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There is evidence of the presence of intercalated water between graphene and the substrate in electronic devices. However, a proper understanding of the impact of this phenomenon, which causes important limitations for the optimization of graphene-based devices operating in aqueous electrolytes, is missing. We used graphene-based electrodes on insulating and conducting substrates to evaluate the impact of intercalated water by combining experimental techniques with numerical simulations. Results show that the capacitance of the conductive substrate/graphene electrodes is significantly higher than that of the insulating substrate/graphene ones. Meanwhile, Raman spectroscopy demonstrates that graphene charge modulation with the applied potential is independent of the substrate conductivity. We found that this intriguing behavior is influenced by the water intercalation phenomena and governed by the substrate conductive nature. This work contributes to the understanding of the electric response of graphene-based devices in an aqueous environment and of the methods to measure and model it.

Objective: Our aim was to evaluate the effect of emigration on fetal birth weight (BW) in a group of pregnant women coming from the Indian subcontinent., Methods: This was a retrospective study in a mixed population of pregnant women from the Indian subcontinent that either moved to Europe or stayed in their original countries. The influence of emigration along with several pregnancy characteristics: GA at delivery, fetal gender, maternal age, height, weight, body mass index (BMI) and parity on BW was evaluated by means of multivariable linear regression analysis., Results: According to European standards, babies born to Indo-Pakistan emigrants and babies born to women staying in the Indian subcontinent were similarly small (BW centile 30± 29 and 30.1 ± 28, p <0.68). Multivariable regression demonstrated that emigration by itself did not exert a direct influence on BW ( p   = 0.27), being BMI and gestational age at delivery the true determinants of BW ( p <0.0001)., Conclusions: Maternal BMI is the most relevant parameter affecting fetal growth regardless of the place of residence., Competing Interests: Declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier Ltd.)

Nutrition during pregnancy is one of the most important factors that determine the health of a mother and the proper development of her fetus. The main objective of this study was to analyze the association between adherence to a Mediterranean dietary (MedDiet) pattern and cardiovascular (CV) risk factors in pregnant women. Accordingly, we carried out an observational, population-based study using data from pregnant women present in a hospital during the entire course of their pregnancy. Adherence to the MedDiet was assessed using the MedDiet score questionnaire. Our study identified that 87.25% (95%CI: 83.48-90.27) of the women had a cardiovascular risk in relation to their dietary intake. Women with diet-related CV risk were more likely to smoke ( p = 0.004), weighed more at the beginning of pregnancy, engaged in little physical activity, and had lower adherence to the MedDiet pattern than women without a diet-related CV risk. Dietary analysis showed low consumption of cereals, vegetables, and fish, which failed to satisfy the recommended portions in Spain. Adequate adherence to the MedDiet was found for 54.2% of women who were considered to be without CV risk and 45.8% of women with CV risk. Our data suggest that the MedDiet could be improved in relation to the consumption of cereals, vegetables, and fish during pregnancy in order to reduce CV risk.

Leukocytoclastic vasculitis (LCV) is a small vessel vasculitis characterized by an inflammatory infiltrate composed of neutrophils with fibrinoid necrosis and "leukocytoclasia", a term that refers to nuclei disintegration into fragments. LCV is related to multiple conditions including ANCA-associated vasculitis, cryoglobulinemia, IgA vasculitis, infectious and systemic diseases such as rheumatoid arthritis and systemic erythematous lupus (SLE) as well as infections and malignancy. We describe the clinical case of severe systemic vasculitis in a young male patient with secondary syphilis and HIV coinfection manifested by cutaneous and neurological involvement, as well as peripheral necrosis that requires bilateral lower limb amputation. The skin biopsy revealed histopathological changes compatible with endarteritis obliterans and LCV related to treponemal infection. This case highlights the plethora of clinical manifestations of treponemal infection and the diagnostic challenge this poses in current clinical practice.

