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Kip E. Panter - One of the best experts on this subject based on the ideXlab platform.
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Running title: Optical isomers of coniine inhibit Fetal Movement.
2016Co-Authors: Benedict T Green, Kevin D Welch, James A Pfister, Stephen T. Lee, Kip E. PanterAbstract:Fetal-muscle type nicotinic acetylcholine receptor activation in TE-671 cells, and inhibition of Fetal Movement in a day 40 pregnant goat model by optical isomers of the piperidine alkaloid coniine
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piperidine pyridine alkaloid inhibition of Fetal Movement in a day 40 pregnant goat model
Food and Chemical Toxicology, 2013Co-Authors: Benedict T Green, Kevin D Welch, James A Pfister, Kip E. PanterAbstract:Abstract Inhibition of Fetal Movement is one mechanism behind the development of multiple congenital contracture-type defects in developing fetuses of humans and animals. We tested the alkaloids anabasine, lobeline, and myosmine for agonist actions, and sensitivity to alpha conotoxins EI and GI blockade at Fetal muscle-type nicotinic acetylcholine receptors (nAChR) expressed by TE-671 cells. We also determined if the alkaloids decreased Fetal Movement in an IV dosed, day 40 pregnant goat model. In TE-671 cells, all three alkaloids elicited concentration-dependent changes in membrane potential sensing dye fluorescence. 1.0 μM alpha conotoxin GI shifted the concentration–effect curves of anabasine and myosmine to the right, and decreased maximal responses. Neither of the conotoxins blocked the actions of lobeline in TE-671 cells. In the day 40 pregnant goats, 0.8 mg/kg anabasine abolished Fetal Movement at 30 and 60 min after dosing and Fetal Movement was reduced by lobeline and myosmine. The blockade of anabasine and myosmine actions in TE-671 cells by alpha conotoxin GI indicates that they are agonists at Fetal muscle-type nAChR. All three alkaloids did significantly decrease Fetal Movement in the day 40 pregnant goat model suggesting a potential for these alkaloids to cause multiple congenital contracture-type defects in developing fetuses.
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Fetal muscle type nicotinic acetylcholine receptor activation in te 671 cells and inhibition of Fetal Movement in a day 40 pregnant goat model by optical isomers of the piperidine alkaloid coniine
Journal of Pharmacology and Experimental Therapeutics, 2013Co-Authors: Benedict T Green, Kevin D Welch, James A Pfister, Kip E. PanterAbstract:Coniine is an optically active toxic piperidine alkaloid and nicotinic acetylcholine receptor (nAChR) agonist found in poison hemlock ( Conium maculatum L. ). Coniine teratogenicity is hypothesized to be attributable to the binding, activation, and prolonged desensitization of Fetal muscle-type nAChR, which results in the complete inhibition of Fetal Movement. However, pharmacological evidence of coniine actions at Fetal muscle-type nAChR is lacking. The present study compared (−)-coniine, (+)-coniine, and nicotine for the ability to inhibit Fetal Movement in a day 40 pregnant goat model and in TE-671 cells that express Fetal muscle-type nAChR. Furthermore, α-conotoxins (CTx) EI and GI were used to antagonize the actions of (+)- and (−)-coniine in TE-671 cells. (−)-Coniine was more effective at eliciting electrical changes in TE-671 cells and inhibiting Fetal Movement than was (+)-coniine, suggesting stereoselectivity by the receptor. The pyridine alkaloid nicotine did not inhibit Fetal Movement in a day 40 pregnant goat model, suggesting agonist specificity for the inhibition of Fetal Movement. Low concentrations of both CTxs potentiated the TE-671 cell response and higher concentrations of CTx EI, and GI antagonized the actions of both coniine enantiomers demonstrating concentration-dependent coagonism and selective antagonism. These results provide pharmacological evidence that the piperidine alkaloid coniine is acting at Fetal muscle-type nAChR in a concentration-dependent manner.
