Teratogenicity of valproic acid and its constitutional isomer, amide derivative valnoctamide in mice.

OBJECTIVES: The anticonvulsant valproic acid (VPA) has a known teratogenic effect capable of inducing major congenital malformations and developmental disorders. A comparative teratogenicity study of VPA and its analog valnoctamide (VCD), which is a new generation candidate antiepileptic drug, was carried out using Swiss Vancouver (SWV) mice. METHODS: Pregnant SWV dams were treated with either a single intraperitoneal injection of VPA (1.8 and 2.7 mmol/kg), VCD (1.8 and 2.7 mmol/kg), or vehicle on E8:12 (gestational day:hour). The numbers of implantation and resorption, viable and dead fetuses, and the presence of gross fetal visceral and skeletal abnormalities were determined (E18). Real-time Polymerase chain reaction (RT-PCR) arrays were used to analyze the expression of 84 genes related to the processes of neurogenesis and neural stem cell differentiation. RESULTS: Significant decreases in pregnancy weight gain and the number of live fetuses were observed when VPA was administered at the high dose, whereas the percentage of exencephalic fetuses was significantly increased in VPA treated compared with an equivalent VCD dosage group. There was a dose-related increase in visceral defects in the VPA-exposed fetuses. Missing skull bones and fused vertebrae in fetuses occurred at the high dose of VPA. Three genes (Mtap2, Bmp8b, and Stat3) were significantly upregulated and one (Heyl) was downregulated in samples from VPA-treated dams. CONCLUSIONS: The study demonstrates that the teratogenicity of VPA was significantly greater than that of an equimolar dose of VCD. Four genes (Mtap2, Bmp8b, Stat3, and Heyl) represent candidate target genes for the underlying teratogenic mechanism responsible for VPA-induced malformations.

Evaluation of embryotoxic and teratogenic effects of the oil extracted from Caryocar brasiliense Cambess pulp in rats.

The objective of this study was to evaluate the maternal, embryotoxic and teratogenic effects of Caryocar brasiliense pulp oil (OPCB), oil widely used in Brazilian cuisine and traditional medicine. Pregnant Wistar female rats were used in this study for three treatment groups (250, 500 and 1000 mg/kg/day) and a control group. The OPCB was administered orally throughout the period of organogenesis of females (6th until the 15th day of gestation). The pregnant females were gross necropsied on d20, followed by maternal and fetus examination, to evaluate the teratogenicity, reproductive and developmental performance of OPCB. The results showed there was no significant statistical difference in the ponderal evolution of the pregnant females, as well as in the behavioral, hematological, biochemical or histopathological data, indicating the absence of maternal toxicity of the oil. The mean number of corpora lutea, implantation and resorption sites, as well as all calculated reproductive rates, also remained statistically similar between the groups, indicating low embryotoxic effects of the tested plant specie. In fetal examination, external anomalies and skeletal abnormalities were observed in all treated and control groups. The NOAEL for maternal toxicity and embryo/fetal development for the OPCB administered by gavage, was 1000 mg/kg/bw/day.

Cognitive and Affective Symptoms Experienced by Cancer Patients Receiving High-Dose Intravenous Interleukin 2 Therapy: An Integrative Literature Review.

BACKGROUND: Alterations in cognitive/affective functioning are among the most challenging adverse effects experienced by 80% of patients with metastatic melanoma and metastatic renal cell carcinoma undergoing high-dose interleukin 2 (IL-2) therapy. OBJECTIVE: The purpose of this literature review is to describe what is known about IL-2-induced cognitive/affective symptoms, their prevalence, and level of severity and synthesize findings to determine areas for future research to address symptom management challenges. This review describes the IL-2 patient experience and the pathophysiology leading to these changes. METHODS: An online electronic search using PubMed was performed to identify relevant literature published between 1992 and 2015. Of the original 113 articles, information was extracted from 9 articles regarding cognitive symptoms, affective symptoms, sample size, research design, reliability, and validity. RESULTS: Our review suggests that the trajectories, breadth, and depth of cognitive/affective symptoms have yet to be described. Despite intervention studies designed to address the psychosocial complications of IL-2, an understanding of the level of altered cognitive/affective symptoms experienced by IL-2 patients remains unclear. CONCLUSION: Our literature review reveals a lack of standardization when assessing, reporting, and managing cognitive/affective symptoms. Patients/family members have reported cognitive/affective symptoms to be the most alarming and difficult symptoms, yet these symptoms are not adequately screened for, and patients were not informed about potential changes. IMPLICATIONS FOR PRACTICE: Assessing patients for cognitive/affective alterations is important to reduce anxiety while improving outcomes. Education about the illness trajectory (what to expect during/after treatment) can help care partners/patients set realistic shared expectations and increase coping.

