Antitumor activity of 3,4-dihydroquinazoline dihydrochloride in A549 xenograft nude mice

In the previous article we have reported that 3,4-dihydroquinazoline 1 is a potent and selective T-type calcium channel blocker that exhibited strong anti-cancer activity in vitro. Compound 1·2HCl was further in vivo evaluated against A549 xenograft in BALB/c nude mice, which exhibited 49% tumor-weight inhibition through intravenous administration of 2 mg/kg of body weight and was more potent than doxorubicin. Moreover, compound 1·2HCl has an oral bioavailability of 98% with LD(50) values of 693 mg/kg (p.o. route) and 40.0 mg/kg (i.v. route) of body weight. In addition, its efficient scale-up synthetic method was developed.     

Hepatoprotective activity of Hemidesmus indicus R. br. in rats

Treatment of rats with paracetamol and CCl4 produced a significant increase in the levels of serum glutamate pyruvate transaminase (SGPT), serum glutamate oxaloacetate transaminase (SGOT), alkaline phosphatase (ALP), total and direct bilirubin. Rats pretreated with methanolic extract of roots of H. indicus (100-500 mg/kg body weight, po) exhibited rise in the levels of these enzymes but it was significantly less as compared to those treated with paracetamol or CCl4 alone. The results of methanolic extract of H. indicus were comparable with the standard hepatoprotective agent silymarin (100 mg/kg). Maximum hepatoprotective effect was found to be at the dose of 250 mg/kg body weight in case of CCl4 induced hepatic damage while 500 mg/kg body weight in case of paracetamol induced hepatic damage. The results suggest that methanolic extract of H. indicus roots possesses a potential antihepatotoxic activity.     

Ticarcillin administration to the equine: Intrauterine and intramuscular

Serum levels of ticarcillin disodium, a semi-synthetic penicillin (Beecham Laboratories, Bristol, Tennessee, 37620), were measured at various time intervals up to and including 24 h after intrauterine and intramuscular administration in adult female horses. Three separate studies were conducted in Part I: in the first and second studies, serum levels were measured after intrauterine administration of 1 and 3 g of ticarcillin, respectively, and in the third study, levels were measured after intramuscular administration of 6 g of ticarcillin. In Part II, serum levels of ticarcillin were measured after intramuscular administration of ticarcillin at dosages based on body weight: 10 mg/lb (22 mg/kg) of body weight, 15 mg/lb (33 mg/kg) of body weight and 20 mg/lb (44 mg/kg) of body weight. Results showed little if any absorption of the antibiotics into the systemic circulation after intrauterine administration. All serum levels measured after administration of both intrauterine dosages of 1 and 3 g were less than 4.0 ug/ml. Peak serum concentrations, after intramuscular administration of 6 g of ticarcillin, occurred between 20 and 45 min after administration and averaged 15.97 +/- 5.0 ug/ml. Average peak serum concentrations, after intramuscular administration of 10 mg/lb (22 mg/kg) of body weight, 15 mg/lb (33 mg/kg) of body weight, 15 mg/lb (33 mg/kg) and 20 mg/lb (44 mg/kg) of body weight, were 16.12 ug/ml, 25.75 ug/ml and 50.25 ug/ml, respectively. After intramuscular administration of 6 g of ticaracilin, average serum half-life was determined to be 2.9 h.     

Hypouricemic Actions of Exopolysaccharide Produced by Cordyceps militaris in Potassium Oxonate-Induced Hyperuricemic Mice

