Bryophyllum pinnatum Inhibits Oxytocin and Vasopressin Signaling in Myometrial Cells.

The medicinal plant Bryophyllum pinnatum was previously shown to block oxytocin (OT)-induced signals in myometrial cells, consistent with its tocolytic effect observed in patients. OT activates not only OT receptors but also V1A receptors, two receptors with high receptor homology that are both expressed in the myometrium and play a crucial role in myometrial contraction signaling. We aimed to study the molecular pharmacology of B. pinnatum herbal preparations using specific receptor ligands, the human myometrial cell line hTERT-C3, and cell lines expressing recombinant human OT and V1A receptors.We found that press juice from B. pinnatum (BPJ) inhibits both OT- and vasopressin (AVP)-induced intracellular calcium increases in hTERT-C3 myometrial cells. In additional assays performed with cells expressing recombinant receptors, BPJ also inhibited OT and V1A receptor-mediated signals with a similar potency (IC50 about 0.5 mg/mL). We further studied endogenous OT- and AVP-sensitive receptors in hTERT-C3 cells and found that OT and AVP stimulated those receptors with similar potency (EC50 of ~ 1 nM), suggesting expression of both receptor subtypes. This interpretation was corroborated by the antagonist potencies of atosiban and relcovaptan that we found. However, using qPCR, we almost exclusively found expression of OT receptors suggesting a pharmacological difference between recombinant OT receptors and native receptors expressed in hTERT-C3 cells.In conclusion, we show that B. pinnatum inhibits both OT and AVP signaling, which may point beyond its tocolytic effects to other indications involving a disbalance in the vasopressinergic system.

Use of GLP1 receptor agonists in early pregnancy and reproductive safety: a multicentre, observational, prospective cohort study based on the databases of six Teratology Information Services.

OBJECTIVES: Glucagon-like peptide 1 receptor agonists (GLP1-RA) are indicated for the treatment of type 2 diabetes and more recently for weight loss. The aim of this study was to assess the risks associated with GLP1-RA exposure during early pregnancy. DESIGN: This multicentre, observational prospective cohort study compared pregnancy outcomes in women exposed to GLP1-RA in early pregnancy either for diabetes or obesity treatment with those in two reference groups: (1) women with diabetes exposed to at least one non-GLP1-RA antidiabetic drug during the first trimester and (2) a reference group of overweight/obese women without diabetes, between 2009 and 2022. SETTING: Data were collected from the databases of six Teratology Information Services. PARTICIPANTS: This study included 168 pregnancies of women exposed to GLP1-RA during the first trimester, alongside a reference group of 156 pregnancies of women with diabetes and 163 pregnancies of overweight/obese women. RESULTS: Exposure to GLP1-RA in the first trimester was not associated with a risk of major birth defects when compared with diabetes (2.6% vs 2.3%; adjusted OR, 0.98 (95% CI, 0.16 to 5.82)) or to overweight/obese (2.6% vs 3.9%; adjusted OR 0.54 (0.11 to 2.75)). For the GLP1-RA group, cumulative incidence for live births, pregnancy losses and pregnancy terminations was 59%, 23% and 18%, respectively. In the diabetes reference group, corresponding estimates were 69%, 26% and 6%, while in the overweight/obese reference group, they were 63%, 29% and 8%, respectively. Cox proportional cause-specific hazard models indicated no increased risk of pregnancy losses in the GLP1-RA versus the diabetes and the overweight/obese reference groups, in both crude and adjusted analyses. CONCLUSIONS: This study offers reassurance in cases of inadvertent exposure to GLP1-RA during the first trimester of pregnancy. Due to the limited sample size, larger studies are required to validate these findings.

How Physicians and Nursing Staff Perceive Effectiveness and Tolerability of Bryophyllum Preparations: An Online Survey in an Anthroposophic Hospital.

