Acute and subchronic toxicity studies of the new quinolone antibacterial agent irloxacin in rodents.

Irloxacin (6-fluorine-7-(pyrrol-1-yl)-1-ethyl-1, 4-dihydro-4-oxo-quinolone-3-carboxylic acid, CAS 91524-15-1), a new quinolone antibacterial agent, was administered as a single dose to rats and mice both by oral and intraperitoneal route in oder to study its acute toxicity. Its oral subchronic toxicity was also assessed by treating rats for 4 and 13 weeks. The results obtained showed that irloxacin was well tolerated after single administration in mice and rats, with LD50 values above 2000 and 5000 mg/kg for intraperitoneal and oral administration, respectively. In the oral subchronic toxicity studies, the histopathological examination performed after the 13-week treatment period confirmed the kidney as the target organ for toxicity. Increased presence of lipofuscin in the kidneys was observed in animals receiving 2000 or 450 mg/kg/d, and degeneration and/or dilatation of proximal renal tubules and chronic interstitial nephritis in males receiving these dosages. No histopathological findings were observed in the kidneys of animals receiving 100 mg/kg/d for 13 weeks. Other relevant findings were, presence of dark or cloudy urine with slightly lower pH in animals receiving dosages of 450 mg/kg/d and above, increased urinary protein concentration in animals receiving 2000 or 450 mg/kg/d, and increased plasma urea concentration in those receiving 2000 mg/kg/d. Moreover, increased plasma phospholipids and total cholesterol concentration, and increased liver and kidney weights were observed among treated animals. As a summary, the results have shown that irloxacin has a low acute toxicity in both mice and rats. For repeat oral administration in rats, 100 mg/kg can be considered as the non-toxic effect level after a treatment period of 13 weeks.     

Subchronic toxicity of the new quinolone antibacterial agent irloxacin in beagle dogs

The subchronic oral toxicity of the new quinolone antibacterial agent irloxacin (6-fluorine-7-(pyrrol-1-yl)-1-ethyl-1,4-dihydro-4-oxo-quinolone- 3-carboxylic acid, CAS 91524-15-1) in Beagle dogs was investigated in studies of 4 and 29 weeks of duration. In both studies animals received dosages of 10, 120 and 1400 mg/kg/d. Pale coloured faeces were seen on animals receiving 1400 mg/kg/d. Animals receiving 1400 mg/kg/d for 29 weeks showed an increased incidence of wax in the ears during the latter half of the treatment period, and one male and one female experienced transitory locomotive difficulties at the end of the first week of treatment. The liver was identified as the target organ for toxicity with presence of lipofuscin in the hepatocytes of animals receiving 120 or 1400 mg/kg/d for 29 weeks. Slight increases in liver weights were observed in animals receiving 120 or 1400 mg/kg/d for 4 weeks, and in all groups receiving irloxacin for 29 weeks. However, no histopathological findings were observed in the liver of animals receiving irloxacin for 4 weeks or those receiving 10 mg/kg/d for 29 weeks. Other relevant findings observed in the 29 week study were increased triglyceride, phospholipid and cholesterol levels in males receiving 120 mg/kg/d and animals receiving 1400 mg/kg/d, increased albumin and decreased beta-globulin concentrations in females receiving 1400 mg/kg/d, and prolonged activated partial thromboplastin time in animals receiving 1400 mg/kg/d. On the basis of the results obtained it is concluded that 10 mg/kg/d can be considered as the non-toxic dose after 29 week oral administration of irloxacin in dogs.     

Four-week oral toxicity studies of the new quinolone antibacterial agent cetefloxacin tosylate in rats and marmoset monkeys.

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.     