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Pregnant Goat Model by Optical Isomers of the Piperidine Alkaloid Coniine
2012Co-Authors: Benedict T Green, Kevin D Welch, James A Pfister, Stephen T. Lee, Kip E. PanterAbstract:Coniine is an optically active toxic piperidine alkaloid and nicotinic acetylcholine receptor (nAChR) agonist found in poison hemlock (Conium maculatum L.). Coniine teratogenicity is hypothesized to be attributable to the binding, activation, and prolonged de-sensitization of Fetal muscle-type nAChR, which results in the complete inhibition of Fetal Movement. However, pharmacological evidence of coniine actions at Fetal muscle-type nAChR is lacking. The present study compared (2)-coniine, (1)-coniine, and nicotine for the ability to inhibit Fetal Movement in a day 40 pregnant goat model and in TE-671 cells that express Fetal muscle-type nAChR. Furthermore, a-conotoxins (CTx) EI and GI were used to antagonize the actions of (1)- and (2)-coniine in TE-671 cells. (2)-Coniine was more effective at eliciting electrical changes in TE-671 cells and inhibiting Fetal Movement than was (1)-coniine, suggesting stereoselectivity by the receptor. The pyridine alkaloid nicotine did not inhibit Fetal Movement in a day 40 pregnant goat model, suggesting agonist specificity for the inhibition of Fetal Movement. Low concentrations of both CTxs potentiated the TE-671 cell response and higher concentrations of CTx EI, and GI antagonized the actions of both coniine enantiomers demon-strating concentration-dependent coagonism and selective an-tagonism. These results provide pharmacological evidence that the piperidine alkaloid coniine is acting at Fetal muscle-type nAChR in a concentration-dependent manner
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the Fetal cleft palate v elucidation of the mechanism of palatal clefting in the congenital caprine model
Plastic and Reconstructive Surgery, 2008Co-Authors: Jeffrey Weinzweig, Jagruti Patel, Darren M Smith, Anthony Spangenberger, Kip E. Panter, Brandon M FreemanAbstract:Background: Failure of palatal shelf fusion at the precise gestational time point when shelf elevation and migration normally occur results in clefting. The present study defined the mechanism of clefting in the congenital caprine model by evaluating the temporal sequence of palatal shelf fusion. Methods: Six Spanish-type goats pregnant with twins were gavaged for 10 days (gestational days 32 to 41) with anabasine. Goats were examined with ultrasound throughout this period to assess Fetal Movement and evaluated histologically. Twelve untreated, unclefted fetuses served as controls. Results: After anabasine induction, real-time ultrasound confirmed a dramatic decrease in Fetal Movement. Hyperflexion of the neck occurred throughout the experimental period compared with control fetuses, in which spontaneous neck Movements occurred. Histologic evaluation of the induced fetuses demonstrated the tongue wedged between the palatal shelves throughout the period of fusion. The shelves remained vertically oriented without elevation, ultimately resulting in clefting. The unclefted, control group demonstrated progressive elevation and migration of the palatal shelves between gestational days 38 and 40, with contact and fusion of the medial edge epithelia in the midline. Conclusions: Palatal clefting in the congenital caprine model occurred concomitant with reduced Fetal Movement. Resultant neck hyperflexion causes the tongue to obstruct medial migration of the palatal shelves and fusion, whereas the shelves themselves are either directly prevented from elevation secondary to anabasine impairment or indirectly secondary to the obstructing tongue. Although the molecular mechanism for the teratogenic effects of anabasine remains elusive, the authors have demonstrated an association between reduced Fetal Movement and palatal clefting in their congenital caprine model.
Benedict T Green - One of the best experts on this subject based on the ideXlab platform.
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complete inhibition of Fetal Movement in the day 40 pregnant goat model by the piperidine alkaloid anabasine but not related alkaloids
Toxicon, 2018Co-Authors: Benedict T Green, John W. Keele, Kevin D Welch, Daniel Cook, James A PfisterAbstract:Abstract Four chemically similar alkaloids, anabasine, anabaseine, epibatidine and dimethylphenylpiperazinium (DMPP), are potent nicotinic acetylcholine receptor agonists of Fetal muscle nicotinic acetylcholine receptors in human TE-671 cells. Based on results with these cells, we hypothesized that the alkaloids would completely inhibit ultrasound-monitored Fetal Movement in a goat model. Different, single doses of anabasine, anabaseine, epibatidine, DMPP, or saline control were administered I.V. to pregnant goats on day 40 of gestation and the number of Fetal Movements per 5 min sample was measured by ultrasound at times 0, 0.5, 1, 2, 4 and 8 h. The differences among does in Fetal Movements were more consistent at dosing and following recovery for doses of anabasine above 0.125 mg/kg compared to the other compounds and dosages. Anabasine actions were dose-dependent with an IC 50 value of ∼0.1 mg/kg, and, at a dose of 0.8 mg/kg, completely inhibited Fetal Movement for 1.5 h after dosing. Anabaseine, epibatidine, and DMPP failed to completely inhibit Fetal Movement in day 40 pregnant goats at doses predicted to be effective. These results suggest that while experiments with TE-671 cells provide valuable information and predictions of the actions of plant alkaloids on Fetal Movement, in vivo experiments are still required in order to determine the ability of an alkaloid to inhibit Fetal Movement in livestock species. Moreover, other pharmacological properties such as receptor differences between mammalian species and differences in the pharmacokinetic properties of the alkaloids also are likely to weaken teratologic predictions based solely on the in vitro data.
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Running title: Optical isomers of coniine inhibit Fetal Movement.
