Induction of Mid-term Abortion by Ricin A Chain in Mice

Ricin A chain, the potent inhibitor of protein synthesis, was evaluated for abortifacient activity using pregnant mice at mid-gestation. In a preliminary experiment, the intraperitoneal dose 50 µg per mouse killed all pregnant mice within 24 h with signs of vaginal bleeding and abortion. In subsequent experiments, pregnant mice given 100 ng each resulted in a decrease in maternal weight gain (48%, P<.05), while fetal weight showed a dose-related decrease of 19 and 22% in mice which received 50 or 100 ng respectively. In another experiment, the ricin A chain, administered as two successive doses (100 ng or 200 ng) on days 12 and 13 gestation, induced abortion in 16 to 67% of mice. At the same time 3 mice out of six, that received a dose of 100 ng/mouse lost w eight, whereas of those that received 200 ng. Four mice out of six lost weight and one died. Furthermore, laparotomized mice exhibited dead fetuses, separation of placenta and blood clots. These observations clearly indicate that the ricin A chain exhibits abortifacient effect, maternal and fetal toxicity in pregnant mice at mid-term.     

Final report on the safety assessment of Juniperus communis Extract, Juniperus oxycedrus Extract, Juniperus oxycedrus Tar, Juniperus phoenicea extract, and Juniperus virginiana Extract

The common juniper is a tree that grows in Europe, Asia, and North America. The ripe fruit of Juniperus communis and Juniperus oxycedrus is alcohol extracted to produce Juniperus Communis Extract and Juniperus Oxycedrus Extract, respectively. Juniperus Oxycedrus Tar is the volatile oil from the wood of J. oxycedrus. Juniperus Phoenicea Extract comes from the gum of Juniperus phoenicea, and Juniperus Virginiana Extract is extracted from the wood of Juniperus virginiana. Although Juniperus Oxycedrus Tar is produced as a by-product of distillation, no information was available on the manufacturing process for any of the Extracts. Oils derived from these varieties of juniper are used solely as fragrance ingredients; they are commonly produced using steam distillation of the source material, but it is not known if that procedure is used to produce extracts. One report does state that the chemical composition of Juniper Communis Oil and Juniperus Communis Extract is similar, each containing a wide variety of terpenoids and aromatic compounds, with the occasional aliphatic alcohols and aldehydes, and, more rarely, alkanes. The principle component of Juniperus Oxycedrus Tar is cadinene, a sesquiterpene, but cresol and guaiacol are also found. No data were available, however, indicating the extent to which there would be variations in composition that may occur as a result of extraction differences or any other factor such as plant growth conditions. Information on the composition of the other ingredients was not available. All of the Extracts function as biological additives in cosmetic formulations, and Juniperus Oxycedrus Tar is used as a hair-conditioning agent and a fragrance component. Most of the available safety test data are from studies using oils derived from the various varieties of juniper. Because of the expected similarity in composition to the extract, these data were considered. Acute studies using animals show little toxicity of the oil or tar. The oils derived from J. communis and J. virginiana and Juniperus Oxycedrus Tar were not skin irritants in animals. The oil from J. virginiana was not a sensitizer, and the oil from J. communis was not phototoxic in animal tests. Juniperus Oxycedrus Tar was genotoxic in several assays. No genotoxicity data were available for any of the extracts. Juniperus Communis Extract did affect fertility and was abortifacient in studies using albino rats. Clinical tests showed no evidence of irritation or sensitization with any of the tested oils, but some evidence of sensitization to the tar. These data were not considered sufficient to assess the safety of these ingredients. Additional data needs include current concentration of use data; function in cosmetics; methods of manufacturing and impurities data, especially pesticides; ultraviolet (UV) absorption data; if absorption occurs in the UVA or UVB range, photosensitization data are needed; dermal reproductive/developmental toxicity data (to include determination of a no-effect level); two genotoxicity assays (one in a mammalian system) for each extract; if positive, a 2-year dermal carcinogenicity assay performed using National Toxicology Program (NTP) methods is needed; a 2-year dermal carcinogenicity assay performed using NTP methods on Juniperus Oxycedrus Tar; and irritation and sensitization data on each extract and the tar (these data are needed because the available data on the oils cannot be extrapolated). Until these data are available, it is concluded that the available data are insufficient to support the safety of these ingredients in cosmetic formulations.     

