The teratogenicity of cadmium-metallothionein in the rat

A single dose in the range 0.25–1.0 mg metallothionein-bound cadmium (MT-Cd)/kg body weight, when administered parenterally to the rat between day 8 and day 14 of gestation (gd 8–gd 14), is teratogenic. In vitro, the development of the isolated rat conceptus, explanted at 8.5 days of gestation, is unaffected by the addition of 1.5 M MT-Cd to the culture medium, whereas the same concentration of ionic Cd (as CdCl₂) is lethal. The incorporation of appreciable amounts of Cd into the embryo (860 pg), placenta (970 pg) and yolk sac (65.4 ng) without toxic manifestations under the former conditions suggests that the metalloprotein is incorporated pinocytotically, but without degradation, by the conceptus in vitro. It does not follow, therefore, that MT-Cd is without embryo/foetotoxicity in the pregnant rat since, in vivo, liberation of some of the protein-bound Cd is known to occur in the blood. At short times after injection of 0.25 mg MT-Cd/kg body weight on gd 12, however, the maximal foetal and placental contents of Cd (<25 pg and 2 ng, respectively) are low in comparison with those after a teratogenic dose of CdCl₂ and are of the same order as those in the embryo (46 pg) and placenta (100 pg) + yolk sac (3.8 ng) of the rat conceptus, cultured in the presence of the highest no-effect concentration of CdCl₂ (0.065 M). From this evidence, therefore, it is concluded that the uptake by the conceptus in vivo of either CdMT, or of Cd liberated therefrom, is unlikely to contribute to the teratogenic response. In the pregnant, as in the non-pregnant rat, the kidney appears to be the only organ that is affected directly by the metallo-protein. All doses in the range 0.25–1.0 mg MT-Cd/kg body weight are nephrotoxic and, because of this, result in prolonged anorexia in the pregnant animal. While some of the foetal deformities that occur in the CdMT-dosed animal seem to be direct consequences of the renal dysfunction, others apparently are secondary to the maternal anorexia, since they are induced in pregnant, normal rats by appropriate reductions in food intake. In rats that are injected i.p. on gd 12 with 0.25 mg MT-Cd/kg body weight, renal uptake of Cd is slower, but the final concentration is higher than in animals that are given the same dose i.v. At this and the higher dose levels structural and/or functional damage to the kidneys also is greater in i.p.-, than in i.v.-dosed animals. The incidence of foetal malformations, however, is similar in the i.p. and i.v. groups and, irrespective of the route of administration, varies little over the dose range of 0.25–1.0 mg MT-Cd/kg body weight. The absence of clearly defined dose-response relationships suggests the possibility that limited damage to the maternal kidneys may be sufficient to interfere severely with the homeostasis of the conceptus.     

The effects of tricentric chromium(III) propionate complex supplementation on pregnancy outcome and maternal and foetal mineral status in rat

Chromium(III) is an essential element for carbohydrate and lipid metabolism, and various chemical forms of this element are widely used as dietary supplements. Of particular interest is [Cr₃O(O₂CCH₂CH₃)₆(H₂O)₃]⁺ cation (CrProp), that has been proposed as an alternative source of Cr. However, its safety has not been studied completely. In this study we investigated the effects of CrProp supplementation on pregnancy outcome and maternal and foetal mineral status in the rat. Female Wistar rats (n = 20, 14 weeks old) were mated with males and, after successful conception were fed either AIN-93G diet supplemented with CrProp (100 mg Cr/kg diet, equals to 7.2 mg Cr/kg body mass/day) or non-supplemented diet (0.27 mg Cr/kg diet, equals to 0.02 mg Cr/kg body mass/day) for 21 days. Dams were sacrificed on 21 day of gestation, and their foetuses were examined for adverse effects. Maternal and foetal organs were analysed for minerals contents (Fe, Cu, Zn, Cr) using the AAS-method. Supplemental Cr given did not affect pregnancy outcome, litter size, body and inner organ masses, maternal blood biochemical indices. No abnormalities in gross organ morphology of foetuses were detected. Supplemental CrProp increased maternal liver and kidney Cr levels by 177% and 455%, decreased liver Cu and Zn concentrations by 9% and 12%, increased foetal liver Zn by 181%, and decreased kidney Cu level by 34%.     