The hypouricemic actions of exopolysaccharide produced by Cordyceps militaris (EPCM) in potassium oxonate-induced hyperuricemia in mice were examined. Hyperuricemic mice were administered intragastrically with EPCM (200, 400 and 800 mg/kg body weight) or allopurinol (5 mg/kg body weight) once daily. Serum uric acid, blood urea nitrogen and liver xanthine oxidase (XOD) activities of each treatment were measured after administration for 7 days. EPCM showed dose-dependent uric acid-lowering actions. EPCM at a dose of 400 mg/kg body weight and allopurinol showed the same effect in serum uric acid, blood urea nitrogen and liver XOD activities in hyperuricemic mice. An increase in liver XOD activities was observed in hyperuricemic mice due to administration of EPCM at a dose of 200 mg/kg body weight. EPCM at a dose of 800 mg/kg body weight did not show significant effects on serum uric acid and XOD activities. We conclude that EPCM has a hypouricemic effect caused by decreases in urate production and the inhibition of XOD activities in hyperuricemic mice, and this natural product exhibited more potential efficacy than allopurinol in renal protection.     

Protective Effect of Selenium on Nicotine-Induced Testicular Toxicity in Rats

Effect of exogenous selenium at a dose of 10 mug/kg body weight on the testicular toxicity induced by nicotine in rats was investigated. Male albino rats were maintained for 60 days as follows: (1) control group (normal diet), (2) nicotine group (0.6 mg /kg body weight), (3) selenium (10 microg/kg body weight), and (4) nicotine (0.6 mg/kg body weight) + selenium (10 microg/ kg body weight). Administration of nicotine caused reduction in sperm count and sperm motility. Activity of HMG CoA reductase and concentration of cholesterol were increased in the testes of the nicotine administered group. Activities of testicular enzymes 3beta hydroxysteroid dehyrogenase (3 betaHSD), 17beta hydroxysteroid dehyrogenase (17 betaHSD) were decreased. Levels of testosterone in the serum were also reduced. However, the extent of these alterations was lesser in the group administered with nicotine along with selenium. Analysis of plasma revealed reduced quantity of cotinine in the group co-administered with nicotine along with selenium in comparison with the nicotine group. Nondetectable levels of nicotine were present in the co-administered group. This indicates altered metabolism of nicotine when administered along with selenium.     

Neuroprotective effect of rutin against colistin-induced oxidative stress,inflammation and apoptosis in rat brain associated with the CREB/BDNF expressions

The purpose of the current study was to examine the neuroprotective effect of rutin against colistin-induced neurotoxicity in rats. Thirty-five male Sprague Dawley rats were randomly divided into 5 groups. The control group (orally received physiological saline), the rutin group (orally administered 100 mg/kg body weight), the colistin group (i.p. administered 15 mg/kg body weight), the Col?+?Rut 50 group (i.p. administered 15 mg/kg body weight of colistin, and orally received 50 mg/kg body weight of rutin), the Col?+?Rut 100 group (i.p. administered 15 mg/kg body weight of colistin, and orally received 100 mg/kg body weight of rutin). Administration of colistin increased levels of glial fibrillary acidic protein and brain-derived neurotrophic factor and acetylcholinesterase and butyrylcholinesterase activities while decreasing level of cyclic AMP response element binding protein and extracellular signal regulated kinases 1 and 2 (ERK1/2) expressions. Colistin increased oxidative impairments as evidenced by a decrease in level of nuclear factor erythroid 2-related factor 2 (Nrf-2), glutathione, superoxide dismutase, glutathione peroxidase and catalase activities, and increased malondialdehyde content. Colistin also increased the levels of the apoptotic and inflammatoric parameters such as cysteine aspartate specific protease-3 (caspase-3), p53, B-cell lymphoma-2 (Bcl-2), nuclear factor kappa B (NF-κB), Bcl-2 associated X protein (Bax), tumor necrosis factor-α (TNF-α) and neuronal nitric oxide synthase (nNOS). Rutin treatment restored the brain function by attenuating colistin-induced oxidative stress, apoptosis, inflammation, histopathological and immunohistochemical alteration suggesting that rutin supplementation mitigated colistin-induced neurotoxicity in male rats.