BACKGROUND: Bryophyllum preparations are widely used in anthroposophic medicine, most often for mental and behavioural disorders. Three prospective studies have revealed positive effects of Bryophyllum pinnatum on sleep quality, and various trials have shown very good tolerability. Results from animal models have indicated CNS depressant and anxiolytic effects. This survey was conducted at the hospital "Klinik Arlesheim" in Switzerland to find out how the physicians and the nursing staff perceive the effectiveness and the tolerability of the Bryophyllum preparations they most frequently use. DESIGN: Internal, anonymous online survey of healthcare professionals (April 8-May 31, 2022). The questionnaire comprised 105 multiple-choice questions. Answering the questions was taken as consent to participate in the survey. PARTICIPANTS AND METHODS: All physicians and nursing staff with a valid email address at the hospital "Klinik Arlesheim AG" were invited via email to participate in this REDCap survey. The data were analysed descriptively. RESULTS: Out of 266 invited participants, 48 answered some and 36 answered all questions (response rate between 18.0% and 13.5%). The participants had long experience with Bryophyllum preparations and were comprised approximately equal numbers of physicians and nursing staff. Various Bryophyllum preparations from the hospital's own production and Wala Heilmittel GmbH (in both cases produced from the species B. daigremontianum) and from Weleda AG (species B. pinnatum) were used. The indications for which most participants had prescribed or administered Bryophyllum preparations "very frequently" were anxiety, sleep disorders, crisis situations in oncology, posttraumatic stress disorder, benzodiazepine dependence/withdrawal, and depression. Improvements such as relief from restlessness, decreased anxiety, balance, easier falling asleep, better sleeping through, increased resilience, mood elevation, and less urge to move one's legs were reported "frequently" or "very frequently." Almost all participants agreed that Bryophyllum can be used to reduce the intake of synthetic sedatives or psychotropic drugs, but only approximately half believed that it could replace them. The majority of participants mentioned good tolerability of the various products, but a few reported occasional stomach or intestinal irritation, daytime fatigue, drowsiness, diarrhoea, and nausea. CONCLUSION: Bryophyllum preparations are perceived as helpful in the treatment of various mental disorders, particularly anxiety, and are generally well tolerated. Most of these preparations are used for indications that have not yet been clinically investigated.Bryophyllum-Präparate werden in der Anthroposophischen Medizin sehr häufig zur Behandlung von psychischen und Verhaltensstörungen eingesetzt. Drei prospektive Studien zeigten zudem positive Wirkungen von Bryophyllum pinnatum (BP) auf die Schlafqualität. Auch die Verträglichkeit wurde in allen bisherigen Studien als sehr gut bewertet. In Tiermodellen wurden ZNS-depressive und anxiolytische Effekte von BP festgestellt. Die hier durchgeführte Umfrage fand an der Klinik Arlesheim (Schweiz) statt. Sie diente dazu herauszufinden, wie Ärztinnen und Ärzte sowie das Pflegepersonal die Wirksamkeit und Verträglichkeit der von ihnen am häufigsten verwendeten Bryophyllum-Präparate wahrnehmen.Interne, anonyme, Online-Befragung unter ärztlichen und pflegerischen Fachkräften (8. April­31. Mai 2022). Der Fragebogen umfasste 105 Multiple-Choice-Fragen. Die Beantwortung der Fragen wurde als Zustimmung zur Teilnahme an der Umfrage interpretiert.Alle Ärztinnen, Ärzte und Pflegefachpersonen mit einer gültigen E-Mail-Adresse der "Klinik Arlesheim AG" wurden per E-Mail eingeladen, an dieser REDCap-Umfrage teilzunehmen. Die Daten wurden deskriptiv ausgewertet.Von den 266 eingeladenen Teilnehmenden beantworteten 48 einige und 36 alle Fragen (Antwortquote zwischen 18.0% und 13.5%). Die Teilnehmenden hatten langjährige Erfahrung mit Bryophyllum-Präparaten und setzten sich etwa zu gleichen Teilen aus ärztlichen und pflegerischen Fachkräften zusammen. Die Resultate zeigen, dass verschiedenste Bryophyllum-Präparate aus klinikeigener Herstellung, von der Wala Heilmittel GmbH (Art B. daigremontianum) und von der Weleda AG (Art B. pinnatum) verwendet werden. Zu den Indikationen, bei denen die meisten Teilnehmenden Bryophyllum-Präparate "sehr häufig" verordnet oder angewendet haben, gehören Angstzustände, Schlafstörungen, Krisensituationen in der Onkologie, Posttraumatische Belastungsstörung, Benzodiazepin-Abhängigkeit/Entzug und Depressionen. Gesundheitsverbesserungen wie Linderung von Unruhe, verminderte Angst, Ausgeglichenheit, leichteres Einschlafen, besseres Durchschlafen, erhöhte Belastbarkeit, Stimmungsaufhellung und weniger Drang, die Beine zu bewegen, wurden als "häufig" oder "sehr häufig" angegeben. Fast alle Teilnehmenden waren sich einig, dass Bryophyllum verwendet werden kann, um die Einnahme von synthetischen Beruhigungsmitteln oder Psychopharmaka zu reduzieren, aber nur etwa die Hälfte gab an, dass es diese ersetzen kann. Die Mehrheit der Teilnehmenden spricht von einer guten Verträglichkeit der verschiedenen Produkte. Einige wenige berichteten von gelegentlicher Magen- oder Darmreizung, Tagesmüdigkeit, Schläfrigkeit, Durchfall und Übelkeit.Bryophyllum-Präparate werden als hilfreich bei der Behandlung verschiedener psychischen Störungen, insbesondere bei Angstzuständen, angesehen und im Allgemeinen gut vertragen. Die meisten der angegebenen Präparate werden für Indikationen verwendet, die noch nicht klinisch untersucht worden sind.

