Dimethylacetamide-induced toxic hepatitis in spandex workers: clinical presentation and treatment outcomes.

BACKGROUND: Dimethylacetamide (DMAc) exposure has been associated with toxic hepatitis, and no clinical treatment has been reported. AIM: To investigate the clinical manifestations of DMAc-induced symptoms and how to rescue the functional loss due to occupational exposure. DESIGN: Clinical observations of 60 spandex factory workers with the exposure to DMAc from January, 2017-19. METHODS: Chinese drugs (reduced glutathione, polyene phosphatidylcholine, glycyrrhizin compound, Hugan tablets and ornithine aspartate) were used to evaluate the therapeutic improvements in DMAc-exposed patients. RESULTS: Our data found that 58.3% patients had no distinct clinical symptoms, but 41.7% patients felt fatigue, and 21.7% patients suffered abdominal discomfort and appetite loss, and 8.3% patients had yellow skin and sclera. The ultrasonic and CT imaging revealed that some patients have fatty livers, intrahepatic calcifications, hepatomegaly, gallbladder wall edema and abdominal effusions. Biochemical analysis showed that the alanine aminotransferase (ALT) (P < 0.001), aspartate aminotransferase (AST) (P < 0.001), lactate dehydrogenase (LDH) (P < 0.001) and bilirubin (P < 0.01) statistically decreased after the drug treatment, but alkaline phosphatase (P >0.05) and glutamyl transpeptidase (P> 0.05) did not decrease. Twenty-nine out of the thirty-one patients' abnormal blood ammonia recovered. The risk factor of ALT on hospitalization time was significantly related (P < 0.01). CONCLUSIONS: The drugs above are sufficient to rescue functional loss in DMAc-induced toxic hepatitis, in part via the regulations of ALT, AST, LDH, bilirubin and ammonia. Workers with the exposure to DMAc should receive specific drugs to maintain the health and prevent functional loss in the long term.

The influence of natural dissolved organic matter on herbicide toxicity to marine microalgae is species-dependent.

Microalgae, which are the foundation of aquatic food webs, may be the indirect target of herbicides used for agricultural and urban applications. Microalgae also interact with other compounds from their environment, such as natural dissolved organic matter (DOM), which can itself interact with herbicides. This study aimed to evaluate the influence of natural DOM on the toxicity of three herbicides (diuron, irgarol and S-metolachlor), singly and in ternary mixtures, to two marine microalgae, Chaetoceros calcitrans and Tetraselmis suecica, in monospecific, non-axenic cultures. Effects on growth, photosynthetic efficiency (Ф'M) and relative lipid content were evaluated. The chemical environment (herbicide and nutrient concentrations, dissolved organic carbon and DOM optical properties) was also monitored to assess any changes during the experiments. The results show that, without DOM, the highest irgarol concentration (I0.5: 0.5 mg.L-1) and the strongest mixture (M2: irgarol 0.5 µg.L-1 + diuron 0.5 µg.L-1 + S-metolachlor 5.0 µg.L-1) significantly decreased all parameters for both species. Similar impacts were induced by I0.5 and M2 in C. calcitrans (around -56% for growth, -50% for relative lipid content and -28% for Ф'M), but a significantly higher toxicity of M2 was observed in T. suecica (-56% and -62% with I0.5 and M2 for growth, respectively), suggesting a possible interaction between molecules. With DOM added to the culture media, a significant inhibition of these three parameters was also observed with I0.5 and M2 for both species. Furthermore, DOM modulated herbicide toxicity, which was decreased for C. calcitrans (-51% growth at I0.5 and M2) and increased for T. suecica (-64% and -75% growth at I0.5 and M2, respectively). In addition to the direct and/or indirect (via their associated bacteria) use of molecules present in natural DOM, the characterization of the chemical environment showed that the toxic effects observed on microalgae were accompanied by modifications of DOM composition and the quantity of dissolved organic carbon excreted and/or secreted by microorganisms. This toxicity modulation in presence of DOM could be explained by (i) the modification of herbicide bioavailability, (ii) a difference in cell wall composition between the two species, and/or (iii) a higher detoxification capacity of C. calcitrans by the use of molecules contained in DOM. This study therefore demonstrated, for the first time, the major modulating role of natural DOM on the toxicity of herbicides to marine microalgae.

