Treatment of mild mental disorders in pregnancy: how safe are phytomedicines?

Pregnancy and associated physiological changes, which begin in the first trimester and are most pronounced in the third trimester, alter the pharmacokinetics of drugs. In addition, most drugs enter the fetal-placental unit, which pose several challenges to medical care, as it affects both the unborn child as well as the expectant mother. This also applies to the treatment of non-psychotic mental disorders (NMDs) such as depression, restlessness, sleep disorders, and anxiety since the use of synthetic, central nervous system (CNS)-active drugs for treatment should be carefully considered in a risk-benefit ratio. Nevertheless, pregnancy is a vulnerable period for such disorders and preexisting mental illnesses may even worsen or relapse. Alternatively, there are some herbal medicines, so called phytopharmaceuticals, which possess antidepressant, sedative, or anxiolytic properties. St. John’s wort, for example, is used to treat mild to moderate depression, whereas California poppy, valerian, and hops are mainly known for their sleep-inducing effects. Finally, lavender essential oil represents an option for the treatment of restlessness and anxiety due to its calming, sedative, and anxiolytic effects. Most products based on these phytopharmaceuticals are available over the counter (OTC) and are generally recommended by a considerable proportion of health care professionals who deal with pregnant women, such as midwives and obstetricians. Despite the limited experimental and clinical evidence, and especially lack of safety data, pregnant women often resort to herbal medicines and perceive them as safe. We designed a cross-sectional survey with which we determined the use of most common herbal medicines in pregnancy by obstetrics patients. Furthermore, some questions targeted the perceived effectiveness and tolerability of some of these plants. The survey revealed that a large majority of pregnant women make use of herbal medicines, and lavender (22%), valerian (4.7%), St. John’s wort (3.0%), and hops (1.7%) were among the most mentioned pharmaceutical herbal products for the treatment of mental disorders and/or symptoms (MDS). Although 52.0% of all participants suffered from MDS during pregnancy, only 1.3% reported taking (synthetic) psychoactive medications. The fact that the prevalence of MDS was higher in pharmaceutical herbal products users than in non-users suggests that pregnant women rely on herbal medicines to treat mild MDS. St. John’s wort, valerian, hops, and lavender were used to reduce mood and sleep disorders, restlessness, and stress with perceived good to very good effectiveness and tolerability; no participant reported the use of California poppy.  To verify whether various herbal extracts such as St. John's wort, California poppy, valerian, hops, and lavender can be used for the treatment of NMD in pregnancy, their safety must be thoroughly investigated with a palette of in vitro assays. Those extracts and some of their active marker compounds were therefore evaluated for their cytotoxic and genotoxic potential and for their effects on metabolism and cell differentiation. The in-depth in vitro safety assessment indicates that extracts of St. John’s wort, California poppy, valerian, hops, and lavender – at concentrations up to 30 µg/mL – have no cytotoxic or genotoxic potential and do not compromise the viability, metabolic activity, and differentiation of placental cells. Moreover, none of the five extracts was able to significantly alter protein expression of BeWo b30 cells. For active marker substances, protopine (found in California poppy), valerenic acid (in valerian), and linalool (in lavender) showed no adverse effects in all experiments performed. The following phytochemicals might conceivably cause safety issues: hyperforin (in St. John’s wort) induced cell apoptosis (≥ 3 µM) and inhibited BeWo b30 cell differentiation (≥ 1 µM). Hypericin (in St. John's wort) decreased cell viability (≥ 1 µM) and induced cell apoptosis (30 µM). Valtrate (in valerian) decreased cell viability (≥ 10 µM), induced cell apoptosis (≥ 10 µM), and decreased the metabolic cell activity by reducing glucose consumption and concomitant lactate production. However, none of the tested phytochemicals resulted in genotoxic effects and thus are not DNA damaging. In summary, most of the phytochemicals were not of concern, but the attainment of high plasma concentrations of a few relevant phytochemicals – hyperforin, hypericin, and valtrate – deserves special attention. In addition to investigating effects on placental cells, the question of transplacental permeation of certain phytochemicals needs to be addressed in order to better assess the risk of fetal exposure. For this purpose, an ex vivo placental perfusion model was optimized and modified that it can be used for the application of phytochemicals. Furthermore, an in vitro Transwell model with placental cells was established which served to complement the placental perfusion model. We successfully used the human ex vivo placental perfusion model for the first time for transport experiments with phytochemicals, after a thorough validation with various compounds, such as antipyrine, citalopram, and diazepam. Only a small fraction of the initially present hyperforin (< 10%) reached the fetal circuit after 4 h, whereas hypericin did not cross the placental barrier and therefore remained in the maternal circuit. In contrast, protopine was transferred from the maternal to the fetal circuit, reaching a steady state after 90 min with no further changes in concentration. Also, valerenic acid was transferred gradually over a 4-hour period and reached an equilibrium with the maternal concentration. None of the phytochemicals affected placental viability or functionality, and histopathological evaluation of all placental specimens revealed no pathologic findings. In addition, in vitro translocation studies have confirmed that valerenic acid, from valerian, cannot cross the placental cell layer within 60 min, which might indicate that this phytochemical is not accessible to the unborn child in early pregnancy. We were able to gain more detailed knowledge into the safety of St. John’s wort, California poppy, valerian, hops, and lavender extracts and a few of their active phytochemicals through in-depth in vitro assessments and an ex vivo model. In addition, we know that phytomedicines of these extracts, except California poopy, are already used in pregnancy in Switzerland with well-perceived effectiveness and tolerability. We hope that this thesis contributes to a rational basis for future decisions on the treatment of NMDs during pregnancy

