Pregnancy and COVID-19: pharmacologic considerations.

In this review, we summarize evidence regarding the use of routine and investigational pharmacologic interventions for pregnant and lactating patients with coronavirus disease 2019 (COVID-19). Antenatal corticosteroids may be used routinely for fetal lung maturation between 24 and 34 weeks' gestation, but decisions in those with critical illness and those < 24 or > 34 weeks' gestation should be made on a case-by-case basis. Magnesium sulfate may be used for seizure prophylaxis and fetal neuroprotection, albeit cautiously in those with hypoxia and renal compromise. There are no contraindications to using low-dose aspirin to prevent placenta-mediated pregnancy complications when indicated. An algorithm for thromboprophylaxis in pregnant patients with COVID-19 is presented, which considers disease severity, timing of delivery in relation to disease onset, inpatient vs outpatient status, underlying comorbidities and contraindications to the use of anticoagulation. Nitrous oxide may be administered for labor analgesia while using appropriate personal protective equipment. Intravenous remifentanil patient-controlled analgesia should be used with caution in patients with respiratory depression. Liberal use of neuraxial labor analgesia may reduce the need for emergency general anesthesia which results in aerosolization. Short courses of non-steroidal anti-inflammatory drugs can be administered for postpartum analgesia, but opioids should be used with caution due to the risk of respiratory depression. For mechanically ventilated pregnant patients, neuromuscular blockade should be used for the shortest duration possible and reversal agents should be available on hand if delivery is imminent. To date, dexamethasone is the only proven and recommended experimental treatment for pregnant patients with COVID-19 who are mechanically ventilated or who require supplemental oxygen. Although hydroxycholoroquine, lopinavir/ritonavir and remdesivir may be used during pregnancy and lactation within the context of clinical trials, data from non-pregnant populations have not shown benefit. The role of monoclonal antibodies (tocilizumab), immunomodulators (tacrolimus), interferon, inhaled nitric oxide and convalescent plasma in pregnancy and lactation needs further evaluation. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Postnatal demoralisation among women admitted to a hospital mother-baby unit: validation of a psychometric measure.

Demoralisation is a psychological state characterised by experiences of distress and sadness, helplessness, subjective incompetence and hopelessness, in the context of a stressful situation. Experiences of demoralisation may be particularly relevant to women who have recently given birth, who can feel incompetent, isolated and helpless. The psychometric properties of the Demoralisation Scale among women in the postnatal period participating in a clinical program were examined. Women admitted with their infants to a hospital mother-baby unit in Australia for five nights were recruited consecutively (N = 209) and assessed at admission and discharge. The Demoralisation Scale was perceived as relevant and exhibited high reliability, acceptable construct validity and good sensitivity to change. The mean demoralisation score was high (M = 30.9, SD = 15.5) and associated with negative experiences of motherhood and functional impairment, independent of depression and anxiety symptoms. Mean demoralisation decreased significantly after program completion (M = 18.4, SD = 12.4). More participants showed a significant improvement in demoralisation (57.5 %) than in depression (34.8 %) and anxiety (9.8 %) symptoms. Demoralisation can provide a useful framework for understanding and measuring the experiences of women participating in postnatal clinical programs and in directing treatment towards helping women to acquire the necessary caregiving skills and increasing parental efficacy. The Demoralisation Scale is a useful clinical tool for assessing intervention effects.

Mothers' perceptions of primary health-care providers: thematic analysis of responses to open-ended survey questions.

General practitioners and maternal, child and family health nurses have a central role in postpartum primary health care for women and their infants. Positive client-provider relationships are particularly important for women experiencing mental health problems or unsettled infant behaviour. However, little is known about their experiences of postnatal primary health care. The study aimed to describe views of postnatal primary health care among women completing a residential early parenting programme and to identify potential strategies to enhance provider-patient interactions. Participants (n=138) were women admitted with their infants to a private or a public early parenting service in Melbourne, Australia. Women completed a detailed self-report survey, including open-ended questions about experiences of primary health-care services, and a structured psychiatric interview to diagnose anxiety and depression. Survey responses were analysed thematically. Womens' experiences of primary health care were influenced by their perceptions of provider competence and the quality of interactions. While similar positive characteristics of doctor and nurse care were valued, medical and nursing practices were judged in different ways. Women described GPs who listened, understood and were thorough as providing good care, and maternal, child and family health nurses were valued for providing support, advice and encouragement. Threats to therapeutic relationships with doctors included feeling rushed during consultations, believing that GPs were not mental health-care providers and the clinician not being 'good' with the infant; with nurses, problems included feeling judged or given advice that was inconsistent or lacked an evidence-base. Postpartum primary health care will be improved by unhurried consultations, empathic recognition, encouragement, evidence-informed guidance and absence of criticism.