Pharmacodynamics of the Orotomides against Aspergillus fumigatus: New Opportunities for Treatment of Multidrug-Resistant Fungal Disease.

F901318 is an antifungal agent with a novel mechanism of action and potent activity against Aspergillus spp. An understanding of the pharmacodynamics (PD) of F901318 is required for selection of effective regimens for study in phase II and III clinical trials. Neutropenic murine and rabbit models of invasive pulmonary aspergillosis were used. The primary PD endpoint was serum galactomannan. The relationships between drug exposure and the impacts of dose fractionation on galactomannan, survival, and histopathology were determined. The results were benchmarked against a clinically relevant exposure of posaconazole. In the murine model, administration of a total daily dose of 24 mg/kg of body weight produced consistently better responses with increasingly fractionated regimens. The ratio of the minimum total plasma concentration/MIC (Cmin/MIC) was the PD index that best linked drug exposure with observed effect. An average Cmin (mg/liter) and Cmin/MIC of 0.3 and 9.1, respectively, resulted in antifungal effects equivalent to the effect of posaconazole at the upper boundary of its expected human exposures. This pattern was confirmed in a rabbit model, where Cmin and Cmin/MIC targets of 0.1 and 3.3, respectively, produced effects previously reported for expected human exposures of isavuconazole. These targets were independent of triazole susceptibility. The pattern of maximal effect evident with these drug exposure targets was also apparent when survival and histopathological clearance were used as study endpoints. F901318 exhibits time-dependent antifungal activity. The PD targets can now be used to select regimens for phase II and III clinical trials.IMPORTANCE Invasive fungal infections are common and often lethal. There are relatively few antifungal agents licensed for clinical use. Antifungal drug toxicity and the emergence of drug resistance make the treatment of these infections very challenging. F901318 is the first in a new class of antifungal agents called the orotomides. This class has a novel mechanism of action that involves the inhibition of the fungal enzyme dihydroorotate dehydrogenase. F901318 is being developed for clinical use. A deep understanding of the relationship between dosages, drug concentrations in the body, and the antifungal effect is fundamental to the identification of the regimens to administer to patients with invasive fungal infections. This study provides the necessary information to ensure that the right dose of F901318 is used the first time. Such an approach considerably reduces the risks in drug development programs and ensures that patients with few therapeutic options can receive potentially life-saving antifungal therapy at the earliest opportunity.

Impact of agrochemicals on non-target species: Calathus fuscipes Goeze 1777 (Coleoptera: Carabidae) as model.

Carabid beetles are important in the biological control of arable crop pests. Agricultural practices can produce over time a delayed toxic effect at the organismal and population levels and can compromise the survival on these species. In this research, we quantified the cumulative sublethal effect on body size, Malpighian tubules and immune responses in Calathus fuscipes adults living in the potato field and exposed to lambda-cyhalothrin and cymoxanil-based commercial formulates. Reductions of morphological parameters such as body, pronotum and elytron in both males and females from the potato field indicated that the pre-imaginal stages (larvae and pupae) suffer the sublethal effects of exposure to the larvicide control action of lambda-cyhalothrin. Ultrastructural alterations recorded in Malpighian tubules at the level of plasma membrane, mitochondria and nucleus indicated the reduction of the detoxification capability. The basal phenoloxidase and lysozyme-like enzyme activities have measured as markers of immune competence. Spectrophometric analyses showed that the chronic exposure in field causes an increase of basal phenoloxidase enzyme activity, while the lytic activity of haemolymph was not affected. As a result, the use of larvicides and fungicides have a harmful effect on beneficial species such C. fuscipes living in the soil of potato fields. These morphological and physiological results recorded at the organismal level can provide useful information of effects at the population and community levels to preserve the biodiversity of agroecosystem.

Identification of sperm mRNA biomarkers associated with testis injury during preclinical testing of pharmaceutical compounds.