Advanced in Vitro Safety Assessment of Herbal Medicines for the Treatment of Non-Psychotic Mental Disorders in Pregnancy

When confronted with non-psychotic mental disorders, pregnant women often refrain from using synthetic drugs and resort to herbal medicines such as St. John’s wort, California poppy, valerian, lavender, and hops. Nevertheless, these herbal medicines have not yet been officially approved in pregnancy due to lack of safety data. Using a variety of in vitro methods (determination of cytotoxicity, apoptosis induction, genotoxicity, effects on metabolic properties, and inhibition/induction of differentiation) in a commonly used placental cell line (BeWo b30), we were previously able to show that extracts from these plants are likely to be safe at the usual clinical doses. In the present work, we wanted to extend our safety assessment of these herbal medicines by 1) looking for possible effects on gene expression and 2) using the same in vitro methods to characterize effects of selected phytochemicals that might conceivably lead to safety issues. Proteomics results were promising, as none of the five extracts significantly affected protein expression by up- or down-regulation. Protopine (contained in California poppy), valerenic acid (in valerian), and linalool (in lavender) were inconspicuous in all experiments and showed no adverse effects. Hyperforin and hypericin (two constituents of St. John’s wort) and valtrate (typical for valerian) were the most obvious phytochemicals with respect to cytotoxic and apoptotic effects. A decrease in cell viability was evident with hypericin (≥1 µM) and valtrate (≥10 µM), whereas hyperforin (≥3 µM), hypericin (30 µM) and valtrate (≥10 µM) induced cell apoptosis. None of the tested phytochemicals resulted in genotoxic effects at concentrations of 0.1 and 1 µM and thus are not DNA damaging. No decrease in glucose consumption or lactate production was observed under the influence of the phytochemicals, except for valtrate (at all concentrations). No compound affected cell differentiation, except for hyperforin (≥1 µM), which had an inhibitory effect. This study suggests that extracts from St. John’s wort, California poppy, valerian, lavender, and hops are likely to be safe during pregnancy. High plasma concentrations of some relevant compounds—hyperforin and hypericin from St. John’s wort and valtrate from valerian—deserve special attention, however

Medicinal Plants for the Treatment of Mental Diseases in Pregnancy: An In Vitro Safety Assessment