Developmental toxicity assessment of the new fluoroquinolone antibacterial DW-116 in rabbits

DW-116 is a newly developed fluoroquinolone antibacterial with a broad spectrum against both Gram-positive and Gram-negative bacteria. We have reported recently that DW-116 is embryotoxic and teratogenic in rats. The present study was conducted to investigate the teratogenicity of DW-116, together with maternal toxicity and developmental toxicity using New Zealand White rabbits. The test chemical was administered by gavage to pregnant rabbits from gestational day (GD) 6 through to GD 18 at dose levels of 0, 5, 19.5 and 76.1 mg kg(-1) day(-1). All does were subjected to caesarean section on day 28 of gestation and their foetuses were examined for external, visceral and skeletal abnormalities. In the 76.1 mg kg(-1) group, a minimal maternal toxicity, as evidenced by decreased body weight gain during treatment period, was observed in pregnant rabbits. Significant embryo-foetal toxicity, including increased number of foetal deaths and delayed foetal ossification, was seen. However, no treatment-related morphological changes were detected in foetal external, visceral and skeletal examinations. There were no adverse effects on either pregnant dams or embryo-foetal development at 19.5 and 5 mg kg(-1). It was concluded that administration of DW-116 during the major organogenetic period in rabbits produced decreased maternal body weight gain, increased number of foetal deaths and foetal developmental delay but no evidence of teratogenicity. The no-observed-adverse-effect levels (NOAELs) of DW-116 are considered to be 19.5 mg kg(-1) day(-1) for does and embryo-foetuses, respectively.     

Developmental toxicity studies of methyl ethyl ketoxime (MEKO) in rats and rabbits

The developmental toxicity of methyl ethyl ketoxime (MEKO), an industrial antioxidant used primarily as an antiskinning agent in alkyd paint, was investigated in rats and rabbits. Following preliminary dose range finding studies, groups of 25 pregnant rats or 18 pregnant rabbits were dosed by gavage with aqueous solutions of MEKO at 0, 60, 200, or 600 mg/kg (rats) or 0, 8, 14, 24, or 40 mg/kg (rabbits) on gestation days 6-15 or 6-18, respectively. In rats, dose-dependent clinical signs of maternal toxicity including reduced body weight gains were noted at 200 and 600 mg/kg. At 60 mg/kg and above enlarged spleens were observed at necropsy. The preliminary study found methemoglobin formation and reticulocytosis indicative of anemia at these dose levels. No treatment-related gestational effects, malformations or developmental variations were observed in the rats. In rabbits, 3 females aborted and 8 females were found dead at 40 mg/kg between gestation days 11 and 24. Clinical signs of maternal toxicity were present in surviving doses at this dose level. Body weight gains were reduced at 24 and 40 mg/kg. The preliminary study indicated maternal hematological effects in the rabbits similar to the rats at dose levels as low as 10 mg/kg. MEKO was not considered to have produced any treatment-related gestational effects, malformations or developmental variations in the rabbit at dose levels at or below 24 mg/kg. Because of excessive maternal mortality and abortions at the 40 mg/kg dose level, only 6 rabbits produced litters. The severe maternal toxicity and limited number of litters precluded a full assessment of developmental toxicity at 40 mg/kg. Nonetheless, MEKO did not appear to be teratogenic to the rabbit at this dose level.     

Developmental toxicity studies in rats and rabbits on 2,4-dichlorophenoxyacetic acid and its forms.

The potential for 2,4-D and its salts and esters to induce developmental toxicity was investigated in rats (8 studies) and rabbits (7 studies). Maternal toxicity associated with exposure was dependent on the dose level expressed as 2,4-D acid equivalents. The severity of the maternal effect was correlated to the 2,4-D acid-equivalent dose, with increasing dose levels that exceeded renal clearance causing increasingly more severe maternal effects. In both species, maternal body weight effects began to be manifested at dose levels of 30 mg 2,4-D acid equivalent/kg/day. At higher dose levels (50-75 mg/kg/day in rats and 75-90 mg/kg/day in rabbits), body weights and feed consumption were more severely affected. At dose levels > or =90 mg/kg/day in rats, clinical signs of toxicity (ataxia, muscular stiffness, and decreased motor activity) and mortality were noted. The no-observed-adverse-effect level (NOAEL) for maternal toxicity in both species across the family of 2,4-D salts and esters was approximately 10 mg/kg/day. Significantly decreased fetal body weights and increased fetal variations were seen in rats only at maternally toxic dose levels in excess of 90 mg/kg/day acid equivalent. At maternally toxic doses in rabbits, embryonal and fetal development were essentially unaffected. There were no effect on maternal reproductive measures such as litter size, resorption rates, or fetal body weights, and there was no evidence of teratogenic activity. In summary, equivalent toxicity of the salts and esters is consistent with rapid and complete metabolic conversion to 2,4-D acid. No adverse fetal effects were noted at dose levels that did not also produce evidence of maternal toxicity or exceed renal clearance of 2,4-D indicating that the developing rat and rabbit fetus were not uniquely sensitive to 2,4-D and its forms.     