The human testis is sensitive to toxicant-induced injury but current methods for detecting adverse effects are limited, insensitive and unreliable. Animal studies use sensitive histopathological endpoints to assess toxicity, but require testicular tissue that is not available during human clinical trials. More sensitive and reliable molecular biomarkers of testicular injury are needed to better monitor testicular toxicity in both clinical and preclinical. Adult male Wistar Han rats were exposed for 4weeks to compounds previously associated with testicular injury, including cisplatin (0, 0.2, 0.3, or 0.4mg/kg/day), BI665915 (0, 20, 70, 100mg/kg/d), BI665636 (0, 20, 100mg/kg/d) or BI163538 (0, 70, 150, 300mg/kg/d) to evaluate reproductive toxicity and assess changes in sperm mRNA levels. None of the compounds resulted in any significant changes in body, testis or epididymis weights, nor were there decreases in testicular homogenization resistant spermatid head counts. Histopathological evaluation found that only BI665915 treatment caused any testicular effects, including minor germ cell loss and disorganization of the seminiferous tubule epithelium, and an increase in the number of retained spermatid heads. A custom PCR-array panel was used to assess induced changes in sperm mRNA. BI665915 treatment resulted in a significant increase in clusterin (Clu) levels and decreases in GTPase, IMAP family member 4 (Gimap4), prostaglandin D2 synthase (Ptgds) and transmembrane protein with EGF like and two follistatin like domains 1 (Tmeff1) levels. Correlation analysis between transcript levels and quantitative histopathological endpoints found a modest association between Clu with retained spermatid heads. These results demonstrate that sperm mRNA levels are sensitive molecular indicators of testicular injury that can potentially be translated into a clinical setting.

The Saccharomyces cerevisiae response to stress caused by the herbicidal active substance alachlor requires the iron regulon transcription factor Aft1p.

In the Saccharomyces cerevisiae eukaryotic model, the induction of the iron regulon genes ARN1, FIT2 and CTH2 by growth-inhibitory concentrations of alachlor (ALA) was dependent on Aft1p expression. This transcription factor was found to be activated through its nuclear localization. The hypersensitivity of the aft1Δ mutant to ALA was abrogated by surplus exogenous iron, suggesting that the role of Aft1p in ALA tolerance may be associated with iron limitation under ALA stress. A transient decrease in the cellular iron content in the ALA-stressed cells supported this idea. In contrast to the upregulation of the nonreductive iron uptake genes ARN1 and FIT2 by ALA, the quantity of FET3 and FTR1 transcripts encoding the high-affinity iron uptake reductive pathway decreased. Yeast cells were apparently more sensitive to ALA when iron uptake occurred through the reductive pathway than when the nonreductive uptake of ferrichrome-bound ferric iron was dominant. On the other hand, the ALA hypersensitivity of the aft1Δ mutant was reversed by medium supplementation with glutathione or N-acetyl-L-cysteine. The results are compatible with possible links between ALA toxicity and perturbations in metal and antioxidant homeostasis, which may be relevant for environmental microbes and higher eukaryotes in situations of inadvertent herbicide contamination.

A novel intravenous vehicle for preclinical cardiovascular screening of small molecule drug candidates in rat.

Screening novel, poorly soluble small-molecule candidates for cardiovascular liabilities represents a key challenge in early drug discovery. This report describes a novel vehicle composed of 20% N,N-Dimethylacetamide (DMA)/40% Propylene glycol (PG)/40% Polyethylene Glycol (PEG-400) (DPP) for administration of new chemical entities (NCEs) by slow intravenous (i.v.) infusion in a preclinical anesthetized rat model. The vehicle was designed considering both available excipient safety information and solubilization potential for poorly soluble NCEs. DPP solubilized 11 drugs, 8 of which were insoluble in 5% dextrose in water (D5W), and 5 insoluble in PEG-400 to a target concentration of 30mg/mL. DPP elicits no adverse cardiovascular responses in the anesthetized rat model despite containing 40% PEG-400, a commonly used organic solvent which elicits hypertension and bradycardia that often confounds interpretation of drug effects. Three compounds demonstrating adequate solubility in both DPP and D5W were screened in the anesthetized rat model. When normalized to plasma exposure, atenolol, sotalol and enalaprilat exhibited comparable mean arterial pressure, heart rate, and cardiac contractility responses regardless of formulation. While the antihypertensive effect of nifedipine was evident with both DPP and PEG-400 formulations, pressor effects from PEG-400 confounded interpretation of the magnitude of nifedipine's response. Plasma concentrations of atenolol and enalaprilat were greater in D5W formulation whereas sotalol exposures were greater when using DPP as a vehicle. These results demonstrate the utility of DPP as an intravenous vehicle for formulating poorly soluble compounds in early preclinical screening for cardiovascular safety studies.