Cizolirtine is a substance-P and calcitonin gene-related peptide release modulator developed for the treatment of pain and urinary incontinence. To assess its carcinogenic potential, cizolirtine was administered by oral route once daily for up to 104 weeks to CD-1 mice at doses of 40, 90, or 200 mg/kg/day, and to Han Wistar rats at doses of 40, 90 or 200 mg/kg/day to males and 40, 110 or 160 mg/kg/day to females. There were treatment-related neoplastic findings both in mice and rats. In mice, administration of cizolirtine was associated to an increase in skin fibrosarcomas and sarcomas among high-dose males, considered secondary to increased aggression and specific to the animal model. In rats, there was an increased incidence of liver adenomas in males and females, and carcinomas in males, in association with an increased incidence of hepatocyte hypertrophy, vacuolation and clear cell foci, and considered related to sustained long-term enzyme induction resulting in increased liver metabolism and associated hypertrophic changes. The observed neoplastic findings in mouse skin and rat liver after life-time oral administration of cizolirtine are considered related to rodent-specific non-genotoxic mechanisms of questionable relevance to man., (Copyright © 2022. Published by Elsevier Inc.)

Cizolirtine, a substance-P and calcitonin gene-related peptide release modulator developed for the treatment of pain and urinary incontinence, was orally administered for 26-weeks to rats at dosages of 20, 60 and 200 mg/kg/day. Clinical signs were limited to post-dosing salivation and brown staining on head and muzzle. There were slight decreases in bodyweight gain and slight increases in water consumption among cizolirtine-treated animals. Slight increases in plasma alkaline phosphatase activity, and cholesterol and phospholipid concentrations were observed in mid- and/or high-dose animals. Low urinary volume, pH and sodium and potassium outputs were observed after 12-weeks, and low urinary pH, low sodium and high potassium outputs at end of treatment. Increased relative (to bodyweight) liver weight was observed in high-dose animals. Treated males and high-dose females showed a dose-related increase in the incidence and severity of periacinar hepatocytic hypertrophy and midzonal/periacinar hepatocytic fat vacuolization. Increased incidences of hepatic clear cell foci were observed in all cizolirtine-treated male groups and, to a lesser extent, in treated females. Ovaries of treated females showed a dose-dependent increased incidence of absent corpora lutea and, occasionally, follicular cysts. The dosages of 20 and 60 mg/kg/day were considered as the No-Observed-Adverse-Effect Levels for males and females, respectively., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The analysis of the genotoxic potential of cizolirtine, a compound being developed as a drug for analgesia and for urinary incontinence, was carried out using a battery of in vitro and in vivo assays as recommended in the guidelines for medicinal products. Negative results were obtained in an Ames test (up to 5000 µg/plate), in a Mouse Lymphoma assay (up to 2000 µg/ml) and in a single dose mouse bone marrow micronucleus assay (up to 300 mg/kg). In a human lymphocyte chromosome aberration assay, a slight statistical increase in the frequency of cells with chromosome aberrations including gaps was reported for the concentrations of 200 and 1600 μg/ml at the 24-h sampling time. This minor increase in chromosome aberrations was considered of questionable biological relevance since it was moderate, was within the laboratory historical control values, did no show a dose-dependent effect and was not observed at similar concentrations in a repeat assay. Taking into considerations the results obtained in the different in vitro and in vivo assays and a weight-of-evidence analysis, it suggests that cizolirtine would not pose a genotoxic risk when administered to humans., Competing Interests: The authors were employees of Esteve Pharmaceuticals., (Thieme. All rights reserved.)

Since the last century, the air surface temperature has increased at a global scale, showing trends and inhomogeneities that vary from place to place. Many statistical methods can be used to analyze whether or not an inhomogeneity or break point exists in a meteorological data series, and even to detect the time of the break. Sometimes, there is no agreement in the year at which the inhomogeneity occurs detected by different tests. The scale invariance of a process can be studied through its multifractal properties that can be related to the existence of break points in it. In this work, the multifractal properties of monthly temperature data series are used to test what is the right break point year in those situations at which different dates are found by two different tests: the Pettitt and the Standard Normal Homogeneity tests. The comparison of the fractal dimension function D q and the multifractal spectrum obtained by the box counting method for both the original data sets and for those obtained by splitting the original into two considering the break point years was made. When different multifractal functions and parameters were obtained, a break point was confirmed. Whereas, if equal values appeared, the break point year was discarded. These results let to select the most suitable test to be applied to detect inhomogeneities in a certain data set that will be very useful for climate change studies.

