Infant Exposure to Armodafinil Through Human Milk Following Maternal Use of Modafinil.

INTRODUCTION: Narcolepsy, a condition adversely affecting psychological, social, and cognitive function, is more prevalent in females of childbearing age than the general population. Modafinil and armodafinil are central nervous system stimulants approved for treatment of narcolepsy. Infant exposure to these agents through human milk has not been investigated. Poor quality medication safety information during lactation is associated with early cessation of breastfeeding and suboptimal healthcare for the breastfeeding family. MAIN ISSUE: In this case study, we measured the concentration of armodafinil (the most active form of modafinil) in human milk and infant plasma to quantify infant exposure. MANAGEMENT: The participant was a 30-year-old primipara with narcolepsy, taking modafinil (300 mg morning, 100 mg noon) while breastfeeding her 6-week-old infant despite the paucity of safety information. Armodafinil concentrations were measured in eight serial human milk samples collected over a 26-hr period and in single maternal and infant plasma samples using ultra performance liquid chromatography - tandem mass spectrometry. The average concentration of armodafinil in human milk was 1.96 mg/L; the relative infant dose was 4.85%; the theoretical infant dose was 0.294 mg/kg/day. Maternal and infant plasma concentrations of armodafinil were 12.02 mg/L and 0.19 mg/L, respectively. The participant continued to exclusively breastfeed the infant, who had normal growth and development. CONCLUSION: Based on these findings, relatively small amounts of armodafinil pass into human milk, with consequent limited infant exposure. Consideration can be given to the use of modafinil or armodafinil during breastfeeding, provided the infant is monitored. Further studies are needed to confirm these findings.

Administration of medicines to children: a practical guide.

Getting children to take medicines can be difficult. There is no 'one-size-fits-all' approach. When selecting medicines for children, it is important to consider the child's age, swallowing ability, ease of administration and accessibility of the product. Ask the child, parent or caregiver about their preference for formulations and flavours. There are different ways to alter the taste, aftertaste and mouth feel of medicines, which may help improve palatability. Pharmacists or medicines information services can assist with advice on suitable formulations or methods of administration.

Perindopril in Breast Milk and Determination of Breastfed Infant Exposure: A Prospective Observational Study.

OBJECTIVE: This study aimed to quantify the amount of perindopril and its active metabolite perindoprilat present in breast milk and corresponding maternal and infant plasma concentrations. DESIGN: Prospective, longitudinal, observational. SETTING: Tertiary specialist paediatric and obstetric hospital in Adelaide, South Australia. POPULATION: Breastfeeding women actively treated with perindopril for hypertensive disorders postpartum. METHODS: Eight breast milk samples and a single plasma sample were collected from each participant over a 24 hrs period, and plasma samples were taken from eligible breastfed infants. Breast milk and plasma concentrations of perindopril and perindoprilat were analysed using a validated Liquid Chromatography tandem-Mass Spectrometry (LC-MS/MS) method. MAIN OUTCOME MEASURES: Mean breast milk concentrations of perindopril and perindoprilat, Relative Infant Dose (RID) <10%, and Theoretical Infant Dose (TID). RESULTS: Ten women and three infants participated in the study. The mean concentration of perindopril in breast milk for each participant ranged from 0.003 to 1.2 ng/mL and perindoprilat 0.2-36 ng/mL. RID for perindopril was 0.0005-0.2% and perindoprilat 0.03-4.6%. TID for perindopril was 0.00045-0.18 µg/kg/day and perindoprilat 0.032-5.4 µg/kg/day. Infant plasma levels for perindopril ranged from 0.44 to 1.12 ng/mL and perindoprilat undetectable - 10.14 ng/mL. Maternal reports described normal infant growth and development. CONCLUSION: Infant exposure to perindopril and perindoprilat through breast milk is low. However, some infants were found to have plasma perindoprilat concentrations consistent with pharmacodynamic effects. Perindopril may be used in mothers of healthy term infants, provided the infant is carefully monitored.

Adherence to metformin is reduced during school holidays and weekends in children with type 1 diabetes participating in a randomised controlled trial.