     

Potent anti-obese principle from Rosa canina: structural requirements and mode of action of trans-tiliroside

The 80% aqueous acetone extracts from the fruit (50 mg/kg/d) and seeds (12.5 and 25 mg/kg/d) of Rosa canina L., but not from the pericarps, were found to show substantial inhibitory effect on the gain of body weight and/or weight of visceral fat without affecting food intake in mice for 2 weeks after administration of the extracts. With regard to the active constituents, the principal constituent, trans-tiliroside (0.1-10 mg/kg/d), potently inhibited the gain of body weight, especially visceral fat weight, and significantly reduced blood glucose levels after glucose loading (1 g/kg, ip) in mice. On the other hand, kaempferol and p-coumaric acid lacked such effect and kaempferol 3-O-beta-D-glucopyranoside tended to reduce the gain of body weight and visceral fat weight, but not significantly, at a dose of 10 mg/kg/d. These results indicate the importance of both kaempferol 3-O-beta-D-glucopyranoside and p-coumaroyl moieties for anti-obese effects. Furthermore, a single oral administration of trans-tiliroside at a dose of 10 mg/kg increased the expression of PPAR-alpha mRNA of liver tissue in mice.     

Antioxidant effects of Emblica officinalis and Zingiber officinalis on arsenic and lead induced toxicity on Albino rats

It is of interest to document the effect of Emblica officinalis (E. officinalis) and Zingiber officinalae (Z. officinalae) leaf extract on reactive oxygen species, antioxidant potential changes in arsenic and lead-induced toxicity in male rats. We used 8 groups of adult male Wistar rats with 1 control group for this study. The animals were divided into Group I: Control and Group II: Lead and sodium arsenite induced rats (animals were induced for metal toxicity by the combined administration of arsenic (13.8 mg/ kg body weight) and lead (116.4 mg/kg body weight). These doses were administered by gastric intubation during 14 consecutive days using known standard procedures. Arsenic and lead induced rats treated with ethanolic extract of Emblica officinalis (60 mg/kg body weight/day, orally for 45 days) are group III rats. Group IV animals are arsenic and lead induced rats treated orally with ethanolic extracts of E. officinalis (120 mg/kg body weight/day for 45 days). Group V animals are arsenic and lead induced rats treated orally with ethanolic extracts of Z. officinalae (60 mg/kg body weight/day for 45 days). Group VI animals are arsenic and lead induced rats orally treated with ethanolic extracts of Zingiber officinalis (120 mg/kg body weight/day for 45 days). Group VII animals are arsenic and lead induced rats treated orally with ethanolic extracts of E. officinalis and Z. officinalae (60 + 60 mg/kg body weight/day for 45 days). Group VIII animals are arsenic and lead induced rats treated orally with ethanolic extracts of E. officinalis and Z. officinalae (120 + 120 mg/kg body weight/day, orally for 45 days). Normal Control animals were treated orally with ethanolic extracts of E. officinalis (120mg/kg body weight) + Z. officinalae (120mg/kg body weight) for 45 days. The control and experimental animals were then subjected to analysis for oxidative stress markers such as H2O2, *OH, and lipid peroxidation (LPO), antioxidant enzymes in addition to liver and kidney function markers. Results: Arsenic and lead induced rats showed a significant increase in the levels of reactive oxygen species (H2O2, OH* and LPO) with concomitant alterations in the renal and liver tissues. However, enzymic and non-enzymic antioxidant levels were decreased. Nevertheless, an oral effective dose of E. officinalis and Z. officinalae (120 + 120 mg/kg body weight/day increased the antioxidant enzymes and retrieved the altered levels of ROS and LPO that were induced by arsenic and lead. Thus, we show that E. officinalis and Z. officinalae leaf extract exhibits nephroprotective and hepatoprotective role through the restoration of reactive oxygen species and antioxidant enzymes in the kidney and liver tissue of Arsenic and Lead-induced nephrotoxicity and hepatotoxicity in rats. Hence, E. officinalis and Z. officinalae leaf extract are potential therapeutic options for the treatment of metal toxicity-induced kidney and liver diseases.     