Toward the discovery of dual HCMV-VZV inhibitors: Synthesis, structure activity relationship analysis, and cytotoxicity studies of long chained 2-uracil-3-yl-N-(4-phenoxyphenyl)acetamides.

The need for novel therapeutic options to fight herpesvirus infections still persists. Herein we report the design, synthesis and antiviral evaluation of a new family of non-nucleoside antivirals, derived from 1-[ω-(4-bromophenoxy)alkyl]uracil derivatives--previously reported inhibitors of human cytomegalovirus (HCMV). Introduction of the N-(4-phenoxyphenyl)acetamide side chain at N(3) increased their potency and widened activity spectrum. The most active compounds in the series exhibit submicromolar activity against different viral strains of HCMV and varicella zoster virus (VZV) replication in HEL cell cultures. Inactivity against other DNA and RNA viruses, including herpes simplex virus 1/2, points to a novel mechanism of antiviral action.

A novel function of sanshools: the alleviation of injury from metolachlor in rice seedlings.

Szechuan peppers are extensively used as a spice and in traditional medicine in Asia, primarily because of its active compounds, sanshools (S). However, there is only limited mention in agriculture, and there are no papers reporting its use as an herbicide safener. In this study, we provide the first evidence that S can effectively alleviate rice-seedling injury from metolachlor (M). We observed that the M-treated (0.25 µM) rice seedlings, which were 56.0%, 66.0%, and 57.0% of the non-treated control in shoot height, root length, and fresh biomass, respectively, were recovered by S to 93.1%, 97.6%, and 94.8%, respectively. The emergence rate was enhanced to over 80% in the M+S treatment, whereas it was below 60% in the M treatment. This M+S mixture elevated the rice-seedling root activity to higher than 87.0% of the value for the non-treated control. The activity of glutathione transferases in the combined treatments approximately doubles that of the M treatment and quadruples that of the non-treated controls. This effect was positively correlated with the induced expression of OsGSTU3. Our results suggest that S may represent a new group of safeners and enable the possibility of using these compounds for improving plant production or protecting rice from the phytotoxicity of metolachlor.

Toxicity of pesticides associated with potato production, including soil fumigants, to snapping turtle eggs (Chelydra serpentina).

Turtles frequently oviposit in soils associated with agriculture and, thus, may be exposed to pesticides or fertilizers. The toxicity of a pesticide regime that is used for potato production in Ontario on the survivorship of snapping turtle (Chelydra serpentina) eggs was evaluated. The following treatments were applied to clean soil: 1) a mixture of the pesticides chlorothalonil, S-metolachlor, metribuzin, and chlorpyrifos, and 2) the soil fumigant metam sodium. Turtle eggs were incubated in soil in outdoor plots in which these mixtures were applied at typical and higher field application rates, where the eggs were subject to ambient temperature and weather conditions. The pesticide mixture consisting of chlorothalonil, S-metolachlor, metribuzin, and chlorpyrifos did not affect survivorship, deformities, or body size at applications up to 10 times the typical field application rates. Hatching success ranged between 87% and 100% for these treatments. Metam sodium was applied at 0.1¯ times, 0.3¯ times, 1 times, and 3 times field application rates. Eggs exposed to any application of metam sodium had 100% mortality. At typical field application rates, the chemical regime associated with potato production does not appear to have any detrimental impacts on turtle egg development, except for the use of the soil fumigant metam sodium, which is highly toxic to turtle eggs at the lowest recommended application rate.

Responses of phytoplankton and Hyalella azteca to agrichemical mixtures in a constructed wetland mesocosm.