Developmental (embryo-fetal toxicity/teratogenicity) toxicity studies of synthetic crystalline lycopene in rats and rabbits.

Synthetic crystalline lycopene is a nutritional supplement to increase dietary intake of lycopene, an antioxidant carotenoid. Its potential oral developmental toxicity was studied in rats and rabbits. Each study included 3 control groups (water and matrix for Lycopene 10 CWD or LycoVit 10%), 3 Lycopene 10 CWD groups [500, 1500 and 3000 (rats)/2000 (rabbits) mg/kg/day] and 1 LycoVit 10% group [3000 mg/kg/day (rats)/2000 (rabbits)]. The high dosages were at maximum achievable concentrations and dosage volumes (15 and 10 ml/kg for rats and rabbits, respectively) of the highly viscous test material suspensions. Dosages were administered on gestation days (GDs) 6 through 19 (rats) or GDs 6 through 28 (rabbits). Endpoints evaluated included viability, body weight, feed consumption, necropsy observations [GD 20 (rats)/GD 29 (rabbits)], uterine contents and fetal viability, gender, body weight and morphology (skeletons double-stained). Feed consumption and weight gain were essentially unaffected in rats and rabbits, despite intubation problems in both species and reduced gastrointestinal motility and mortality in rabbits attributable to the physical properties of the gels. Neither Lycopene 10 CWD nor LycoVit 10% caused direct maternal or developmental toxicity in rats or rabbits at dosages as high as 3000 or 2000 mg/kg/day, respectively.     

Developmental toxicity study of pure trans-capsaicin in rats and rabbits

Human environmental and dietary exposure to trans-capsaicin--the pungent ingredient in chili peppers--is ubiquitous. Moreover, based on the highly selective agonism of trans-capsaicin for TRPV1 receptors, drug products containing high concentrations of trans-capsaicin are under development as analgesics. For instance, a high-concentration (8% w/w) pure trans-capsaicin dermal patch (designated NGX-4010) is in advanced clinical evaluation for the management of neuropathic pain of peripheral origin. Our objective was to investigate effects of trans-capsaicin on embryo/fetal development, consequent to maternal exposure, from implantation to closure of the hard palate. trans-Capsaicin was delivered systemically by means of either a patch [NGX-4010 (25, 37.5, or 50 cm(2))] to pregnant Sprague-Dawley rats on days of presumed gestation (DGs) 7 through 17, or via a 10% w/v capsaicin liquid formulation (CLF), at dosages of 3, 6.5 or 13 mul/cm(2) applied to a 200-cm(2) area on the back on DGs 7 though 19 to timed-mated New Zealand white rabbits. In rats, the maternal no-observable-effect level (NOEL) was less than 25 cm(2) but no cesarean-sectioning or litter parameters were affected by application of NGX-4010 at patch sizes as high as 50 cm(2). The only test article-related observations were delays in skeletal ossification, evident as significant reductions in the average number of metatarsals and ossified hindlimb and forelimb phalanges that occurred in the 50 cm(2) NGX-4010 dose group. Although the values for ossified metatarsals were outside the historical control range, ossified hindlimb and forelimb phalanges were within historical control ranges. No other gross external, soft tissue, or skeletal fetal alterations (malformations or variations) were caused by application of the NGX-4010. In rabbits, the maternal NOEL was less than 3 mul/cm(2) CLF (or 0.3 mg/cm(2)trans-capsaicin) per 200 cm(2), but no cesarean-sectioning or litter parameters were affected. No fetal alterations (malformations or variations) were caused by dosages of CLF as high as 13 mul/cm(2) (or 1.3 mg/cm(2)trans-capsaicin). Taken together, these data suggest that tran s-capsaicin should not be considered a developmental toxicant.     