Treatment and survival study in the C57BL/6J-APC(Min)/+(Min) mouse with R-flurbiprofen

Our previous studies with the mouse model of familial adenomatous polyposis (FAP), C57BL/6J-APC(Min)/+ or Min mouse, demonstrated the optimal dose for adenoma reduction with R-flurbiprofen was 10 mg/kg/day as an undivided dose. Divided doses exhibited no increased efficaciousness. This study examines 10 mg/kg R-flurbiprofen daily (qd) on survival as well as a second daily (q.o.d.) schedule and compares it with sulindac sulfone. The q.o.d. schedule at 10 mg/kg was equally efficacious as qd treatment at the same dose. For the q.o.d. group, tumor number decreased similarly (p<0.01); while body weight gain (p<0.01), hematocrit and average tumor area (both, p<0.05) were improved compared with qd treatment. Treatment with R-flurbiprofen (10 mg/kg/day) increased survival significantly (p=0.0004, log-rank) compared to vehicle treated animals. Major biological endpoints (hematocrit, weight gain, tumor number, average and total area [99% reduction]) were significantly improved in treated animals (p<0.01). Sulindac sulfone treatment (50 mg/kg/day) of the Min mouse produced no significant biological benefit. The dose schedule study suggests that for tumor reduction it is necessary to attain a threshold drug-level but not necessarily sustain it over 24 hrs (pharmacodynamic t1/2 > pharmacokinetic t1/2). During the period of administration R-flurbiprofen dramatically prolongs survival for the mouse model of the human disease, FAP.     

Genotoxic effects of deltamethrin in the mouse bone marrow micronucleus assay

The genotoxicity of deltamethrin was studied in Swiss albino male mice (five animals/group) using the bone marrow micronucleus assay. Deltamethrin (two i.p. injections, 30 h and 6 h before sample collection) was found to induce micronuclei at 162.5 and 300.0 mg/kg body weight. A lower dose (32.5 mg/kg body weight) failed to induce a significant increase in micronuclei over the control level.     

Lack of teratogenicity of trans-2-ene-valproic acid compared to valproic acid in rats

The teratogenicity of trans-2-ene-valproic acid (300 and 400 mg/kg) was compared with that of valproic acid (VPA; 300 mg/kg) and controls (corn oil) administered by gavage to Sprague-Dawley CD rats on embryonic (E) days 7-18. At the 300 mg/kg dose, trans-2-ene-VPA produced no change in maternal weight, number of implantations, proportion of resorptions, proportion of malformations, or fetal weight. By contrast, the same dose of VPA (300 mg/kg) reduced maternal weight during gestation, increased malformations (12.0% vs. 0.7% in controls), and reduced fetal body weight by 25.1%. An even higher dose of trans-2-ene-VPA (400 mg/kg) produced a reduction in maternal body weight during treatment and reduced fetal body weight (by 7.9%), but did not increase resorptions or malformations in the fetuses. On day E18, maternal serum drug concentrations of VPA were higher in the VPA-treated group compared with those of trans-2-ene-VPA in the trans-2-ene-VPA-treated groups at 1 hr posttreatment. At 6 hr posttreatment the reverse was seen. trans-2-ene-VPA may be absorbed more rapidly and distributed differently than VPA. Overall, the data support the view that trans-2-ene-VPA at equal or higher doses than VPA is not teratogenic in rats.     

Effect of alcohol and kolanut interaction on brain sodium pump activity in Wistar Albino rats.

