Studies on Mutagenicity and Teratogenicity of Sarafloxacin

Wistar rats and closed Kunming strain mice were selected to study the genetic toxicity of sarafloxacin. The results indicated that sarafloxacin had no significant toxic effect of an excreted mutagen in S. typhimurium strains, and did not induce significantly higher percentages of polychromatic erythrocytes with micronuclei (MNPCE) in mice. No significant mutagenic activity was observed in dominant lethal assay. At 5 and 50mg/kg b.w. , sarafloxacin did not produce significant effects on the reproductive parameters of litters and fetal growth, and did not induce the teratogenic effects on fetuses. Sarafloxacin induced some toxic effects on body length and skeletal growth in fetuses of 500mg/kg b.w., but had no significant dose - response relationship among the administered dosages of sarafloxacin. The results of the genetic toxicology above indicated that no evidence showing sarafloxacin was mutagenic and potentially teratogenic for animals.

Studies on the Mutagenicity and Teratogenicity of Kuianchun and Its Potential Carcinogenicity Prediction

Kuianchun is a newly synthesized antibacterial and growth-promoting drug. This paper selected a battery of three short-term tests, including Ames test, micronucleus test and sperm abnormality test, to detect the mutagenicity of Kuianchun. The carcinogenicity prediction and battery selection method (CPBS method) was used to determine the probability of carcinogenicity of Kuianchun based upon the results of short-term tests mentioned above. In addition, traditional teratogenic test was selected to study teratogenicity of Kuianchun. In Ames test, Kuianchun showed mutagenic for Salmonella typhimurium strains TA98 and TA100 in the absence and presence of microsomal metabolic activation system (S9-mix). However, the mutagenicity was reduced by the addition of S9-mix. In micronucleus test, Kuianchun was administered intra-peritoneally to male mouse 30 hours and 6 hours before they were killed respectively. The result indicated that there was no significant difference on the number of micronucleated polychromatic erythrocytes (PCEs) in the mouse bone marrow induced by Kuianchun compared with the negative contrast (50% DMSO) (P>0.05). In sperm abnormality test, Kuianchun was administered through a gastric incubation to male mouse as a suspension in 2% Tween-80. The dosage levels were 450, 750, 1000 and 1500mg/kg per day for 5 days. The result indicated that the percentage of abnormal sperms induced by Kuianchun was not significant compared with the negative contrast (P > 0.05). In traditional teratogenic test, Kuianchun was given orally to pregnant mouse at 1730, 1/20 and 1/15 LD50 during 6 - 15days of pregnancy period (the LD50 = 9000mg/kg). No toxicity was found either on mother and embryo in mouse, and teratogenic effects were also not observed at all tested dosages.The probability of carcinogenicity of Kuianchun is 23.8%(6 = 0.238). The result demonstrated that Kuianchun is a non-carcinogen.

Teratogenicity Studies of a New Potent Tetanus Vaccine in Rabbit (Oryctolagus cuniculus)

Glaxo Laboratories, Bombay, have prepared a potent tetanus vaccine of 250 Lf as a substitute of the previous 5 Lf tetanus vaccine. The safety evaluation of the vaccine has been reported, but the teratogenic potential was not studied. In the experiment reported herein we have studied the teratogenic action of the vaccine in the progeny of rabbits. No congenital anomalies were observed.

Developmental Toxicity and Potential Teratogenicity of Compound Danshen Tablet, Angong Niuhuang Pill, and Lidan Paishi Tablet in Zebrafish Embryos

Objective Herbal medicines containing toxic herbs or minerals such as Compound Danshen Tablet （CDT）, Angong Niuhuang Pill （ANP）, and Lidan Paishi Tablet （LPT） are avoided or used with caution for pregnant women because of potential teratogenicity. To understand their mechanism, they were chosen as model subjects for the research. Methods Zebrafish embryos were used to evaluate their potential teratogenic risk in vitro. Results All of them showed teratogenic and lethal effects in zebrafish embryos, with the ECs0 values at 351,793, and 220 μg/mL, and LC50 values at 41 7, 596, and 380 μg/mL, respectively. CDT and LPT, displaying week potential teratogenicity as their teratogenicity indexes were greater than 1, induced tail malformation and cardiac edema mainly in zebrafish embryos, respectively. Conclusion The results provide the significant guidance of clinical safety of medication.