2016Co-Authors: Benedict T Green, Kevin D Welch, James A Pfister, Stephen T. Lee, Kip E. PanterAbstract:Fetal-muscle type nicotinic acetylcholine receptor activation in TE-671 cells, and inhibition of Fetal Movement in a day 40 pregnant goat model by optical isomers of the piperidine alkaloid coniine
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piperidine pyridine alkaloid inhibition of Fetal Movement in a day 40 pregnant goat model
Food and Chemical Toxicology, 2013Co-Authors: Benedict T Green, Kevin D Welch, James A Pfister, Kip E. PanterAbstract:Abstract Inhibition of Fetal Movement is one mechanism behind the development of multiple congenital contracture-type defects in developing fetuses of humans and animals. We tested the alkaloids anabasine, lobeline, and myosmine for agonist actions, and sensitivity to alpha conotoxins EI and GI blockade at Fetal muscle-type nicotinic acetylcholine receptors (nAChR) expressed by TE-671 cells. We also determined if the alkaloids decreased Fetal Movement in an IV dosed, day 40 pregnant goat model. In TE-671 cells, all three alkaloids elicited concentration-dependent changes in membrane potential sensing dye fluorescence. 1.0 μM alpha conotoxin GI shifted the concentration–effect curves of anabasine and myosmine to the right, and decreased maximal responses. Neither of the conotoxins blocked the actions of lobeline in TE-671 cells. In the day 40 pregnant goats, 0.8 mg/kg anabasine abolished Fetal Movement at 30 and 60 min after dosing and Fetal Movement was reduced by lobeline and myosmine. The blockade of anabasine and myosmine actions in TE-671 cells by alpha conotoxin GI indicates that they are agonists at Fetal muscle-type nAChR. All three alkaloids did significantly decrease Fetal Movement in the day 40 pregnant goat model suggesting a potential for these alkaloids to cause multiple congenital contracture-type defects in developing fetuses.
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Fetal muscle type nicotinic acetylcholine receptor activation in te 671 cells and inhibition of Fetal Movement in a day 40 pregnant goat model by optical isomers of the piperidine alkaloid coniine
Journal of Pharmacology and Experimental Therapeutics, 2013Co-Authors: Benedict T Green, Kevin D Welch, James A Pfister, Kip E. PanterAbstract:Coniine is an optically active toxic piperidine alkaloid and nicotinic acetylcholine receptor (nAChR) agonist found in poison hemlock ( Conium maculatum L. ). Coniine teratogenicity is hypothesized to be attributable to the binding, activation, and prolonged desensitization of Fetal muscle-type nAChR, which results in the complete inhibition of Fetal Movement. However, pharmacological evidence of coniine actions at Fetal muscle-type nAChR is lacking. The present study compared (−)-coniine, (+)-coniine, and nicotine for the ability to inhibit Fetal Movement in a day 40 pregnant goat model and in TE-671 cells that express Fetal muscle-type nAChR. Furthermore, α-conotoxins (CTx) EI and GI were used to antagonize the actions of (+)- and (−)-coniine in TE-671 cells. (−)-Coniine was more effective at eliciting electrical changes in TE-671 cells and inhibiting Fetal Movement than was (+)-coniine, suggesting stereoselectivity by the receptor. The pyridine alkaloid nicotine did not inhibit Fetal Movement in a day 40 pregnant goat model, suggesting agonist specificity for the inhibition of Fetal Movement. Low concentrations of both CTxs potentiated the TE-671 cell response and higher concentrations of CTx EI, and GI antagonized the actions of both coniine enantiomers demonstrating concentration-dependent coagonism and selective antagonism. These results provide pharmacological evidence that the piperidine alkaloid coniine is acting at Fetal muscle-type nAChR in a concentration-dependent manner.
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Pregnant Goat Model by Optical Isomers of the Piperidine Alkaloid Coniine
2012Co-Authors: Benedict T Green, Kevin D Welch, James A Pfister, Stephen T. Lee, Kip E. PanterAbstract:Coniine is an optically active toxic piperidine alkaloid and nicotinic acetylcholine receptor (nAChR) agonist found in poison hemlock (Conium maculatum L.). Coniine teratogenicity is hypothesized to be attributable to the binding, activation, and prolonged de-sensitization of Fetal muscle-type nAChR, which results in the complete inhibition of Fetal Movement. However, pharmacological evidence of coniine actions at Fetal muscle-type nAChR is lacking. The present study compared (2)-coniine, (1)-coniine, and nicotine for the ability to inhibit Fetal Movement in a day 40 pregnant goat model and in TE-671 cells that express Fetal muscle-type nAChR. Furthermore, a-conotoxins (CTx) EI and GI were used to antagonize the actions of (1)- and (2)-coniine in TE-671 cells. (2)-Coniine was more effective at eliciting electrical changes in TE-671 cells and inhibiting Fetal Movement than was (1)-coniine, suggesting stereoselectivity by the receptor. The pyridine alkaloid nicotine did not inhibit Fetal Movement in a day 40 pregnant goat model, suggesting agonist specificity for the inhibition of Fetal Movement. Low concentrations of both CTxs potentiated the TE-671 cell response and higher concentrations of CTx EI, and GI antagonized the actions of both coniine enantiomers demon-strating concentration-dependent coagonism and selective an-tagonism. These results provide pharmacological evidence that the piperidine alkaloid coniine is acting at Fetal muscle-type nAChR in a concentration-dependent manner
Alexander E P Heazell - One of the best experts on this subject based on the ideXlab platform.