Evaluation of the teratogenic potential of the dopamine agonist bromocryptine in rats

Single subcutaneous injections of bromocryptine (BCR; 2 mg/kg) to rats on days 5, 7 or 10 of gestation caused a lowering of the serum prolactin (PRL) concentration and, on days up to and including day 8 of gestation, abortion of entire litters. Coincident with the end of the PRL-dependent phase of gestation (approximately day 9), BCR was no longer abortifacient, allowing higher doses of the drug to be administered from this time without the risk of abortion. Treatment at 50 or 100 mg/kg from day 10 to 16 of pregnancy, despite affecting the dams (increased water consumption), had no adverse effects on pregnancy or fetal development.     

β-Trichosanthin: a new abortifacient protein from the Chinese drug,Wangua, Trichosanthes cucumeroides

β-Trichosanthin was a new abortifacient protein purified from the Chinese drug, Wangua, root tubers of Trichosanthes cucumeroides (Cucurbitaceae). The purification procedure involved acetone fractionation, ammonium sulfate precipitation, ion-exchange chromatography on CM-Sepharose and preparative agarose electrophoresis. Homogeneity of β-trichosanthin was demonstrated in immunoelectrophoresis, agarose electrophoresis and SDS-polyacrylamide gel electrophoresis. It had a molecular weight of 28 000 and no cysteine in its molecule. It differed from trichosanthin, a known abortifacient protein isolated from a related Chinese drug, Tianhuafen, root tubers of Trichosanthes kirilowii (Cucurbitaceae), in molecular weight, carbohydrate content, charge and amino acid composition. β-Trichosanthin was, however, immunochemically identical to trichosanthin and was about twice as potent as trichosanthin in inducing mid-term abortion in mice.     

米非司酮合并米索前列醇终止10～16周妊娠的疗效

目的：观察口服米非司酮合并米索前列醇终止１０～１６ｗｋ妊娠的临床疗效。方法：１７５例妊娠１０～１６ｗｋ妇女用２种不同剂量米非司酮（组Ⅰ２５ｍｇｂｉｄ×３ｄ，总量１５０ｍｇ；组Ⅱ２００ｍｇ单次用药），合并米索前列醇（最大剂量不超过１．６ｍｇ）口服。结果：２组流产成功率分别为８９％和８４％，Ｐ＞０．０５。组Ⅰ胎儿排出时间（７ｈ）明显短于组Ⅱ（９ｈ），Ｐ＜０．０１。组Ⅰ米索前列醇用量（０．７ｍｇ）明显少于组Ⅱ（１．０ｍｇ），Ｐ＜０．０１。结论：口服米非司酮合并米索前列醇终止１０～１６ｗｋ妊娠是安全有效的；给药方法以米非司酮小剂量多次给药法更可取。     

Effects of Tall Fescue Endophyte Type and Dopamine Receptor D2 Genotype on Cow-Calf Performance during Late Gestation and Early Lactation