Systematic review of safety and efficacy of therapeutic endoscopic-retrograde-cholangiopancreatography during pregnancy including studies of radiation-free therapeutic endoscopic-retrograde-cholangiopancreatography

AIM To systematically review safety/efficacy of therapeutic endoscopic-retrograde-cholangiopancreatography(ERCP) performed during pregnancy, considering fetal viability, fetal teratogenicity, premature delivery, and future postpartum development of the infant.METHODS Systematic computerized literature search performed using PubMed with the key words "ERCP" and "pregnancy". Two clinicians independently reviewed the literature, and decided on which articles to incorporate in this review based on consensus and preassigned priorities. Large clinical trials, meta-analyses, systematic reviews, and controlled trials were assigned higher priority than review articles or small clinical series, and individual case reports were assigned lowest priority. Dr. Cappell has formal training and considerable experience in conducting systematic reviews, with 4 published systematic reviews in peer-reviewed journals indexed in PubM ed during the last 2 years, and with a PhD in neurophysiology that involved 5 years of training and research in biomedical statistics.RESULTS Advances in imaging modalities, including abdominal ultrasound, MRCP, and endoscopic ultrasound, have generally obviated the need for diagnostic ERCP in nonpregnant and pregnant patients. Clinical experience with performing ERCP during pregnancy is burgeoning, with > 500 cases of therapeutic ERCP reported in the literature, aside from a national registry study of 58 patients. These studies show that therapeutic ERCP has a very high rate of technical success in clearing the bile duct of gallstones, and has a relatively low and acceptable rate of maternal and fetal complications. The great majority of births after therapeutic ERCP are full-term, have normal birth weights, and are healthy. A recent trend is performing ERCP without radiation to eliminate radiation teratogenicity. Systematic literature review reveals 147 cases of ERCP without fluoroscopy in 8 clinical series. These studies demonstrate extremely high technical success in endoscopically removing choledocholithiasis, favorable maternal outcomes with rare maternal ERCP complications, and excellent fetal outcomes. ERCP without fluoroscopy generally confirms proper biliary cannulation by aspiration of yellow bile per sphincterotome or leakage of yellow bile around an inserted guide-wire.CONCLUSION This systematic literature review reveals ERCP is relatively safe and efficacious during pregnancy, with relatively favorable maternal and fetal outcomes after ERCP. Recommendations are provided about ERCP indications, special ERCP techniques during pregnancy, and prospects for future research.

Gastrointestinal endoscopy in the pregnant woman

About 20000 gastrointestinal endoscopies are performed annually in America in pregnant women. Gastrointestinal endoscopy during pregnancy raises the critical issue of fetal safety in addition to patient safety. Endoscopic medications may be potentially abortifacient or teratogenic. Generally, Food and Drug Administration category B or C drugs should be used for endoscopy. Esophagogastroduodenoscopy(EGD) seems to be relatively safe for both mother and fetus based on two retrospective studies of 83 and 60 pregnant patients. The diagnostic yield is about 95% when EGD is performed for gastrointestinal bleeding. EGD indications during pregnancy include acute gastrointestinal bleeding, dysphagia > 1 wk, or endoscopic therapy. Therapeutic EGD is experimental due to scant data, but should be strongly considered for urgent indications such as active bleeding. One study of 48 sigmoidoscopies performed during pregnancy showed relatively favorable fetal outcomes, rare bad fetal outcomes, and bad outcomes linked to very sick mothers. Sigmoidoscopy should be strongly considered for strong indications,including significant acute lower gastrointestinal bleeding, chronic diarrhea, distal colonic stricture, suspected inflammatory bowel disease flare, and potential colonic malignancy. Data on colonoscopy during pregnancy are limited. One study of 20 pregnant patients showed rare poor fetal outcomes. Colonoscopy is generally experimental during pregnancy, but can be considered for strong indications: known colonic mass/stricture, active lower gastrointestinal bleeding, or colonoscopic therapy. Endoscopic retrograde cholangiopancreatography(ERCP) entails fetal risks from fetal radiation exposure. ERCP risks to mother and fetus appear to be acceptable when performed for ERCP therapy, as demonstrated by analysis of nearly 350 cases during pregnancy. Justifiable indications include symptomatic or complicated choledocholithiasis, manifested by jaundice, cholangitis, gallstone pancreatitis, or dilated choledochus. ERCP should be performed by an expert endoscopist, with informed consent about fetal radiation risks, minimizing fetal radiation exposure, and using an attending anesthesiologist. Endoscopy is likely most safe during the second trimester of pregnancy.