RAD in the realm of next-generation sequencing technologies.

The first North American RAD Sequencing and Genomics Symposium, sponsored by Floragenex (http://www.floragenex.com/radmeeting/), took place in Portland, Oregon (USA) on 19 April 2011. This symposium was convened to promote and discuss the use of restriction-site-associated DNA (RAD) sequencing technologies. RAD sequencing is one of several strategies recently developed to increase the power of data generated via short-read sequencing technologies by reducing their complexity (Baird et al. 2008; Huang et al. 2009; Andolfatto et al. 2011; Elshire et al. 2011). RAD sequencing, as a form of genotyping by sequencing, has been effectively applied in genetic mapping and quantitative trait loci (QTL) analyses in a range of organisms including nonmodel, genetically highly heterogeneous organisms (Table 1; Baird et al. 2008; Baxter et al. 2011; Chutimanitsakun et al. 2011; Pfender et al. 2011). RAD sequencing has recently found applications in phylogeography (Emerson et al. 2010) and population genomics (Hohenlohe et al. 2010). Considering the diversity of talks presented during this meeting, more developments are to be expected in the very near future.

Breastfeeding after assisted conception: a prospective cohort study.

AIM: The aims were to investigate the prevalence of breastfeeding after conception with assisted reproductive technology (ART) and identify risk factors for breastfeeding duration <6 weeks and cessation of breastfeeding before the baby is 8 months old. METHODS: A consecutive cohort of women who had conceived at one of two ART centres in Melbourne, Australia, was recruited in early pregnancy. The women completed telephone interviews and postal questionnaires in pregnancy and 3, 8 and 18 months after the birth. RESULTS: Of 239 eligible women, 183 (77%) agreed to take part. Participants were more likely than the general population of childbearing Australian women to initiate breastfeeding (89% vs 83.3%, p=0.05) but by 3 months, a smaller proportion was breastfeeding exclusively (46% vs 57.3%, p=0.004). The proportions not providing any breast milk at 6 weeks and 8 months were 23% and 57%, respectively. More anxiety in late pregnancy and sub-optimal breastfeeding advice predicted breastfeeding duration <6 weeks and breastfeeding cessation before 8 months. CONCLUSION: The predictors of less favourable breastfeeding outcomes after ART identified may be modifiable. Antenatal strategies to reduce anxiety in pregnancy and postnatal strategies to ensure consistent breastfeeding advice may improve breastfeeding outcomes among women who give birth after ART.

Early post-partum adjustment and admission to parenting services in Victoria, Australia after assisted conception.

BACKGROUND: Higher rates of admission to residential early parenting services (REPSs) after assisted conception compared with spontaneous conception have been reported. The aim of this study was to characterize early post-partum psychological functioning and the rate of, and risks factors for, admission to REPSs in women conceiving with assisted reproductive technology (ART) in Australia. METHODS: A consecutive cohort of women who had conceived through ART was recruited systematically in early pregnancy. At 3 months post-partum, participants completed postal questionnaires which included a new measure of the degree of difficulty involved in conceiving, the Burden of Infertility and Treatment (BIT) scale. RESULTS: Of 166 women who participated, 8% had already been admitted to a REPS within 3 months, which is a higher rate compared with other women in the first 12 months (5%). Compared with community samples of new mothers, there was no difference in rate of depression. A higher proportion reported dysregulated infant behaviours (P < 0.0001) and a smaller proportion was breast feeding exclusively (P < 0.0001). Greater difficulty conceiving (higher BIT score) was associated with lower maternal confidence. CONCLUSIONS: Clinical care of the increasing group of women who conceive with ART should include explicit assessment of early post-partum psychological functioning and early intervention if difficulties in managing infant behaviour are reported.