Differential action of KR‐31378, a novel potassium channel activator,on cardioprotective and hemodynamic effects

The cardioprotective and hemodynamic effects of KR‐31378, a highly cardioselective ATP‐sensitive potassium channel activator with minimal hypotensive effect, were evaluated in rats and dogs, and compared with those of BMS‐191095 and lemakalim. KR‐31378 did not show any significant effect on methoxamine‐induced aortic constriction up to doses of 300 μM, whereas BMS 191095 produced a moderately potent relaxant effect (IC₅₀: 9.0 μM). In conscious rats, KR‐31378 slightly increased blood pressure only at high dose (100 mg/kg, iv), unlike BMS‐191095 that dose‐dependently decreased blood pressure (ED₂₀: 2.03 mg/kg). In anesthetized beagle dogs, KR‐31378 was approximately 100‐fold less potent than BMS‐191095 for most hemodynamic parameters (iv ED₂₀ for blood pressure lowering: 33.7 and 0.37 mg/kg, respectively). In anesthetized rats subjected to 45‐min coronary occlusion and 90‐min reperfusion, KR‐31378 (iv) dose‐dependently reduced the infarct zone from 58.6% to 42.1%, 36.6%, and 34.3% for 0.1, 0.3, and 1.0 mg/kg, respectively (P < 0.05), the effects being comparable to those of BMS 191095. In anesthetized beagle dogs that underwent 2‐h occlusion followed by 4.5‐h reperfusion, KR‐31378 (2 mg/kg, iv infusion) markedly reduced the infarct zone from 48.7% in controls to 19.1% at a dose of 2 mg/kg (P < 0.05). The reduction in infarct zone afforded by KR‐31378 in rats was inhibited by pretreatment with selective ATP‐sensitive potassium channel blockers, sodium 5‐hydroxydecanoate and glibenclamide. These results indicate that KR‐31378 is a potent cardioprotective agent with potentially minimal hypotensive effects. Thus, it could be potentially useful in the prevention and treatment of acute myocardial infarction. Drug Dev. Res. 54:182–190, 2001. © 2002 Wiley‐Liss, Inc.     

Developmental Toxicity Evaluation of Acrylamide in Rats and Mice

Developmental Toxicity Evaluation of Acrylamide in Rats andMice. FIELD, E. A., PRICE, C. J., SLEET, R. B., MARR, M. C,MORRISSEY, R. E., AND SCHWETZ, B. A. (1990). Fundam. Appl. Toxicol.14, 502–512. Acrylamide (ACRL), a widely used industrialchemical with neurotoxic effects, was evaluated for developmentaltoxicity. ACRL in distilled water was administered once dailyby gavage on gestational days (gd) 6–17 to mice (0, 3,15, or 45 mg/kg) and on gd 6–20 to rats (0, 2.5, 7.5,or 15 mg/kg). Following termination (gd 17, mice; gd 20, rats)fetuses were examined for external, visceral, and skeletal malformations.Maternal toxicity during treatment was observed at the highestdose as reduced body weight gain in both species and hindlimbsplaying in treated mice only. Weight gain corrected for graviduterine weight was also reduced in rats at 7.5 and 15 mg/kg/day.Embryo/fetal toxicity was not observed in rats, but fetal weightwas reduced in mice administered 45 mg/kg/day. No increase inthe incidence of malformations was observed in either species;however, the incidence of variations (predominately extra rib)increased with dose. In summary, administration of ACRL duringorganogene-sis produced maternal and developmental toxicityat 45 mg/kg/day in mice and maternal, but not developmental,toxicity at doses 7.5 mg/kg/day in rats.     

Treatment of life-threatening H2S intoxication: Lessons from the trapping agent tetranitrocobinamide

We sought to evaluate the efficacy of trapping free hydrogen sulfide (H₂S) following severe H₂S intoxication. Sodium hydrosulfide solution (NaHS, 20 mg/kg) was administered intraperitoneally in 69 freely moving rats. In a first group (protocol 1), 40 rats were randomly assigned to receive saline (n = 20) or the cobalt compound tetranitrocobinamide (TNCbi) (n = 20, 75 mg/kg iv), one minute into coma, when free H₂S was still present in the blood. A second group of 27 rats received TNCbi or saline, following epinephrine, 5 min into coma, when the concentration of free H₂S has drastically decreased in the blood. In protocol 1, TNCbi significantly increased immediate survival (65 vs 20 %, p < 0.01) while in protocol 2, administration of TNCbi led to the same outcome as untreated animals. We hypothesize that the decreased efficacy of TNCbi with time likely reflects the rapid spontaneous disappearance of the pool of free H₂S in the blood following H₂S exposure.     