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standard care informed by the result of a placental growth factor blood test versus standard care alone in women with reduced Fetal Movement at or after 36 0 weeks gestation a pilot randomised controlled trial
Pilot and Feasibility Studies, 2020Co-Authors: Lindsay Armstrongbuisseret, Alexander E P Heazell, Eleanor J Mitchell, C Storey, Peter J Godolphin, Lucy Bradshaw, Sam RatcliffeAbstract:Biomarkers of placental function can potentially aid the diagnosis and prediction of pregnancy complications. This randomised controlled pilot trial assessed whether for women with reduced Fetal Movement (RFM), intervention directed by the measurement of a placental biomarker in addition to standard care was feasible and improved pregnancy outcome compared with standard care alone. Women aged 16–50 years presenting at eight UK maternity units with RFM between 36+0 and 41+0 weeks’ gestation with a viable singleton pregnancy and no indication for immediate delivery were eligible. Participants were randomised 1:1 in an unblinded manner to standard care and a biomarker blood test result revealed and acted on (intervention arm) or standard care where the biomarker result was not available (control arm). The objectives were to determine the feasibility of a main trial by recruiting 175–225 participants over 9 months and to provide proof of concept that informing care by measurement of placental biomarkers may improve outcome. Feasibility was assessed via the number of potentially eligible women, number recruited, reasons for non-recruitment and compliance. Proof of concept outcomes included the rates of the induction of labour and caesarean birth, and a composite adverse pregnancy outcome. Overall, 2917 women presented with RFM ≥ 36 weeks, 352 were approached to participate and 216 (61%) were randomised (intervention n = 109, control n = 107). The main reason for not approaching women was resource/staff issues (n = 1510). Ninety-seven women declined the trial, mainly due to not liking blood tests (n = 24) or not wanting to be in a trial (n = 21). Compliance with the trial interventions was 100% in both arms. Labour was induced in 97 (45%) participants (intervention n = 49, control n = 48), while 17 (9%) had planned caesarean sections (intervention n = 9, control n = 8). Overall, 9 (8%) babies in the intervention arm had the composite adverse pregnancy outcome versus 4 (4%) in the control arm. A main trial using a placental biomarker in combination with delivery, as indicated by the biomarker, in women with RFM is feasible. The frequency of adverse outcomes in this population is low, hence, a large sample size would be required along with consideration of the most appropriate outcome measures. ISRCTN, ISRCTN12067514; registered 8 September 2017.
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reduced Fetal Movement intervention trial 2 remit 2 protocol for a pilot randomised controlled trial of standard care informed by the result of a placental growth factor plgf blood test versus standard care alone in women presenting with reduced Fetal Movement at or after 36 0 weeks gestation
Trials, 2018Co-Authors: Lindsay Armstrongbuisseret, Alexander E P Heazell, J G Thornton, Eleanor J Mitchell, Trish Hepburn, Lelia Duley, Tracy E Roberts, C Storey, Rebecca SmythAbstract:Forty percent of babies who are stillborn born die after 36 weeks gestation and have no lethal structural abnormality. Maternal perception of reduced Fetal Movement (RFM) is associated with stillbirth and is related to abnormal placental structure and function. The ultimate objective of this trial is to assess whether for women with RFM, intervention directed by measurement of placental biochemical factors in addition to standard care improves pregnancy outcome compared with standard care alone. This is the protocol for a pilot trial to determine the feasibility of a definitive trial and also provide proof of concept that informing care by measurement of placental factors improves neonatal outcomes. ReMIT-2 is a multicentre, pilot randomised controlled trial of care informed by results of an additional placental factor blood test versus standard care alone for women presenting with RFM at or after 36+ 0 weeks gestation. Participants will be randomised 1:1 to the intervention arm where the blood test result is revealed and acted on, or to the control arm where the blood sample is not tested immediately and therefore the result cannot be acted on. All participants will be followed up six weeks after delivery to assess their health status and views of the trial, along with healthcare costs. A sub-group will be interviewed within 16 weeks after delivery to further explore their views of the trial. Outcomes to determine feasibility of a definitive trial include number of potentially eligible women, proportion lost to follow-up, clinical characteristics at randomisation, reasons for non-recruitment, compliance with the trial intervention and views of participants and clinicians about the trial. Proof of concept outcomes include: rates of induction of labour; Caesarean birth; and a composite neonatal outcome of stillbirths and deaths before discharge, 5-min Apgar score 48 h. Results from this pilot trial will help determine whether a large definitive trial is feasible. Such a study would provide evidence to guide management of women with RFM and reduce stillbirths. ISRCTN Registry, ISRCTN12067514 . Registered on 8 September 2017.