Pregnancy is a critical period for medical care, during which the well-being of woman and fetus must be considered. This is particularly relevant in managing non-psychotic mental disorders since treatment with central nervous system-active drugs and untreated NMDs may have negative effects. Some well-known herbal preparations (phytopharmaceuticals), including St. Johnʼs wort, California poppy, valerian, lavender, and hops, possess antidepressant, sedative, anxiolytic, or antidepressant properties and could be used to treat mental diseases such as depression, restlessness, and anxiety in pregnancy. Our goal was to assess their safety in vitro, focusing on cytotoxicity, induction of apoptosis, genotoxicity, and effects on metabolic properties and differentiation in cells widely used as a placental cell model (BeWo b30 placenta choriocarcinoma cells). The lavender essential oil was inconspicuous in all experiments and showed no detrimental effects. At low-to-high concentrations, no extract markedly affected the chosen safety parameters. At an artificially high concentration of 100 µg/mL, extracts from St. Johnʼs wort, California poppy, valerian, and hops had minimal cytotoxic effects. None of the extracts resulted in genotoxic effects or altered glucose consumption or lactate production, nor did they induce or inhibit BeWo b30 cell differentiation. This study suggests that all tested preparations from St. Johnʼs wort, California poppy, valerian, lavender, and hops, in concentrations up to 30 µg/mL, do not possess any cytotoxic or genotoxic potential and do not compromise placental cell viability, metabolic activity, and differentiation. Empirical and clinical studies during pregnancy are needed to support these in vitro data

Transplacental passage of hyperforin, hypericin, and valerenic acid

Safe medications for mild mental diseases in pregnancy are needed. Phytomedicines from St. John’s wort and valerian are valid candidates, but safety data in pregnancy are lacking. The transplacental transport of hyperforin and hypericin (from St. John’s wort), and valerenic acid (from valerian) was evaluated using the ex vivo cotyledon perfusion model (4 h perfusions, term placentae) and, in part, the in vitro Transwell assay with BeWo b30 cells. Antipyrine was used for comparison in both models. U(H)PLC-MS/MS bioanalytical methods were developed to quantify the compounds. Perfusion data obtained with term placentae showed that only minor amounts of hyperforin passed into the fetal circuit, while hypericin did not cross the placental barrier and valerenic acid equilibrated between the maternal and fetal compartments. None of the investigated compounds affected metabolic, functional, and histopathological parameters of the placenta during the perfusion experiments. Data from the Transwell model suggested that valerenic acid does not cross the placental cell layer. Taken together, our data suggest that throughout the pregnancy the potential fetal exposure to hypericin and hyperforin – but not to valerenic acid – is likely to be minimal

Placental Passage of Protopine in an Ex Vivo Human Perfusion System

The placental passage of protopine was investigated with a human ex vivo placental perfusion model. The model was first validated with diazepam and citalopram, 2 compounds known to cross the placental barrier, and antipyrine as a positive control. All compounds were quantified by partially validated U(H)PLC-MS/MS bioanalytical methods. Protopine was transferred from the maternal to the fetal circuit, with a steady-state reached after 90 min. The study compound did not affect placental viability or functionality, as glucose consumption, lactate production, and beta-human chorionic gonadotropin, and leptin release remained constant. Histopathological evaluation of all placental specimens showed unremarkable, age-appropriate parenchymal maturation with no pathologic findings

Transplacental passage of hyperforin, hypericin, and valerenic acid

Safe medications for mild mental diseases in pregnancy are needed. Phytomedicines from St. John’s wort and valerian are valid candidates, but safety data in pregnancy are lacking. The transplacental transport of hyperforin and hypericin (from St. John’s wort), and valerenic acid (from valerian) was evaluated using the ex vivo cotyledon perfusion model (4 h perfusions, term placentae) and, in part, the in vitro Transwell assay with BeWo b30 cells. Antipyrine was used for comparison in both models. U(H)PLC-MS/MS bioanalytical methods were developed to quantify the compounds. Perfusion data obtained with term placentae showed that only minor amounts of hyperforin passed into the fetal circuit, while hypericin did not cross the placental barrier and valerenic acid equilibrated between the maternal and fetal compartments. None of the investigated compounds affected metabolic, functional, and histopathological parameters of the placenta during the perfusion experiments. Data from the Transwell model suggested that valerenic acid does not cross the placental cell layer. Taken together, our data suggest that throughout the pregnancy the potential fetal exposure to hypericin and hyperforin – but not to valerenic acid – is likely to be minimal

Advanced Robotic Therapy Integrated Centers (ARTIC): an international collaboration facilitating the application of rehabilitation technologies