Grazing endophyte-infected, toxic tall fescue reduces cow/calf production; therefore, this study examines alternate strategies such as use of novel endophyte fescue varieties during late gestation and early lactation or genetic selection of resistant cows. Pregnant cows (n = 75) were randomly assigned to fescue endophyte type: 1) endophyte-infected ergot alkaloid producing tall fescue (E+) or 2) novel endophyte-infected, non-toxic tall fescue (NOV) within maternal (A|A, n = 38 and G|G, n = 37) DRD2 genotype to examine changes in cow/calf performance and milk production during late gestation and early lactation. Grazing E+ fescue pastures during late gestation reduced cow body weight gain but did not alter calf birth weight compared to NOV. Milk production and calf ADG during the first 30 day of lactation were lower for E+ than NOV. The calving rate was reduced, but not calving interval for E+ cows. The adjusted 205-day weight of calves was lower in those grazing E+ with their dams compared to NOV. There were no interactions between DRD2 genotype and fescue endophyte type indicating that genotype was not associated with response to E+ fescue in this study. Overall, grazing NOV tall fescue pastures rather than E+ during critical stages of production improved cow gain during late gestation, calving rate, early milk production and calf growth.     

Evaluation of the antiabortifacient and embryotoxic effects of methylenedioxyindene and methylenedioxyindan calcium antagonists

Calcium channel blockers have been advocated as potential therapeutic agents in the management of premature labor. In the present study, the class of intracellular calcium antagonistic methylenedioxyindenes (MDIs) was investigated for potential antiabortifacient activity in mice. Pretreatment of pregnant mice from day 15 of gestation with the MDIs did not afford protection against the abortifacient effect of prostaglandin F2alpha administered from day 17 of gestation. The MDIs demonstrated embryotoxic and fetotoxic activity as shown by a significant increase in the incidence of resorptions and stillbirths. Similar embryotoxicity was previously reported for the calcium channel blockers. It appears doubtful that any of the calcium antagonists so far examined will be clinically useful in the management of premature labor.     

2种药流方法终止8～14周妊娠临床疗效比较

目的探讨2种药流方法终止8～14周妊娠的临床效果。方法将要求终止妊娠的8．14周正常早孕女性135例,随机分成两组：复方组67例,晨服复方米非司酮1片／24h02次（总量：米非司酮60mg,双炔失碳酯10mg）,首次服药后48h加服米索前列醇0．6mg,每隔4小时阴道内放置米索前列醇0．4mg,米索前列醇最多一天不超过9片（1．8mg）;单方组68例,一次顿服米非司酮150mg,米索前列醇用法同复方组。用药后观察患者的不良反应、阴道开始出血情况、腹痛情况、胎儿娩出距首次阴道塞药时间、胎儿娩出时阴道出血量、米索前列醇用量,是否需要清宫,同时随访流产后15天、45天,观察患者阴道出血持续时间、出血量的多少及月经转经时间。结果复方组在流产成功率、完全流产率优于单方组,但在米索前列醇用量及妊振物排出时间、流产后阴道流血持续时间、出血量及下次月经转经时间上两组之间差异无显著性（P〉0．05）。结论复方米非司酮配伍米索前列醇能安全有效终止8—14周正常妊振,疗效较好,流产成功率较满意。具有米非司酮剂量小,服药简便等优点。     

Effects of amethopterin (methotrexate) on the evolution of pregnancy in rats.

Amethopterin (4-amino-N-10-methyl-glutamic acid) was given to pregnant rats in varying doses at different periods of gestation to evaluate its effects upon both the mother and the fetoplacental unit. The maternal organism is more sensitive to this drug at days 14 to 17 than at a larger stage of gestation. When administered to rats from day 14 to day 18 of pregnancy the drug is capable of inducing a series of deleterious effects: maternal weight loss, resorption, abortion or hypotrophy of fetuses. Day 16 appears to be a critical moment in the evolution of rat pregnancy, after which injection of amethopterin does no longer impair fetoplacental growth. Before this date, the drug directly inhibits fetal weight gain, whereas the sensitivity of the placenta is only transient at day 16 resulting in maximum weight decrease of this organ 24 h later. Its action on rat pregnancy follows a direct dose-effect relationship reflecting increasing damage to the products of conception (resorption, abortion and hypotrophy).     

