The pre- and post-natal toxicity of penequine hydrochloride in mice

Penequine hydrochloride, a novel anticholinergic agent, was developed as an effective treatment for organophosphorus intoxication (e.g., soman poisoning). The current study was performed to assess the potential pre- and post-natal toxicity of penequine hydrochloride in mice. Approximately 120 timed-pregnant mice were assigned to four dose groups (n = 30 per group). Dams were exposed orally to 0, 2.5, 12.5, 62.5 mg/L penequine hydrochloride in drinking water from gestation day 6 to lactation day 21. The F1 generation mice, which were not exposed directly to penequine hydrochloride as pups or as adults, were bred to produce F2 generation fetuses for the fertility test of the F1 population. Various pre- and post-natal measurements, including neurobehavioral tests, were performed with the F0 and F1 mice. Among the significant findings were decreases in water consumption, viability, organ weights and delay of physical landmarks in 62.5 mg/L groups. With the exception of treatment-unrelated abnormality in surface righting reflex in the F1 generation, penequine hydrochloride did not produce any adverse effects at doses up to and including 12.5 mg/L (equal to 2.5 mg/kg/day in mice) that were at least 75 times of human therapeutic dosage.     

Fertility and early embryonic development toxicity of penequine hydrochloride in mice.

Penequine hydrochloride, a novel anticholinergic agent, was developed as an effective treatment for organophosphorus intoxication. The potential for penequine hydrochloride to induce fertility and early embryonic developmental toxicity was evaluated in AMMS-1 mice. Totally 320 healthy, sexual mature and nulliparous AMMS-1 mice were orally treated with the chemical in drinking water at dose levels of 0, 2.5, 12.5 and 62.5 mg/L from 60 days before cohabitation to successful copulation in 160 males and from two weeks before cohabitation to GD 6 in 160 females, respectively. All the parental mice were observed for body weights, water consumption and any abnormal change during treatment period. Caesarean sections were carried out on day 14 of pregnancy in half assumed-pregnant females, and all the intrauterine data were recorded. Pups naturally delivered by the other half females were weighed, and examined for viability, sex ratio and gross malformations. About 7 days after cohabitation period, all the paternal males were examined for epididymal and testicular weights, sperm number and sperm motility. The decreases in fertility/fecundity indices and maternal weight gain were found at high-dose level in both caesarean sections and natural delivery observations. The primary developmental toxicity of the chemical included decreases in relative organ (epididymis, liver and lung) weights at mid- and high-dose levels in pups on postnatal day (PND) 35. The cause of both the decreased fertility/fecundity indices in F0 males and the decreased relative organ weights in F1 pups are not well known but are presently under investigation. Under the experimental conditions, penequine hydrochloride did not produce any adverse effects (expect the decreases in certain relative organ weights) up to and including 12.5 mg/L (2.53 mg/kg/day in males and 2.19 mg/kg/day in females) corresponding to approximately 72 times above anticipated dosage in human.     

Embryo-fetal development toxicity of prenatal exposure to penequine hydrochloride intramuscularly in rats.

The potential for penequine hydrochloride to induce maternal and embryo-fetal developmental toxicity was evaluated in Wistar rats. The drug was administered intramuscularly (i.m.) at dose levels of 0, 10, 30 or 50mg/kg/day to groups of pregnant rats from day 6 to 15 of gestation. All dams were observed for maternal body weights, food consumption and any abnormal change, and subjected to caesarean-section on gestation day (GD) 20; all fetuses obtained from caesarean-section were assessed by external inspection, visceral and skeletal examinations. In the 50mg/kg/day group, maternal toxicity included an increase in the incidence of abnormal clinical signs, and decrease in the body weight and body weight gain. Developmental toxicity included an increase in the postimplantation loss, a decrease in the litter size, and a reduction in the gravid uterus weight. In addition, a statistically non-significant increase in the incidence of fetal external, visceral, and skeletal alterations including malformations and variations were seen in high-dose group. There were no treatment-related findings in maternal clinical and intrauterine observations, and fetal morphological examinations in mid-, low-dose and control groups. Thus, under the conditions of this study, the no-observed-adverse-effect-level (NOAEL) and lowest-observed-adverse-effect-level (LOAEL) of penequine hydrochloride for both maternal and embryo-fetal toxicity in the Wistar rats were considered to be 30mg/kg/day and 50mg/kg/day, which are approximately 900 and 1500 above the therapeutic dosage, respectively.     