Safety assessment of the SGLT2 inhibitors empagliflozin, dapagliflozin and canagliflozin during pregnancy: An ex vivo human placenta perfusion and in vitro study.

Although uncontrolled hyperglycaemia during pregnancy can cause complications for both the mother and her offspring, pharmacological treatment options for gestational and type 2 diabetes in pregnancy are still limited. Empagliflozin (EMPA), dapagliflozin (DAPA) and canagliflozin (CANA) are three sodium glucose co-transporter 2 (SGLT2) inhibitors, a newer group of oral antidiabetics that are well established in the treatment of type 2 diabetes mellitus in non-pregnant patients. To date, no data regarding their placental transfer and safety in pregnant women are available. We performed ex vivo human placental perfusions (n = 4, term placentas, creatinine and antipyrine as connectivity controls) to evaluate the transplacental transfer of EMPA, DAPA and CANA across the placental barrier and assessed their influence on the secretion of two placental peptide hormones, leptin and ß-human chorionic gonadotropin (ß-hCG). We discovered that all three SGLT2 inhibitors cross the placental barrier and attained maximal foetal to maternal concentration ratios of 0.38 ± 0.09 (EMPA), 0.67 ± 0.05 (DAPA) and 0.62 ± 0.05 (CANA) within the tested 360 min. A moderate but statistically significant decrease in placental leptin - but not ß-hCG - secretion was observed during perfusions with SGLT2 inhibitors, which was confirmed in experiments performed with human placental BeWo cells. SGLT2 inhibitors are able to cross the human placental barrier and seem to interfere with placental leptin production. These observations should be considered in the ongoing discussion on the optimal treatment for gestational diabetes and type 2 diabetes mellitus in pregnancy.

Repurposing of Bryophyllum pinnatum for dysmenorrhea treatment: a systematic scoping review and case series.