牛蒡子苷元对大鼠和家兔的胚胎-胎仔发育毒性研究

目的 以受精大鼠和家兔为实验系统,评价牛蒡子苷元对动物胚胎-胎仔发育的影响,为其药用价值的进一步开发提供参考。方法 100只受精雌鼠分为溶媒对照组和牛蒡子苷元高、中、低剂量（64、16、4 mg/kg）组,每组25只;72只受精雌兔分为溶媒对照组和牛蒡子苷元高、中、低剂量（25、10、4 mg/kg）组,每组18只。全部动物于妊娠第6天（GD6）开始给药,每天ip给药1次,大鼠连续给药至GD15,停药至GD20解剖检查,家兔连续给药至GD18,停药至GD29解剖检查。试验期间,每天观察动物一般状态,定期检测动物体质量和摄食量,解剖时计数卵巢黄体数量、检查着床数和活胎数,测量活胎顶臀长和尾长,检查活胎外观、内脏和骨骼。结果 给药期间,动物除给药方法导致的注射部位炎症反应外,其他未见异常体征变化;与溶媒对照组比较,牛蒡子苷元未引起大鼠和家兔体质量异常增长;母本动物受孕率、平均黄体数量和受精卵着床丢失率也未见异常改变;窝均活胎率、死胎率和吸收胎率,胎仔顶臀长和尾长也未见明显改变;也未见受试物导致的胎仔外观、内脏和骨骼畸形。结论 牛蒡子苷元未见潜在的大鼠和家兔胚胎-胎仔发育毒性。在本试验条件下,牛蒡子苷元大鼠和家兔胚胎-胎仔发育毒性的无明显损害作用剂量（NOAEL）分别为64和25 mg/kg。     

Developmental toxicity studies of four fragrances in rats

Four fragrances, 6-acetyl-1,1,2,4,4,7-hexamethyltetraline (AHTN), 1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethylcyclopenta-gamma-2-ben zopyran (HHCB), musk ketone and musk xylene were tested for developmental toxicity in Sprague-Dawley rats (25/group, 3 groups/fragrance, 2 fragrances/corn oil control). Dosages tested were HHCB: 50, 150, 500 mg/kg per day; AHTN: 5, 15, 50 mg/kg per day; musk ketone: 15, 45, 150 mg/kg per day; musk xylene: 20, 60, 200 mg/kg per day. All dosages tested exceeded multiples of the estimated maximal daily human dermal exposure. Treatment (gavage, 5 ml/kg) occurred on GDs 7-17 and Caesarean-sectioning on GD 20. Based on the results of these studies, none of the four fragrances tested were more toxic in the conceptuses than in the dams. Maternal NOAELs were 50, 5, 15 and 20 mg/kg per day for HHCB, AHTN, musk ketone and musk xylene, respectively (150, 50, 45 and 60 mg/kg per day caused clinical signs and reduced weight gain and feed consumption). Developmental NOAELs were 150, 50, 45 and 200 mg/kg per day for HHCB, AHTN, musk ketone and musk xylene, respectively. No adverse effects on embryo-fetal viability, growth or morphology occurred at the highest dosages of AHTN (50 mg/kg per day) or musk xylene (200 mg/kg per day). Developmental toxicity occurred at the high-dosages of HHCB (axial skeletal malformations at 500 mg/kg per day) and musk ketone (increased postimplantation loss and reduced fetal body weight at 150 mg/kg per day). The results of this study indicate that under conditions of normal use, the tested fragrances do not pose a risk to human conceptuses.     