BACKGROUND: Non-adherence to treatment in childhood chronic illness has serious consequences for health and healthcare costs. Accurate detailed objective data on adherence are minimal in this age group. OBJECTIVE: To evaluate medication adherence using electronic monitoring systems in children with type 1 diabetes (T1D). DESIGN: A cohort study of 90 T1D children (aged 13.6±2.5 years, 41 males) from two paediatric diabetes clinics, participated in a 12-month double-blind, randomised, placebo-controlled trial (1:1 allocation). This cohort provided 28 336 days of study observations; 7138 school holiday and 8875 weekend/public holiday days. METHOD: Adherence to intervention (metformin (n=45) or placebo (n=45)) was measured objectively by Medication Event Monitoring Systems (MEMS) including proportion of medication doses taken and daily adherence patterns and by tablet count at 3, 6 and 12 months. The trial was completed in June 2015. RESULTS: There was an average (SD) of 363.3 (42) days of MEMS observations available for each study participant (94.1 (12.6) school holiday days and 117.1 (13.4) weekend/public holiday days). Adherence reduced during school holidays (adjusted OR (aOR) 0.81; 95% CI 0.72 to 0.91; p<0.001) and during weekends/public holidays (aOR 0.74; 95% CI 0.69 to 0.80; p<0.001). Adverse effects to the intervention did not affect overall adherence (aOR 0.77; 95% CI 0.3 to 2.01; p=0.6). Age, gender, body mass index, diabetes duration, insulin dose, HbA1c (Haemoglobin A1c) or socioeconomic status did not predict adherence. CONCLUSION: Medication adherence was reduced during school holidays and on weekends in children with T1D. Clinical characteristics including socioeconomic status and the presence of adverse effects did not predict adherence. TRIAL REGISTRATION NUMBER: ACTRN12611000148976.

Transfer of rosuvastatin into breast milk: liquid chromatography-mass spectrometry methodology and clinical recommendations.

INTRODUCTION: Rosuvastatin reduces concentrations of total cholesterol (TC) and is used for the management of hypercholesterolemia and prevention of acute coronary syndromes. There are no published reports estimating infant exposure to rosuvastatin through breast milk. PURPOSE: The aims of this study were to quantify concentrations of rosuvastatin in human milk and plasma from a lactating woman taking rosuvastatin and to investigate potential infant exposure. MATERIALS AND METHODS: A 38-year-old breastfeeding mother was commenced on rosuvastatin 20 mg daily for secondary prevention of an acute coronary syndrome. Eight maternal breast milk samples and a single plasma sample were collected over a 24-hour period. The samples were quantified using a sensitive liquid chromatography-mass spectrometry (LC-MS/MS) method. RESULTS: The average concentration of rosuvastatin in breast milk was 30.84 ng/mL, and a peak concentration of 58.59 ng/mL occurred at 17 hours after oral administration. Although the milk-to-plasma (M/P) ratio was 16.49 at 14 hours, the theoretical infant dosage (TID) and relative infant dose (RID) were 0.005 mg/kg/day and 1.50%, respectively. CONCLUSION: The findings suggest that only small amounts of rosuvastatin pass into breast milk. Should the maternal condition necessitate treatment, consideration could be given to the use of rosuvastatin during breastfeeding provided the infant is monitored.

Estimation of Atenolol Transfer Into Milk and Infant Exposure During Its Use in Lactating Women.

BACKGROUND: Atenolol lactation information is limited, and controversy exists over the safety of its use during breastfeeding. In this study, important parameters including milk-to-plasma ratio, ratio of infant plasma to maternal plasma, infant daily dosage, and relative infant dose were investigated. The findings from this study add information to existing data about atenolol transfer in human milk. This may help guide health professionals in decision making regarding the safety of beta blockers used by mothers during breastfeeding. Research aim: The aims of the study were to quantify concentrations of atenolol in human plasma and milk, to evaluate atenolol pharmacokinetics in lactating women, and to investigate subsequent infant exposure to atenolol via mother's milk. METHODS: In this prospective, longitudinal observational study, participants were lactating mothers ( N = 3), 1 to 4 months postpartum, who had been taking atenolol for therapeutic reasons, and one 4-month-old breastfed infant. Eight milk samples were collected over 24 hr at different time points, together with a single blood sample from each lactating mother and the infant, and quantified using a new sensitive liquid chromatography mass spectrometry method developed for this study. RESULTS: Peak milk concentrations of atenolol were observed in the women at 4 hr (Tmax) after oral administration. The dose-normalized maximum concentrations (Cmax) of all patients were similar. The mean milk-to-plasma ratio of the patients who were taking 25 to 100 mg of atenolol was 8.57%. In the mother-infant pair study, the ratio (%) of infant plasma drug concentration to maternal plasma drug concentration observed (18.87%) was similar to the relative infant dose estimated (18.20%). The relative infant dose values (13.96%-18.20%) for all patients were within 10% to 25% of maternal dosage. CONCLUSION: Atenolol use during breastfeeding should be undertaken with some precaution. If clinically indicated, an alternate beta blocker may be preferred.