Dysmenorrhea affects women throughout their reproductive years but there has been a lack of effective and well-tolerated treatment options. Pain symptoms mainly result from inflammatory processes and increased contractile activity in the myometrium. The reported use of Bryophyllum pinnatum preparations against inflammation and pain in ethnomedicine as well as current pharmacological data on their inhibition of myometrial contractility led us to hypothesize that this medicinal plant might be a new treatment option for dysmenorrhea. In the first part of the present work, clinical, in vivo, and in vitro studies on the anti-nociceptive and anti-inflammatory, as well as on myometrium relaxing properties of B. pinnatum are reviewed. In the second part, cases of five women with dysmenorrhea who were tentatively treated with a B. pinnatum product are described. The review revealed thirty-three experimental in vivo and in vitro studies, but no clinical study, reporting anti-nociceptive and anti-inflammatory effects of B. pinnatum extracts and compounds in a wide range of conditions. Moreover, sixteen publications on smooth muscle contractility revealed relaxing effects. The latter consisted of clinical evidence, as well as of in vivo and in vitro data. The evidence reviewed therefore provided a rational basis for the use of B. pinnatum in the treatment of dysmenorrhea. We subsequently set out to tentatively treat patients with a well-tolerated B. pinnatum product that is registered (without indication) and commonly used in obstetrics and gynecology in Switzerland. All five treated patients reported a reduction in pain symptoms and 4 out of 5 indicated a reduced intake of painkillers during menstruation. Taken together, the reviewed information on the pharmacological properties and clinical evidence of B. pinnatum extracts and compounds as well as the outcomes of all five patients in the case series support our hypothesis in favor of B. pinnatum as a new, well-tolerated therapeutic approach for dysmenorrhea. Prospective clinical studies are urgently needed.

Simultaneous LC-MS/MS quantification of SGLT2 inhibitors and antipyrine in medium and tissue from human ex vivo placenta perfusions.

A liquid chromatography - tandem mass spectrometry (LC-MS/MS) method has been developed to simultaneously measure four sodium glucose co-transporter 2 (SGLT2) inhibitors and the transfer marker antipyrine (ANTI) in perfusion medium and placental tissue collected from ex vivo human placental perfusions. The four SGLT2 inhibitors were empagliflozin (EMPA), dapagliflozin (DAPA), ertugliflozin (ERTU) and canagliflozin (CANA). Chromatographic separation was achieved on an Uptisphere® C18 reversed phase column (50 mm × 4.6 mm × 5 µm) within 2.85 min, using a gradient elution with 10 mM ammonium formate in water (mobile phase A) and acetonitrile (mobile phase B) both with 0.1% formic acid. Analysis of ammonium adduct ions was performed on an AB SCIEX 6500+ triple quadrupole mass spectrometer using positive electrospray ionisation and scheduled multiple reaction monitoring (sMRM). The transitions were m/z 468.00 â†’ 355.20 (EMPA), m/z 426.00 â†’ 167.20 (DAPA), m/z 437.10 â†’ 206.90 (ERTU), m/z 462.00 â†’ 249.00 (CANA) and m/z 189.20 â†’ 55.90 (ANTI). The method was validated according to the European Medicines Agency guidelines and was proven to be selective, linear within a concentration range of 1-1000 µg/L (DAPA, CANA, ANTI) and 1-500 µg/L (EMPA, ERTU), accurate, precise and free of carry-over, instabilities, recovery and matrix effect issues. This newly developed method is suitable to analyse perfusion medium and placenta tissue samples collected during ex vivo human placenta perfusions. It thereby enables quantification of transport across the placental barrier of the SGLT2 inhibitors EMPA, DAPA, ERTU and CANA as well as the transfer marker ANTI.

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.

Intestinal permeability and gut microbiota interactions of pharmacologically active compounds in valerian and St. John's wort.

Phytomedicines such as valerian and St. John's wort are widely used for the treatment of sleeping disorders, anxiety and mild depression. They are perceived as safe alternatives to synthetic drugs, but limited information is available on the intestinal absorption and interaction with human intestinal microbiota of pharmacologically relevant constituents valerenic acid in valerian, and hyperforin and hypericin in St. John's wort. The intestinal permeability of these compounds and the antidepressant and anxiolytic drugs citalopram and diazepam was investigated in the Caco-2 cell model with bidirectional transport experiments. In addition, interaction of compounds and herbal extracts with intestinal microbiota was evaluated in artificial human gut microbiota. Microbiota-mediated metabolisation of compounds was assessed, and bacterial viability and short-chain fatty acids (SCFA) production were measured in the presence of compounds or herbal extracts. Valerenic acid and hyperforin were highly permeable in Caco-2 cell monolayers. Hypericin showed low-to-moderate permeability. An active transport process was potentially involved in the transfer of valerenic acid. Hyperforin and hypericin were mainly transported through passive transcellular diffusion. All compounds were not metabolized over 24 h in the artificial gut microbiota. Microbial SCFA production and bacterial viability was not substantially impaired nor promoted by exposure to the compounds or herbal extracts.

