Fetal protective effect of Indonesian propolis from Apis mellifera against rifampicin-pyrazinamide induced impaired pregnancy in BALB/c mice.

OBJECTIVES: Anti-tuberculosis drugs rifampicin and pyrazinamide combination in pregnancy can cause morphological, visceral and skeletal damage. Several studies showed that propolis improves pregnancy outcomes. This study aims to determine the fetal protective effect of propolis in BALB/c mice given the anti-tuberculosis drug combination rifampicin and pyrazinamide. METHODS: A total of 21 pregnant mice were randomly divided into three groups: the normal group (N) was given distilled water as a vehicle, the positive control group (RP) were given rifampicin 15 mg/kg BW, pyrazinamide 35 mg/kg BW and the treatment group (IP) were given rifampicin 15 mg/kg BB, pyrazinamide 35 mg/kg BW and propolis 400 mg/kg BW. The treatment was given during the period of organogenesis, from day 6 to day 15. Laparotomy was performed on the 18th day of pregnancy. Maternal and fetal body weight, fetal length, number of fetuses, and skeletal defects of fetuses were used as parameters to identify the teratogenic effect. All data were analyzed using the ANOVA. RESULTS: All groups significantly differed between maternal and fetal body weights (p<0.05). The administration of rifampicin-pyrazinamide and propolis during pregnancy did not significantly affect the number of fetuses (p>0.05). The administration of propolis protects the fetus from skeletal abnormalities. While in the RP and IP groups, we can find resorption sites and haemorrhagic. CONCLUSIONS: This study may suggest the protective effects of propolis against rifampicin pyrazinamide-induced impaired pregnancy.

Optimizing Isotretinoin Treatment of Acne: Update on Current Recommendations for Monitoring, Dosing, Safety, Adverse Effects, Compliance, and Outcomes.

Acne vulgaris is the most common skin disease treated by dermatologists. It can be severe and result in permanent scars. Isotretinoin is the most effective treatment for acne and has the potential for long-term clearance. Prescribing and monitoring protocols can vary widely among prescribers. Recent studies, reports, and consensus statements help shed light on optimizing the use of isotretinoin for acne. A recent literature review is summarized in this article to help the practitioner optimize isotretinoin use for acne. The article outlines the advantages and disadvantages of standard, high-dose, and low-dose isotretinoin regimens; discusses the current status of controversies surrounding isotretinoin (including depression/suicide, pregnancy, and inflammatory bowel disease); reviews monitoring recommendations and treatment for hypertriglyceridemia and elevated transaminase levels; and discusses common adverse effects seen with isotretinoin, along with their treatment and prevention.

Ameliorative effects of Moringa oleifera leaf and flower extracts on sodium arsenate induced oxidative stress and histopathological changes in mice embryo.

The study is aimed to investigate the protective role of Moringa oleifera extracts against sodium arsenate induced embryo toxicity in albino mice. Forty four pregnant mice were divided into 11groups (A-K). Group A was control while B and C were sodium arsenate treated groups with dose, A (0.00), B (6.00, 0.00), C (12.00, 0.00). Group D to G were of sodium arsenate+Moringa oleifera flower extract treated groups with doses D (6.00, 150.00), E (6.00, 300.00), F (12.00, 150.00), G (12.00, 300.00) and groups H to K were sodium arsenate+Moringa oleifera leaf extract treated groups H (6.00, 150.00), I (6.00, 300.00), J (12.00, 150.00) and K (12.00, 300.00) mg/kg B.W. Moringa oleifera leaf extract treated groups showed significant (p<0.05) amelioration against sodium arsenate induced histopathological changes as malformed heart, spina bifida, enlarged ventricles, poorly developed kidneys, anopthalmia and cavitation in brain. Significant (p<0.05) increased in malondialdehyde 36±0.81 and decreased glutathione 8.25±0.95 values in sodium arsenate treated groups were observed as compared to control 22.5±0.57 and 19±0.81.Whereas Moringa oleifera leaf extract at dose of 300mg/kg B.W normalizesd the malondialdehyde 23±0.81 and glutathione 17.75±3.20 values. So concluded that Moringa oleifera leaf extract has ameliorative effects against sodium arsenate induced embryotoxicity.