Identification of influx transporter for the quinolone antibacterial agent levofloxacin

Quinolone antibacterial agents exhibit high intestinal absorption, selective tissue distribution, and renal and biliary excretion. Several ATP-binding cassette transporters are involved in efflux transport of these agents, but no influx transporters have yet been molecularly identified. In the present study, we aimed to identify the influx transporter(s) of quinolone antibiotics using levofloxacin as a model compound. Several candidate transporter genes were selected based on differential expression of mRNAs among Caco-2 cell subclones that exhibited differential uptake activities for levofloxacin. Based on a functional analysis of each transporter gene for which a good correlation was found between expression level and levofloxacin transport activity in the Caco-2 subclones, organic anion transporting polypeptide 1A2 (OATP1A2 (OATP-A), SLCO1A2) was concluded to transport levofloxacin. When OATP1A2 was expressed in Xenopus oocytes, levofloxacin transport was essentially pH-independent and was not stereoselective. OATP1A2-mediated uptake of levofloxacin showed a K(m) value of 136 microM. Apparent uptake of levofloxacin by Caco-2 cells showed high- and low-affinity components with K(m) values of 0.489 and 14.6 mM, respectively. Accordingly, plural transporters are functional for the transport of levofloxacin in Caco-2 cells, and OATP1A2 is likely to function as a high-affinity transporter. The inhibitory effects and the expression of transport activity of other quinolone antibacterial agents suggested that OATP1A2 commonly transports all the agents tested. In conclusion, this is the first identification of an influx transporter for fluoroquinolones, and the results suggest that active influx transport at least partially explains the high membrane permeability of the quinolone agents in various tissues.     

Developmental toxicity studies in rats and rabbits with 3,5,6-trichloro-2-pyridinol, the major metabolite of chlorpyrifos.

3,5,6-Trichloro-2-pyridinol (TCP), the primary metabolite of chlorpyrifos and chlorpyrifos-methyl, was evaluated for potential developmental toxicity. Groups of 32-34 bred female Fischer 344 rats were given 0, 50, 100, or 150 mg TCP/kg/day by gavage on gestation days 6-15; the fetuses were evaluated on gestation day 21. Similarly, groups of 16 inseminated female New Zealand White rabbits were given 0, 25, 100, or 250 mg TCP/kg/day by gavage on gestation days 7-19, and fetuses were evaluated on gestation day 28. No clinical signs of toxicity attributed to TCP were noted in either species. In rats, at 150 mg/kg/day, maternal effects included slight decreases in feed consumption, significantly depressed body weight gain (25% relative to controls) resulting in significantly lower maternal terminal body weights, and increased relative liver weight. At 100 mg/kg/day, maternal body weight gain in rats was depressed approximately 22%. Among rabbits, maternal effects were limited to the group given 250 mg/kg/day, which lost an average of approximately 70 g during the treatment period (vs. 140 g in the controls). There were no effects on fetal weight or viability, nor were there significant increases in any fetal alteration in either species. A slightly higher (not statistically significant) than usual incidence of central nervous system anomalies occurred in rabbits, but these anomalies were found in both treated and control groups in this study as well as contemporaneous studies of unrelated compounds. This, and the fact that these anomalies were not seen with the parent compound, chlorpyrifos, suggest that their origin was spontaneous. Thus, TCP was not considered fetotoxic or teratogenic in either rats or rabbits, even at dose levels that produced maternal toxicity.     

Developmental toxicity studies of 2-(difluoromethyl)-dl-ornithine (DFMO) in rats and rabbits.