We assessed the capability of a constructed wetland to mitigate toxicity of a variety of possible mixtures, such as nutrients only (NO) (nitrogen [N], phosphorus [P]), pesticides only (PO) (atrazine, S-metolachlor, permethrin), and nutrients + pesticides on phytoplankton chlorophyll-a, on 48-h aqueous Hyalella azteca survival and 10-day sediment H. azteca survival and growth. Water and sediment were collected at 10-, 20-, and 40-m distances from inflow and analyzed for nutrients, pesticides, chlorophyll-a, and H. azteca laboratory bioassays. Phytoplankton chlorophyll-a increased 4- to 10 -fold at 7 days after NO treatment. However, responses of chlorophyll-a to PO and nutrients + pesticides were more complex with associated decreases at only 20 m for pesticides only and 10 and 40 m for nutrients + pesticides treatments. H. azteca aqueous survival decreased within the first 48 h of dosing at 10- and 20-m distances during PO and nutrients + pesticides treatments in association with permethrin concentrations. H. azteca sediment survival was unaffected, whereas 10-day growth decreased within 1 day of dosing at all sites during nutrients + pesticides treatment. Constructed wetlands were shown to be an effective agricultural best-management tool for trapping pollutants and mitigating ecological impacts of run-off in agricultural watersheds.

Toxicity of metalaxyl, azoxystrobin, dimethomorph, cymoxanil, zoxamide and mancozeb to Phytophthora infestans isolates from Serbia.

A study of the in vitro sensitivity of 12 isolates of Phytophthora infestans to metalaxyl, azoxystrobin, dimethomorph, cymoxanil, zoxamide and mancozeb, was conducted. The isolates derived from infected potato leaves collected at eight different localities in Serbia during 2005-2007. The widest range of EC(50) values for mycelial growth of the isolates was recorded for metalaxyl. They varied from 0.3 to 3.9 µg mL(-1) and were higher than those expected in a susceptible population of P. infestans. The EC(50) values of the isolates were 0.16-0.30 µg mL(-1) for dimethomorph, 0.27-0.57 µg mL(-1) for cymoxanil, 0.0026-0.0049 µg mL(-1) for zoxamide and 2.9-5.0 µg mL(-1) for mancozeb. The results indicated that according to effective concentration (EC(50)) the 12 isolates of P. infestans were sensitive to azoxystrobin (0.019-0.074 µg mL(-1)), and intermediate resistant to metalaxyl, dimethomorph and cymoxanil. According to resistance factor, all P. infestans isolates were sensitive to dimethomorph, cymoxanil, mancozeb and zoxamide, 58.3% of isolates were sensitive to azoxystrobin and 50% to metalaxyl. Gout's scale indicated that 41.7% isolates were moderately sensitive to azoxystrobin and 50% to metalaxyl.

Refinement of structural leads for centrally acting oxime reactivators of phosphylated cholinesterases.

We present a systematic structural optimization of uncharged but ionizable N-substituted 2-hydroxyiminoacetamido alkylamine reactivators of phosphylated human acetylcholinesterase (hAChE) intended to catalyze the hydrolysis of organophosphate (OP)-inhibited hAChE in the CNS. Starting with the initial lead oxime RS41A identified in our earlier study and extending to the azepine analog RS194B, reactivation rates for OP-hAChE conjugates formed by sarin, cyclosarin, VX, paraoxon, and tabun are enhanced severalfold in vitro. To analyze the mechanism of intrinsic reactivation of the OP-AChE conjugate and penetration of the blood-brain barrier, the pH dependence of the oxime and amine ionizing groups of the compounds and their nucleophilic potential were examined by UV-visible spectroscopy, (1)H NMR, and oximolysis rates for acetylthiocholine and phosphoester hydrolysis. Oximolysis rates were compared in solution and on AChE conjugates and analyzed in terms of the ionization states for reactivation of the OP-conjugated AChE. In addition, toxicity and pharmacokinetic studies in mice show significantly improved CNS penetration and retention for RS194B when compared with RS41A. The enhanced intrinsic reactivity against the OP-AChE target combined with favorable pharmacokinetic properties resulted in great improvement of antidotal properties of RS194B compared with RS41A and the standard peripherally active oxime, 2-pyridinealdoxime methiodide. Improvement was particularly noticeable when pretreatment of mice with RS194B before OP exposure was combined with RS194B reactivation therapy after the OP insult.

Effects of an antagonist of neurokinin receptors 1, 2 and 3 on reproductive hormones in male beagle dogs.