11-hydroxy- 9 -tetrahydrocannabinol: pharmacology, disposition, and metabolism of a major metabolite of marihuana in man.

11-Hydroxy-Delta(9)-tetrahydrocannabinol, administered intravenously to man, produces psychologic and pharmacologic effects that persist for several hours. The drug and its metabolites are excreted in urine and feces for more than 1 week. The pharmacology, disposition, and metabolism of 11-hydroxy-Delta(9)-tetra-hydrocannabinol mimic that of Delta(9)-tetrahydrocannabinol, thus providing evidence that Delta(9)-tetrahydrocannabinol (the major active component of marihuana) is converted to the 11-hydroxy compound in man, the latter compound being responsible for the effects.

Pharmacologic effects in man of a specific serotonin-reuptake inhibitor.

Fluoxetine (Li-ly 110140) caused a 63 percent inhibition of [3H]serotonin uptake into platelets obtained from normal volunteers to whom the drug was administered daily for 7 days. This dose had no effect on the usual pressor response produced by injections of norepinephrine or tyramine.

The history of South American tropical precipitation for the past 25,000 years.

Long sediment cores recovered from the deep portions of Lake Titicaca are used to reconstruct the precipitation history of tropical South America for the past 25,000 years. Lake Titicaca was a deep, fresh, and continuously overflowing lake during the last glacial stage, from before 25,000 to 15,000 calibrated years before the present (cal yr B.P.), signifying that during the last glacial maximum (LGM), the Altiplano of Bolivia and Peru and much of the Amazon basin were wetter than today. The LGM in this part of the Andes is dated at 21,000 cal yr B.P., approximately coincident with the global LGM. Maximum aridity and lowest lake level occurred in the early and middle Holocene (8000 to 5500 cal yr B.P.) during a time of low summer insolation. Today, rising levels of Lake Titicaca and wet conditions in Amazonia are correlated with anomalously cold sea-surface temperatures in the northern equatorial Atlantic. Likewise, during the deglacial and Holocene periods, there were several millennial-scale wet phases on the Altiplano and in Amazonia that coincided with anomalously cold periods in the equatorial and high-latitude North Atlantic, such as the Younger Dryas.

Women's experiences of childbirth and post-natal healthcare after assisted conception.

BACKGROUND: The proportion of women who give birth after assisted reproduction technology (ART) treatment is increasing. To date, little is known about their experience of childbirth. One of the aims of this study was to investigate the experience of childbirth and the post-natal healthcare after ART. METHODS: A prospective, longitudinal study of a systematically recruited consecutive cohort of women who had conceived with ART in Melbourne, Australia, in 2001 was investigated using telephone interviews and self-report questionnaires. The experience of birth was explored 3 months post-partum. RESULTS: One hundred and sixty-six women who had conceived through ART participated. Compared with other Australian women, participants were more likely to have a Caesarean birth (51% versus 25%, P < 0.0001). Women who had a Caesarean birth were less likely to report having had an active say about the management of the birth (P < 0.01) and to have held their baby at birth (P < 0.0001) and more likely to report disappointment with the birth event (P < 0.0001), severe post-natal pain (P = 0.02) and needing a lot of help or advice with infant feeding (P = 0.001) than those who had a vaginal birth. CONCLUSIONS: After ART, there are highly elevated rates of operative birth which appear to influence early post-natal adjustment.

Comparative pharmacology of Delta9-tetrahydrocannabinol and its metabolite, 11-OH-Delta9-tetrahydrocannabinol.