Medication Use During Pregnancy and Lactation in a Dutch Population.

BACKGROUND:: Medication use during pregnancy and lactation can be unavoidable, but knowledge on safety for the fetus or breastfed infant is limited among patients and healthcare providers. RESEARCH AIM:: This study aimed to determine (a) the prevalence of medication use in pregnant and lactating women in a tertiary academic center, (b) the types and safety of these medicines, and (c) the influence of medication use on initiation of breastfeeding. METHODS:: This study used a cross-sectional survey among women ( N = 292) who underwent high-risk or low-risk deliveries. Data about their use of prescribed, over-the-counter, and homeopathic medication during pregnancy were obtained through a structured interview, followed by a questionnaire during lactation. Safety was classified according to the risk classification system from the Dutch Teratological Information Service. RESULTS:: Overall, 95.5% of participants used medication. One third of participants used at least one medicine with an unknown risk for the fetus. Teratogenic medication was used by 6.5% of participants, whereas 29.5% used medication with a (suspected) pharmacological effect on the fetus. Lactation was initiated by 258 (88.7%) participants, of which 84.2% used medication while breastfeeding. In 3.8% of participants, this medication was classified unsafe, but none used medication with an unknown risk. One-third of the nonlactating participants decided not to initiate breastfeeding because of medication use. In 70% of participants, this decision was appropriate. CONCLUSION:: The prevalence of overall use of medication in Dutch pregnant and lactating women admitted to a tertiary center was high. There is an urgent need for pharmacometric studies for determination of the safe use of the most frequently used medicines during pregnancy or lactation.

Is post exposure prevention of teratogenic damage possible: Studies on diabetes, valproic acid, alcohol and anti folates in pregnancy: Animal studies with reflection to human.

We discuss the possibilities to prevent the post-exposure teratogenic effects of several teratogens: valproic acid (VPA), diabetes and alcohol. Co-administration of folic acid with VPA reduced the rate of Neural Tube Defects (NTD) and other anomalies in rodents, but apparently not in pregnant women. Antioxidants or the methyl donor S-adenosyl methionine prevented Autism Spectrum Disorder (ASD) like behavior in mice and rats. In vivo and in vitro studies demonstrated that antioxidants, arachidonic acid, myoinositol and nutritional agents may prevent diabetes-embryopathy. Prevention of alcohol-induced embryonic and fetal injuries and neurodevelopmental deficits was achieved by supplementation of zinc, choline, vasoactive intestinal proteins (VIP related peptides), antioxidants and folic acid. While the animal research described in this review is indicative of possible preventions of the different teratogenic effects, this is not yet the focus in human research. Future research should promote further knowledge where our current understanding is the vaguest, human prevention.

Dietary strategies for primary prevention of atopic diseases - what do we know?

The paper refers to the recently published empirical data and systematic reviews on the impact of diets, foods, nutrients and bioactive substance exposures in pregnancy and in early infancy, on the development of atopic disorders. The results of studies referring to a broad range on dietary factors are mostly conflicting. There are several limitations of these researches. Based on the existing information, it is not possible to establish the role of antioxidants and vitamin D supplementation in atopic disease development. There is no evidence of major effects of prenatal use of folic acid on asthma or allergies. The association of some nutritional interventions with less atopic sensitization seems rather speculative even if such an effect has not been found for some other foods. The findings indicate rather a balanced and diverse diet without restrictions than a special dietary protocol. Farming-related exposures may protect against the development of atopic disorders in children. The hypothesis that the early introduction of complementary food, including the potentially allergenic foods, may reduce the risk of food allergy and atopic dermatitis is currently tested. Long-chain polyunsaturated fatty acids and probiotics seem to be promising candidates for allergy prevention. But specific recommendations regarding pre- and postnatal supplementation strategies, dose, treatment duration etc., are still undetermined. Longitudinal intervention studies in cohorts of pregnant women or newborn infants are needed to match the proper strategies in these issues.

Plant lignan secoisolariciresinol suppresses pericardial edema caused by dioxin-like compounds in developing zebrafish: Implications for suppression of morphological abnormalities.