Developmental Toxicity Study with N-Methyldiethanolamine by Repeated Cutaneous Application to CD Rats

Abstract

Timed pregnant CD rats were dosed cutaneously with aqueous N-methyldiethanolamine (MDEA) daily from gestational day (gd) 6 to 15, inclusive. Dosages employed were 0, 250, 500, and 1000 mg/kg/day and were selected on the basis of maternal toxicity responses determined from a range-finding study. Observations for maternal toxicity included body weight, food consumption, and clinical signs. Prior to scheduled necropsy on gd 21, blood was obtained for hematological study. At necropsy, liver and kidney, which are putative target organs of ethanolamine toxicity, were weighed. Fetuses were evaluated for body weight, and for external, visceral, and skeletal anomalies. Severe skin irritation characterized by necrosis, ecchymoses, exfoliation, crusting, excoriation, erythema, and edema was noted in dams receiving 1000 mg/kg/day during the dosing period. Exfoliation, crusting, necrosis, and erythema persisted subsequent to the dosing period, but by sacrifice on gd 21, substantial repair of the dosing site had occurred. In dams receiving 500 mg/kg/day less severe skin irritation was noted, but no local irritation was seen at the dosage of 250 mg/kg/day. There were no effects on maternal body weight; gestational weight gain; food consumption; or liver, kidney, or gravid uterine weights at any of the MDEA-dosed groups. Dams from the 1000 mg/kg/day group had decreases in erythrocyte count, hemoglobin, and hematocrit. There were no effects on any gestational parameters, and no increases in the total number of malformations or variations (external, visceral, or skeletal) by category or individually. In conclusion, rat dams showed dose-dependent skin irritation following repeated cutaneous application of MDEA during pregnancy. In addition, maternal toxicity was also present as anemia in dams receiving 1000 mg/kg/day. Despite maternal toxicity, there was no evidence of developmental effects. The no-observed-adverse effect level was 250 mg/kg/day for maternal toxicity, and at or above 1000 mg/kg/day for embryofetal toxicity and teratogenicity.     

Investigation of maternal and fetal exposure to an IgG2 monoclonal antibody following biweekly intravaginal administration to cynomolgus monkeys throughout pregnancy

To assess the potential for male-mediated drug transfer to their female partner and/or developing conceptus, vaginal uptake of a monoclonal antibody (mAb) biotherapeutic was assessed in cynomolgus monkeys. A human IgG2 mAb (IgG2X; bound human and cynomolgus monkey neonatal Fc-receptor, FcRn, with similar high affinity) was administered intravaginally (IvG; 100 mg/dose) to 5 pregnant cynomolgus monkeys biweekly from gestation day (gd) 21 to gd133. In all maternal samples collected before gd119, IgG2X plasma concentrations were below the limit of quantification (BLQ; <25 ng/mL). After dosing on gd119 and 133, maternal IgG2X plasma concentrations remained BLQ in 3/5 monkeys and were very low in 2/5 (up to 116 ng/mL; ∼0.01% of the IvG dose). IgG2X was BLQ in all fetal plasma samples. These data indicate that male-mediated mAb drug transfer via seminal fluid does not present a health risk to the female partner and is not bioavailable to the developing conceptus.     

Teratologic and postnatal evaluation of aniline hydrochloride in the Fischer 344 rat

Timed-pregnant Fischer 344 rats were dosed by gavage with aniline hydrochloride (10, 30, or 100 mg/kg/day), a positive control agent (hydroxyurea, 200 mg/kg/day), or vehicle (distilled water) on gestational days (gd) 7 through 20 or gd 7 through parturition. At termination on gd 20 confirmed-pregnant dams exhibited characteristic signs of aniline HCl toxicity, i.e., methemoglobinemia, increased relative spleen weight, decreased red blood cell (RBC) count, and hematological changes indicative of increased hematopoietic activity. High-dose dams exhibited mild methemoglobinemia, increased relative spleen weight, and increased RBC size at termination on postnatal day (pnd) 30. At termination on gd 20, fetuses from aniline-treated dams exhibited increased relative liver weight and enhanced hematopoietic activity, but no evidence of an embryolethal or teratogenic effect was observed. Postnatal signs of toxicity in litters from aniline-treated dams (i.e., decreased body weight, elevated relative liver weight, and elevated relative spleen weight) were transient, and no evidence of toxicity was observed in pups surviving to pnd 60. Hydroxyurea (200 mg/kg/day) administered by gavage proved to be an excellent positive control for embryotoxicity, maternal toxicity, teratogenicity, and postnatal maturational deficits in the Fischer 344 rat. In conclusion, aniline hydrochloride was not teratogenic to Fischer 344 rats, even at maternally toxic doses; transient signs of toxicity were observed postnatally in the offspring in conjunction with mild, but persistent signs of maternal toxicity through pnd 30.     