DFMO, an irreversible inhibitor of ornithine decarboxylase (ODC), is under development as a chemopreventive drug against cancers with pronounced proliferative phases. In support of human clinical trials, preclinical developmental toxicity studies were conducted in pregnant rats and rabbits. Rats were treated during GD 6-17, and fetuses were obtained by C-section on GD 20. Rabbits were treated during GD 7-20, and fetuses were obtained by C-section on GD 29. The dose range-finding study in rats (5/group at 0, 50, 125, 300, 800, or 1000 mg/kg/day) revealed maternal toxicity at doses > or = 800 mg/kg/day (decreased body weights and food consumption) and developmental toxicity at doses > or = 300 mg/kg/day (increased early resorptions and reduced fetal body weights). In the main study, rats (25/group) received 0, 30, 80, or 200 mg/kg/day. Developmental toxicity in the absence of maternal toxicity was observed at 200 mg/kg/day as significantly decreased fetal weights and increased incidence of litters with skeletal variations of 14th rudimentary rib, 14th full rib, and/or 27th presacral vertebrae. There were no treatment-related fetal skeletal malformations or external or visceral anomalies at any dose level. The dose range-finding study in rabbits (5/group at 0, 30, 60, 120, 240, or 500 mg/kg/day) revealed developmental toxicity at doses > or = 60 mg/kg/day (increased resorptions and reduced fetal body weights) in the absence of maternal toxicity. In the main study, rabbits (20/group) received 0, 15, 45, or 135 mg/kg/day. Developmental toxicity in the absence of maternal toxicity was observed at 135 mg/kg/day as nonsignificantly increased early resorptions, decreased implantation sites, decreased viable fetuses, and reduced fetal weights. There were no external, visceral, or skeletal anomalies at any dose level. Thus, in the main developmental toxicity studies, DFMO produced developmental but not maternal toxicity at 200 and 135 mg/kg/day in rats and rabbits, respectively. Accordingly, in rats, the maternal no-observable-effect level (NOEL) was 200 mg/kg/day and the fetal NOEL was 80 mg/kg/day; while in rabbits the maternal NOEL was 135 mg/kg/day and the fetal NOEL was 45 mg/kg/day. These fetal NOELs are several-fold higher than the dose level currently used in Phase II and III clinical trials (approximately 13 mg/kg).     

Delafloxacin:一种新型喹诺酮类抗菌药物

2017年6月19日FDA首次批准Delafloxacin(DLX)上市,为临床医师治疗耐甲氧西林金黄色葡萄球菌(MRSA)及其他病原菌引起的急性细菌性皮肤和皮肤结构感染提供了一种新的选择。DLX是一种喹诺酮类广谱抗菌药物,临床研究显示,其在酸性环境中的抗菌效果更佳,无QT间期延长和光毒性,也没有显示对肝功能、肾功能和葡萄糖利用的不良影响。除与螯合剂外,几乎不与其他药物发生不良相互作用。本文就DLX的作用机制和抗菌活性、药动学、药效学、安全性和耐受性及在抗菌治疗中的前景进行综述。     

26-Week repeated oral dose toxicity study of the new quinolone antibacterial DW-116 in Sprague-Dawley rats.

The purpose of this study is to investigate the potential subchronic toxicity of DW-116 by a 26-week repeated oral dose in Sprague-Dawley rats. The test article, DW-116, was administered daily by gavage to male and female rats at dose levels of 0, 5, 25 and 125 mg/kg/day. At the end of the treatment period, 12 rats/sex/group were sacrificed, while six extra rats/sex in the vehicle control and highest dose groups were sacrificed after a 4-week recovery. During the test period, clinical signs, mortality, body weights, food and water consumption, ophthalmoscopy, urinalysis, hematology, serum biochemistry, gross findings, organ weights and histopathology were examined. There was no treatment-related mortality. An increase in the incidence of post-dosing salivation was observed in both sexes of the highest dose group. At the scheduled autopsy, an increase in the liver weight was observed in males of the highest dose group in a dose-dependent manner. Hematological investigations revealed a dose-dependent increase in the total white blood cell (WBC) and lymphocyte counts in males treated with the 125 mg/kg dose. Total bilirubin and alanine aminotransferase (ALT) values were also increased in males at the same dose. These effects were completely reversible during the recovery period. There were no adverse effects on body weight, food and water consumption, ophthalmoscopy, urinalysis, necropsy findings and histopathology in any treatment group. Based on these results, it was concluded that the 26-week repeated oral dose of DW-116 caused increases in the liver weight, WBC counts, total bilirubin and ALT values in males at a dose level of 125 mg/kg/day. The target organ was determined to be the liver and WBC in males, but not in females. The no-observed-adverse-effect level (NOAEL) was considered to be 25 mg/kg/day for males and 125 mg/kg/day for females.     