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alterations in maternally perceived Fetal Movement and their association with late stillbirth findings from the midland and north of england stillbirth case control study
BMJ Open, 2018Co-Authors: Alexander E P Heazell, Billie Bradford, Robin S Cronin, Lesley M E Mccowan, Jayne Budd, Edwin A Mitchell, Tomasina Stacey, Bill Martin, Devender Roberts, John M D ThompsonAbstract:Objective To report perception of Fetal Movements in women who experienced a stillbirth compared with controls at a similar gestation with a live birth. Design Case–control study. Setting 41 maternity units in the UK. Participants Cases were women who had a late stillbirth ≥28 weeks gestation (n=291) and controls were women with an ongoing pregnancy at the time of the interview (n=733). Controls were frequency matched to cases by obstetric unit and gestational age. Methods Data were collected using an interviewer-administered questionnaire which included questions on maternal perception of Fetal Movement (frequency, strength, increased and decreased Movements and hiccups) in the 2 weeks before the interview/stillbirth. Five Fetal Movement patterns were identified incorporating the changes in strength and frequency in the last 2 weeks by combining groups of similar pattern and risk. Multivariable analysis adjusted for known confounders. Primary outcome measure Association of maternally perceived Fetal Movements in relation to late stillbirth. Results In multivariable analyses, women who reported increased strength of Movements in the last 2 weeks had decreased risk of late stillbirth compared with those whose Movements were unchanged (adjusted OR (aOR) 0.18, 95% CI 0.13 to 0.26). Women with decreased frequency (without increase in strength) of Fetal Movements were at increased risk (aOR 4.51, 95% CI 2.38 to 8.55). Daily perception of Fetal hiccups was protective (aOR 0.31, 95% CI 0.17 to 0.56). Conclusions Increased strength of Fetal Movements and Fetal hiccups is associated with decreased risk of stillbirth. Alterations in frequency of Fetal Movements are important in identifying pregnancies at increased risk of stillbirth, with the greatest risk in women noting a reduction in Fetal activity. Clinical guidance should be updated to reflect that increase in strength and frequency of Fetal Movements is associated with the lowest risk of stillbirth, and that decreased Fetal Movements are associated with stillbirth. Trial registration number NCT02025530.
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maternal perception of Fetal Movements in late pregnancy is affected by type and duration of Fetal Movement
Journal of Maternal-fetal & Neonatal Medicine, 2016Co-Authors: Rebecca Brown, Lucy Higgins, Edward Johnstone, Jayawan H B Wijekoon, Alexander E P HeazellAbstract:AbstractObjective: A reduction in Fetal Movements has been proposed to identify pregnancies at risk of stillbirth. The utility of this approach is limited by variability in maternal perception of Fetal Movements. We aimed to determine the proportion of Fetal Movements observed by ultrasound that were maternally perceived and identify factors that affected maternal perception.Method: During 30-min recordings, women (n = 21) depressed a trigger upon perception of a Fetal Movement, while an ultrasound operator recorded observed Movements according to the Fetal parts involved.Results: Women perceived between 2.4% and 81.0% (median 44.8%) of Movements observed on scan. Synchronous Movement of the Fetal trunk and limbs was more likely to be recognized than either part in isolation (60.5% versus 37.5% and 30%, respectively). The ultrasound operator judged the fetus to be moving for a significantly greater proportion of the time than mothers (median 1.5% of total recording time versus 0.7%). There was no signific...
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Fetal Movement assessment
Seminars in Perinatology, 2008Co-Authors: Frederik J Froen, Alexander E P Heazell, Julie Victoria Holm Tveit, Eli Saastad, Ruth C Fretts, Vicki FlenadyAbstract:Maternal perception of Fetal Movements is the oldest and most commonly used method to assess Fetal well-being. While almost all pregnant women adhere to it, organized screening by Fetal Movements has seen variable popularity among health professionals. Early results of screening were promising and Fetal Movement counting is the only antepartum testing method that has shown effect in reducing mortality in a randomized controlled trial comparing testing versus no testing. Although awareness of Fetal Movements is associated with improved perinatal outcomes, the quest to define a quantitative "alarm limit" to define decreased Fetal Movements has so far been unsuccessful, and the use of most such limits developed for Fetal Movement counting should be discouraged.
James A Pfister - One of the best experts on this subject based on the ideXlab platform.