Maternal and developmental toxicity evaluation of melatonin administered orally to pregnant Sprague-Dawley rats.

Melatonin (MEL) is a widely used, over-the-counter sleep aid, and it has putative contraceptive, antioxidant, antiaging, and anticancer effects. The developmental toxicity potential for repeated oral doses of MEL had not previously been evaluated. In the present studies, time-mated, Sprague-Dawley-derived (CD) rats were administered MEL or vehicle by gavage on gestation days (gd) 6-19. MEL-treated groups received 1-, 10-, 100-, 150-, or 200-mg/kg body weight/day in the screening study (15 rats/group), and 50, 100, or 200 mg/kg/day in the definitive study (25 rats/group). In both studies, maternal food/water consumption, body weight, and clinical signs were monitored at regular intervals throughout gestation. At termination (gd 20, both studies), maternal liver and gravid uterine weights, number of ovarian corpora lutea, conceptus survival, fetal sex, and fetal body weight were evaluated. Fetal morphological examination included external structures (both studies) as well as visceral and skeletal structures (definitive study). In the screening study, maternal serum levels of 17beta-estradiol, progesterone, prolactin, and luteinizing hormone were determined by radioimmunoassay, and mammary tissue was fixed, stained, and evaluated for percent glandular area within the fat pad. No maternal morbidity/mortality was found in either study. In the screening study, aversion to treatment (> or =100 mg/kg/day) and reduced maternal weight gain (> or =150 mg/kg/day) were noted, but reproductive/endocrine parameters and fetal development were not affected. In the definitive study, aversion to treatment was noted at > or =50 mg/kg/day, and mild sedation, reduced maternal food intake, and reduced body weight gain were found during initial treatment with 200 mg/kg/day. MEL had no effect on prenatal survival, fetal body weight, or incidences of fetal malformations/variations. Thus, in the definitive study, the maternal toxicity NOAEL and LOAEL were 100 and 200 mg/kg/day, respectively, and the developmental toxicity NOAEL was > or =200 mg/kg/day.     

Evaluation of the developmental toxicity of formamide in Sprague-Dawley (CD) rats.

Timed-pregnant CD(R) outbred albino Sprague-Dawley rats received formamide (50, 100, or 200 mg/kg/day) or vehicle (5 ml/kg deionized/distilled water, po) on gestational days (gd) 6 through 19. Maternal food and water consumption (absolute and relative), body weight, and clinical signs were monitored at regular intervals throughout gestation. At termination (gd 20), confirmed-pregnant females (21-23 per group) were evaluated for clinical status and gestational outcome; live fetuses were examined for external, visceral, and skeletal malformations and variations. There were no maternal deaths and no dose-related clinical signs. At 200 mg/kg/day, maternal body weight on gd 20, weight gain, and gravid uterine weight were significantly decreased. Maternal weight gain, corrected for gravid uterine weight, liver weight (absolute or relative), and food and water consumption (absolute or relative), were not affected. Formamide did not affect prenatal viability or incidences of fetal malformations or variations. Average fetal body weight/litter was decreased at 100 and 200 mg/kg/day. Fetal body weight was affected at lower daily doses than in previously published studies, possibly due to the longer total exposure period and/or lack of a recovery period between cessation of exposure and termination. In summary, the maternal toxicity no-observed-adverse-effect level (NOAEL) was 100 mg/kg/day and the low observed adverse effect level (LOAEL) was 200 mg/kg/day under the conditions of this study. Similarly, the developmental toxicity NOAEL was 50 mg/kg/day and the LOAEL was 100 mg/kg/day.     