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.

Embryo and fetal toxicity of Mentha x villosa essential oil in Wistar rats.

CONTEXT: Mentha x villosa Hudson (Lamiaceae) is an aromatic herb employed as a food spice. In folk medicine, it leaves are used as a tranquilizer and anti-hypertensive, even by pregnant women. OBJECTIVE: There are no reports about its effects in gestation and exposed fetuses, the aim of this study. MATERIALS AND METHODS: At gestation day (GD) 01, 24 rats were divided in four groups: one control and three experimental groups (n = 6/group). The experimental groups received, by gavage, from GD06 to GD16, 10, 25 or 50 µg/kg/day of Mentha x villosa essential oil. The control group received the vehicle (Tween 80 and distilled water--2%). The parameters of body weight gain, water and food intake were recorded. At GD20 the females were euthanized. Half of the fetuses from each litter were directed for the study of visceral malformations and the remaining fetuses for the study of skeletal malformations. RESULTS: The statistical analyses revealed absence of alterations in body weight gain, water and food intake, litter weight, fetuses number and weight, reabsorptions and implantations. The treatment revealed absence of visceral and skeletal malformations. The visceral analysis revealed mild hemorrhagic points at brain, but more numerous at kidney, liver and blood vessels near heart, in some fetuses from some experimental litters. CONCLUSION: The essential oil was not able to promote impairment to the pregnant rats and to gestation. Even occurring lack of malformations, fetotoxicity was revealed by mild hemorrhagic points at liver, kidney, brain and blood vessels of some exposed fetuses.

Vitamin A: too much of a good thing?

UNLABELLED: Vitamin A has the unique distinction of being readily available over the counter, yet conferring significant toxic and teratogenic potential. Although vitamin A deficiency is relatively rare in the United States, globally it is the most common cause of blindness. The following is a review of the various forms and derivatives of vitamin A and their associations with potential adverse perinatal outcomes. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES: After participating in this CME activity, physicians should be better able to identify sources of Vitamin A, distinguish between toxic and non toxic forms of Vitamin A and counsel patients regarding the dosages of Vitamin A that are tolerable during pregnancy.

First trimester curtailment of iron absorption: innate suppression of a teratogen?

In human pregnancies, maternal absorption of iron is markedly curtailed in the first trimester. In a murine model, iron was teratogenic in the analogous embryonic period. Although iron is a weak mutagen, it is a powerful oxidant and a catalyst of formation of hydroxyl radicals. Studies are needed to determine if there might be an association of first trimester iron supplementation with miscarriage/fetal abnormalities.

Teratological consequences of nitric oxide synthesis inhibition.

Nitric oxide (NO) is generated by a family of NO synthase (NOS) enzymes, including endothelial (eNOS), inducible (iNOS) and neuronal (nNOS). NO is an important bioregulator of a wide variety of physiological processes. Recent experimental evidence indicates that inhibition of NO synthesis can lead to teratogenesis. The current review focuses on this aspect of NOS. Exposure of pregnant rodents to non-selective NOS inhibitors, such as N(G)-nitro-L-arginine-methyl ester (L-NAME) and N(G)-nitro-L-arginine (L-NNA), has been linked to limb reduction defects. The teratogenic phenotype, characterized by hemorrhage and transverse terminal tissue destruction, has been regarded to be compatible with a vascular origin. The critical time for teratogenic response was traced to advanced stages of gestation. Similar limb reduction defects have been described in mice deficient in eNOS, but not in other NOS isoforms. Several observations have led to the proposal that hypoxia and possible consequential generation of reactive oxygen species are involved in the causation of NOS inhibitors induced limb defects.

Maternal factors affecting teratogenic response: a need for assessment.

A review of current literature suggests that maternal nutritional status can be an important modulator of the developmental toxicity of a number of agents in the environment. While the provision of multivitamin/multimineral supplements during the periconceptional period is often associated with improved pregnancy outcome, it has been difficult to identify specific nutrient deficiencies as causative factors of abnormal development in humans. One explanation for this is that nutrient deficiencies can arise through a number of means in addition to a simple dietary deficit of the nutrient. The hypothesis is proposed that one mechanism contributing to the embryotoxicity of a diverse group of insults is an alteration in the metabolism of select nutrients. Evidence is presented that zinc is one nutrient whose metabolism can be markedly influenced by a variety of insults. One consequence of this alteration can be a reduction in embryonic zinc uptake, the development of embryonic zinc deficiency and abnormal development.

The state and future requirements of teratogenic testing.

The results obtained in various laboratories are compared with the authors experiences in the field of experimental teratology. From these findings some conclusions are derived to support teratological test programmes. Some basic requirements of embryotoxicity tests are also formulated.