Multifractal properties of diurnal temperature range (DTR) have been analyzed in this work, using validated data of maximum and minimum temperature from 197 weather stations in Southern Spain (Andalusia region). DTR is a crucial factor to characterize the regional climate, providing more information than the average daily temperature. Apart from climate change studies, one of the most important applications of DTR in Agrometeorology is as an input variable in the solar radiation or reference evapotranspiration estimation models based on the temperature. With the aim of obtaining a detailed information for different time scales, different multifractal approaches have been applied. Different quality control methods such as range/limits or persistence tests were previously applied in order to detect incorrect and anomalous values, being discarded in the subsequent analysis. The DTR scaling of moments has been analyzed and the moment scaling exponent function K(q) has been obtained, finding some differences between weather stations. In addition, multifractal dimension (D1) and multifractal degree (MD) were also estimated, revealing differences at coastal and inland locations that show heterogeneity across the region, including its multifractal nature and its invariance for a range of scales. The nonlinear characterization carried out in this work improves the understanding of DTR as an indicator of climate changes, and it can have a very positive impact on the calibration of regional models for estimating solar radiation or reference evapotranspiration based on the temperature. This multifractal characterization can be used to group stations with similar nonlinear dynamics, regardless of their geographical features, in such a way that more accurate coefficients than conventional ones are used.

Thermoelectricity (TE) is proving to be a promising way to harvest energy for small applications and to produce a new range of thermal sensors. Recently, several thermoelectric generators (TEGs) based on nanomaterials have been developed, outperforming the efficiencies of many previous bulk generators. Here, we presented the thermoelectric characterization at different temperatures (from 50 to 350 K) of the Si thin-film based on Phosphorous (n) and Boron (p) doped thermocouples that conform to a planar micro TEG. The thermocouples were defined through selective doping by ion implantation, using boron and phosphorous, on a 100 nm thin Si film. The thermal conductivity, the Seebeck coefficient, and the electrical resistivity of each Si thermocouple was experimentally determined using the in-built heater/sensor probes and the resulting values were refined with the aid of finite element modeling (FEM). The results showed a thermoelectric figure of merit for the Si thin films of z T = 0.0093, at room temperature, which was about 12% higher than the bulk Si. In addition, we tested the thermoelectric performance of the TEG by measuring its own figure of merit, yielding a result of ZT = 0.0046 at room temperature.

The replacement of acylamino by cyclic substituents in the position 4 of the pyrazolo[3,4- d ]pyrimidine scaffold, led to highly active sigma-1 receptor (σ 1 R) ligands. Phenyl or pyrazolyl groups were the best in terms of affinity for the σ 1 R and the 4-(1-methylpyrazol-5-yl) derivative, 12f , was the most selective. Compound 12f is also one of the best σ 1 R ligands ever described in terms of lipophilic ligand efficiency, which translates into a good physicochemical and ADMET profile. In addition, 12f was identified as an antagonist of the σ 1 R in view of its potent antinociceptive profile in several pain models in mice.

Multifractal properties of 30 min wind data series recorded at six locations in Cadiz (Southern Spain) have been studied in this work with the aim of obtaining detailed information for a range of time scales. Wind speed records have been validated, applying various quality control tests as a pre-requisite before their use, improving the reliability of the results due to the identification of incorrect values which have been discarded in the analysis. The scaling of the wind speed moments has been analysed and empirical moments scaling exponent functions K(q) have been obtained. Although the same critical moment (qcrit) has been obtained for all the places, some differences appear in other multifractal parameters like γmax and the value of K(0). These differences have been related to the presence of extreme events and zero data values in the data series analysed, respectively.