Corrigendum: Bryophyllum pinnatum compounds inhibit oxytocin-induced signaling pathways in human myometrial cells.

[This corrects the article DOI: 10.3389/fphar.2021.632986.].

Bryophyllum pinnatum and Improvement of Nocturia and Sleep Quality in Women: A Multicentre, Nonrandomised Prospective Trial.

Nocturia is a pathologic condition that significantly affects the quality of sleep. The aetiology of nocturia is multifactorial, and the evidence available on its management remains limited. Besides behavioural measures, validated pharmaceutical treatment options exist but are, however, associated with marked side effects. Prospective clinical studies with tablets prepared from the leaf press juice of the plant Bryophyllum pinnatum revealed a tendency towards reduction of micturition in patients with overactive bladder (OAB) and several improvements in sleep quality. These observations are in part supported by in vitro and in vivo data. In the present study, we investigated the effectiveness of Bryophyllum 50% chewable tablets in the treatment of nocturia and associated sleep disorders. Altogether, 49 women with idiopathic OAB and nocturia of ≥2 voids/night were treated with Bryophyllum 50% tablets for 3 weeks (350 mg chewable tablets, dosage 0-0-2-2 oral tablets; WELEDA AG, Arlesheim, Switzerland). Nocturia, voiding volumes at night (ml), quality of life, sleep quality, and daily sleepiness were assessed before and after treatment with a 3-day micturition diary, the International Consultation on Incontinence evaluating overactive bladder and related impact on quality of life (QoL) [ICIQ-OAB], the Pittsburgh Sleep Quality Index (PSQI), and the Epworth Sleepiness Scale (ESS), respectively. The age of the study population was 68.5 ± 11.6 y. After treatment, nocturia diminished from 3.2 ± 1.4 to 2.3 ± 1.3 (P < 0.001) and the PSQI score decreased from 7.7 ± 3.7 to 6.6 ± 3.4 (P=0.004). Urgency, the ICIQ score, and the ESS lowered significantly, and the micturition volume showed a tendency to increase. No serious adverse drug reactions were reported, and compliance was good. The results show a beneficial effect on the nocturnal voids and sleep quality of women with OAB. Bryophyllum 50% tablets can be regarded as a well-tolerated alternative in the treatment of nocturia and broaden the repertoire of standard management.

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.

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.

Queries on medication use during pregnancy: characterisation of the Swiss Teratogen Information Service database.