The phytochemical and genetic survey of common and dwarf juniper (Juniperus communis and Juniperus nana) identifies chemical races and close taxonomic identity of the species

Juniperus communis L. (= J. communis var. communis) and Juniperus nana Willd. (= J. communis var. SAXATILIS) are subspecies of juniper. J. communis grows widely in both hemispheres, primarily in lower elevations while J. nana is mainly observed in high mountains. Although they can be distinguished by morphological features, it is not known whether they are genetically and phytochemically distinct entities. We aimed to check whether it is possible to distinguish these two plants (i) by pharmaceutically important chemical traits and (ii) on the basis of intraspecifically highly polymorphic fragment of chloroplast DNA. We used GC with achiral as well as with enantioselective stationary phase columns to identify the main monoterpenes of the essential oil. Sequence analysis of the TRNL (UAA)- TRNF (GAA) intergenic spacer of the chloroplast genome was used as a genetic marker of taxonomic identity between these two subspecies. The chromatographic analysis showed the existence of three chemical races - the alpha-pinene type, the sabinene type and one with intermediate contents of these terpenes among both J. communis and J. nana. Surprisingly, sequence analysis of TRNL (UAA)- TRNF (GAA) revealed 100 % similarity between the common and the dwarf juniper. Thus, the monoterpene pattern is related to geographical origin, and not to the species identity. We suggest that the three chemical races identified in the present study should be considered as separate sources of pharmaceutical raw material. Our results demonstrate that the contents of alpha-pinene and sabinene may be applied as a quick diagnostic test for preliminary evaluation of plant material.     

Isolation and characterization of an abortifacient protein,momorcochin, from root tubers of Momordica cochinchinensis (Family Cucurbitaceae)

A glycoprotein with a molecular weight of 32 000 as estimated by SDS-polyacrylamide gel electrophoresis, and characterized by an abundance of Asp and Glu residues and an absence of Cys residues in its amino acid analysis, was isolated from fresh root tubers of Momordica cochinchinensis using a procedure that involved acetone precipitation, ammonium sulfate precipitation, ion exchange chromatography on DEAE Sepharose CL-6B and gel filtration on Sephadex G-75. The protein was capable of inducing mid-term abortion in mice. The characteristics of this protein were compared and contrasted with those of the abortifacient proteins isolated from other plants of the Cucurbitaceae family.     

Trichosanthin, α-momorcharin and β-momorcharin: identity of abortifacient and ribosome-inactivating proteins

The abortifacient proteins trichosanthin, α-momorcharin and β-momorcharin at nM concentrations inhibit cell-free protein synthesis. The momorcharins and the ribosome-inactivating proteins isolated from Momordica charantia seeds cross-react with the respective antisera. The ribosome-inactivating proteins saporins, pokeweed antiviral protein (PAP) and, to a lesser extent, gelonin have abortifacient activity on pregnant mice.     

Effects of locoweed (Oxytropis sericea) on reproduction in cows with a history of locoweed consumption.

Locoweed (Oxytropis sericea) was fed to 4 open cycling cows that had repeatedly consumed locoweed in previous grazing trails. They received locoweed at 20% of their diet for 30 d (0.68-0.76 mg swainsonine/kg/d). Locoweed induced an immediate rise in serum swainsonine (the locoweed toxin) and a concomitant drop in serum alpha-mannosidase activity in all cows accompanied by abnormal estrus behavior, increased estrous cycle lengths and failure to conceive. Serum progesterone (P4) profiles demonstrated that estrous cycles lengthened from an average of 19 d before locoweed feeding to an average of 34 d (range 24-43 d) while on locoweed. After locoweed feeding ceased, normal estrous cycles returned within an average of 14 d (range 7-25 d). Two of the 4 cows conceived on their first post-locoweed estrus at 7 and 25 d. The third cow bred twice at 13 and 31 d after lowoweed feeding stopped, and the fourth cow bred 3 times at 11, 31 and 52 d before conception occurred. Pregnancies in all 4 cows progressed normally to 7 mo gestation when locoweed was again fed at 20% of the diet for 40 d (gestation days 213 and 253) to 2/4 cows, 1 of which aborted 10 d after lowoweed feeding stopped (263 days gestation). The other cow fed lowoweed calved normally as did the 2 pregnancy control cows. Serum P4 and estradiol (E2) profiles during pregnancy appeared normal before, during and after locoweed feeding except in the cow that aborted, whose P4 declined and E2 increased prematurely. The general trend of serum prolactin was similar in locoweed-fed and control cows.     