A comparison of the psychologic and physiologic effects of intravenously administered Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and 11-hydroxy-Delta(9)-tetrahydrocannabinol (11-OH-Delta(9)-THC) was carried out in nine casual marihuana smokers. A marked tachycardia and psychologic "high" occurred within 3-5 min after the i.v. administration of 11-OH-Delta(9)-THC (1 mg) to all subjects. In contrast, the peak psychologic "high" was delayed 10-20 min after the i.v. administration of Delta(9)-THC (1 mg). There was some individual variation in response among subjects. Psychologic effects correlated well with plasma levels of unchanged [(3)H]11-OH-Delta(9)-THC. About 75% of the administered radioactive dose was excreted in urine (25%) and feces (50%) after [(3)H]11-OH-Delta(9)-THC administration. The disposition, excretion, and metabolism of [(3)H]11-OH-Delta(9)-THC appear to be similar to that previously reported after [(14)C]Delta(9)-THC administration. These findings, in conjunction with the marked psychologic high seen after 11-OH-Delta(9)-THC, suggest that in man, Delta(9)-THC, the active constituent in marihuana, is converted to 11-OH-Delta(9)-THC, which is in part responsible for the psychologic effects.

Comparative pharmacokinetics and glucodynamics of two human insulin mixtures. 70/30 and 50/50 insulin mixtures.

OBJECTIVE: To compare and contrast the pharmacokinetics and glucodynamics of two insulin mixtures, one of 50% NPH human insulin and 50% Regular human insulin (50/50) and one of 70% NPH human insulin and 30% Regular human insulin (70/30), in healthy male volunteers after subcutaneous administrations of 0.3 U/kg. RESEARCH DESIGN AND METHODS: We administered single doses of 50/50 and 70/30 insulins to 18 volunteers in a randomized crossover fashion. All subjects received 0.3 U/kg of each mixture separated by at least 7 days. Each dose was given after an overnight fast and during a glucose clamp to maintain a euglycemic state. We measured serum insulin and C-peptide concentrations through frequent blood sampling after each treatment. Pharmacokinetic measurements were calculated from insulin data corrected for C-peptide, including maximum insulin concentration (Cmax), time to maximum insulin concentration (tmax), terminal rate constant (beta), area under the curve from 0 to infinity (AUCinfinity0), and mean residence time (MRT). Pharmacodynamic measurements were summarized from C-peptide concentrations (minimum C-peptide concentration [Cmin], time to minimum C-peptide concentration [tmin], area between the C-peptide baseline and the C-peptide suppression curve [AOCc], absolute maximal difference from baseline [Sdiff] and glucose clamp measurements. The glucose clamp measurements included maximum infusion rates (Rmax) and time to Rmax (TRmax) from glucose infusion rate (GIR) documentation, as well as cumulative glucose infused during the first 4 h ((0)4Gtot) and total glucose infused (Gtot) during the study. RESULTS: For the pharmacokinetic assessment, statistically greater values of insulin Cmax and beta were found for the 50/50 mixture, whereas the 70/30 mixture had a greater MRT. Statistical differences were also detected in glucodynamics, with greater values of Rmax and (0)4Gtot found with the 50/50 mixture. Notably, differences were not detected for insulin AUCinfinity0 and Gtot values. CONCLUSIONS: Higher insulin concentrations and a greater initial response were present with the 50/50 mixture, but the two mixtures had equivalent bioavailability and cumulative effects. These results support use of the 50/50 mixture in situations where greater initial glucose control is required.

Clinical pharmacology of nabilone, a cannabinol derivative.

Nabilone is a modified cannabinol derivative with central nervous system activity. Administration of nabilone in single doses of 1 to 5 mg results in dose-related pharmacologic effects in man. One and 2.5 mg doses of nabilone induced relaxant and sedative effects in all subjects. No euphoria, dry mouth, tachycardia, or postural hypotension was seen after 1 mg, minimal effects were seen after 2.5 mg, and marked effects were seen after 5 mg. Effects were evident within 60 to 90 min and persisted for 8 to 12 hr. Nabilone produced no significant tachycardia. There were no changes in supine blood pressure; however, marked postural hypotension occurred after the 5-mg dose. The administration of nabilone at doses of 1 mg or 2 mg two times daily resulted in euphoria and dry mouth during the first two days of drug; thereafter tolerance developed to these effects but there was no apparent decrease in relaxation. Subjects challenged with a single 5-mg dose of nabilone showed a 66% reduction in symptoms and signs after the 7-day drug period compared to that of the same dose after 1 wk of placebo. Comparison of nabilone with other cannabinol derivatives suggests that some of the undesirable pharmacologic effects can be separated within the group.