Effect of alcohol-kolanut interaction on Sodium Pump activity in wistar albino rats was studied. Thirty wistar albino rats were divided into six groups of five (5) rats per group and used for the study. The control group (1) received via oral route a placebo (4ml of distilled water). Groups 2 to 6 were treated for a period of 21 days, with (10% v/v) of alcohol (group 2), 50mg/kg body weight of kolanut (group 3), 50 mg/kg body weight of caffeine (group 4), 4ml of 10% v/v of alcohol and 50 mg/kg body weight kolanut (group 5), 4ml of 10% v/v of alcohol and 50 mg/kg body weight of caffeine in 4.0ml of the vehicle via gastric intubation respectively. A day after the final exposure, the brain of each rat was harvested and processed to examine several biochemical parameters, i.e., total ATpase, ouabain-insensitive ATpase, ouabain sensitive ATpase (Na(+)-K(+)ATPase), non-enzymatic breakdown of ATP and inorganic phosphate (Pi) released. The results showed that the essential enzyme of the brain responsible for neuronal function, Na(+)-K(+)ATPase, was inhibited by alcohol-kolanut co-administration relative to control, resulting in a decrease in Na(+)-K(+)ATPase activity, ATP production, ion transport and action potential, leading to loss of neuronal activities.     

Dimethylthiourea protects against mitochondrial oxidative damage induced by cisplatin in liver of rats

Cisplatin is one of the most effective chemotherapeutic agents. However, at higher doses liver injury may occur. The purpose of this study was to explore whether the hydroxyl radical scavenger dimethylthiourea (DMTU) protects against cisplatin-induced oxidative damage in vivo and to define the mitochondrial pathways involved in cytoprotection. Adult male Wistar rats (200–220 g) were divided into four groups of eight animals each. The control group was treated only with an intraperitoneal (i.p.) injection of saline solution (1 ml/100 g body weight). The DMTU group was given only DMTU (500 mg/kg body weight, i.p), followed by 125 mg/kg body weight, i.p. (twice a day) until sacrifice. The cisplatin group was given a single injection of cisplatin (10 mg/kg body weight, i.p.). The DMTU + cisplatin group was given DMTU (500 mg/kg body weight, i.p.), just before the cisplatin injection (10 mg/kg body weight, i.p.), followed by injections of DMTU (125 mg/kg body weight, i.p.) twice a day until sacrifice (72 h after the treatment). DMTU did not present any direct effect on mitochondria and substantially inhibited cisplatin-induced mitochondrial damage in liver, therefore preventing elevation of AST and ALT serum levels. DMTU protected against (a) decreased hepatic ATP levels; (b) lipid peroxidation; (c) cardiolipin oxidation; (d) sulfhydryl protein oxidation; (e) mitochondrial membrane rigidification; (f) GSH oxidation; (g) NADPH oxidation; (h) apoptosis. Results suggest that antioxidants, particularly hydroxyl radical scavengers, protect liver mitochondria against cisplatin-induced oxidative damage. Several mitochondrial changes were delineated and proposed as interesting targets for cytoprotective strategy.     

Modulation of balance between apoptosis and proliferation by lipid peroxidation (LPO) during rat liver regeneration

BACKGROUND: This work aims to investigate the role of lipid peroxidation (LPO) at early stages of liver regeneration and to evaluate the balance between apoptosis and cell proliferation during this process. METHODS: Sham and partial hepatectomized (PH) male Wistar rats were randomized in seven groups: Control (untreated), E-Control (injected with vitamin E-vehicle), C-Control (injected with vitamin C-vehicle), E1 (vitamin E 100 mg/kg body weight), E2 (vitamin E 600 mg/kg body weight), C1 (vitamin C 30 mg/kg body weight), C2 (vitamin C 100 mg/kg body weight). RESULTS: Vitamin treatments attenuated the increase of LPO level observed in total homogenate and microsomes at 3 and 5 hr after PH. Both antioxidant vitamins attenuated the increase in Bax pro-apoptotic protein and augmented Bcl-xL antiapoptotic protein levels (35%) at 3 and 5 hr post-PH; Bcl-xL/Bax ratio was, therefore, increased. A direct linear relationship between LPO levels and Bax mitochondrial protein levels was seen. Vitamin-treatments diminished the apoptosis index with respect to PH-Control values, so that this parameter showed a linear relationship with LPO levels. At 24 hr after PH, the vitamin treatments increased the peak of [(3) H]-thymidine incorporation into DNA and the proliferative index (PI), measured as PCNA expression; an inverse relationship between PI and LPO levels could be demonstrated. CONCLUSION: Our data show that the diminution of LPO levels by vitamin-treatment post-PH produces both an attenuation of cellular apoptosis and a marked increase in the proliferation process, suggesting that the modulation of LPO has a role in liver regeneration process.     