Dioxins and dioxin-like compounds (DLCs) enter the body mainly through diet and cause various toxicological effects through activation of the aryl hydrocarbon receptor (AhR), a ligand activated transcription factor. Some plant extracts and phytochemicals are reported to suppress this transformation. However, most of these reports have been from in vitro experiments and few reports have been from in vivo experiments. In addition, there has been no report of foodstuffs that effectively prevent AhR-associated morphological abnormalities such as deformities caused by dioxins and DLCs in vivo. In this study, we show that secoisolariciresinol (SECO), a natural lignan-type polyphenolic phytochemical found mainly in flaxseed, has a rescuing effect, actually suppressing morphological abnormalities (pericardial edema) in zebrafish embryos exposed to 3,3',4,4',5-pentachlorobiphenyl (PCB126), a dioxin-like PCB congener. Importantly, the rescuing effect of SECO was still evident when it was applied 16 h after the beginning of exposure to PCB126. This study suggests that SECO may be useful as a natural suppressive agent for morphological abnormalities caused by dioxins and DLCs.

Guideline adherence for mentally ill reproductive-aged women on treatment with valproic acid: a retrospective chart review.

OBJECTIVE: Valproic acid (VPA) use during pregnancy increases fetal risk of major congenital malformations and cognitive impairment. Given these risks, several medical societies have put forth guidelines suggesting to either limit the use of VPA or take certain precautions, such as making sure effective contraception practices and/or appropriate folic acid supplementation are in place, when treating reproductive-aged women. Our study aimed to review and assess adherence to these guidelines. METHODS: Using electronic medical record (EMR) and administrative claims data over a 19-month period (January 1, 2013-July 31, 2014), a retrospective chart review was conducted of all reproductive-aged female patients at a major medical center in the Midwest who were prescribed VPA as treatment for their psychiatric illness (n = 190; aged from 15 to 49 years). Psychiatric diagnoses were determined via ICD-9 billing codes. We assessed 3 variables of interest as an index of adherence to guidelines: chart documentation of provider-patient discussion regarding potential teratogenicity associated with VPA use, prescription of contraceptives, and co-prescription of folic acid. RESULTS: EMR documentation of provider-patient discussions regarding possible teratogenicity of VPA was rare (13.2%), as was documentation of contraception use (30%) and co-prescription of folate (7.9%). Neither patient demographic characteristics nor diagnoses were associated with outcomes. Among those not receiving treatment in the inpatient setting, patients who were seen by outpatient psychiatry or neurology clinics (rather than other outpatient settings) were more likely to have documented discussions about teratogenicity (23% and 30%, respectively; P = .003), and patients receiving neurologic care were more likely to be prescribed folate than those seen by other providers (26%, P = .004). Women who had contact with inpatient psychiatric services were less likely to be taking contraception (n = 12 [20%], P = .041). Only 22% of women under 34 years of age were documented as using contraception (P = .03). CONCLUSIONS: Adherence to standard guidelines is low even at an academic tertiary care center. To the extent that there is any documentation or co-prescription of folate, it varies by provider specialty.

Congenital Anomalies in Children of Mothers Taking Antiepileptic Drugs with and without Periconceptional High Dose Folic Acid Use: A Population-Based Cohort Study.

