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

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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.

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Bryophyllum pinnatum has been used in the treatment of premature labor, first in anthroposophic hospitals and, recently, in conventional settings as an add-on medication. In vitro work with hTERT human myometrial cells showed that B. pinnatum leaf press juice inhibits the increase of intracellular free calcium concentration induced by oxytocin, a hormone known to play a role in labor. Our aim was to identify fractions/compounds in B. pinnatum press juice that contribute to this inhibitory effect, and to investigate their effect on oxytocin-driven activation of the MAPK cascade. Several fractions/compounds from B. pinnatum press juice led to a concentration-dependent decrease of oxytocin-induced increase of intracellular free calcium concentration, but none of them was as strong as B. pinnatum press juice. However, the combination of a bufadienolide and a flavonoid-enriched fraction was as effective as B. pinnatum press juice, and their combination had a synergistic effect. B. pinnatum press juice inhibited oxytocin-driven activation of MAPKs SAPK/JNK and ERK1/2, an effect also exerted by the bufadienolide-enriched fraction. The effect of B. pinnatum press juice on oxytocin-induced signaling pathways was comparable to that of the oxytocin-receptor antagonist and tocolytic agent atosiban. Our findings further substantiate the use of B. pinnatum press juice preparations in the treatment of preterm labor.

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Restless legs syndrome may seriously affect patients' sleep and quality of life, but established pharmacological therapy can often have severe side effects. Therefore, new therapeutic approaches such as well-tolerated preparations from the medicinal plant Bryophyllum pinnatum should be considered as alternatives. Their sedative and spasmolytic properties might contribute to improve patients' condition.

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Bryophyllum pinnatum has been used since the 1970s to prevent premature labour, first in anthroposophic hospitals and, more recently, also in the main Swiss perinatal centres. However, it is not known which compounds in B. pinnatum leaves contribute to the tocolytic effect. Here we studied the effects of a flavonoid-enriched fraction, the corresponding flavonoid aglycon mixture, a bufadienolide-enriched fraction, and B. pinnatum leaf press juice on human myometrial contractility in vitro. The strength (area under the curve and amplitude) and frequency of contractions were recorded using strips of human myometrium mounted in an organ bath system. Cell viability assays were performed with the human myometrium hTERT-C3 and PHM1 - 41 cell lines. Repeated addition of the flavonoid-enriched fraction, flavonoid aglycon mixture, bufadienolide-enriched fraction, or B. pinnatum leaf press juice led to a progressive decrease of contraction strength, without jeopardising the vitality of myometrium strips. The bufadienolide-enriched fraction was the most active, since 1 µg/mL of the bufadienolide-enriched fraction lowered the area under the curve to 40.1 ± 11.8% of the initial value, whereas 150 µg/mL of the flavonoid-enriched fraction, 6.2 µg/mL of the flavonoid aglycon mixture, and 10 µg/mL of the B. pinnatum leaf press juice were required to achieve comparable inhibition. A progressive increase of contraction frequency was observed, except in the case of the flavonoid aglycon mixture, which did not affect frequency. None of the test substances decreased myometrial cell viability, even at concentrations of 500 µg/mL of the flavonoid-enriched fraction, 40 µg/mL of the flavonoid aglycon mixture, 3.8 µg/mL of the bufadienolide-enriched fraction, and 75 µg/mL of the B. pinnatum leaf press juice, i.e., higher than those used in the myometrium experiments. Given the concentrations of flavonoids in the flavonoid-enriched fraction and B. pinnatum leaf press juice, and of bufadienolides in the bufadienolide-enriched fraction and B. pinnatum leaf press juice, it appears that bufadienolides may be mainly responsible for the relaxant effect.