Cortical alpha-adrenoceptor downregulation by tricyclic antidepressants in the rat brain

The aim of the present study was to examine the effect of chronic tricyclic antidepressants (TCAs) treatment on the density of -adrenoceptors in the rat brain. Density of ₁- and ₂-adrenoceptors was measured in cortex and hippocampus of rats treated with imipramine (IMI, 5 mg/kg body weight), desipramine (DMI, 10 mg/kg body weight), clomipramine (CMI, 10 mg/kg body weight) and amitriptyline (AMI, 10 mg/kg body weight), for 40 days, using [³H]prazosin and [³H]clonidine, respectively. The density of cortical ₁-adrenoceptors was significantly decreased with IMI (46%), DMI (21%), CMI (50%) and AMI (67%) treatment, without altering the affinity of the receptor. The density of cortical ₂-adrenoceptors was also significantly decreased with DMI (69%), CMI (81%) and AMI (80%) treatment, without affecting the affinity for [³H]clonidine. The density of hippocampal ₁-adrenoceptors was significantly decreased only with AMI treatment (47%), without affecting the affinity for [³H]prazosin. However, no change in hippocampal ₂-adrenoceptor density was observed with any of these TCAs. The results suggest that chronic antidepressant (AD) treatment downregulates the cortical, but not hippocampal, ₁- and ₂-adrenoceptors in rat brain. The region-specific downregulation of ₁- and ₂-adrenoceptors density, which occur after prolonged AD treatment, may underline the therapeutic mechanism of action.     

腹腔注射乙酰唑胺对大鼠氧惊厥潜伏期的影响

为探讨脑血流调节与氧惊厥的关系,本研究在复制大鼠氧惊厥模型的基础上,采用行为学方法测定氧惊厥潜伏期,并测定脑皮质氧化指标内二醛（maleic dialdehyde,MDA）含量,采用腹腔注射不同剂量脑血管扩张药物乙酰唑胺（acetazolamide,ACZ）,以及联合注射ACZ及其拈抗刺吲哚美辛（indomethacin,IND）后,观察脑血管扩张对氧化状态以及氧惊厥潜伏期的影响。结果观察到：（1）腹腔注射ACZ（不小于7．5mg／kg体重）后,氧惊厥潜伏期明显缩短（P〈0．05）,剂量越大,缩短越明显。腹腔注射IND对氧惊厥潜伏期无显著影响。腹腔注射IND（20mg／kg体重）,30min后再注射ACZ（7．5mg／kg体重）,ACZ的氧惊厥潜伏期缩短作川被对抗（P〈0．05）。（2）腹腔注射ACZ7．5mg／kg后,与各组相比,6及16min暴露后,脑组织MDA含量明显增多（P〈0．01,P〈0．05）;腹腔注射IND对脑皮质MDA含量无显著影响;在预注射IND,再注射ACZ后,MDA含量显著降低（P〈0．01,P〈0．05）。结果表明,ACZ外周注射加重氧化损伤,缩短氧惊厥潜伏期;而IND可以对抗其氧惊厥潜伏期缩短作用以及氧化损伤加重作用,碳酸酐酶活力变化很可能是通过影响脑血管状态而影响氧化损伤以及氧惊厥潜伏期。     