Pharmacotherapy of mood disorders and psychosis in pre- and post-natal women

Introduction: Untreated mood and psychotic disorders can have substantial adverse impacts on the patient, the fetus and the family, while treatment can ameliorate such problems. To address concerns by clinicians about the risks of psychotropic medications, this review addresses the risk/benefit analysis of somatic therapies for psychiatric disorders during pregnancy and lactation.

Areas covered: All available research was reviewed on the impact on pregnancy and breastfeeding of mood and psychotic disorders, and of antidepressants, mood stabilizers, antipsychotic drugs, and electroconvulsive therapy. References cited in other reviews, case series, formal studies, pharmacologic discussions, and theoretical pieces were added. Available case control and other studies were critically reviewed and diverse explanations for their findings were considered.

Expert opinion: The potential benefits of treatment of mood and psychotic disorders often outweigh the risks after alternative therapies have been considered. Some medications, particularly paroxetine and valproate, pose greater risks during pregnancy, while the teratogenic risks of lithium have probably been overstated. There is more experience with first than with second generation antipsychotic drugs during pregnancy and lactation. Nursing an infant is possible while taking a number of antidepressants, mood stabilizers or antipsychotic drugs.     

盐酸苯环壬酯对小鼠的围产期毒性试验研究

盐酸苯环壬酯分成２．５、１２．５和６２．５ｐｐｍ３个浓度组，溶于自一不中，供孕鼠从妊娠ｄ１５开始至断乳时饮用。结果显示，在相当于人临床用量１５－７５倍剂量范围内，该药对小鼠胚胎后期生长发育、母鼠分娩、哺乳及新生小鼠神经行为发育无明显影响。６２．５ｐｐｍ组孕鼠给药期间体重增长抑制，死产仔鼠数增多，雄仔鼠肝脏重量增加，表现出一定的母体毒性和发育毒性。     

Reproductive toxicity of gamma-ethyl-gamma-phenyl-butyrolactone,a new anticonvulsant and hypnotic drug,in mice. Fertility and peri- and post-natal studies

The reproductive toxicity of gamma-ethyl-gamma-phenyl-butyrolactone (EPBL, CAS 53380-21-5), a new anticonvulsant and hypnotic drug, was investigated by performing fertility and peri- and post-natal studies in mice. In both studies, EPBL was administered by gavage at 0, 50, 10, or 200 mg/kg doses. The first study found parent toxicity as measured by reduced body weight at the higher dose. At the same dose, the number of live fetuses was decreased. However, neither male or female fertility nor the reproductive performance of mice were affected. The results of the second study showed that the only negative effects were a depression of maternal weight gain and a decrease in body weight of the litter at birth which was 200 mg/kg. A reduction in the survival rate was also seen. There was no evidence that treatment of F0 females from day 15 of pregnancy to day 21 post-partum affected either the reproductive capacity of the F1 offspring or the development of F2 progenies. The non observed effects levels (NOEL) for both studies can be estimated at 100 mg/kg.     

盐酸川丁特罗遗传毒性研究

目的：研究盐酸川丁特罗（SPFF）的遗传毒性。方法：采用Ames试验、哺乳动物培养细胞染色体畸变试验、小鼠微核试验，考察SPFF对鼠伤寒沙门菌和细胞的遗传毒性。结果：经Ames试验、CHL细胞染色体畸变试验、小鼠微核试验，SPFF的结果均呈阴性。结论：SPFF无遗传毒性。     