BACKGROUND: SCH 206272, a neurokinin 1, 2, and 3 receptor antagonist, administered to beagle dogs results in testicular toxicity. Therefore, a series of experiments were conducted to determine whether this observed toxicity was associated with changes in reproductive hormones and hypothalamic gonadotrophin releasing hormone (GnRH) levels. METHODS: Male beagle dogs were administered 30 mg/kg SCH 206272 for up to 7 days. Blood samples were collected at the end of the dosing period for reproductive hormone analysis. Male reproductive organs were stained with hematoxylin and eosin and the hypothalamus was stained for GnRH. RESULTS: Intact male dogs exhibited SCH 206272-related decreases in pulsatility and magnitude of luteinizing hormone (LH) and testosterone, which were associated with seminiferous tubule degeneration, oligospermia, and epithelial atrophy in the prostate gland. Neutered dogs also exhibited SCH 206272-related decreases in LH and FSH. In a subsequent reversibility study, intact male dogs exhibited decreased LH, testosterone, and FSH, which exhibited recovery by 2 weeks post-dosing; however, seminiferous tubule degeneration and oligospermia did not exhibit recovery by 2 weeks post-dosing. Dogs administered SCH 206272 also exhibited an increase in mean number of GnRH-containing neurons in the hypothalamus and an increase in GnRH mRNA/neuron, which exhibited recovery by 2 weeks post-dosing. CONCLUSIONS: SCH 206272-dosed dogs exhibited rapid decreases in reproductive hormones and subsequent testicular pathology. Collectively, these changes in hormone levels suggest that the observed SCH 206272-related reproductive tract findings are the result of alterations in hypothalamic-pituitary-gonadal function. However, a direct effect on the testes cannot be definitively ruled out.

Almorexant, a dual orexin receptor antagonist for the treatment of insomnia.

Almorexant (ACT-078573) is an orally active dual orexin receptor antagonist that is being developed by Actelion Ltd, in collaboration with GlaxoSmithKline plc, for the treatment of primary insomnia. Almorexant is a first-in-class compound that targets the orexin system, which plays a key role in wake promotion and stabilization, in addition to having other regulatory functions. Decreasing orexin activity was hypothesized to have a sleep-promoting effect. Preclinical studies and phase I clinical trials have demonstrated that almorexant decreases alertness and increases sleep in healthy rats, dogs and humans when administered during the active phase of the circadian cycle, at peak endogenous orexin tone. No significant toxicological or safety concerns have been identified in studies in animals and humans, including no evidence of cataplexy, a sudden postural muscle tone weakening that is triggered by emotional stimuli and is considered unique to narcolepsy. The reported efficacy and safety data for almorexant support the continued development of the compound. At the time of publication, phase III clinical trials were underway, but no results had been reported; Actelion and GlaxoSmithKline were also investigating almorexant for other orexin-related neurological disorders. The use of an orexin receptor antagonist for the treatment of sleep disorders appears to be an approach that may provide unique benefits.

Larval responses of three midwestern anurans to chronic, low-dose exposures of four herbicides.

Low levels of agricultural herbicides often contaminate surface water and might persist throughout the growing season, potentially acting as stressors on aquatic organisms. Although low-dose, chronic exposures to agrochemicals are likely common for many nontarget organisms, studies addressing these effects using end-use herbicide formulations are rare. We exposed three common species of tadpoles to conservative levels of atrazine, S-metolachlor, and glyphosate end-use herbicide formulations throughout the larval period to test for survival differences or life-history trait alterations. Exposure to the glyphosate product Roundup WeatherMax at 572 ppb glyphosate acid equivalents (a.e.) resulted in 80% mortality of western chorus frog tadpoles, likely as a result of a unique surfactant formulation. Exposure to WeatherMax or Roundup Original Max at 572 ppb a.e. also lengthened the larval period for American toads. Chronic atrazine and S-metolachlor exposures induced no significant negative effects on survival, mass at metamorphosis, or larval period length at the levels tested. These results highlight the importance of explicitly tying chronic tests to the natural environment and considering contributions of surfactant/adjuvant components to end-use formulation toxicities, even between very similar products.

A whole sample toxicity assessment to evaluate the sub-lethal toxicity of water and sediment elutriates from a lake exposed to diffuse pollution.