BACKGROUND: Antenatal antiepileptic drug (AED) use has been found to be associated with increased major congenital anomaly (CA) risks. However whether such AED-associated risks were different according to periconceptional high dose (5mg daily) folic acid supplementation is still unclear. METHODS: We included 258,591 singleton live-born children of mothers aged 15-44 years in 1990-2013 from The Health Improvement Network, a large UK primary care database. We identified all major CAs according to the European Surveillance of Congenital Anomalies classification. Absolute risks and adjusted odds ratios (aOR) were calculated comparing children of mothers prescribed AEDs to those without such prescriptions, stratified by folic acid prescriptions around the time of conception (one month before conception to two months post-conception). RESULTS: CA risk was 476/10,000 in children of mothers with first trimester AEDs compared with 269/10,000 in those without AEDs equating to an aOR of 1.82, 95% confidence interval 1.30-2.56. The highest system-specific risks were for heart anomalies (198/10,000 and 79/10,000 respectively, aOR 2.49,1.47-4.21). Sodium valproate and lamotrigine were both associated with increased risks of any CA (aOR 2.63,1.46-4.74 and aOR 2.01,1.12-3.59 respectively) and system-specific risks. Stratification by folic acid supplementation did not show marked reductions in AED-associated risks (e.g. for CAs overall aOR 1.75, 1.01-3.03 in the high dose folic acid group and 1.94, 95%CI 1.21-3.13 in the low dose or no folic acid group); however, the majority of mothers taking AEDs only initiated high dose folic acid from the second month of pregnancy. CONCLUSIONS: Children of mothers with AEDs in the first trimester of pregnancy have a 2-fold increased risk of major CA compared to those unexposed. We found no evidence that prescribed high dose folic acid supplementation reduced such AED-associated risks. Although statistical power was limited, prescribing of folic acid too late for it to be effective during the organogenic period or selective prescribing to those with more severe morbidity may explain these findings.

Safety of dermatologic medications in pregnancy and lactation: Part I. Pregnancy.

Dermatologists are frequently faced with questions about the safety of commonly prescribed topical and systemic medications during pregnancy and lactation from women of childbearing age who are pregnant, considering pregnancy, or breastfeeding. Safety data, particularly regarding medications that are unique to dermatology, can be difficult to locate and are not consolidated in a single reference guide for clinicians. Parts I and II of this continuing medical education article provide a capsule summary of key points for the most commonly prescribed dermatologic medications to facilitate patient medication risk counseling in pregnancy. A summary table details safety classification data for 3 primary international classification systems: the US Food and Drug Administration, the Swedish Catalogue of Approved Drugs, and the Australian Drug Evaluation Committee. In addition, this table includes an alternative pregnancy classification system developed by a consortium of active members of teratology societies in the US and Europe detailed in Drugs during Pregnancy and Lactation: Treatment Options and Risk Assessment and a safety classification system developed for breastfeeding mothers detailed in Medications and Mother's Milk.

Safety of dermatologic medications in pregnancy and lactation: Part II. Lactation.

Dermatologists are frequently faced with questions from women who are breastfeeding about the safety of commonly prescribed topical and systemic medications during lactation. Safety data in lactation, particularly regarding medications that are unique to dermatology, are limited and can be difficult to locate. We have consolidated the available safety data in a single reference guide for clinicians. We review literature pertaining to the safety of common dermatologic therapies in lactation and offer recommendations based on the available evidence.

Chronopharmacology of anti-convulsive therapy.

Approximately one-third of patients with epilepsy continue to have seizures despite antiepileptic therapy. Many seizures occur in diurnal, sleep/wake, circadian, or even monthly patterns. The relationship between biomarkers and state changes is still being investigated, but early results suggest that some of these patterns may be related to endogenous circadian patterns whereas others may be related to wakefulness and sleep or both. Chronotherapy, the application of treatment at times of greatest seizure susceptibility, is a technique that may optimize seizure control in selected patients. It may be used in the form of differential dosing, as preparations designed to deliver sustained or pulsatile drug delivery or in the form of 'zeitgebers' that shift endogenous rhythms. Early trials in epilepsy suggest that chronopharmacology may provide improved seizure control compared with conventional treatment in some patients. The present article reviews chronopharmacology in the treatment of epilepsy as well as future treatment avenues.

Safety evaluation of commonly used Chinese herbal medicines during pregnancy in mice.

BACKGROUND: It is unclear how safe the use of Chinese herbal medicine is during pregnancy and if the herbal medicines do any harm to pregnancy, embryo-fetal development and prenatal and post-natal growth. A large-scale preclinical study was conducted to detect the adverse effects of Chinese herbal medicines during pregnancy. METHODS: Twenty of the most commonly used Chinese herbal medicines prescribed for pregnancy were selected and the crude extract was administered to pregnant mice at clinical doses during five different gestational stages, namely post-implantation, gastrulation, organogenesis, maturation and whole gestation periods. Maternal effects on side effects, weight loss, litter reduction, implantation failure and fetal resorption and perinatal effects on growth restriction, developmental delay, congenital malformations and post-natal mortality were determined. RESULTS: Adverse pregnancy outcomes were commonly observed after maternal exposure to the herbal medicines, particularly during early pregnancy. Major events included maternal and perinatal mortality were recorded. Maternal weight gain, embryo growth and post-natal weight gain were significantly decreased. Fetal resorption and skeletal malformations were significantly increased. CONCLUSIONS: Reproductive toxicity of Chinese herbal medicines commonly used during pregnancy was identified in mice. Caution should be taken in the clinical use of herbal medicines during pregnancy.