盐酸丁螺环酮的围产期毒性作用

盐酸丁螺环酮是一种具有较强抗焦虑作用的新药，大鼠围产期及哺乳期毒性试验结果表明。本品对Ｃｒｉ：ＣＤ大鼠无致畸胎作用，剂量高于１２ｍｇ／ｋｇ时对母鼠及胎仔有一定的性作用，其无作用剂量为每天给药２ｍｇ／ｋｇ，该剂量相当于人临床用量的３倍，提示就生殖一毒性而言，盐酸丁螺环酮在人临床用量的剂量范围内使用是比较安全的。     

盐酸米托蒽醌脂质体的药效学及毒性研究

目的对盐酸米托蒽醌脂质体(Mit-lipo)与盐酸米托蒽醌普通制剂(Mit-inj)进行药效学及毒性比较研究。方法采用小鼠肝癌H22、小鼠前列腺癌RM-1移植肿瘤模型探讨Mit-lipo的抗肿瘤作用;犬急性毒性、大鼠和犬长期毒性研究比较Mit-lipo和Mit-inj毒性差异。结果 Mit-lipo 1、2、4和6 mg.kg-1各剂量对H22实体瘤的抑瘤率分别为75.1%、76.5%、90.1%和93.8%,也可剂量依赖性抑制小鼠前列腺癌RM-1肿瘤的生长,与等剂量的Mit-inj相比疗效明显增强。犬急性毒性结果表明Mit-lipo最大耐受剂量(MTD)为2.0 mg.kg-1,毒性表现为轻微至中度的皮肤毒性,给药4周后皮肤毒性逐渐减轻。大鼠长期毒性结果表明Mit-lipo可明显降低Mit-inj引起的骨髓毒性,并产生新的皮肤毒性反应。犬长期毒性结果表明Mit-lipo 0.1、0.3和0.45mg.kg-1组主要毒性反应为轻微至轻度的皮肤毒性反应,主要毒性靶器官为睾丸和皮肤,MTD为0.45 mg.kg-1,Mit-inj0.45 mg.kg-1可致WBC和PLT值降低和睾丸毒性病变。结论与普通制剂相比,米托蒽醌脂质体的体内抑瘤效果明显增强,且骨髓毒性明显降低。     

百草枯对小鼠的急性毒性试验

目的 观察百草枯(Paraquat,PQ)对小鼠的急性毒性,计算其半数致死量(LD50).方法 给小鼠灌服不同浓度的PQ溶液,通过观察小鼠的活动和毒性反应,记录小鼠的死亡数,用概率单位法计算LD50.结果 给药后不同时间内,小鼠出现自由活动减少,濒死时呼吸频率加快、张口呼吸、鼻翼扇动等中毒症状,死亡高峰在2 h内,死亡原因为多脏器损伤.♂小鼠LD50=106.99 mg·kg-1,95%可信限范围为97.01～118.03 mg·kg-1;♀小鼠LD50=86.40 mg·kg-1,95%可信限范围74.54～100.14 mg·kg-1.结论 PQ属于中等毒农药,♀小鼠更敏感.     

The developmental toxicity of uranium in mice

To evaluate the developmental toxicity of uranium, 5 groups of 20 pregnant Swiss mice were given by gavage daily doses of 0, 5, 10, 25 and 50 mg/kg of uranyl acetate dihydrate on gestational days 6-15. Cesarean sections were performed on all females on gestation day 18. Fetuses were examined for external, visceral, and skeletal abnormalities. The results indicated that such exposure resulted in maternal toxicity as evidenced by reduced weight gain and food consumption during treatment, and increased relative liver weight. There were no treatment-related effects on the number of implantation sites per dam, or on the incidence of postimplantation loss (resorptions plus dead fetuses). The number of live fetuses per litter and the fetal sex ratio were not affected by the treatment. However, dose-related fetal toxicity, consisting primarily of reduced fetal body weight and body length, and an increased incidence of abnormalities was observed. Malformations (cleft palate, bipartite sternebrae) and developmental variations (reduced ossification and unossified skeletal variations) were noted at the 25 and 50 mg/kg per day test levels. Therefore, administration of uranyl acetate dihydrate during organogenesis in mice produced maternal toxicity at 5, 10, 25 and 50 mg/kg per day. The "no observable effect level" (NOEL) for fetotoxicity including teratogenicity was below 5 mg/kg per day, as some anomalies were observed at this dose. There was no evidence of embryolethality at any dosage level used in this study.     