Isolation of a ribosome-inactivating and abortifacient protein from seeds of Luff a acutangula

A glycoprotein with a molecular weight of 28 000 as estimated by SDS-polyacrylamide gel electrophoresis was isolated from seeds of Luffa acutangula using a procedure that involved acetone precipitation, ion exchange chromatography on CM Sepharose CL-6B and gel filtration on Sephadex G-50. In immunodiffusion studies it was found to be immunologically distinct from abortifacient proteins isolated from other members of the Cucurbitaceae family including Momordica charantia, Momordica cochinchinensis, Trichosanthes kirilowii and Trichosanthes cucumeroides. There were some differences in amino acid composition among the proteins although there was a gross similarity. The protein from L. acutangula was capable of inducing mid-term abortion in mice and inhibiting protein synthesis in a cell-free system.     

Sensitivity to diethylstilbestrol-(DES)-induced abortions is influenced by the Whitten effect

Group-housed female mice, when introduced to a male, will undergo a synchronized estrous cycle with a characteristic pattern of mating where the majority of animals mate on the third day. This phenomenon is termed the Whitten effect. Exposure of pregnant mice to diethylstilbestrol (DES), a potent nonsteroidal estrogen, is capable of inducing premature parturition. The purpose of this study was to evaluate abortion induced by a single injection of DES on day 15 of gestation and compare the sensitivity depending on the day of mating. Initial observations confirmed that those animals that mated on day 3 were significantly more susceptible to DES-induced abortion than animals that mated on any other day. The possibility that this increase in sensitivity to abortion may be the result of differences in number or size of embryos at the time of DES exposure was examined. No significant difference was observed in the number of embryos at day 4 of gestation, at day 15 of gestation, or at birth. There was no difference in the weight of embryos at day 15 of gestation or at birth. A significant increase in the ratio of embryos between uterine horns was observed in the animals that mated on day 3 (ratio = 2.13) compared to animals mating on other days (ratio = 1.23 to 1.48). The cause of increased sensitivity to DES in animals that mated on day 3 is unclear. Our results may indicate that the induction of ovulation associated with the Whitten effect causes unequal embryo distribution leading to functional differences in sensitivity of the pregnancy to exogenous stimuli.(ABSTRACT TRUNCATED AT 250 WORDS)     

Teratological evaluation of Juniperus sabina essential oil in mice

Juniperus sabina essential oil was evaluated for its fetotoxic potential on mice. Pregnant dams were injected s.c. (15-45 or 135 mg essential oil/kg body weight) on days 6 to 15 of gestation. They were killed and the uterine contents were examined on day 19 of pregnancy. The fetuses were removed for examination. The dams of the two higher treated groups showed a significant weight loss as compared to controls. An hepatotoxicity was observed among females that resorbed their whole litter, thus indicating a greater susceptibility towards Juniperus sabina essential oil during pregnancy. The essential oil induced, in the three treated groups, an embryotoxicity as manifested by a statistically significant increase in the number of affected litters; but no fetotoxicity.     