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complete inhibition of Fetal Movement in the day 40 pregnant goat model by the piperidine alkaloid anabasine but not related alkaloids
Toxicon, 2018Co-Authors: Benedict T Green, John W. Keele, Kevin D Welch, Daniel Cook, James A PfisterAbstract:Abstract Four chemically similar alkaloids, anabasine, anabaseine, epibatidine and dimethylphenylpiperazinium (DMPP), are potent nicotinic acetylcholine receptor agonists of Fetal muscle nicotinic acetylcholine receptors in human TE-671 cells. Based on results with these cells, we hypothesized that the alkaloids would completely inhibit ultrasound-monitored Fetal Movement in a goat model. Different, single doses of anabasine, anabaseine, epibatidine, DMPP, or saline control were administered I.V. to pregnant goats on day 40 of gestation and the number of Fetal Movements per 5 min sample was measured by ultrasound at times 0, 0.5, 1, 2, 4 and 8 h. The differences among does in Fetal Movements were more consistent at dosing and following recovery for doses of anabasine above 0.125 mg/kg compared to the other compounds and dosages. Anabasine actions were dose-dependent with an IC 50 value of ∼0.1 mg/kg, and, at a dose of 0.8 mg/kg, completely inhibited Fetal Movement for 1.5 h after dosing. Anabaseine, epibatidine, and DMPP failed to completely inhibit Fetal Movement in day 40 pregnant goats at doses predicted to be effective. These results suggest that while experiments with TE-671 cells provide valuable information and predictions of the actions of plant alkaloids on Fetal Movement, in vivo experiments are still required in order to determine the ability of an alkaloid to inhibit Fetal Movement in livestock species. Moreover, other pharmacological properties such as receptor differences between mammalian species and differences in the pharmacokinetic properties of the alkaloids also are likely to weaken teratologic predictions based solely on the in vitro data.
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Running title: Optical isomers of coniine inhibit Fetal Movement.
2016Co-Authors: Benedict T Green, Kevin D Welch, James A Pfister, Stephen T. Lee, Kip E. PanterAbstract:Fetal-muscle type nicotinic acetylcholine receptor activation in TE-671 cells, and inhibition of Fetal Movement in a day 40 pregnant goat model by optical isomers of the piperidine alkaloid coniine
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piperidine pyridine alkaloid inhibition of Fetal Movement in a day 40 pregnant goat model
Food and Chemical Toxicology, 2013Co-Authors: Benedict T Green, Kevin D Welch, James A Pfister, Kip E. PanterAbstract:Abstract Inhibition of Fetal Movement is one mechanism behind the development of multiple congenital contracture-type defects in developing fetuses of humans and animals. We tested the alkaloids anabasine, lobeline, and myosmine for agonist actions, and sensitivity to alpha conotoxins EI and GI blockade at Fetal muscle-type nicotinic acetylcholine receptors (nAChR) expressed by TE-671 cells. We also determined if the alkaloids decreased Fetal Movement in an IV dosed, day 40 pregnant goat model. In TE-671 cells, all three alkaloids elicited concentration-dependent changes in membrane potential sensing dye fluorescence. 1.0 μM alpha conotoxin GI shifted the concentration–effect curves of anabasine and myosmine to the right, and decreased maximal responses. Neither of the conotoxins blocked the actions of lobeline in TE-671 cells. In the day 40 pregnant goats, 0.8 mg/kg anabasine abolished Fetal Movement at 30 and 60 min after dosing and Fetal Movement was reduced by lobeline and myosmine. The blockade of anabasine and myosmine actions in TE-671 cells by alpha conotoxin GI indicates that they are agonists at Fetal muscle-type nAChR. All three alkaloids did significantly decrease Fetal Movement in the day 40 pregnant goat model suggesting a potential for these alkaloids to cause multiple congenital contracture-type defects in developing fetuses.
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Fetal muscle type nicotinic acetylcholine receptor activation in te 671 cells and inhibition of Fetal Movement in a day 40 pregnant goat model by optical isomers of the piperidine alkaloid coniine
Journal of Pharmacology and Experimental Therapeutics, 2013Co-Authors: Benedict T Green, Kevin D Welch, James A Pfister, Kip E. PanterAbstract:Coniine is an optically active toxic piperidine alkaloid and nicotinic acetylcholine receptor (nAChR) agonist found in poison hemlock ( Conium maculatum L. ). Coniine teratogenicity is hypothesized to be attributable to the binding, activation, and prolonged desensitization of Fetal muscle-type nAChR, which results in the complete inhibition of Fetal Movement. However, pharmacological evidence of coniine actions at Fetal muscle-type nAChR is lacking. The present study compared (−)-coniine, (+)-coniine, and nicotine for the ability to inhibit Fetal Movement in a day 40 pregnant goat model and in TE-671 cells that express Fetal muscle-type nAChR. Furthermore, α-conotoxins (CTx) EI and GI were used to antagonize the actions of (+)- and (−)-coniine in TE-671 cells. (−)-Coniine was more effective at eliciting electrical changes in TE-671 cells and inhibiting Fetal Movement than was (+)-coniine, suggesting stereoselectivity by the receptor. The pyridine alkaloid nicotine did not inhibit Fetal Movement in a day 40 pregnant goat model, suggesting agonist specificity for the inhibition of Fetal Movement. Low concentrations of both CTxs potentiated the TE-671 cell response and higher concentrations of CTx EI, and GI antagonized the actions of both coniine enantiomers demonstrating concentration-dependent coagonism and selective antagonism. These results provide pharmacological evidence that the piperidine alkaloid coniine is acting at Fetal muscle-type nAChR in a concentration-dependent manner.