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BACKGROUND: In order to improve the safety for drugs in pregnancy and lactation, data on the clinical practice must be collected and validated. METHODS: Data on the medications routinely used were requested from the university hospitals for obstetrics and the non-university perinatal centres in Switzerland and recommendations and guidelines of scientific societies for the various fields of application were sought. RESULTS: Part I: For during pregnancy and the peripartal period respectively, 69 and 21 different active constituents of medications were identified from at least 4 centres. For during pregnancy, the active constituents used in most of the centres are nifedipine, iron i. v. and oral, labetalol and magnesium sulphate, amoxicillin with clavulanic acid, paracetamol, dalteparine, metoclopramide as well as atosiban and hexoprenaline; for during the peripartal period betamethasone, misoprostol, oxytocin, clindamycin as well as fibrinogen, sulprostone and tranexamic acid were most frequently cited. Recommendations of various scientific societies were found primarily for pregnancy-specific fields of application. CONCLUSION: The same active constituents of medications are consistently used in Swiss perinatal centres for the main indications in pregnant women. Despite the existing experience and available evidence, they are mainly used off-label. Official authorisations for frequently or consistently used active ingredients should be granted.

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An earlier prospective, randomised, placebo-controlled clinical trial had suggested that Bryophyllum pinnatum might have potential in the treatment of overactive bladder. Here we investigated the effects of B. pinnatum leaf press juice, fractions enriched in flavonoids and bufadienolides, and a flavonoid aglycon mixture and individual aglycons on detrusor contractility as a major target in overactive bladder treatment. The strength of the detrusor contractions was investigated using porcine muscle strips stimulated with KCl. B. pinnatum leaf press juice increased the contraction force of muscle strips. Treatment with the flavonoid-enriched fraction had almost no effect on contractility, while the bufadienolide-enriched fraction and flavonoid aglycons led to a concentration-dependent lowering of the contraction force. The data indicate that several components of B. pinnatum leaf press juice may contribute to the inhibitory effect on detrusor contractility, which in turn provides support to overactive bladder treatment with B. pinnatum.

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The aim of this paper is to show aspects of dental treatment in pregnancy. The reader should gain security in the election of the proper drugs for antibiotic therapy and rinsing solutions. Antibiotics as penicillins are the first choice in case of dental infections in pregnancy. In allergic patients, macrolides may be an alternative. Wound and mouth rinsing solutions containing chlorhexidine should be preferred in pregnancy. Ledermix(®) in endodontic treatment should be avoided in the pregnant woman. Solcoseryl(®) can be used for wound healing. Elective dental procedures should be postponed after delivery and after lactation period.

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The aim of this paper is to show aspects of dental treatment in pregnancy. The reader should gain security in the election of the proper drugs for antibiotic therapy and rinsing solutions. Antibiotics as penicillins are the first choice in case of dental infections in pregnancy. In allergic patients, macrolides may be an alternative. Wound and mouth rinsing solutions containing chlorhexidine should be preferred in pregnancy. Ledermix(®) in endodontic treatment should be avoided in the pregnant woman. Solcoseryl(®) can be used for wound healing. Elective dental procedures should be postponed after delivery and after lactation period.

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Bryophyllum pinnatum (syn. Kalanchoe pinnata) is a succulent perennial plant native to Madagascar that was introduced in anthroposophic medicine in the early 20th century. In recent years, we conducted a large collaborative project to provide reliable data on the chemical composition, pharmacological properties, and clinical efficacy of Bryophyllum. Here, we comprehensively review the phytochemistry, as well as the pharmacological and clinical data. As to the pharmacology, special emphasis is given to properties related to the use in anthroposophic medicine as a treatment for "hyperactivity diseases", such as preterm labor, restlessness, and sleep disorders. Studies suggesting that B. pinnatum may become a new treatment option for overactive bladder syndrome are also reviewed. Tolerability is addressed, and toxicological data are discussed in conjunction with the presence of potentially toxic bufadienolides in Bryophyllum species. The few data available on two related species with medicinal uses, Bryophyllum daigremontianum and Bryophyllum delagoense, have also been included. Taken together, current data support the use of B. pinnatum for the mentioned indications, but further studies are needed to fully understand the modes of action, and to identify the pharmacologically active constituents.

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The aim of this paper is to show relevant aspects of dental treatment in pregnancy. Common medication used in dental offices should be highlighted in special regard to the pregnant patient during dental treatment. The reader should gain more security in the election of the proper drugs for local anesthesia and oral analgesics. Local anaesthetics such as articain with adrenalin in a dilution of 1 : 200 000 can be used for dental treatment at any time. Paracetamol should be used as first line oral analgesic. Elective dental procedures should be postponed after delivery and after lactation period.