The toxicity of some halomethanes in mice

Freshly excised cat brain tissues were preincubated for 15 min in artificial cerebrospinal fluid (CSF) only or in CSF plus lead nitrate (5 × 10^?6m) and then incubated for an additional 5 min with varying concentrations of l-[³H]tyrosine. The time course (from 5 to 60 min) for the accumulation of l-[³H]tyrosine showed the highest uptake in the choroid plexus (CP); the mean steady-state distribution ratio at 60 min was close to 15. This value exceeded by twofold the uptake by the neural tissues. The relationship between V_net and the medium l-[³H]tyrosine concentration was a rectangular hyperbola. The apparent K_m value for all three tissues was similar, but the V_max of the CP was more than three times that of the neural tissues. Addition of lead nitrate altered the kinetics of uptake of l-[³H]tyrosine by the CP; the V_max was reduced by one-half, whereas the affinity of carrier for the amino acid was approximately tripled. There was no effect on the transport of l-[³H]tyrosine by caudate nucleus or hypothalamus.     

Reproduction study of carteolol hydrochloride in mice. Part 2. Peri -and postnatal toxicity.

Carteolol was orally administered to mice once a day at doses of 3, 30 and 150 mg/kg/day during the perinatal and lactation periods and evaluated on its adverse effects on pregnant animals and their offspring. No appreciably abnormal findings related to the drug administration were revealed. Therefore, it was concluded that carteolol have no serious toxic potential on parturition and lactation by mother animals, no adverse effects on growth and development, and behavioral and reproductive performance of offspring and no carcinogenic action through placental and milk transfer.     

Postnatal toxicity of carbon monoxide after pre- and postnatal exposure

Rats were exposed prenatally through 21 days postnatally to 230 ppm carbon monoxide (CO). Offspring weights at 1 day and 5 days were depressed, and values for carboxyhemoglobin, hematocrit, hemoglobin, and heart weight: body weight ratio were elevated, compared to controls. At 21 days survival was markedly reduced in CO-exposed rats (36%) compared to controls (94%). These results, in view of other studies involving only prenatal or neonatal exposure at higher CO levels, suggest that neonatal and postnatal toxicity of CO may be enhanced by prenatal exposure.     

盐酸三环哌酯在小鼠体内的药代动力学

目的研究抗胆碱新药盐酸三环哌酯（ＴＣＰＮ）在小鼠体内的药代动力学及组织分布。方法药代动力学采用放射受体分析法研究，组织中的分布用放射同位素分析法研究。结果小鼠ｓｃＴＣＰＮ后，血液中药物浓度的经时过程符合一级吸收二室模型（Ｔ１／２β为２．２８ｈ，Ｔｍａｘ为０．１２５ｈ，Ｃｍａｘ为３．４４μｇ·Ｌ－１，Ｃｌ为２３．０Ｌ·ｋｇ－１·ｈ－１）。小鼠ｓｃ［３Ｈ］－ＴＣＰＮ后，分布高峰放射性依次为肾＞肝＞脑＞颌下腺＞肠１９９８－０４－０３收稿，１９９８－０７－２６修回＊国家自然科学基金资助课题，Ｎｏ３９１３００９０－２作者简介：葛召恒，男，３２岁，硕士，助理研究员；阮金秀，男，６２岁，研究员，博士生导师，中国毒理学会副理事长，中国药理学会药物代谢专业委员会主任委员＞心＞肌肉，唯有脑组织的放射性以较高的水平维持较长的时间。预先给小鼠ｓｃ不同剂量的ＱＮＢ，可不同程度地降低脑中放射性的分布。结论ＴＣＰＮ从血中的消除较快，但在脑组织分布时间长，这与药物与脑中Ｍ受体的特异性结合有关。     