The impact of diffuse pollution in aquatic systems is of great concern due to the difficult to measure and regulate it. As part of an ecological risk assessment (ERA), this study aims to use a whole sample toxicity assessment to evaluate the toxicity of water and sediment from Lake Vela, a lake that has been exposed to diffuse pollution. In this way, standard (algae: Pseudokirchneriella subcapitata; cladoceran: Daphnia magna) and local species (algae: Aphanizomenon flos-aquae; cladoceran: Daphnia longispina) were exposed to surface water, and sediment elutriates were collected seasonally from two sites at Lake Vela: one near the east bank (ES), surrounded by agricultural lands; and the other near the west bank (WS), surrounded by a forest. The results confirmed the seasonal contamination of both environmental compartments by pesticides, including organochlorine pesticides, and the presence of high concentrations of nutrients. Although both sites were contaminated, higher levels of pesticides and nutrients were detected in ES, particularly in the sediments. Bioassays showed that water samples (100% concentration) collected in summer and autumn significantly affected the growth rate of P. subcapitata, which could be attributed to the presence of pesticides. Likewise, they revealed an apparent toxicity of elutriates for P. subcapitata and for both daphnids, in summer and autumn. In fact, although pesticides were not detected in elutriates, high levels of un-ionized ammonia were recorded, which is considered highly toxic to aquatic life. By comparing the several species, P. subcapitata was revealed to be the most sensitive one, followed by the daphnids, and then by A. flos-aquae. Results obtained in this study underlined the importance of whole samples toxicity assessment for characterizing the ecological effects of complex mixtures from diffuse inputs, in the ERA processes.

Agomelatine targets a range of major depressive disorder symptoms.

Servier, and US licensee Novartis AG, are developing the oral melatonin MT1 and MT2 agonist and 5-HT2B and 5-HT2C antagonist agomelatine as a once-daily treatment for major depressive disorder (MDD) and its symptoms, particularly anxiety, and sleep and circadian disturbances. Phase III trials have been completed and a registration dossier has been submitted to the EMEA in Western Europe.

Alachlor and carbaryl suppress lipopolysaccharide-induced iNOS expression by differentially inhibiting NF-kappaB activation.

Nitric oxide (NO) produced by macrophages plays an important role in host defense and inflammation. We found that two agrochemicals, alachlor and carbaryl, inhibit lipopolysaccharide (LPS)-induced NO production by macrophages. In the present study, we investigated this inhibitory mechanism in RAW 264 cells. Both chemicals inhibited LPS-induced iNOS protein and mRNA expression as well as murine iNOS promoter activity. When treating these chemicals with reducing agents, the inhibition by carbaryl was reversed, but not the inhibition by alachlor. These chemicals also inhibited LPS-induced interferon-beta (IFN-beta) expression, an indispensable factor for LPS-induced iNOS expression. The inhibited iNOS expression, however, was not restored by exogenous IFN-beta supplementation. LPS-induced nuclear translocation of NF-kappaB, which is necessary for the expression of IFN-beta and iNOS, was inhibited by these chemicals: however, the LPS-induced degradation of IkappaB-alpha and IkappaB-beta was inhibited only by alachlor. These results indicate that alachlor and carbaryl differentially impair the LPS-induced NF-kappaB activation, leading to the inhibition of NO production.

Comparison of two screening bioassays, based on the frog sciatic nerve and yeast cells, for the assessment of herbicide toxicity.

Two different test systems, one based on the isolated sciatic nerve of an amphibian and the other on a microbial eukaryote, were used for the assessment of herbicide toxicity. More specifically, we determined the deleterious effects of increasing concentrations of herbicides of different chemical classes (phenoxyacetic acids, triazines, and acetamides), and of 2,4-dichlorophenol (2,4-DCP), a degradation product of the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D), on electrophysiological parameters and the vitality of the axons of the isolated sciatic nerve of the frog (Rana ridibunda) and on the growth curve of the yeast Saccharomyces cerevisiae based on microtiter plate susceptibility assays. The no-observed-effect-concentration (NOEC), defined as the maximum concentration of the tested compound that has no effect on these biological parameters, was estimated. In spite of the different methodological approaches and biological systems compared, the NOEC values were identical and correlated with the lipophilicity of the tested compounds. The relative toxicity established here, 2,4-DCP > alachlor, metolachlor >> metribuzin > 2,4-D, 2-methyl-4-chlorophenoxyacetic acid (MCPA), correlates with the toxicity indexes reported in the literature for freshwater organisms. Based on these results, we suggest that the relatively simple, rapid, and low-cost test systems examined here may be of interest as alternative or complementary tests for toxicological assessment of herbicides.