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The aim of this paper is to show relevant aspects of dental treatment in pregnancy. Common medication used in dental offices should be highlighted in special regard to the pregnant patient during dental treatment. The reader should gain more security in the election of the proper drugs for local anesthesia and oral analgesics. Local anaesthetics such as articain with adrenalin in a dilution of 1 : 200 000 can be used for dental treatment at any time. Paracetamol should be used as first line oral analgesic. Elective dental procedures should be postponed after delivery and after lactation period.

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BACKGROUND: Bryophyllum pinnatum has been introduced in anthroposophic medicine in Europe and is nowadays also widely used in conventional medicine. The aim of this study was to assess the prescriptions in the field of gynaecology and obstetrics in Switzerland and to document potential effects and possible adverse events of B. pinnatum. PATIENTS AND METHODS: Private practices and clinics for obstetrics and gynaecology were asked to document each prescription of B. pinnatum for their female patients during 31 months with an online questionnaire. RESULTS: At the University Hospital Zurich, at the Cantonal Hospital Winterthur as well as at 2 private practices, a total of 174 women and 208 prescriptions of B. pinnatum were recorded (several prescriptions per patient were possible). Most of the patients were pregnant (87%). B. pinnatum was prescribed as a tocolytic agent to 83% of all patients and to 95% of all pregnant patients and showed a good or a very good effectiveness. Further, 14% of the patients received B. pinnatum for sedation against their restlessness during the day and 5% for sedation against sleep problems. A decrease of the restlessness was achieved for these 2 indications. 13% of the patients suffered from a hyperactive bladder and in two-thirds of them the effectiveness of the treatment with B. pinnatum was classified as very good. In 92% of the cases, Bryophyllum 50% chewable tablets were prescribed. CONCLUSIONS: In conventional gynaecology and obstetrics, B. pinnatum is predominantly prescribed for pregnant women in case of prematurel abour, against restlessness and for hyperactive bladder. B. pinnatum showed a good effectiveness with a high benefit in the treatment of hyperactivity-associated health problems.

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A quantitative assay for determination of the main bufadienolides bersaldegenin-1-acetate (1), bersaldegenin-3-acetate (2), bryophyllin A (3), and bersaldegenin-1,3,5-orthoacetate (4) in Bryophyllum pinnatum leaves and manufactured products was developed and validated. The assay involved extraction by pressurised liquid extraction, followed by quantification by ultrahigh performance liquid chromatography-tandem mass spectroscopy. The ultrahigh performance liquid chromatography-tandem mass spectroscopy method was applied to various batches of leaves harvested on several dates from plants grown at two locations (Brazil and Germany). In addition, press juices prepared from plants cultivated in Germany and Brazil were analysed. The total bufadienolide content ranged from 16.28 to 40.50 mg/100 g dry weight in leaves from plants grown in Brazil. The total content of these four bufadienolides was significantly lower in plants cultivated in Germany (3.78-12.49 mg/100 g dry weight, resp.). The total amounts of bufadienolides were 0.091-0.163 mg/100 mL and 0.89-1.16 mg/100 mL in press juices obtained from plants cultivated in Germany and Brazil, respectively. When analysing single leaves from individual plants, the content of bufadienolides was markedly higher in young leaves. For comparative purposes, the content of these bufadienolides was also determined in Bryophyllum daigremontianum and Bryophyllum tubiflorum. Bersaldegenin-1,3,5-orthoacetate (4) was predominant in the leaves of B. daigremontianum and in the stems of B. tubiflorum, while the leaves of B. tubiflorum contained very low amounts of 1-4.

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BACKGROUND: Nanoparticle exposure in utero might not be a major concern yet, but it could become more important with the increasing application of nanomaterials in consumer and medical products. Several epidemiologic and in vitro studies have shown that nanoparticles can have potential toxic effects. However, nanoparticles also offer the opportunity to develop new therapeutic strategies to treat specifically either the pregnant mother or the fetus. Previous studies mainly addressed whether nanoparticles are able to cross the placental barrier. However, the transport mechanisms underlying nanoparticle translocation across the placenta are still unknown. OBJECTIVES: In this study we examined which transport mechanisms underlie the placental transfer of nanoparticles. METHODS: We used the ex vivo human placental perfusion model to analyze the bidirectional transfer of plain and carboxylate modified polystyrene particles in a size range between 50 and 300 nm. RESULTS: We observed that the transport of polystyrene particles in the fetal to maternal direction was significantly higher than for the maternal to fetal direction. Regardless of their ability to cross the placental barrier and the direction of perfusion, all polystyrene particles accumulated in the syncytiotrophoblast of the placental tissue. CONCLUSIONS: Our results indicate that the syncytiotrophoblast is the key player in regulating nanoparticle transport across the human placenta. The main mechanism underlying this translocation is not based on passive diffusion, but is likely to involve an active, energy-dependent transport pathway. These findings will be important for reproductive toxicology as well as for pharmaceutical engineering of new drug carriers.