Developmental toxicity of diethanolamine applied cutaneously to CD rats and New Zealand White rabbits

Diethanolamine (DEA) was administered cutaneously to pregnant CD rats and New Zealand White rabbits during the periods of major organogenesis, Gestation Days 6-15 for rats and 6-18 for rabbits. Doses employed were 0, 150, 500, and 1500 mg/kg/day for rats and 0, 35, 100, and 350 mg/kg/day for rabbits. Rat dams exhibited reduced body weight at 1500 mg/kg/day, skin irritation and increased kidney weights at 500 and 1500 mg/kg/day, and a slight microcytic anemia with abnormal red blood cell morphology at all dose levels. Rat fetuses had increased incidences of six skeletal variations at 1500 mg/kg/day. Lower doses were without effect on the fetuses. Rabbit dams administered 350 mg/kg/day exhibited various skin lesions, reduced food consumption, and color changes in the kidneys but no hematological changes. Body weight gain was reduced at >/=100 mg/kg/day. There was no evidence of maternal toxicity at 35 mg/kg/day and no evidence of developmental toxicity in rabbits at any dose level. Developmental toxicity was observed only in the rat and only at doses causing significant maternal toxicity, including hematological effects. Due to a dose discrepancy, the no observable effect level (NOEL) for DEA developmental toxicity in rats was adjusted to 380 mg/kg/day. In rabbits, the embryonal/fetal NOEL was 350 mg/kg/day.     

新喹诺酮类抗菌药甲磺酸帕珠沙星

甲磺酸帕珠沙星是与左氧氟沙星(LVFX)同一母环系的10-(1-氨基环丙基)喹诺酮类药物.本品对葡萄球菌属的MIC90为3.13～25mg·L-1,其活性相当于或优于LVFX和环丙沙星(CPFX);对链球菌属和肠球菌属的MIC90为3.13～ 6.25mg·L-1,其活性除了对屎肠球菌优于LVFX外,其余均逊于LVFX和CPFX;对绝大多数G-菌的MIC90为0.013～ 6.25mg·L-1,其活性大体上与LVFX和CPFX相当.日本的临床研究表明,静注本品对呼吸道感染的总有效率为75.1%(181/241);对复杂性尿路感染的总有效率为78.7%(118/150);对外科感染的总有效率为81.8%(63/77).不良反应发生率为2.4%(13/532),主要是轻或中度的头疼、头晕、药疹、腹泻、胃部不适感等.     

Developmental toxicity of isomalt in rats

The sugar replacer isomalt, a 1:1 mixture of the disaccharides glucopyranosylsorbitol and glucopyranosylmannitol, was incorporated in the diet of rats. Female Bay FB:30 rats were adapted to isomalt by feeding them a diet containing a gradually increasing amount of isomalt for several days, prior to mating. Subsequently, they were mated. Isomalt was fed continuously in concentrations of 2.5, 5 and 10% up to day 20 of pregnancy. In addition, one group of female Wistar rats was mated and fed 10% isomalt incorporated in the diet from day 0 up to day 20 of pregnancy, without previous adaptation to isomalt. Finally, one group of untreated female Wistar rats served as controls. Half of the number of females in each group was selected for caesarian section on day 20 of pregnancy. The other half was allowed to litter and rear their pups for 2 weeks (Wistar rats) or 3 weeks (Bay FB:30 rats). In the females of the Bay FB:30 rats, a decreased body-weight gain and food consumption were observed in the 5 and 10% isomalt group. Minor retardation in the development of the foetuses was observed in the 10% isomalt group only with the Bay FB:30 rats and was therefore considered to be related to maternal toxicity. In addition, a dose-related increase in the incidence of wavy ribs occurred in foetuses of the Bay FB:30 rats. However, none of the observed effects were persistent in neonates. Isomalt appeared to have slight toxic effects in the dams of the Bay FB:30 strain but no toxicity in the offspring. In Wistar rats no toxicity and no effects on maternal performance or on embryonic, foetal or neonatal development were seen. Isomalt, when fed at dietary levels up to 10%, did not induce structural or functional teratogenic effects in rats of either the Wistar or the Bay FB:30 strain.