The toxic effects of nickel chloride on liver,erythropoiesis, and development in Wistar albino preimplanted rats can be reversed with selenium pretreatment

The exposure to nickel chloride (NiCl₂) can cause hematotoxicity and hepatotoxicity and canaffect development. The present study pertains to the protective effect of selenium (Se) against NiCl₂‐induced toxicity in preimplanted Wistar albino rats. The subcutaneous (s.c.) administration of 25 or 50 mg/kg of NiCl₂ to Wistar albino rats on day 3 of gestation induced an immediate and significant decrease in maternal body weight and anemia 2 days after treatment. In addition, an increase in plasma aspartate aminotransferase (AST) was observed. These effects were maintained on day 20 of gestation. Moreover, a significant increase in plasma alanine aminotransferase (ALT) levels was observed with the administration of 25 mg/kg of NiCl₂. Conversely, administration of 50 mg/kg of NiCl₂ by s.c. injection increased erythropoiesis at day 20 of gestation and decreased platelets counts. In addition, administration of 100 mg/kg of NiCl₂ markedly reduced the maternal body weight and number of live fetuses and increased fetal loss, predominantly at the end of the experimental period. All dose levels of NiCl₂ caused an alteration in the hepatic histoarchitecture. When 0.3‐mg/kg Se was injected s.c. with 100‐mg/kg NiCl₂, the levels of plasma AST and ALT and the structure of the liver were restored. Administration of 20 mg/L/day of NiCl₂ in the drinking water significantly reduced the maternal body weight at day five of gestation as well as erythropoiesis during the exposure period. The present study suggests that Se can counteract the nocuous effect of nickel on the liver; however this antioxidant did not prevent alterations in development and erythropoiesis. © 2011 Wiley Periodicals, Inc. Environ Toxicol 2013.     

复方丹参对动物耐缺氧和心脏血流动力学的研究

腹腔注射复方丹参20 g/kg,可显著延长小鼠在常压缺氧情况下的存活时间,作用持续时间达3小时以上。腹腔注射10～20 g/kg,可显著延长小鼠在低压缺氧条件下的存活时间和提高存活率。腹腔注射5 g/kg,也能显著延长大鼠在低压缺氧的存活时间。胍乙啶的初和晚时相,均可降低小鼠对低压缺氧的耐受力,而复方丹参只能提高晚时相所降低的耐缺氧能力。腹腔注射复方丹参30 g/kg,显著延长常压缺氧的存活时间和减慢小鼠氧耗速率,死亡时余存氧含量亦较对照组显著减低,表明复方丹参可能是提高小鼠在低氧状态下对氧的利用。复方丹参浓度为10 mg/ml,显著增加离体豚鼠心脏的冠脉流量,但不增加颤动心脏的冠脉流量。静注复方丹参4g/kg,不增加大鼠心肌摄取~(86)Rb率,表明不增加心肌血流量。麻醉开胸狗,静注复方丹参1 g/kg,对冠脉流量和冠脉阻力无明显作用。麻醉狗静注复方丹参0.75 g/kg,对心脏血流动力作用也无明显影响。     

Amelioration of hyperglycaemia and modulation of antioxidant status by Alcea rosea seeds in alloxan-induced diabetic rats

Context: Alcea rosea L. (Malvaceae) has various medicinal uses including anticancer, anti-inflammatory and analgesic properties. However, there is no report on its antidiabetic activity.

Objective: Alcea rosea seed extracts were evaluated for antihyperglycaemic and antioxidative potential in diabetic rats.

Materials and methods: Single intra-peritoneal injection of alloxan (130?mg/kg b.w.) was used for induction of diabetes in Albino Wistar rats. Antihyperglycaemic and antioxidant activities of methanol and aqueous extracts of Alcea rosea seed (100 and 300?mg/kg b.w.), administered orally on daily basis for 15 days, were assessed in vivo for fasting blood glucose level and antioxidant status of liver and pancreas. Metformin was used as a positive control.

Results: Aqueous and methanol extracts (300?mg/kg b.w.) decreased blood glucose level in diabetic rats by 24% and 46%, respectively. Administration of aqueous and methanol extracts at 300?mg/kg b.w. significantly (p?2O₂ decomposed/min/mg of protein), respectively. Similar results were observed for pancreas.

Discussion and conclusions: Antihyperglycaemic and antioxidative potentials of Alcea rosea seeds suggest its usefulness in management of diabetes and its complications. This is the first report on antidiabetic activity of this plant.     