The optical constants of ion-beam-sputtered B₄C films have been measured by ellipsometry in the 190-950 nm range. The set of data has been extended toward both shorter and longer wavelengths with data in the literature, along with interpolations and extrapolations, in order to obtain a self-consistent set of data by means of Kramers-Krönig analysis. All data correspond to films that were deposited by sputtering on nonheated substrates, and hence they are expected to be amorphous. The B₄C bandgap was calculated as a fitting parameter of Tauc equations for indirect transitions using the present optical constants. Good global accuracy of the data was estimated through the use of various sum rules. The consistent data set includes the visible to the extreme UV (EUV); this large spectrum of characterization will enable the design of multilayer coatings that combine a relatively high reflectance in parts of the EUV with a desired performance at a secondary range, such as the visible.

The optical constants of ion-beam-sputtered SiC films have been measured by ellipsometry in the 190 to 950 nm range. The set of data has been extended both toward shorter and longer wavelengths with data in the literature, along with inter- and extrapolations, in order to obtain a self-consistent set of data by means of Kramers-Krönig analysis. All data correspond to films that were deposited by sputtering on nonheated substrates, and hence they are expected to be amorphous. A bandgap of 1.9 eV for the films was fitted from the obtained optical constants. A good global accuracy of the data was estimated through the use of various sum rules. The consistent dataset includes the visible to the extreme ultraviolet (EUV); this large spectrum of characterization will enable the design of multilayer coatings that combine a high reflectance in parts of the EUV with desired performance at a secondary range, such as the visible. To our knowledge, this paper provides the first compilation of the optical constants of amorphous SiC films.

Bladder cancer, in its advanced stage, has very few therapeutic strategies with proven efficacy. Platinum-combination chemotherapy can be considered a standard for first-line therapy, but after progression there is no standard therapy, and the prognosis is very poor. The development of targeted therapies in the last few years has significantly changed the prognosis of a wide variety of tumors. In bladder cancer, there is no targeted therapy currently approved for its use in advanced disease. There is evidence that Her-2 amplification and/or overexpression is seen in bladder cancer, and may influence prognosis. Anti-Her-2 drugs, such as trastuzumab or lapatinib, are under investigation in urothelial neoplasms, but there is no phase III trial that has evaluated their use in bladder cancer. We review the published evidence about Her-2 determination, its influence on bladder carcinoma prognosis, the clinical development of anti-Her-2-targeted therapies, and the possible future research directions involving this pathway in bladder cancer.

Complaints of loss of memory and lack of concentration have been reported by long-term survivors of breast cancer. This mild cognitive impairment (MCI), also called "chemobrain" or "chemofog," has been the subject of a number of studies in the last few years. This cognitive impairment, although usually mild, must be studied to define possible risk factors for its development, and for future research into a preventive or therapeutic treatment approach. Long-term survivors of breast cancer must be followed to detect possible treatment sequelae as soon as possible. Since the number of these long-term survivors has increased in the last years, in part because of more active adjuvant treatments, our knowledge about the long-term side effects of these therapies has also grown.

The antipsychotic sigma-1 (sigma(1)) receptor ligand E-5842 has been shown to increase micronucleated polychromatic erythrocyte (MNPCE) frequency in mouse bone marrow secondary to compound-induced hypothermia. Interaction with sigma(1) receptor has been considered a plausible contributing factor for E-5842-induced hypothermia, raising concern for a possible class effect of sigma receptor ligands in the mouse micronucleus (MN) test. We assessed the potential of E-5842 (200 mg/kg, oral) to produce hypothermic conditions associated with increased micronuclei formation in sigma(1) receptor knockout (sigma(1)R-KO) and wild type (WT) mice. After administration, animal's rectal temperature was recorded and peripheral blood and bone marrow samples were obtained (48 hr) and assessed for induction of micronucleated reticulocytes (MNRET) and MNPCE, respectively. E-5842 administration produced marked hypothermia both in sigma(1)R-KO and WT mice. Maximum decreases from preadministration temperature were 12.2 and 13.5 degrees C in sigma(1)R-KO and WT mice, respectively. Temperature returned to normal approximately 32 hr after administration. Bone marrow examination revealed a statistical significant increase (P < 0.05) in MNPCE frequency both in sigma(1)R-KO and WT animals. Examination of peripheral blood samples showed a slight, although nonstatistical significant, increase in MNRET frequency in sigma(1)R-KO mice. No similar effect was observed among WT animals. The results obtained after E-5842 administration to sigma(1)R-KO mice indicate that induction of hypothermic conditions associated with increased MNPCE formation is not mediated by compound interaction with sigma(1) receptor, ruling out concern for a possible class effect of similar high affinity sigma(1) receptor ligands in the mouse MN test.