Evaluation of teratogenic effects of risperidone following simultaneous administration with antihypertensive and antiemetic drugs.

Multiple drug administration is an important aspect of clinical practice particularly in specific physiological situation such as in neonates, elderly or pregnancy, since in all such situations, possibility of unwanted effects increases due to altered body physiology. In present study, the teratogenic effects of multiple drug administration risperidone, meclizine/pyridoxine and hydralazine have been compared with the teratogenic effects of individual drugs in pregnant mice. Moreover the role of folic acid and α-tocopherol if any had also been investigated in reducing the teratogenic effects of these drugs in combinations.

Establishment of a rescue program for anorectal malformations induced by retinoic acid in mice.

AIMS OF STUDY: Retinoid-mediated signal transduction plays a crucial role in the embryogenesis of various organs. We previously reported the successful induction of anorectal malformations in mice using retinoic acid (RA). Retinoic acid controls the expression of essential target genes for cell differentiation, morphogenesis, and apoptosis through a complicated interaction in which RA receptors form heterodimers with retinoid X receptors. In the present study, we investigated whether the retinoid antagonist, LE135, could prevent the induction of anorectal malformations (ARMs) in mice. METHODS: Retinoic acid was intraperitoneally administered as 100 mg/kg of all-trans RA on E9; and then the retinoid antagonist, LE135, was intraperitoneally administered to pregnant ICR strain mice on the eighth gestational day (E8), 1 day before administration of RA (group B) or on E9, simultaneously (group C) with RA administration. All of the embryos were obtained from the uteri on E18. Frozen sections were evaluated for concentric layers around the endodermal epithelium by hematoxylin and eosin staining. RESULTS: In group A, all of the embryos demonstrated ARM with rectoprostatic urethral fistula, or rectocloacal fistula, and all of the embryos showed the absence of a tail. In group B, 36% of the embryos could be rescued from ARM. However, all of the rescued embryos had a short tail that was shorter than their hind limb. The ARM rescue rates in group B were significantly improved compared to those in group A (P < .01). In group C, 45% of the embryos were rescued from ARM, but all of the rescued embryos had short tail. The ARM rescue rate in group C was significantly improved compared to that in group A (P < .01). However, there was no significant difference in the ARM rescue rate between group B and Group C. CONCLUSION: The present study provides evidence that in the hindgut region, RAR selective retinoid antagonist, LE135, could rescue embryos from ARM. However, the disturbance of all-trans RA acid was limited to the caudal region. Further study to establish an appropriate rescue program for ARM in a mouse model might suggest a step toward protection against human ARM in the future.

Chronic ethanol exposure and folic acid supplementation: fetal growth and folate status in the maternal and fetal guinea pig.

Chronic ethanol exposure (CEE) can produce developmental abnormalities in the CNS of the embryo and developing fetus. Folic acid (FA) is an important nutrient during pregnancy and low folate status exacerbates ethanol-induced teratogenicity. This study tested the hypotheses that (1) CEE depletes folate stores in the mother and fetus; and (2) maternal FA supplementation maintains folate stores. CEE decreased fetal body, brain, hippocampus weights, and brain to body weight ratio but not hippocampus to body weight ratio. These effects of CEE were not mitigated by maternal FA administration. The FA regimen prevented the CEE-induced decrease of term fetal liver folate. However, it did not affect maternal liver folate or fetal RBC folate at term, and did not mitigate the nutritional deficit-induced decrease of term fetal hippocampus folate. This study suggests that maternal FA supplementation may have differential effects on folate status in the mother and the fetus.