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Pregnant Goat Model by Optical Isomers of the Piperidine Alkaloid Coniine
2012Co-Authors: Benedict T Green, Kevin D Welch, James A Pfister, Stephen T. Lee, Kip E. PanterAbstract:Coniine is an optically active toxic piperidine alkaloid and nicotinic acetylcholine receptor (nAChR) agonist found in poison hemlock (Conium maculatum L.). Coniine teratogenicity is hypothesized to be attributable to the binding, activation, and prolonged de-sensitization of Fetal muscle-type nAChR, which results in the complete inhibition of Fetal Movement. However, pharmacological evidence of coniine actions at Fetal muscle-type nAChR is lacking. The present study compared (2)-coniine, (1)-coniine, and nicotine for the ability to inhibit Fetal Movement in a day 40 pregnant goat model and in TE-671 cells that express Fetal muscle-type nAChR. Furthermore, a-conotoxins (CTx) EI and GI were used to antagonize the actions of (1)- and (2)-coniine in TE-671 cells. (2)-Coniine was more effective at eliciting electrical changes in TE-671 cells and inhibiting Fetal Movement than was (1)-coniine, suggesting stereoselectivity by the receptor. The pyridine alkaloid nicotine did not inhibit Fetal Movement in a day 40 pregnant goat model, suggesting agonist specificity for the inhibition of Fetal Movement. Low concentrations of both CTxs potentiated the TE-671 cell response and higher concentrations of CTx EI, and GI antagonized the actions of both coniine enantiomers demon-strating concentration-dependent coagonism and selective an-tagonism. These results provide pharmacological evidence that the piperidine alkaloid coniine is acting at Fetal muscle-type nAChR in a concentration-dependent manner
Frederik J Froen - One of the best experts on this subject based on the ideXlab platform.
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wavelet principal component analysis of Fetal Movement counting data preceding hospital examinations due to decreased Fetal Movement a prospective cohort study
BMC Pregnancy and Childbirth, 2013Co-Authors: Brita Askeland Winje, Eli Saastad, Jo Roislien, Jorid Eide, Christopher Finne Riley, Babill Straypedersen, Frederik J FroenAbstract:Background Fetal Movement (FM) counting is a simple and widely used method of assessing Fetal well-being. However, little is known about what women perceive as decreased Fetal Movement (DFM) and how maternally perceived DFM is reflected in FM charts.
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temporal patterns in count to ten Fetal Movement charts and their associations with pregnancy characteristics a prospective cohort study
BMC Pregnancy and Childbirth, 2012Co-Authors: Brita Askeland Winje, Jo Roislien, Frederik J FroenAbstract:Fetal Movement counting has long been suggested as a screening tool to identify impaired placental function. However, quantitative limits for decreased Fetal Movement perform poorly for screening purposes, indicating the need for methodological refinement. We aimed to identify the main individual temporal patterns in Fetal Movement counting charts, and explore their associations with pregnancy characteristics. In a population-based prospective cohort in Norway, 2009–2011, women with singleton pregnancies counted Fetal Movements daily from pregnancy week 24 until delivery using a modified "count-to-ten” procedure. To account for intra-woman correlation of observations, we used functional data analysis and corresponding functional principal component analysis to identify the main individual temporal patterns in Fetal Movement count data. The temporal patterns are described by continuous functional principal component (FPC) curves, with an individual score on each FPC for each woman. These scores were later used as outcome variables in multivariable linear regression analyses, with pregnancy characteristics as explanatory variables. Fetal Movement charts from 1086 pregnancies were included. Three FPC curves explained almost 99% of the variation in the temporal data, with the first FPC, representing the individual overall counting time, accounting for 91% alone. There were several statistically significant associations between the FPCs and various pregnancy characteristics. However, the effects were small and of limited clinical value. This statistical approach for analyzing Fetal Movement counting data successfully captured clinically meaningful individual temporal patterns and how these patterns vary between women. Maternal body mass index, gestational age and placental site explained little of the variation in the temporal Fetal Movement counting patterns. Thus, a perceived decrease in Fetal Movement should not be attributed to a woman’s basic pregnancy characteristics, but assessed as a potential marker of risk.