AIMS OF THE STUDY: Limited information on medication safety may result in concerns on how to treat pregnant and breast-feeding patients. The Swiss Teratogen Information Service (STIS) provides information to healthcare professionals about medications during pregnancy and breast feeding. Our objective was to describe the queries addressed to the STIS over the past two decades. METHODS: The STIS maintains a database of queries on pregnancy outcomes after exposure to various substances, which may be a valuable source of information. We initially analysed the general characteristics of all queries. Thereafter, we focused on exposure to medications during singleton pregnancies and associated health-related aspects. RESULTS: From 2000 to 2019, 7148 queries were entered into the database. An increasing number of queries was recorded over the study period, with an average of 357 queries entered into the database per year. Most of the enquirers were physicians; more specifically, gynaecologists/obstetricians (2389/7148; 33.4%) and psychiatrists (1007/7148; 14.1%). Two thirds (4747/7148; 66.4%) of the queries addressed medication intake during pregnancy; the next most frequent queries concerned planned medication in the context of pregnancy (928/7148; 13.0%) or medication use during breast-feeding (873/7148; 12.2%). In more than 50% (3611/7148) of cases, women were treated with more than one drug; altogether, 15193 medications (taken alone or in combination) were identified. The most frequent queries concerned medicines for the nervous system (ATC group N, n = 7042), with selective serotonin reuptake inhibitors (n = 1271) in the leading position, followed by benzodiazepine derivatives (n = 1102) and other antidepressants (n = 780). The next most frequently mentioned drug classes were anti-infectives for systemic use (J, n = 1586) and drugs for the alimentary tract and metabolism (A, n = 1205). Analysis of follow-up information on cases of medication exposure during singleton pregnancies (n = 2672) revealed an offspring malformation rate of 4.2%. The organ system most often affected was the musculoskeletal system, followed by the circulatory system; congenital malformations of the nervous system and chromosomal abnormalities were also seen. The three most frequently documented congenital diagnoses were malformations of cardiac septa, the brain and major arteries. CONCLUSIONS: Healthcare professionals often have concerns regarding the treatment of pregnant women with medication, and require professional counselling in this area. A variety of drugs are mentioned in queries addressed to the STIS, of which psycholeptics and psychoanaleptics are the most frequent. Proper guidelines on their use during pregnancy appear particularly urgent.

Acceptability and further potential of an app for maternal notes, the eMutterPass: A patient-centered online survey at the University Hospital Zurich.

OBJECTIVES: We wanted to characterize the acceptability of and women's satisfaction with the eMutterPass application. Particular attention was placed on concerns about data confidentiality and on willingness to use the app in an interactive way to share information about medication consumption. STUDY DESIGN: The present analysis is based on self-reported data from obstetric patients participating in an anonymous online survey between April 6th 2021 and April 20th 2021. RESULTS: During the 2-week timeframe, 1123 questionnaires were completed. The eMutterPass application was widely appreciated by our survey population and almost all participants would recommend the application to other pregnant women. A subpopulation analysis indicates that concerns about data confidentiality were higher among younger, multigravid and non-German-speaking pregnant women. The majority of women would be willing to report their medication use by taking pictures, filling in medication dosages or submitting assessments of perceived drug effectiveness. CONCLUSION: The development of our eMutterPass application meets the spirit of the times and gives pregnant women uncomplicated access to their own data. Concerns about data confidentiality can be adequately countered with additional information about the system structure. The largely positive adherence to the idea of reporting medication use on the app lays the groundwork for potential use of the eMutterPass for documentation of non-prescribed drugs.

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. John's 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. John's 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. John's 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.

Drugs in Pregnancy and Lactation - Medications used in Swiss Obstetrics.

BACKGROUND: In order to improve the safety of drugs in pregnancy and lactation, it is imperative that data on clinical practice be collected and validated. METHODS: Data on routinely used medications were requested from 9 Swiss perinatal centres (5 university hospitals for obstetrics and 4 non-university centres). Furthermore, recommendations and guidelines from scientific societies for the fields of application were sought. RESULTS: Part II (lactation): For the lactation period, 48 different active substances were each identified by at least 4 centres. The active constituents most frequently cited by the centres were i. v. iron, lorazepam, nifedipine and paracetamol. Only a few guidelines were found that explicitly refer to the breastfeeding period. Therefore, fewer recommendations for use during lactation could be found compared with during pregnancy. CONCLUSION: As with during pregnancy, the same active ingredients are consistently used in Swiss perinatal centres for many different indications during lactation. Most of these active ingredients are labelled with a warning or are even considered to be contraindicated; their use is therefore mainly off-label. Official authorisation for frequently or consistently used active substances is urgently needed. With this study, a first important step towards national harmonisation has been taken.

Nalbuphine: a candidate for treatment of women overwhelmed with sudden, intense labor pain?