Conditions of marked and long-lasting hypothermia have been shown to increase the formation of micronucleated polychromatic erythrocyte (MNPCE) in mouse bone-marrow. Stimulation of erythropoiesis as a consequence of anoxic conditions associated with decreased body temperature has been suggested as a possible mechanism for hypothermia-induced micronucleus formation. We examined whether chemically induced hypothermic conditions that produced increased MNPCE formation were associated with stimulation of erythropoiesis by measuring erythropoietin (EPO) concentrations in blood. Marked and long-lasting hypothermia was induced in male mice by oral administration of the antipsychotic compounds E-5842 (200 mg/kg) or chlorpromazine (100 mg/kg). Maximum decreases from the basal temperature, achieved 8 h after treatment, were 14.8 and 12.8 degrees C, respectively. A statistically significant increase in bone-marrow MNPCE frequency was observed 48 h after administration of E-5842 (p<0.01) or chlorpromazine (p<0.05). Mice made anaemic by retro-orbital bleeding (0.5 ml), which acted as positive control for stimulation of erythropoiesis, showed no relevant variation in mean rectal temperature and a slight non-statistically significant increase in MNPCE frequency after 48 h. Blood samples for determination of EPO levels were obtained 4 (bleed-control animals only), 8, 16 and 24 h after treatment. In spite of the induced hypothermia, no significant variation in EPO blood levels was observed after administration of E-5842 or chlorpromazine. Bleed-induced anaemic mice showed a clear increase in EPO blood levels at all sampled time points, differences from baseline values being statistically significant (p<0.001) at the 8-h samplings and beyond. These results indicate that induction of MNPCE secondary to chemically induced hypothermia is not mediated by stimulation of erythropoiesis.

Three structurally related phenyltetrahydropyridinyl butylazole (PTHPB)-derived drug candidates with sigma receptor-binding properties were evaluated for genotoxic potential in the ICH standard battery of genetic toxicology assays. These comprised an Ames test, a mouse-lymphoma assay, and a mouse bone-marrow micronucleus test. The maximum test concentrations in the in vitro assays were determined by the solubility and/or the cytotoxicity of the compounds. In the mouse micronucleus assay, the compounds were administered orally at three levels up to the maximum tolerated dose (MTD). Negative results were obtained for all three drug candidates in the Ames test and in the mouse-lymphoma assay, both in the absence or presence of metabolic activation. In the mouse micronucleus test, there was no effect on the frequency of micronucleated polychromatic erythrocytes (MNPCE) in bone marrow after oral administration of any of the three test compounds, at any dose level or sampling time (24 and 48h). Administration of all three compounds at the MTD induced a clear decrease in mouse body-temperature of 3.1-4.8 degrees C below normal; the temperature returned to normal within 8h of dose administration. The produced mild hypothermia and absence of micronucleus induction was in contrast to the induction of MNPCE secondary to marked hypothermia reported for a structurally similar PTHPB-derived sigma-receptor ligand, the antipsychotic compound E-5842. The results obtained in the current series of studies suggest that exposure to the three tested PTHPB-derived drug candidates would not pose a genotoxic risk under clinical conditions.