Hepatic fatty acid conjugation of 2-chloroethanol and 2-bromoethanol in rats

To study the formation of fatty acid conjugates of 2-chloroethanol (2-CE) and 2-bromoethanol (2-BE), rats were administered (by gavage) 50 mg/kg of 2-CE and 2-BE in mineral oil and sacrificed on fifth day of the treatment. Hepatic microsomal lipids were extracted, and the fatty acid esters were separated by preparative thin-layer chromotography. The ester fraction was further purified by reverse-phase, high-performance liquid chromatography and analyzed by ammonia chemical ionization mass spectrometry. Pseudomolecular ions (M + NH4+, base peak) at m/z 336/338, 362/364, and 364/366 in a ratio of 3:1 and 380/382 and 408/410 in a ratio of 1:1 confirmed the in vivo formation of 2-chloroethyl palmitate, 2-chloroethyl oleate, 2-chloroethyl stearate, 2-bromoethyl palmitate, and 2-bromoethyl stearate, respectively. These results demonstrate the formation of fatty acid conjugates of 2-CE and 2-BE in vivo. These fatty acid conjugates may be retained in the body for a longer time and cause toxic manifestations.     

Developmental and reproductive toxicity studies on artemisone

BACKGROUND: In order to justify clinical studies in women of child-bearing age with artemisone, a new artimisinin derivative, studies to assess fertility and early embryonic development in rats, developmental toxicity in rats and rabbits, and peri-post natal development in rats were performed. METHODS AND RESULTS: In the study on fertility and early embryonic development (dose levels 0-5-20-80 mg/kg bw/day), doses inducing clinical and organ toxicity were used. Only in severe toxicity conditions, a reduction of the number of estruses, a prolonged time to insemination, decreased numbers of corpora lutea, implantation sites, and viable fetuses were found. Two developmental toxicity studies were performed in rats (dose levels 0-1-2 mg/kg bw/day) and rabbits (dose levels 0-2.5-5.0-7.5 mg/kg bw/day). It was shown that rats were about 5 times more sensitive than rabbits. In rats, artemisone induced total litter loss (late resorptions) at 2 mg/kg body weight and above with an increased incidence of a common vascular variation and retarded ossification at this dose. In rabbits, maternal toxicity, abortion and a slightly increased incidence of cardiac ventricular septal defects was observed at 7.5 mg/kg body weight. In a pre- and postnatal developmental toxicity study in rats (dose levels 0-1-2-4 mg/kg bw/day), 4 mg/kg body weight artemisone induced clinical symptoms and affected postnatal survival, body weight gain in the F1 pups, and motor activity. CONCLUSIONS: In summary, artemisone was shown to be embryo- and fetotoxic and induced cardiac ventricular septal defects and retarded ossification in dosages where total litter loss and abortions were observed. However, no effect on reproductive and developmental parameters below severe toxic dosages could be observed. Birth Defects Res (Part B)86: 131-143, 2009. © 2009 Wiley-Liss, Inc.     

Maternal and developmental toxicity of low doses of cytosine arabinoside in mice

1-beta-D-Arabinofuranosylcytosine (Ara-C), an effective drug for the treatment of leukemia and breast cancer, was evaluated for developmental toxicity in pregnant Swiss mice. Ara-C was administered by intraperitoneal injection on gestational days 6-15 at doses of 0, 0.5, 2, and 8 mg/kg/day. Maternal observations included clinical signs, body weight change, food consumption, and gross evaluation of organs and uterine contents at necropsy (day 18). Live fetuses were examined for external, visceral, and skeletal alterations. Maternal toxicity was observed at 2 and 8 mg/kg/day, as evidenced by a significant decrease in body weight gain and food consumption during the treatment period. Significantly increased early and late resorptions and reduced number of live fetuses per liter as well as decreased fetal body weight were observed at 8 mg/kg/day. At 2 mg/kg/day, the incidence of cleft palate, renoureteral agenesis or hypoplasia, and poly- or oligodactyly was significantly increased, whereas fetal weight was reduced at 0.5 mg/kg/day. Thus, the developmental no-observed-adverse-effect-level (NOAEL) of Ara-C in the pregnant mouse is lower than 0.5 mg/kg/day, while the NOAEL for maternal toxicity is 0.5 mg/kg/day. We believe that exposure to this agent ought to be avoided during organogenesis.