[Specificities of the epileptic women (oral contraceptives, pregnancy)]. / Particularités de la prise en charge de la femme épileptique (contraception, grossesse).

The enzyme-inducing antiepileptic drugs such as carbamazepine, phenytoin, barbiturates, oxcarbazepine do not allow oral contraceptives. The pregnancy must be planned. Every patient in childbearing age should be informed by her practitioner. The rule is to optimize the antiepileptic treatment before the pregnancy: less drugs, less dosages. This optimization will depend on the epileptic syndrome and the nature of the treatment. Valproate of sodium should be avoided, if possible, during pregnancy. Preconceptional supplementation by folic acid should be considered. Antiepileptic drugs monitoring is required during pregnancy. Natural delivery with peridural anaesthesiology is mandatory. The breast feeding must be considered individually.

Subtle decreases in DNA methylation and gene expression at the mouse Igf2 locus following prenatal alcohol exposure: effects of a methyl-supplemented diet.

C57BL/6J (B6) mice are susceptible to in utero growth retardation and a number of morphological malformations following prenatal alcohol exposure, while DBA/2J (D2) mice are relatively resistant. We have previously shown that genomic imprinting may play a role in differential sensitivity between B6 and D2. The best-characterized mechanism mediating genomic imprinting is differential DNA methylation. In the present study we examined DNA methylation and gene expression, in both embryonic and placental tissue, at the mouse Igf2 locus following in utero ethanol exposure. We also examined the effects of a methyl-supplemented diet on methylation and ethanol teratogenesis. In embryos from susceptible B6 mice, we found small decreases in DNA methylation at four CpG sites in one of the differentially methylated regions of the Igf2 locus; only one of the four sites showed a statistically significant decrease. We observed no significant decreases in methylation in placentae. All Igf2 transcripts showed approximately 1.5-fold decreases following intrauterine alcohol exposure. Placing dams on a methyl-supplemented diet before pregnancy and throughout gestation brought methylation back up to control levels. Methyl supplementation also resulted in lower prenatal mortality, greater prenatal growth, and decreased digit malformations; it dramatically reduced vertebral malformations. Thus, although prenatal alcohol had only small effects on DNA methylation at the Igf2 locus, placing dams on a methyl-supplemented diet partially ameliorated ethanol teratogenesis.

Prevention of cytogenetic, histochemical and biochemical alterations in Oreochromis niloticus by dietary supplement of sorbent materials.

The current study was conducted to evaluate the ability of Egyptian bentonite (EB) and montmorillonite (EM) for the prevention of genotoxicity, histochemical and biochemical changes induced by aflatoxin B(1) (AFB(1)) using the micronucleus (MN) assay, chromosomal aberrations and DNA fragmentation analysis in Tilapia fish. Six groups of fish were treated for 3 weeks and included the control group, AFB(1)-treated group and the groups treated with EB or EM alone or in combination with AFB(1). At the end of experiment period, blood samples were collected for MN, testosterone and biochemical assays. Chromosomal aberrations were determined in kidney tissues, DNA fragmentation test was determined in liver and testis, whereas histochemical study was carried out on liver, testis and gills. The results indicated that a significant decrease in total protein, albumin, globulin, testosterone and DNA content in liver, gills and testis accompanied with a significant increase in number of micronucleated erythrocytes (MnRBCs), total chromosomal aberrations in kidney and DNA fragmentation in testis and liver of fish received AFB(1) alone. Fish treated with EB or EM alone were comparable to the control regarding the biochemical parameters except testosterone in EB-treated group which was significantly decreased. Both clays did not induce any significant differences in number of MnRBCs, chromosomal aberrations in the kidney, DNA fragmentation in testis, but not in liver of EB-treated group. The combined treatment with AFB(1) and EB or EM succeeded to improve all the tested parameters towards the control values although it did not normalize them. Moreover, the improvement was pronounced in the group received EM plus AFB(1). It could be concluded that EB and EM have the ability to tightly bind AFB(1) in the gastrointestinal tract of fish resulting in decreasing its bioavailability. Moreover, the two tested clays were safe and can be used as potential aflatoxin binders in animal feed.