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HYPOTHESIS: Cancer patients frequently suffer from poor sleep quality. Bryophyllum pinnatum is a herbal medication used in anthroposophic medicine, which has been shown to be associated with improvements in sleep quality during pregnancy with only few and minor or moderate side-effects reported. In this study, the sleep quality of cancer patients during treatment with B pinnatum was investigated. STUDY DESIGN: In this prospective, observational study, cancer patients suffering from sleep problems were treated with B pinnatum (350 mg tablets, corresponding to 50% of leaf pressed juice [Weleda AG, Arlesheim, Switzerland], dosage at physician's consideration, but most frequently 2 tablets with evening meal and 2 before going to bed). METHODS: Sleep quality (Pittsburgh Sleep Quality Index [PSQI]), daily sleepiness (Epworth Sleeping Scale [ESS]), and fatigue (Fatigue Severity Scale [FSS]) were assessed at the beginning of the treatment and after 3 weeks. Possible adverse drug reactions perceived by the patients during the treatment were recorded. From the 28 recruited patients, 20 completed both questionnaires and were considered in the present analysis. Data are expressed as mean ± standard deviation. RESULTS: Patients were 61 ± 10.4 years old and the majority were female (17 out of 20). During treatment with B pinnatum, the PSQI decreased from 12.2 ± 3.62 to 9.1 ± 3.61 (P < .01), and ESS changed from 8.4 ± 3.18 to 7.1 ± 3.98 (P < .05). There was no change in FSS. The treatment was well tolerated by the majority of patients, with only 6 patients reporting discomfort that might have been caused by B pinnatum (fatigue n = 3, dry throat n = 1, agitation n = 1, difficult digestion n = 1). No serious adverse drug reactions were detected. CONCLUSION: B pinnatum may be a suitable treatment for sleep problems of cancer patients. Controlled, randomized clinical trials of the use of B pinnatum in sleep disorders are urgently needed.

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Cytochrome P450 3A4 (CYP3A4) is the major human P450 responsible for the metabolism of carbamazepine (CBZ). To explore the mechanisms of interactions of CYP3A4 with this anticonvulsive drug, we carried out multiple molecular dynamics (MD) simulations, starting with the complex of CYP3A4 manually docked with CBZ. On the basis of these simulations, we engineered CYP3A4 mutants I369F, I369L, A370V, and A370L, in which the productive binding orientation was expected to be stabilized, thus leading to increased turnover of CBZ to the 10,11-epoxide product. In addition, we generated CYP3A4 mutant S119A as a control construct with putative destabilization of the productive binding pose. Evaluation of the kinetics profiles of CBZ epoxidation demonstrate that CYP3A4-containing bacterial membranes (bactosomes) as well as purified CYP3A4 (wild-type and mutants I369L/F) exhibit substrate inhibition in reconstituted systems. In contrast, mutants S119A and A370V/L exhibit S-shaped profiles that are indicative of homotropic cooperativity. MD simulations with two to four CBZ molecules provide evidence that the substrate-binding pocket of CYP3A4 can accommodate more than one molecule of CBZ. Analysis of the kinetics profiles of CBZ metabolism with a model that combines the formalism of the Hill equation with an allowance for substrate inhibition demonstrates that the mechanism of interactions of CBZ with CYP3A4 involves multiple substrate-binding events (most likely three). Despite the retention of the multisite binding mechanism in the mutants, functional manifestations reveal an exquisite sensitivity to even minor structural changes in the binding pocket that are introduced by conservative substitutions such as I369F, I369L, and A370V.

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