin. We also provide an insight into toxicity and safety profile of emodin and how emodin has emerged as an effective therapeutic alternative in synergism with established conventional chemotherapeutic regimes for management and treatment of tumor progression.     

The development of hyaluronan as a drug transporter and excipient for chemotherapeutic drugs

Despite advances in chemotherapeutic regimens, the treatment of metastatic cancer remains a challenge. A key problem with chemotherapy drugs is nonspecific drug distribution, resulting in low tumor concentrations and systemic toxicity. The holy grail of clinical cancer research has been to establish more specific ways of directing therapeutics to tumors, whether through more targeted anti-cancer agents or via the method of delivery. Many tumor cells show up-regulated expression of receptors for the polysaccharide hyaluronan (HA), resulting in HA having a high affinity for tumors. This observation has led to the preclinical development of HA-cytotoxin bioconjugates that utilize HA as the tumor recognition moiety. The primary challenges have been organ-directed toxicity and limited efficacy. An alternative, simpler strategy has been to use the large volumetric domain of HA to entrain small chemotherapeutic drugs within the HA matrix. The resultant HA/drug formulation accumulates in the microvascular of the tumor, forming a microembolism that increases drug retention at the tumor site and allows for active tumor uptake through HA receptors. Clinical trials of HA formulations of three anti-cancer drugs have been undertaken and have demonstrated that such formulations are safe and efficacious. Within these formulations we postulate that HA is acting as a novel excipient, capable of improving the therapeutic index of the active anti-cancer agent.     

Tumor necrosis factor: how to make a killer molecule tumor-specific?

The interest in TNF, discovered at the interface between inflammation and cancer, as an anti-cancer agent, has phased out in recent years. Indeed, despite its profound cytostatic and cytotoxic effects in primary tumors, the cytokine's systemic toxicity in general and its hepatotoxic and pro-metastatic nature in particular, prevent its routine use in cancer patients. An elegant approach to circumvent these problems consists in the local application of TNF in an isolated limb or organ setting, preferentially in the presence of cytostatic and alkylating agents, such as melphalan. However, this treatment, when locally applied during the perfusion of liver tumors, results in hepatotoxicity in a significant number of the patients, by means of a still unknown mechanism. The hemorrhagic necrosis of the tumors induced by TNF seems to be predominantly mediated by an induction of apoptosis as well as by an anti-angiogenic effect in the endothelial cells of the microvasculature supplying the tumor. These cells therefore represent a prime target for the action of anti-cancer drugs. In this review, we discuss preclinical studies which elucidated the mechanism of melphalan- and TNF-associated hepatotoxicity and, as a consequence, provided insights for preventing the adverse reactions of the drug. Moreover, we review recent findings aimed at improving the TNF molecule by means of specific mutations, or searching for alternative factors lacking the systemic toxicity of TNF.     

The subchronic oral toxicity of ethane, 1,2-bis(pentabromophenyl) (Saytex 8010) in rats

Ethane, 1,2-bis(pentabromophenyl) (EBP; CAS no. 8452-53-9) dose levels of 0, 100, 320 and 1000 mg/kg/day administered to rats by gavage in corn oil for 90 consecutive days produced no compound-related clinical signs of systemic toxicity, ocular lesions, or alterations in urinalysis, clinical chemistry, and hematology values in the treated or recovery groups. No biologically or toxicologically significant differences were observed in body weights, body weight gains, and food consumption. Statistically significant differences were found between control and high-dose animals in mean absolute or relative liver weights. Histomorphological evaluation showed in male rats low-grade liver changes consisting of minimal to slight hepatocellular vacuolation (high-dose males) and minimal to slight centrilobular hepatocytomegaly (high- and possibly mid-dose males). These changes had resolved by the end of the 28-day recovery period. No treatment-related changes were found in the livers of female rats. No treatment-related histomorphologic changes were present in any of the other tissues examined in either sex, except for evidence of aspirated test article in individual rats. The 90-day EBP no-adverse-effect level in the rat was > or = 1000 mg/kg/day, and was consistent with that of the preceding 28-day study (no-effect level > or = 1250 mg/kg/day). EBP's lack of toxicity is likely related to poor bioavailability due to its high molecular weight and low solubility.     

Toxicological evaluation of the ethanolic extract of Artemisia dracunculus L. for use as a dietary supplement and in functional foods.

TARRALIN is an ethanolic extract of Artemisia dracunculus (Russian tarragon), a common medicinal and culinary herb with centuries of use. Artemisia dracunculus is a close relative of the French or cooking tarragon and contains components common to many herbs that are routinely consumed without reported adverse effects. Since safety information of Artemisia dracunculus and its extract is limited to historical use, TARRALIN was examined in a series of toxicological studies. Complete Ames analysis did not reveal any mutagenic activity either with or without metabolic activation. TARRALIN was tested in an acute limit test at 5000 mg/kg with no signs of toxicity noted. In a 14 day repeated dose oral toxicity study, rats appeared to well tolerate 1000 mg/kg/day. Subsequently, TARRALIN was tested in an oral subchronic 90-day toxicity study (rat) at doses of 10, 100 and 1000 mg/kg/day. No noteworthy signs of toxicity were noted in feeding or body weight, functional observational battery or motor activity. Gross necropsy and clinical chemistry did not reveal any effects on organ mass or blood chemistry and microscopic examinations found no lesions associated with treatment. Therefore, TARRALIN appears to be safe and non-toxic in these studies and a no-observed adverse effect level in rats is established at 1000 mg/kg/day.     

Safety evaluation of polyphenols extracted from hop bracts.

Hop bract polyphenols contain polyphenols as promising functional ingredients. To assess the safety of topical hop bract polyphenols, Hopsphenon, we examined acute, 14-day, 28-day and 90-day toxicity tests in rats, and mutagenicity tests using Ames test and micronucleus test in mice. The acute, 14-day, 28-day and 90-day toxicity tests revealed that Hopsphenon produced no symptoms of significant injury. The lethal dose of hop bract polyphenols is greater than 2000 mg/kg. The Ames test in the absence of S9 mix for TA98 and in the presence of S9 mix for TA1537 revealed that Hopsphenon had slight mutagenicity at a high dose of 5000 microg/plate; however, in the micronucleus test, Hopsphenon was negative. These tests demonstrated that hop bract polyphenols are safe and do not cause any detrimental effects in vivo under the conditions investigated in this study.