Developmental Phase Specificity and Dose–Response Effects of 2-Methoxyethanol in Rats

Methoxyethanol (ME) produces embryotoxic effects in rodents, rabbits, and nonhuman primates. Mechanistic evaluations of ME dysmorphogenesis have focused mainly on developmental insults and chemical disposition in the mouse. These assessments in mice were based on developmental phase specificity (DPS) and dose–response relationship (DRR) of ME. DPS and DRR indicated treatments for selectively inducing defects to study ME disposition and expressed dysmorphogenesis. This study was conducted to establish DPS and DRR of ME in the rat. DPS was determined by injecting 500 mg ME/kg (6.6 mmol/kg) into the tail vein on Gestational Day (gd; sperm-positive day = gd 0) 10, 11, 12, 13, 14, or 15 (n= 6 dams/gd; saline controls on gd 12). On gd 20, embryolethality incidence was 100% after gd 10 dosing; at gd 11 through 15, it was 50, 32, 15, 2, and 5%, respectively (control, 2%). Incidences of external defects in live fetuses exposed on gd 11–15 were 97, 98, 100, 44, and 0% and those of viscera were 100, 62, 44, 10, and 0%, respectively. The predominant anomalies observed were ectrodactyly and renal agenesis. DRR was determined on gd 13, when live embryos/litter and external malformations (ectro- and syndactyly, micromelia) were maximal. Dams (n= 8/dose group) were injected intravenously with 0, 100, 250, 350, or 500 mg ME/kg. On gd 20, fetal defect rates were 0, 0, 82.5, 83.0, and 100% at these concentrations, respectively. Based on these studies, appropriate ME doses, times of maternal exposure, and critical phases of development in the rat model are available for reproducing selective defects to investigate biochemical and pharmacokinetic determinants underlying their expression.     

Developmental Phase Specificity and Dose-Response Effects of 2-Methoxyethanol in Rats

Methoxyethanol (ME) produces embryotoxic effects in rodents,rabbits, and nonhuman primates. Mechanistic evaluations of MEdysmorphogenesis have focused mainly on developmental insultsand chemical disposition in the mouse. These assessments inmice were based on developmental phase specificity (DPS) anddose response relationship (DRR) of ME. DPS and DRR indicatedtreatments for selectively inducing defects to study ME dispositionand expressed dysmorphogenesis. This study was conducted toestablish DPS and DRR of ME in the rat. DPS was determined byinjecting 500 mg ME/kg (6.6 mmol/kg) into the tail vein on GestationalDay (gd; sperm-positive day = gd 0) 10, 11, 12, 13, 14, or 15(n=6 dams/gd; saline controls on gd 12). On gd 20, embryolethalityincidence was 100% after gd 10 dosing; at gd 11 through 15,it was 50, 32, 15, 2, and 5%, respectively (control, 2%). Incidencesof external defects in live fetuses exposed on gd 11–15were 97, 98, 100, 44, and 0% and those of viscera were 100,62, 44, 10, and 0%, respectively. The predominant anomaliesobserved were ectrodactyly and renal agenesis. DRR was determinedon gd 13, when live embryos/litter and external malformations(ectro and syndactyly, micromelia) were maximal. Dams (n=8/dosegroup) were injected intravenously with 0, 100, 250, 350, or500 mg ME/kg. On gd 20, fetal defect rates were 0, 0, 82.5,83.0, and 100% at these concentrations, respectively. Basedon these studies, appropriate ME doses, times of maternal exposure,and critical phases of development in the rat model are availablefor reproducing selective defects to investigate biochemicaland pharmacokinetic determinants underlying their expression.     

Developmental Toxicity of Dinitroaniline Herbicides in Rats and Rabbits

The potential developmental toxicity of trifluralin was evaluatedin rats and rabbits. Pregnant rats and rabbits were dosed oncedaily by gavage on Gestation Days 6–15 and 6–18,respectively. Doses for rats were 0, 100, 225, 475, or 1000mg/kg; doses for rabbits were 0, 100, 225, or 500 mg/kg. Cesareansections were performed on rats and rabbits on Gestation Days20 and 28, respectively. In rats, maternal toxicity was indicatedin the 475 and 1000 mg/kg treatment groups by depression ofbody weights and food consumption. Fetal viability and morphologywere not adversely affected at any dose level. Developmentaltoxicity was indicated at the 1000-mg/kg dose level by depressionof fetal weight. The NOAEL for maternal toxicity in the ratwas 225 mg/kg the NOAEL for developmental toxicity in the ratwas 475 mg/kg. In rabbits, maternal toxicity was indicated atthe 225 and 500 mg/kg dose levels by abortions and/or deathsin conjunction with anorexia and cachexia. Developmental toxicitywas indicated at the 500 mg/kg dose level by depressed fetalviability and weight. Fetal morphology was not adversely affectedat any dose level. The NOAELs for maternal and developmentaltoxicity in the rabbit were 100 and 225 mg/kg, respectively.Based on these data, trifluralin did not exhibit selective toxicitytoward the developing conceptus.     