The genotoxic potential of the natural neurotoxin Tetrodotoxin (TTX) was evaluated in a battery of in vitro and in vivo genotoxicity assays. These comprised a bacterial reverse-mutation assay (Ames test), an in vitro human lymphocyte chromosome-aberration assay, an in vivo mouse bone-marrow micronucleus assay and an in vivo rat-liver UDS assay. Maximum test concentrations in in vitro assays were determined by the TTX limit of solubility in the formulation vehicle (0.02% acetic acid solution). In the Ames test, TTX was tested at concentrations of up to 200 microg/plate. In the chromosome-aberration assay human lymphocytes were exposed to TTX at concentrations of up to 50 microg/ml for 3 and 20 h in the absence of S9, and for 3h in the presence of S9. For the in vivo assays, maximum tested dose levels were determined by the acute lethal toxicity of TTX after subcutaneous administration. In the mouse micronucleus assay TTX dose levels of 2, 4 and 8 microg/kg were administered to male and female animals, and bone-marrow samples taken 24 and 48 h (high-dose animals only) after administration. In the UDS assay, male rats were given TTX on two occasions with a 14-h interval at dose levels of 2.4 and 8 microg/kg, the last dose being administered 2h before liver perfusion and hepatocyte culturing. Relevant vehicle and positive control cultures and animals were included in all assays. TTX was clearly shown to lack in vitro or in vivo genotoxic activity in the assays conducted in this study. The results suggest that administration of TTX as a therapeutic analgesic agent would not pose a genotoxic risk to patients.

The genotoxic potential of E-5842, a sigma ligand compound being developed as an antipsychotic drug, was evaluated by means of an extensive battery of in vitro and in vivo assays. Negative results were obtained in an Ames test (up to 5000 μg/plate), a mouse lymphoma assay (up to 535.1 μg/ml (-S9) and 891.8 μg/ml (+S9)), an in vivo rat hepatocyte micronucleus assay (up to 100 mg/kg/day on 2 days), and a two-dose mouse micronucleus assay (up to 40 mg/kg/day on 2 days). In a single-dose mouse bone-marrow micronucleus assay (up to 400 mg/kg; 24, 48 and 72 h sampling) a slight and non-statistically significant increase in the frequency of micronucleated polychromatic erythrocytes (MNPCE) was observed 48 h after administration of a 200 mg/kg dose, in the absence of bone-marrow toxicity. This minor increase in MNPCE frequency was considered of questionable biological relevance, because it was observed under conditions of marked animal toxicity including mortality. In addition, it occurred in association with a strong hypothermic effect produced by administration of E-5842. A clear increase in the frequency of structural chromosomal aberrations was observed in human lymphocytes at concentrations ≥350.6 and 1685.4 μg/ml in the presence and absence of S9, respectively. Mitotic accumulation was observed at those concentrations at which clastogenic effects were observed, a condition that may have masked toxicity. Concentrations lacking clastogenic effects in this chromosome aberration assay (300.7 and 173.2 μg/ml in the presence and absence of S9, respectively) were well in excess of maximum human plasma concentrations attained in clinical studies at the maximum tolerated dose (19.1 ng/ml). A weight-of-evidence analysis, taking into consideration the results obtained in the different in vitro and in vivo assays and the conditions of clinical use, suggest that E-5842 would not pose a genotoxic risk under clinical conditions.

Oral administration of E-5842, a new sigma1 receptor ligand being developed as an antipsychotic drug, to male mice at single doses of 50, 100, 200 and 400 mg/kg produced marked and sustained decreases in rectal temperature. Both the intensity and the duration of the hypothermic effect increased with dose. Maximum decreases from the mean pre-administration temperature (36.2 degrees C) ranged from 7.5 to 12.9 degrees C for animals receiving 50 and 400 mg/kg doses, respectively. Examination of bone-marrow smears obtained 24, 48 and 72 h after administration revealed a slight but statistically significant (p < 0.05) increase in the frequency of micronucleated polychromatic erythrocytes (MNPCE) at the 48 h sampling for animals receiving the 200 mg/kg dose. These animals showed decreases from pre-administration temperature of approximately 12 degrees C, with recovery being observed 24 h after administration. When the hypothermic effect of E-5842 administration was avoided by housing treated animals under conditions of increased environmental temperature (30 degrees C) for 24 h, MNPCE frequency reverted to vehicle control values. Further, in E-5842-treated animals with an increased MNPCE frequency there was a shift in the distribution of the relative areas of micronuclei in MNPCE towards higher values. In addition, there was a statistically significant increase (p < 0.001) in the number of relatively large micronuclei (micronucleus diameter > or = 1/4 cytoplasm diameter) similar to that produced by administration of the mitotic spindle inhibitor colchicine (1 mg/kg), suggesting disturbance of mitotic apparatus as the possible underlying mechanism. The results suggest that the slight increase in MNPCE frequency observed 48 h after administration of a 200 mg/kg dose of E-5842 is due to a hypothermic effect and not to a direct effect of E-5842 on DNA.