Analogs of the abortifacient aminoglutethimide

The abortifacient properties of analogs of aminoglutethimide were tested in rats. Aminoglutethimide is nonsteroidal and nonestrogenic, and induces abortion in pregnant rats by interfering with the conversion of cholesterol to delta5-pregnenolone. However, the spread between efficacy (100 mg/kg) and toxicity (200 mg/kg) is not large, thus limiting its potential use in humans. A series of derivatives, Schiff b ases and an unsaturated ring system were prepared. None of the prepared analogs demonstrated the abortifacient activity of aminoglutethimide. It is concluded that the abortifacient activity of aminoglutethimide is highly specific, and that all changes made caused the activity to be lost. The experimental procedures involved in preparing the analogs are described.     

剖宫产后再次妊娠引产66例临床分析

目的 通过对66例剖宫产后再次妊娠引产的病例分析,总结其可能出现的危险及观察处理的体会.方法 66例患者中,18例(7～16孕周)予米非司酮配伍米索前列醇药流;48例(16 1～28孕周)予利凡诺羊膜腔内引产术.结果 米非司酮配伍米索前列醇组成功率为88.89%,利凡诺组成功率100%.结论 米非司酮配伍米索前列醇及利凡诺选择用于终止不同孕周的剖宫产后再次妊娠是安全有效的.     

Effects of CKD-602, a new camptothecin anticancer agent, on pregnant does and embryo-fetal development in rabbits

CKD-602 is a newly developed camptothecin anticancer agent. Preclinical studies suggest that it may have greater antitumor activity and lower toxicity than other camptothecin anticancer agents. The potential of CKD-602 to induce developmental toxicity was investigated in the New Zealand White rabbit. Seventy-two artificially inseminated females (artificial insemination=day 0) were distributed among three treatment groups and a control group. CKD-602 was at dose levels of 0, 0.024, 0.048, or 0.096 mg x kg(-1) x day(-1) administered intravenously to pregnant does from days 6 to 18 of gestation. All does were subjected to caesarean section on day 28 of gestation. At 0.096 mg x kg(-1) x day(-1), 2 cases of abortion and 3 cases of death in pregnant rabbits were found in late gestation. In addition, an increase in the embryonic resorptions and a decrease in the litter size were found. At 0.048 mg x kg(-1) x day(-1), a single doe aborted on gestational day 26. An increase in the embryonic resorptions and fetal morphological alterations and a decrease in the litter size were also found. There were no signs of maternal toxicity or developmental toxicity at 0.024 mg x kg(-1) x day(-1). The results show that 13-day repeated intravenous dose of CKD-602 during the major organogenetic period in rabbits produces increased incidence of abortion and death, increased number of embryonic resorptions and fetal morphological alterations, and decreased litter size at dose levels of above 0.048 mg x kg(-1) x day(-1). In the current experimental conditions, the no-observed-adverse-effect levels (NOAELs) of CKD-602 are considered to be 0.048 mg x kg(-1) x day(-1) for does and 0.024 mg x kg(-1) x day(-1) for embryo-fetal development.     

Assessment of the teratogenicity of di(2-ethylhexyl)phthalate and mono(2-ethylhexyl)phthalate in mice

Di(2-ethylhexyl)phthalate (DEHP) and mono(2-ethylhexyl)phthalate (MEHP) were administered PO or IP to pregnant ICR mice at varying doses on days 7, 8, and 9 of gestation. In groups given DEHP orally, resorptions and malformed fetuses increased significantly at 1,000 mg/kg. Fetal weights were also significantly suppressed. Anterior neural tube defects (anencephaly and exencephaly) were the malformations most commonly produced. No teratogenic effects were revealed by IP doses of DEHP and PO or IP doses of MEHP, although high doses were abortifacient and lethal to pregnant females. Thus DEHP is highly embryotoxic and teratogenic in mice when given PO but not IP. The difference in metabolism, disposition, or excretion by the route of administration may be responsible for the difference in DEHP teratogenicity. Although MEHP is a principal metabolite of DEHP and is several times more toxic than DEHP to adult mice, it seems that MEHP and its metabolites are not teratogenic in ICR mice.