盐酸青藤碱的抗心律失常作用

青藤碱(sinomenine,SIN),有多方面的药理作用,国内已有较系统的药理研究,但至今尚未见其抗心律失常作用的报道。本文在几种动物模型观察了SIN的抗实验性心律失常的效果。     

Evaluation of the Developmental Toxicity of 8-2 Telomer B Alcohol

The potential maternal and developmental toxicity of 8-2 Telomer B Alcohol was assessed in rats. Groups of 22 time-mated female Crl:CD (SD)IGS BR rats were administered oral gavage doses as suspensions of 8-2 Telomer B Alcohol in aqueous 0.5% methylcellulose from day 6 through 20 of gestation (G) at daily doses of either 0, 50, 200, or 500 mg/kg. Under the conditions of this study, adverse maternal toxicity was produced at 500 mg kg^{? 1} day^{? 1} and consisted of maternal mortality, decreased body weights and body weight gains, and increased clinical observations of toxicity. One litter at 500 mg kg^{? 1} day^{? 1} consisted of one early resorption and was believed to be secondary to overt maternal toxicity, although single conceptus litters occur historically in this strain of rats. Developmental toxicity at 500 mg kg^{? 1} day^{? 1} consisted of increased fetal skeletal variations (delayed pelvic bone ossification and wavy ribs). At 200 and 500 mg kg^{? 1} day^{? 1}, there were transient reductions in maternal feed consumption. In addition, there were slight increases in the incidence of delayed fetal skull bone ossification at 200 and 500 mg kg^{? 1} day^{? 1}. The no-observed-adverse-effect level (NOAEL), defined as the highest dose at which adverse effects attributable to the test substance were not detected, for both maternal and developmental toxicity, is considered to be 200 mg kg^{? 1} day^{? 1}. Thus, 8-2 Telomer B Alcohol is not considered to be a selective developmental toxicant in rats. The transient and quantitative nature of the observations in the 200 mg/kg group supports the conclusion that these findings were not adverse.     

Effective antidiabetic and antioxidant fractions of Otostegia persica extract and their constituents

Context: Otostegia persica (Burm.) Boiss. (Lamiaceae), “Goldar” in Persian, is widely used in the folk medicine of south Iran for control of diabetes mellitus.

Objective: In the present study, hypoglycemic and antioxidant effects of different fractions of the O. persica extract were investigated and constituents of effective fractions were elucidated.

Materials and method: Different concentrations (100–400?mg/kg) of aqueous infusion (AI) of flowering aerial parts of the plant (traditional preparation) and all fractions of the O. persica extract (i.p. injection) were tested for antidiabetic activity in streptozocin-induced diabetic NMRI mice. Blood glucose level was measured at time 0 and intervals of 1, 2, 4, and 6?h later. Antioxidant activities of different fractions of the plant extract and pure compounds (0.1, 0.5, and 1?mg/ml) were determined with the DPPH method. Four compounds were isolated and identified from potent fractions.

Results and discussion: Antidiabetic activity demonstrated that the effect of the methanol fraction at a dose of 300?mg/kg was equivalent with glibenclamide, and at a dose of 400?mg/kg was comparable with glibenclamide and insulin (p?>?0.05). The EC₅₀ of the methanol fraction was 307.12?mg. Methanol and ethyl acetate fractions showed antioxidant activities (both IC₅₀ equal to 0.49?mg/ml), so these fractions were selected for the purification of compounds. Chrysoeriol from ethyl acetate and three apigenin derivatives (6-methylapigenin, apigenin-7-O-glucoside, and echinaticin) from the methanol fraction were isolated and identified (new for the species). Chrysoeriol exhibited potent antioxidant activity comparable with vitamin E and BHT (p?>?0.05).

Conclusion: The present study confirmed the folklore usage of O. persica for antidiabetic properties.