The effect of fluoxetine on the pharmacokinetics and psychomotor responses of diazepam.

To determine the effect of fluoxetine on diazepam's pharmacokinetic and psychomotor responses, single oral doses of 10 mg diazepam were administered to six normal subjects on three occasions, either alone or in combination with 60 mg fluoxetine. Diazepam was given alone, after a single dose of fluoxetine, and after eight daily doses of fluoxetine. Psychometric data showed that fluoxetine had no significant effect on the psychomotor responses to diazepam. However, the pharmacokinetic data indicated a change in diazepam disposition after fluoxetine administration. Diazepam AUC was larger, the half-life was longer, and the plasma clearance was lower after fluoxetine administration, suggesting that fluoxetine inhibited the metabolism of diazepam. The reduced formation of an active metabolite, N-desmethyldiazepam, also suggested that fluoxetine inhibited diazepam's metabolism. The clinical implications of this pharmacokinetic drug-drug interaction are minor because psychomotor responses were unaffected and offsetting changes in the kinetics of diazepam and its metabolite occurred. Dosage modification of either fluoxetine or diazepam is unlikely to be necessary.

Physiologic disposition of nabilone, a cannabinol derivative, in man.

Nabilone is a cannabinoid that is being evaluated in man as a potentially useful psychoactive drug. We found that nabilone was readily absorbed from the human gastrointestinal tract when administered orally as a coprecipitate with polyvinyl-pyrrolidone. The absorbed drug disappeared from plasma rather rapidly (half-life, approximately 2 hr), evidently due to extensive tissue distribution and rapid metabolism. The metabolites of nabilone persist in plasma for extended periods (half-life of total radioactivity exceeds 20 hr). Circulating metabolites include isomeric carbinols formed by reduction of the ketone in the 9-position of nabilone. Nabilone is eliminated in feces (about 65% of dose) and urine (20%). The excretory products in urine have not been identified, but metabolites that are labile to hydrolysis by beta-glucuronidase or sulfatase do not appear to be formed in significant amounts. A metabolite of nabilone in feces has been identified as a diol formed by reduction of the 9-keto group plus oxidation at the penultimate carbon of the dimethylheptyl side chain. The long duration of action of nabilone in the face of rapid and extensive metabolic elimination suggests that the pharmacologic effects, at least in part, may be exerted by one or more active metabolites.

Effect of fluoxetine on psychomotor performance, physiologic response, and kinetics of ethanol.

The effects of fluoxetine, a specific serotonin reuptake inhibitor, on the psychomotor performance, physiologic response, and kinetic disposition of ethanol were examined. Fluoxetine (30 or 60 mg) with ethanol (45 ml absolute alcohol per 70 kg body weight) did not alter the plasma or blood concentrations of fluoxetine or ethanol, respectively, when compared with levels after either drug alone. There was no significant effect on standing or recumbent blood pressure or heart rate after single or multiple doses of fluoxetine alone or in the combination. Single or multiple doses of fluoxetine had no effect on the psychomotor activity (stability of stance, motor performance, or manual coordination) or subjective effects of alcohol. Data indicate that fluoxetine does not inhibit ethanol metabolism nor does it have any effects on its psychomotor activity.

[Lys(B28), Pro(B29)]-human insulin: effect of injection time on postprandial glycemia.

BACKGROUND: [Lys(B28), Pro(B29)]-human insulin (lispro) is an insulin analogue with a reduced capacity for self-association and faster absorption from subcutaneous injection sites. We hypothesized that administration of lispro closer to a meal would result in better glucose control than that achieved with regular insulin. METHODS: This trial used a randomized crossover design that consisted of a period of metabolic stabilization lasting 9 days followed by an evaluation period lasting 5 days. The patients received weight-maintenance diets, and insulin doses were adjusted as needed. Calorie intake, insulin dose, and activities were kept constant once the evaluation period began. During the evaluation period, we varied the time between insulin injection and mealtime and assessed glucose control. RESULTS: During the evaluation period, the lowest mean glucose concentrations were 117.9 mg/dl for lispro and 119.8 mg/dl (p = 0.817) for regular insulin. To obtain these, we gave lispro, on average, 22.5 minutes before meals and regular insulin 63.8 minutes before meals (p = 0.006). A similar pattern was evident throughout the glucose control parameters. The exception was mean amplitude of glucose excursion, which was lower after lispro (59 versus 75 mg/dl; p = 0.007) compared with regular insulin. CONCLUSIONS: We achieved equal or slightly better glucose control, as reflected by mean amplitude of glucose excursion, with insulin lispro given much closer to meal time than that achieved with regular insulin. As a result of these findings, we propose that a rapidly absorbed analogue of insulin is capable of achieving better control of postprandial glucose at a more convenient injection time.