Embryotoxicity studies on irloxacin (6-fluorine-7-(pyrrol-1-yl)-1-ethyl-1,4-dihydro-4-oxo-quinolone-3-carboxylic acid, CAS-91524-15-1), a new fluoroquinolone antibacterial agent, were performed in rats and rabbits. Oral administration of irloxacin during the fetal period of organogenesis to pregnant rats and rabbits at dose levels of up to 1000 and 350 mg/kg/d, respectively, elicited no evidence of teratogenicity. During the first days of treatment, transient stasis in body weight increase was observed in rat dams receiving doses of 350 or 1000 mg/kg/d, and reduced food consumption was observed in those receiving 1000 mg/kg/d. Necropsy on day 20 of gestation showed dosage related increase in liver and kidney weights in all rat treated groups. Rabbit dams receiving 350 mg/kg/d showed during the first days of treatment decrease in body weight, and decreased food consumption and faecal output. Also, four females receiving 350 mg/kg/d aborted between days 18 and 20 of gestation. Rat fetuses in the 350 and 1000 mg/kg/d showed decreased body weight, and a decrease in placental weights was observed in the 1000 mg/kg/d group. No retardations or malformations were observed in rat or rabbit fetuses at any tested dose level. For maternal and embryo-fetal effects 100 and 150 mg/kg/d can be considered as the no-effect-level (NOEL) for rats and rabbits, respectively.

Four-week oral toxicity studies with cetefloxacin tosylate ((-)-7[3-(R)-amino-2-(S)-methyl-1-azetidinyl]-1-(2,4- difluorophenyl)-1,4-dihydro-6-fluoro-4-oxo-3-quinolinecarboxylic acid tosylate, CAS 141725-88-4 (base), E-4868.Ts) a new quinolone antibacterial agent, were performed in Sprague-Dawley rats and marmoset monkeys at doses of 100, 450, 2000 mg/kg/d and 25, 50, 125, 300 mg/kg/d, respectively. In rats, due to its toxicity the high dose was decreased to 1000 mg/kg/d after 3 days of treatment. Mortality was recorded among high dose rats receiving 2000 or 1000 mg/kg/d. Rats receiving dosages of 450 or 2000/1000 mg/kg/d showed less activated mandibular lymph nodes, cortical lymphocyte depletion of mandibular and/or mesenteric lymph nodes, atrophy of the white pulp of the spleen, cortical atrophy of thymus and thymic apoptosis. Enlarged caeca, increased water consumption and variations in plasma electrolyte levels were observed in animals receiving these dosages and in male rats receiving 100 mg/kg/d. Low neutrophil counts were observed in rats receiving dosages of 100 or 450 mg/kg/d, and increased alkaline phosphatase and alanine transaminase plasma levels and slightly decreased plasma protein levels in females receiving 450 or 2000/1000 mg/kg/d. Marmosets receiving dosages of 50 mg/kg/d and above displayed several clinical signs which included emesis, diarrhoea, ptosis, occasional episodes of under- and overactivity, and excessive scratching activity. Skin reddening was observed during the first week of treatment in marmosets receiving 300 mg/kg/d. On the basis of the results obtained it can be concluded that the non-toxic doses of E-4868. Ts after 4-week oral administration in rats and marmoset monkeys were 100 and 25 mg/kg/d, respectively.