Pregnancy in Coronavirus Disease (COVID-19) Pandemic: Clinical Opinion

Coronavirus disease (COVID-19) is an infectious disease caused by a newly discovered coronavirus. This novel coronavirus is called SARS-COV-2 and the disease that it causes is called COVID-19 causes serious respiratory morbidity and mortality. We aim to spot COVID-19 disease during pregnancy during this pandemic era. COVID-19 has various clinical presentations almost same in pregnant and non-pregnant victims. The hallmark for treatment is supportive management. Vertical transmission is probable but still not well confirmed and no evidence for virus in amniotic fluid, cord blood, neonatal throat swabs, placenta swabs, genital fluid and breastmilk samples from COVID-19 infected mothers. Research is running everywhere looking step ahead for actual treatment and vaccination. COVID-19 is newly emerged disease still not well explored in many aspects looking for soon definite treatment and vaccination for prevention to roll COVID-19.

Effects of Copaiba Oil on Cyclophosphamide-Induced Teratogenesis in Mice

Cyclophosphamide is an anti-neoplastic chemotherapy drug which, when administered to animals during the gestational period, provokes visceral, skeletal and external malformations. Copaiba oil obtained from Copaifera L. genus is traditionally used in popular medicine for its anti-inflammatory and antimicrobial activities. However, the effect of copaiba oil onteratogenesis remains unknown. This study aimed to investigate the possible protector effects of copaiba oil on the model of teratogenesis induced by cyclophosphamide in mice. Pregnant female Swiss mice were divided into 8 groups (n = 15). Three groups received copaiba oil, via gavage, in the following doses: 0.3 mL·Kg-1, 0.6 mL·Kg-1 and 0.9 mL·Kg-1 (b.w.), associated to phosphate-buffered saline (PBS), intraperitoneal (i.p.). The negative control group received medium chain triglyceride (MCT) and PBS. The positive control group received cyclophosphamide (30 mg·Kg-1 (b.w.)) and MCT. The three treatment groups called associated groups (A) received one of the doses of copaiba oil, via gavage and an associated dose of cyclophosphamide intraperitoneally. Copaiba oil presented a protective effect against teratogenesis induced by cyclophosphamide in the following skeletal structures: metacarpals, forepaws proximal phalanges, and tail vertebras. It also reduced the hydrocephalus frequency. These data suggest that copaiba oil could be a potential candidate for an anti-teratogenic agent.

Optimal culture conditions and toxicity assessment of Fomitopsis feei(Fr.):a newly documented macro fungus from Philippines

Mushrooms are known to be utilized by ethnic communities and Paracelis,Mountain Province is one of the places in Philippines inhabited by several of these native groups.Many studies have been conducted on various macrofungi,however no studies have been reported about Fomitopsis feei in the Philippines particularly in Paracelis,Mountain Province.It is a brown-rot bracket fungus,belonging to the family Fomitopsidaceae,characterized by a sessile effuse-reflexed basidiomata,with its color ranging from white to pinkish or brown.This mushroom has been reported to have antimicrobial properties,hence optimization of its culture condition could lead to its mass production for its biopharmaceutical potential.In order to develop a mass cultivation protocol of this mushroom,this study was conducted to determine the optimum conditions for its mycelial growth.The effect of different culture media using local substrates and evaluating environmental factors such as pH,aeration,illumination,and temperature were assessed.Optimum conditions for the secondary mycelial growth of F.feei produced very thick and largest radial growth on coconut water gelatin(CWG)medium(83.57 mm)at pH 6.5(83.13 mm),in sealed(85 mm),dark conditions(85.00 mm)at room temperature(28-32℃)(81.96 mm).The most abundant mycelial growth was found in cracked corn as grain spawning material.This study also determined the teratogenic and cytotoxic activity of the ethanol extract of F.feei against the zebra fish(Danio rerio)embryos and brine shrimp(Artemia salina)nauplii.Fomitopsis feei exhibited teratogenic effects against the developing D.rerio embryos wherein growth retardation,malformation of tail,yolk deformity,pericardial edema,curved body,scoliosis and little pigmentation were the notable teratogenic effects of the ethanol extract to the developing embryos.Embryos treated with≥1000 ppm recorded high mortality rate.Hatchability was most evident at lower concentrations≤750 ppm.In terms of heartbeat,as the concentration of the extract increased,the heartbeat rate significantly decreased.For the cytotoxicity,1250 ppm has the highest mortality rate with 73.33%.Using probit analysis,the LC_(50)is 534.676 ppm which is considered as mildly toxic.Thus,F.feei in higher concentrations exhibit toxic effect.These results indicate that F.feei has a pharmaceutical potential and could be harnessed for its bioactivities.