Physiologic disposition of lergotrile.

Lergotrile, an ergot alkaloid, has been shown to be effective in treating disorders associated with elevated serum prolactin levels (e.g., galactorrhea-amenorrhea). Lergotrile has also been found to be a potent dopaminergic agonist and thus to be effective in Parkinson's disease. This study describes the physiologic disposition of lergotrile after administration to human volunteers. N-14CH3-lergotrile was rapidly absorbed from the gastrointestinal tract. Lergotrile was detected at low concentrations in plasma when subjects received large doses over extended periods of time. The major portion of radioactivity in plasma was attributed to the presence of circulating metabolites of lergotrile. Lergotrile metabolities were eliminated in the feces (ca. 60%), urine (ca. 20%), and breath (ca. 7% as 14CO2). A metabolite in feces was identified as 13-OH-lergotrile (up to 30% of the dose). A metabolite in urine was formed by conversion of the C8-acetonitrile group of lergotrile to a carboxyl group (about 10% of the dose). The presence of 14CO2 in the expired air after administering N-14C-methyl-lergotrile indicated that the drug was N-demethylated to form norlergotrile.

Spontaneous and diet-aggravated atherosclerosis in White Carneau pigeons genetically selected for discordant blood pressure.

White Carneau pigeons, prone to atherosclerosis, were selectively bred for either high (HBP) or low (LBP) blood pressure to study blood pressure-atherosclerosis interaction. Sixty-four HBP and 45 LBP pigeons, of both sexes and 16-30 months of age, were used to evaluate spontaneous atherosclerosis and the response to a moderately atherogenic diet. At 0 time, HBP pigeons had a greater percentage of aortic intima covered with fatty streaks and a lesser involvement with raised plaque. After 4 and 6 months of dietary treatment, the HBP pigeons with plasma cholesterol concentrations elevated only 22 and 8% above basal level responded with greater increases in the extent and severity of raised plaque whereas LBP pigeons changed little. On the average, medial thickness and medial areas of the atherosclerosis-free proximal aorta were greater in HBP compared to LBP at all times. Lower compliance of the aorta in the HBP line at 6 months (0.49 +/- 0.027 microliter/mm Hg/cm thoracic aorta) compared to LBP (0.57 +/- 0.036) suggested stiffer arterial walls in the HBP line. The findings suggest that HBP pigeons selected for increased blood pressure are more responsive to moderate hypercholesterolemia acting as a stimulus for atherosclerosis progression. The HBP pigeon line is therefore a useful animal model in which to investigate genetically derived hypertension-atherosclerosis interactions.

Artery wall derived proteoglycan-plasma lipoprotein interaction: lipoprotein binding properties of extracted proteoglycans.

Artery proteoglycan-lipoprotein binding characteristics were determined using intact, high molecular weight chondroitin sulfate proteoglycans (CS-PG) isolated from grossly appearing normal aortas of atherosclerosis susceptible WC-2 pigeons and plasma lipoproteins from normolipemic, randomly bred White Carneau pigeons. Optimum formation of particulate proteoglycan-lipoprotein complexes occurred in 5 mM Tris, 6 mM KCl, 4 mM CaCl2, 1 mM MgSO4, pH 7.2. The binding of CS-PG was specific for low density lipoprotein (LDL) and not high density lipoprotein (HDL). The relative importance of the intact monomeric structure of the PG was suggested in studies where glycosaminoglycan chains isolated from the PG monomer possessed less than 1% of the binding reactivity of the intact PG. The core protein prepared from the CS-PG monomer formed no measurable particulate complex.