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Fetal Movement counting maternal concern and experiences a multicenter randomized controlled trial
Birth-issues in Perinatal Care, 2012Co-Authors: Eli Saastad, Brita Askeland Winje, Pravin Israel, Frederik J FroenAbstract:Background: Fetal Movement counting may improve timely identification of decreased Fetal activity and thereby contribute to prevent adverse pregnancy outcomes, but it may also contribute to maternal concern. This study aimed to test whether Fetal Movement counting increased maternal concern. Methods: In a multicenter, controlled trial 1,013 women with a singleton pregnancy were randomly assigned either to perform daily Fetal move- ment counting from pregnancy week 28 or to follow standard Norwegian antenatal care where Fetal Movement counting is not encouraged. The primary outcome was maternal concern, mea- sured by the Cambridge Worry Scale. Analysis was by intention-to-treat. Results: The means and SDs on Cambridge Worry Scale scores were 0.77 (0.55) and 0.90 (0.62) for the interven- tion and the control groups, respectively, a mean difference between the groups of 0.14 (95% CI: 0.06-0.21, p < 0.001). Decreased Fetal activity was of concern to 433 women once or more during pregnancy, 45 and 42 percent in the intervention and control groups, respectively (rela- tive risk = 1.1, 95% CI: 0.9-1.2). Seventy-nine percent of the women responded favorably to the use of counting charts. Conclusions: Women who performed Fetal Movement counting in the third trimester reported less concern than those in the control group. The frequency of maternal report of concern about decreased Fetal activity was similar between the groups. Most women considered the use of a counting chart to be positive. (BIRTH 39:1 March 2012)
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Fetal Movement counting improved identification of Fetal growth restriction and perinatal outcomes a multi centre randomized controlled trial
PLOS ONE, 2011Co-Authors: Brita Askeland Winje, Eli Saastad, Babill Stray Pedersen, Frederik J FroenAbstract:Background Fetal Movement counting is a method used by the mother to quantify her baby's Movements, and may prevent adverse pregnancy outcome by a timely evaluation of Fetal health when the woman reports decreased Fetal Movements. We aimed to assess effects of Fetal Movement counting on identification of Fetal pathology and pregnancy outcome. Methodology In a multicentre, randomized, controlled trial, 1076 pregnant women with singleton pregnancies from an unselected population were assigned to either perform Fetal Movement counting from gestational week 28, or to receive standard antenatal care not including Fetal Movement counting (controls). Women were recruited from nine Norwegian hospitals during September 2007 through November 2009. Main outcome was a compound measure of Fetal pathology and adverse pregnancy outcomes. Analysis was performed by intention-to-treat. Principal Findings The frequency of the main outcome was equal in the groups; 63 of 433 (11.6%) in the intervention group, versus 53 of 532 (10.7%) in the control group [RR: 1.1 95% CI 0.7–1.5)]. The growth-restricted fetuses were more often identified prior to birth in the intervention group than in the control group; 20 of 23 fetuses (87.0%) versus 12 of 20 fetuses (60.0%), respectively, [RR: 1.5 (95% CI 1.0–2.1)]. In the intervention group two babies (0.4%) had Apgar scores <4 at 1 minute, versus 12 (2.3%) in the control group [RR: 0.2 (95% CI 0.04–0.7)]. The frequency of consultations for decreased Fetal Movement was 71 (13.1%) and 57 (10.7%) in the intervention and control groups, respectively [RR: 1.2 (95% CI 0.9–1.7)]. The frequency of interventions was similar in the groups. Conclusions Maternal ability to detect clinically important changes in Fetal activity seemed to be improved by Fetal Movement counting; there was an increased identification of Fetal growth restriction and improved perinatal outcome, without inducing more consultations or obstetric interventions. Trial Registration ClinicalTrials.gov NCT00513942
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Fetal Movement counting effects on maternal Fetal attachment a multicenter randomized controlled trial
Birth-issues in Perinatal Care, 2011Co-Authors: Eli Saastad, Pravin Israel, Tone Ahlborg, Nina Gunnes, Frederik J FroenAbstract:Abstract: Background: Women presenting with decreased Fetal Movement have an increased risk of adverse pregnancy outcomes. Fetal Movement counting may be associated with improvement in maternal-Fetal attachment, which in turn, improves pregnancy outcome and postnatal mother–infant attachment. The study aim was to test whether maternal-Fetal attachment differed between groups of mothers who systematically performed Fetal Movement counting and mothers who followed standard antenatal care where routine Fetal Movement counting was discouraged. Methods: In a multicenter, randomized trial, 1,123 women were assigned to either systematic Fetal Movement counting from pregnancy week 28 or to standard antenatal care. This study sample included primarily white, cohabiting, nonsmoking, and relatively well-educated women. The outcome measure was maternal-Fetal attachment, measured by using the Prenatal Attachment Inventory. Analysis was by intention-to-treat. Results: No difference was found between the groups in the scores on prenatal attachment; the means and standard deviations were 59.54 (9.39) and 59.43 (9.35) for the intervention and the control groups, respectively (p = 0.747). The mean difference between the groups was 0.20 (95% CI: 1.02–1.42). Conclusions: Fetal Movement counting in the third trimester does not stimulate antenatal maternal-Fetal attachment. This result differs from a previous study where Fetal Movement counting improved maternal-Fetal attachment. Further research with a focus on possible mediating factors such as levels of stress, concern, and other psychological factors is required. (BIRTH 38:4 December 2011)