Some of the experimental and clinical aspects of the effects of the maternal diabetes on developing hippocampus

Diabetes mellitus during pregnancy is associated with an increased risk of multiple congenital anomalies in progeny.There are sufficient evidence suggesting that the children of diabetic women exhibit intellectual and behavioral abnormalities accompanied by modification of hippocampus structure and function.Although,the exact mechanism by which maternal diabetes affects the developing hippocampus remains to be defined.Multiple biological alterations,including hyperglycemia,hyperinsulinemia,oxidative stress,hypoxia,and iron deficiency occur in pregnancies with diabetes and affect the development of central nervous system(CNS) of the fetus.The conclusion from several studies is that disturbance in glucose and insulin homeostasis in mothers and infants are major teratogenic factor in the development of CNS.Insulin and Insulin-like growth factor-1(IGF-1) are two key regulators of CNS function and development.Insulin and IGF-1 receptors(IR and IGF1 R,respectively) are distributed in a highly specific pattern with the high density in some brain regions such as hippocampus.Recent researches have clearly established that maternal diabetes disrupts the regulation of both IR and IGF1 R in the hippocampus of rat newborn.Dissecting out the mechanisms responsible for maternal diabetes-related changes in the development of hippocampus is helping to prevent from impaired cognitive and memory functions in offspring.

Embryonic Hypertension Following Exposure to Teratogenic Doses of 5-Fluoro-2'-Deoxyuridine

The teratogenicity of 5-fluoro-2'-deoxyuridine (FdU) is well established. Previously, we have demonstrated that teratogenic doses of FdU produce hematomas and suggested that those hematomas produced skeletal malformations in chicken embryos. In this study, the cardiovascular effects of teratogenic doses of FdU in chicken embryos were studied. A dose of either 0.026 μg FdU or 0.030 μg FdU was injected into the yolk sacs of fertile chicken eggs containing embryos at Hamburger and Hamilton stages 17-19 of development. The embryos were then returned to the incubator. Aortic systolic and diastolic blood pressure,blood velocity and heart rate were measured at stages 21, 24 or 27 using a servonull system and Doppler ultrasound. In addition, mean arterial blood pressure, blood flow, and stroke volume were calculated from these data. Similar data were also recorded from uninjected and saline injected control embryos. Systolic and mean arterial blood pressures were significantly increased in FdU-treated embryos at stage 27. The other parameters measured or calculated were not significantly different from control embryos. Our study suggests that elevated systolic blood pressure in chicken embryos treated with FdU may lead to hematoma formation and subsequent birth defects

Usage of Potential Teratogenic Chemical Preparations among Mothers of Children Attending the Multidisciplinary Cleft Clinic at the Komfo Anokye Teaching Hospital, Ghana

Objective: The purpose of this study is to determine the usage of potential teratogenic chemicals among cleft lip and palate mothers attending a multidisciplinary cleft clinic at Komfo Anokye Teaching Hospital (KATH). Method: This is a retrospective study based on records of consecutive patients attending the multidisciplinary cleft clinic at KATH. Mothers of children with cleft lip and palate formed the study sample. Information on the use of chemical agents by the mothers either before or during the first three months of pregnancy was collected on to a specially designed form. The study period was from January 2006 to December 2012. Setting: The study was carried out in a multidisciplinary cleft clinic at Komfo Anokye Teaching Hospital in Ghana. The clinic is the main referral centre for the northern sector of Ghana for cleft lip and palate care. Results: Chemical preparations usage ranged from 0.2% for tobacco to 25.3% for skin lightening creams. Other agents used include, enema, non-proprietary concoctions and prednisolone tablets. 2.1% of the mothers ingested alcohol during pregnancy. Conclusion: There is a high level of usage of potentially teratogenic chemicals among cleft mothers attending the multidisciplinary cleft lip and palate clinic at the Komfo Anokye Teaching Hospital in Ghana. Further studies are, however, required to clarify any relationship this may have with the development of orofacial clefts.