The developmental toxicity of ethylene glycol in rats and mice

Timed-pregnant CD rats and CD-1 mice were dosed by gavage with ethylene glycol (EG) in distilled water on gestational days (gd) 6 through 15 (0, 1250, 2500, or 5000 mg kg-1 day-1 for rats; and 0, 750, 1500, or 3000 mg kg-1 day-1 for mice). Females were observed daily during treatment, but no maternal deaths or distinctive clinical signs were noted. Dose-related decreases in maternal weight gain during treatment were significant at all doses in rats and at the mid and high doses in mice. Gravid uterine weight was reduced in both species at the mid and high doses, and corrected maternal gestational weight gain showed a significant decreasing trend. At termination (gd 20, rats; gd 17, mice), the status of uterine implantation sites was recorded, and live fetuses were weighed and examined for external, visceral, and skeletal malformations. Dose-related increases in postimplantation loss per litter were observed in both species with the high dose significantly above controls only in rats. Fetal body weight per litter was significantly reduced at the mid and high doses in rats and at all doses in mice. The percentage of malformed live fetuses per litter and/or the percentage of litters with malformed fetuses was significantly elevated in all EG dose groups and greater than 95% of litters were affected at the high dose for each species. A wide variety of malformations were observed; the most common in both species were craniofacial and neural tube closure defects and axial skeletal dysplasia. EG produced severe developmental toxicity in two rodent species at doses that apparently failed to produce any serious maternal effects.     

Long-term and multigeneration toxicity studies with cyclohexylamine hydrochloride

Cyclohexylamine (CHA), the metabolite of cyclamate produced in varying degree by gastrointestional microorganism, was subjected to a 2-year multi-generation feeding study in rats, at dosages of 15, 50, 100, and 150 mg/kr/d. Observations included growth, feed efficiency, clinical and hematological tests, reproduction, teratology, mortality and gross and microscocpic pathology. Rats from the litters of each generation from F₀ through F₄ were mated to produce the next succeeding generation. Those from the second litters of F₁ through F₄ also mated, half the dams being delivered by hysterotomy for teratological examination, while litters from the other half were raised to maturity.Except for some non-progressive growth retardation in the higher dosage groups, due to lower food consumption, the physical and clinical observations in the test groups fell substantially within normal limits and were not significantly different from the untreated controls. Reproduction rates were normal in all groups but at the higher dosages the size of the litters and their weaning weights were slightly reduced.At the 150 mg/kg level, histopathological examination revealed mucosal thickening of the bladder walls and evidence of renal calcificationl; however, no bladder tumors were seen, such as occured in the chronic feeding study in which rats recieved 2500 mg/kg of a cyclamate : saccharin (10 : 1) mixture. A significantly higher incidence of testicular atrophy, characteristic of aged rats, was observed in the F₀ group at the highest dosage level; however, these males continued to be fertile, in two cases up to 6 consecutive matings.     

Thirteen-week oral toxicity study of L-lysine hydrochloride in rats

L-Lysine hydrochloride (Lys) is an essential amino acid in humans and animals, and it is used in animal feeds, in prevention of herpes simplex recurrence, and cereal fortification in some developing countries. This study evaluated toxicological and behavioral effects of Lys during a dosing study with male and female Sprague-Dawley rats. The amino acid was incorporated into a standard diet at doses equal to 1.25%, 2.5%, and 5.0% (w/w). A control group of rats received a standard diet. All diets were administered ad libitum for 13 consecutive weeks. To examine stability of any potential effects, the administration period was followed by a 5-week recovery period, during which only the standard diet was provided to all animals. In male and female rats in each concentration group, treatment-related changes were not observed in the clinical signs, body weights, diet consumption, water intake, ophthalmology, gross pathology, organ weights, or histology. A Lys-related drop in serum concentration and an increase in urine excretion of chlorides was a compensatory reaction to the ingested hydrochloride. No functional, biochemical, or histological changes in renal function were found. The no-observed-adverse-effect level (NOAEL) for Lys was estimated at 5.0% for both genders (male, 3.36 +/- 0.12 g/kg/day; female, 3.99 +/- 0.28 g/kg/day).