Background: The application of rehabilitation robots has grown during the last decade. While meta-analyses have shown beneficial effects of robotic interventions for some patient groups, the evidence is less in others. We established the Advanced Robotic Therapy Integrated Centers (ARTIC) network with the goal of advancing the science and clinical practice of rehabilitation robotics. The investigators hope to exploit variations in practice to learn about current clinical application and outcomes. The aim of this paper is to introduce the ARTIC network to the clinical and research community, present the initial data set and its characteristics and compare the outcome data collected so far with data from prior studies. Methods: ARTIC is a pragmatic observational study of clinical care. The database includes patients with various neurological and gait deficits who used the driven gait orthosis Lokomat® as part of their treatment. Patient characteristics, diagnosis-specific information, and indicators of impairment severity are collected. Core clinical assessments include the 10-Meter Walk Test and the Goal Attainment Scaling. Data from each Lokomat® training session are automatically collected. Results: At time of analysis, the database contained data collected from 595 patients (cerebral palsy: n = 208; stroke: n = 129; spinal cord injury: n = 93; traumatic brain injury: n = 39; and various other diagnoses: n = 126). At onset, average walking speeds were slow. The training intensity increased from the first to the final therapy session and most patients achieved their goals. Conclusions: The characteristics of the patients matched epidemiological data for the target populations. When patient characteristics differed from epidemiological data, this was mainly due to the selection criteria used to assess eligibility for Lokomat® training. While patients included in randomized controlled interventional trials have to fulfill many inclusion and exclusion criteria, the only selection criteria applying to patients in the ARTIC database are those required for use of the Lokomat®. We suggest that the ARTIC network offers an opportunity to investigate the clinical application and effectiveness of rehabilitation technologies for various diagnoses. Due to the standardization of assessments and the use of a common technology, this network could serve as a basis for researchers interested in specific interventional studies expanding beyond the Lokomat®

The Effects Of The Teacher\u27s Use Of Guided Inquiry In The Fifth Grade Classroom

THIS STUDY INVESTIGATED THE EFFECTS OF THE TEACHER\u27S USE OF GUIDED INQUIRY IN A FIFTH GRADE SCIENCE CLASSROOM. INQUIRY IS SUPPORTED BY THE NATIONAL RESEARCH COUNCIL(2000), AND INDICATES THAT ALL STUDENTS SHOULD DEVELOP THE ABILITIES NECESSARY TO DO SCIENTIFIC INQUIRY AND DEVELOP UNDERSTANDINGS ABOUT SCIENTIFIC INQUIRY (P.21). THIS STUDY WAS A QUALITATIVE ACTION RESEARCH DESIGN, FOCUSING ON SEVENTEEN STUDENTS AND THEIR RESPONSES TO A GUIDED INQUIRY METHOD OF SCIENCE INSTRUCTION ON MATTER, ENERGY AND MOTION, AND EARTH AND SPACE. AN ANALYSIS OF STUDENTS\u27 PERFORMANCE AND STUDENTS\u27 ATTITUDES ABOUT SCIENCE IN THE CLASSROOM WAS CONDUCTED ABOUT EACH UNIT OF INSTRUCTION. THE 5-E MODEL OF GUIDED INQUIRY WAS USED TO ELICIT MEANINGFUL UNDERSTANDINGS WHILE COMPLETING THE UNITS OF MATTER, ENERGY AND MOTION, AND EARTH AND SPACE. STUDENTS WORKED IN COOPERATIVE GROUPS TO SUPPORT LAB ACTIVITIES, WHICH REQUIRED EACH MEMBER TO PARTICIPATE IN THE INVESTIGATIONS, PROJECTS, AND PRESENTATIONS. STUDENTS KEPT JOURNALS, RECORDED THEIR FINDINGS, AND WROTE RESPONSES ABOUT THEIR FINDINGS AND FEELINGS ON THE ACTIVITIES IN WHICH THEY WERE ENGAGED. STUDENTS\u27 ATTITUDES WERE AFFECTED POSITIVELY BY THE USE OF GUIDED INQUIRY IN LEARNING SCIENCE. STUDENTS\u27 PERFORMANCE FOR LAB ACTIVITIES WAS ALSO POSITIVE AND WAS SUPPORTED BY STUDENTS\u27 RESPONSES IN JOURNALS, TEACHER OBSERVATIONS, AND PERFORMANCE TASKS. THIS STUDY SUPPORTS GUIDED INQUIRY IN THE SCIENCE CLASSROOM FOR IMPROVING STUDENTS\u27 ATTIDUES AND STUDENTS\u27 PERFORMANCE DURING CLASSROOM ACTIVITES