An Ongoing Epidemic of Birth Defects

In the 1990s, misoprostol (synthetic prostaglandin E1 analogue) was found to be an effective abortive agent when taken orally and became widely used in Latin America as a means to terminate unwanted pregnancies. A variety of congenital anomalies have been observed among the children of women who ingested misoprostol, but failed to terminate their pregnancy. We report here eight years of experience in Panama with the detection and follow-up of the malformations seen in infants associated with the use of misoprostol prostaglandin during the first trimester of pregnancy. During the period between April 1995 and March 2003, we identified 63 infants at the Panama’s Children’s Hospital who were exposed to misoprostol while in the womb and who were born with malformations. These infants were evaluated by a team of neonatologists, geneticists, cardiologists, ophthalmologists, and radiologists.

Histological observation on unique phenotypes of malformation induced in Xenopus tropicalis larvae by tributyltin

Tributyltin（TBT）,a biocide used in antifouling paints,has shown strong teratogenic effects on Xenopus tropicalis embryos at environmentally relevant concentrations.X.tropicalis embryos were exposed to 50,100 and 200 ng/L tributyltin chloride for 72 hr.The histological changes were further observed on abnormal eyes,enlarged trunks,enlarged proctodaeums and absence of fins induced by TBT.The lens and the retinal layers of abnormal eyes were slightly or barely differentiated,and that the pigment epithelium was neither continuous nor smooth.The abdomens were full of undifferentiated gut tissue with yolk-rich inclusions in the tadpoles with enlarged trunks.The proctodaeums formed a bump-like or columnar structure.The mass of yolk-rich cells occupied the lumen,blocked the opening and even turned inside out of the proctodaeum.Both the ventral and dorsal fins in trunks and tails became narrow or even disappeared totally.Our results suggest that great changes of histology took place corresponding to the unique phenotypes.The gut tissue was poorly differentiated,which led to the failed elongation of the guts and subsequently the enlarged trunks.The enlarged proctodaeums were due to the undifferentiation of inner layer,the expansion of outer epidermal part and the absence of fins around them.In brief,the histological observations provided insights into the reason of the unique external malformations in some degree.

Pregnancy and Crohn’s disease:concerns and assurance of medical therapy

Approximately 50%of patients with inflammatory bowel disease including both Crohn’s disease and ulcerative colitis are female with many being diagnosed and treated during their reproductive years.It is important for women to be in remission prior to and during pregnancy.There have been many advances in the treatment of inflammatory bowel disease,including new therapies.In this review,we summarize the currently approved medications for Crohn’s disease and their safety in pregnancy and postpartum.The totality of evidence suggests that the majority of therapies are low-risk before and during pregnancy,and should be continued to control maternal disease.

Reproductive toxicity study with a novel deoxyguanosine analogue （Metacavir） in pregnant SD rats