AIM: On very rare occasions, women are overwhelmed with sudden, intense labor pain in the context of ultra-rapid late second stage of labor, especially when the head is crowning. The consequences may comprise serious pelvic floor damage for the mother and hypoxia for the fetus. Drugs like nalbuphine for immediate maternal analgesia and sedation would be helpful. This mixed opioid agonist-antagonist, that was used in obstetric anesthesia in the 1980s, acts quickly while side effects for the mother are minor. To better estimate possible complications for the fetus of a use shortly before birth, it is important to find out how quickly i.v. administered nalbuphine reaches fetal circulation. Therefore, we characterized the transplacental transfer of nalbuphine using an ex vivo model. METHODS: Placentas were obtained from cesarean sections after mothers gave their informed consent. Upon cannulation of one cotyledon, nalbuphine was added to the maternal circuit (calculated final concentration 100 ng/mL) and the ex vivo placenta perfusions were performed. To determine nalbuphine transfer from maternal to fetal circuit in the successful perfusions (n = 5), samples were collected at different time points. RESULTS: At perfusion start, the measured initial nalbuphine concentrations in the maternal and fetal circuits are 93.1 and <0.1 ng/mL, respectively. After 5 min of placenta perfusion, 2.5 ng/mL nalbuphine (i.e. 3% of the initial nalbuphine concentration in the maternal circuit) is reached in the fetal circuit; after 15 and 30 min, 9.7 and 15.8 ng/mL (approximately 10 and 16% of initial maternal, respectively). CONCLUSIONS: Only a small amount of nalbuphine is likely to reach the fetus during the first minutes after (i.v.) maternal administration. Nalbuphine might be a valuable candidate for clinical use in the i.v. analgesia and sedation of women overwhelmed with sudden labor pain in the context of ultra-rapid second stage of labor.

Use of Herbal Medicines for the Treatment of Mild Mental Disorders and/or Symptoms During Pregnancy: A Cross-Sectional Survey.

Little is known about the treatment of mild mental disorders and/or symptoms (MDS) during pregnancy. Our main purpose was to compare the use of herbal medicines during pregnancy in women with and without MDS. A questionnaire consisting of 21 multiple-choice questions was distributed in the participating obstetrics clinics or birth centers in the Canton of Zurich, in Switzerland, from August 2018 to March 2019; 398 questionnaires were considered in the analysis. The use of any type of herbal medicines-including pharmaceutical herbal products as well as teas-during pregnancy was reported by 358 women (out of 398, 89.9%). Of these, 272 participants used pharmaceutical herbal products, whereby ginger (49.2%), raspberry leaf (42.7%), bryophyllum (37.8%), chamomile (27.2%), lavender (22%) and iron-rich herbs (12.3%) were the ones most commonly mentioned. More than half (207/398, 52.0%) of all participants reported suffering from MDS during pregnancy; only a few took (synthetic) psychoactive medications (5/398, 1.3%). The percentage of use of pharmaceutical herbal medicines was higher among women reporting MDS than among the remaining women (90.0 vs 75.9%; p < 0.001). At the same time, the prevalence of MDS was higher among users of pharmaceutical herbal products than among non-users (59.6 vs 34.0%; p = 0.001). Specific questions on candidate herbal medicines for the treatment of mild MDS revealed that bryophyllum (mentioned by 107 women), lavender (56 women) and valerian (20 women) were used to reduce stress, restlessness, sleep disorders and others, in part with perceived good to very good effectiveness and tolerability. The large majority of the pregnant women participating in the survey make use of herbal medicines. The particularly high prevalence of MDS among herbal medicine-users and the very rare use of synthetic psychoactive medications suggest that pregnant women rely on herbal medicines for treatment of mild MDS. The reported good effectiveness and tolerability of a few candidate herbal medicines deserve particular attention.

Placental Passage of Humulone and Protopine in an Ex Vivo Human Perfusion System.

The placental passage of humulone and 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. Only a small portion of humulone initially present in the maternal circuit reached the fetal circuit. The humulone concentration in the maternal circuit rapidly decreased, likely due to metabolization in the placenta. Protopine was transferred from the maternal to the fetal circuit, with a steady-state reached after 90 min. None of the study compounds affected placental viability or functionality, as glucose consumption, lactate production, 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.