Our preliminary studies demonstrated that Metacavir has potential to become a new anti-HBV agent. The main targets of the toxic effects of Metacavir, in rhesus monkeys, were gastrointestinal tracts, liver, blood, and kidneys, which were not related to mitochondrial effects. In this study, the maternal toxicity, embryo-fetal developmental toxicity and teratogenicity were studied in pregnant Sprague-Dawley rats after intragastric administration of Metacavir （200, 100, 50, 0 mg/kg body weight） during the first 6-15 days of pregnancy. Slower weight gain was observed in 5 out of 21 rats subjected to a 200 mg/kg dose, as well as 2 out of 20 subjected to a 100 mg/kg dose. Compared with the solvent control group, the calibration weight gain in the 200 mg/kg and 100 mg/kg dosage groups respectively, during first 6-20 pregnant days were significantly different （P 〈 0.01, P 〈 0.05）. Significant dose related adverse effects to other reproductive parameters were not seen in F0 and F1, but the number of stillbirths in high dose group showed notably difference compared with the control group （P 〈 0.05）, while the litter incidence showed no difference. No Metacavir-associated pathological changes were observed. The present research indicated that at a dose of 200 mg/（kg·d） （i.e., 40 times the effective dose in rats）, Metacavir shows some maternal toxicity to SD rats. The embryotoxicity in the 200 mg/kg group encompass decreased fetal body weight, and higher fetal mortality rates, compared with the control group. However, the litter incidence showed no statistical difference. All the treated rats displayed normal bone development, no teratogenicity and without adverse effects on fetal development, thus indicating that below a dose of 200 mg/（kg· d） there is no teratogenic side effects.

Paroxetine overdose during pregnancy

Paroxetine is a selective serotonin reuptake inhibitor(SSRI)used in the treatment of depression and anxiety disorders.In some epidemiological studies,slightly increased risks of major malformations and cardiac malformations have been reported following paroxetine exposure in the first trimester of pregnancy.However,such findings have been inconsistent.There is only one report of any overdose of an SSRI during pregnancy,and that involved escitalopram.The aim of this case report was to describe the impact of a paroxetine overdose in the first trimester of pregnancy on the health of the foetus.A 21-year-old mother of one child who was pregnant with a second child was prescribed 20 mg/day paroxetine hydrochloride for the treatment of anxiety/depression.The patient ingested 15 or 1620-mg tablets of paroxetine hydrochloride(300-320 mg)during the 5th week of pregnancy as a suicide attempt.Within 15 min of ingestion,she was admitted to hospital and treated for intoxication.No evidence of maternal SSRI intoxication was observed after treatment.The patient consulted our teratology information service for further risk assessment regarding possible major congenital malformations following the paroxetine overdose.We were unable to find previous reports of paroxetine overdose during pregnancy in the literature.The timely administration of the overdose treatment and the lack of maternal intoxication symptoms were considered positive for the foetal well-being,and the patient was referred for perinatology and psychiatry follow-ups.A healthy,3500-g male infant was born at 38 weeks’gestation,and his development at the age of 2 years was normal.This is the first reported case of paroxetine overdose during pregnancy.Comprehensive studies are needed to evaluate pregnancy outcomes after SSRI overdose.

Managing reproductive problems in women with epilepsy of childbearing age

Girls and women constitute nearly 50%of all epilepsy cases.Apart from the disease symptoms,epilepsy and antiseizure medications(ASMs)may also affect the reproductive function,pregnancy and even the health of their offspring.Therefore,it is very important to identify and summarize the problems and risks for women with epilepsy(WWE)of childbearing age,and offer internationally recognized methods through multidisciplinary collaboration.In this review,we summarize the reproduction-related problems with WWE and propose multidisciplinary management by epileptologists,gynecologists and obstetricians,as well as other experts,from preconception to delivery.Large,multicenter registries are needed to advance our knowledge on new ASMs and their effects on WWE and their offspring.

Unexpected phenotypes of malformations induced in Xenopus tropicalis embryos by combined exposure to triphenyltin and 9-cis-retinoic acid

Xenopus tropicalis embryos were exposed for 48 hr to the mixtures of 5 μg Sn/L triphenyltin （TPT）, which is a well-known endocrine disruptor, and 0.25-5 μg/L 9-cis retinoic acid （9c-RA）, which is the natural ligand of retinoid X receptor. The phenotypes induced by combined exposure were more variable than those resulting from single exposure to either TPT or 9c-RA. The prominent phenotypes included underdeveloped head structures, abnormal eyes, narrow fins, enlarged proctodaeum, etc. Especially, combined exposure induced unexpected notochord malformations, which ranged from small swellings of the surface of the tails to the extension and extrusion of notochord out of the posterior tails. Compared with the 5 μg Sn/L TPT-treated group, the index of fin deficiency was not affected, and the index of axis deficiency was significantly increased with increasing RA concentrations in the mixtures. Our results suggest that combined exposure to TPT and 9c-RA induced not only more variable phenotypes of malformations than exposure to single compound but also some new and unexpected phenotypes.