Impact of serotonin reuptake inhibitor use on breast milk supply in mothers of preterm infants: a retrospective cohort study.

AIMS: The aims of the present study were to examine the association between late pregnancy exposure to serotonin reuptake inhibitor (SRI) antidepressants and difficulties in achieving an adequate breast milk supply in women who have given birth to preterm infants, while accounting for the potential impacts of underlying maternal psychiatric illness. METHODS: A retrospective cohort study was carried out of 3024 women delivering liveborn preterm infants (<37 weeks' gestation) between January 2004 and December 2008. The primary outcome was postnatal domperidone use, considered to be a valid proxy for the presence and pharmacological management of low milk supply. Relative risks adjusted for maternal sociodemographic characteristics and comorbidities (aRRs) were calculated for low milk supply, comparing women with late pregnancy exposure to SRI antidepressants (n = 86), women with a psychiatric illness but no antidepressant use (n = 126) and women with neither antenatal exposures (n = 2812). RESULTS: Compared with non-exposed women, nonmedicated psychiatric illness [aRR 1.64; 95% confidence interval (CI) 1.16, 2.30] but not late pregnancy SRI use (aRR 1.00; 95% CI 0.59, 1.70) was associated with an increased risk of domperidone use, indicative of low milk supply. CONCLUSIONS: These findings do not support the previously observed negative impacts of antidepressant use on breastfeeding, instead suggesting that women with an underlying psychiatric illness appear at greatest risk of experiencing low milk supply and could benefit from additional breastfeeding education and support.

Antidepressant Use in Late Gestation and Breastfeeding Rates at Discharge from Hospital.

BACKGROUND: Few studies have investigated breastfeeding outcomes among women exposed to antidepressants. Research aim: This study aimed to evaluate the association between antidepressant use in late gestation and maternal psychiatric illness on breastfeeding rates at discharge from hospital. METHODS: The authors conducted a retrospective cohort study of 32,662 women delivering live-born singletons between January 2001 and December 2008. Electronic hospital records were used to obtain data on antidepressant exposure during late gestation and whether mothers were breastfeeding at discharge from hospital following delivery. RESULTS: Five hundred seventy-five women received a dispensing for an antidepressant in late gestation (exposed), 1,552 did not receive a dispensing for an antidepressant but had a reported psychiatric illness (disease comparison), and 30,535 served as nonexposed controls. Exposed women were significantly less likely to be breastfeeding their infants at discharge from hospital compared with nonexposed women, adjusted odds ratio ( AOR) = 0.63, 95% confidence interval (CI) [0.50-0.80], but no statistically significant difference was observed when compared with women in the disease comparison group, AOR = 0.83, 95% CI [0.65-1.07]. In stratified analyses, compared with women in the disease comparison group, exposed women were significantly less likely to be breastfeeding their infants at discharge from hospital if their neonate was delivered at term, AOR = 0.73, 95% CI [0.55-0.98], but not preterm, AOR = 1.24, 95% CI [0.66-2.32]. CONCLUSION: While antidepressant use is associated with a reduction in breastfeeding rates, this association appears to be strongly influenced by factors such as underlying maternal psychiatric illness. Overall, these results highlight that these women may benefit from additional education and support to improve breastfeeding rates.

Effect of Metformin on Vascular Function in Children With Type 1 Diabetes: A 12-Month Randomized Controlled Trial.

Context: Children with type 1 diabetes have vascular dysfunction preceding atherosclerosis. Early interventions are needed to reduce cardiovascular disease. Objective: To evaluate the effect of metformin on vascular function in children with type 1 diabetes. Design: Twelve-month double-blind, randomized, placebo-controlled trial. Setting: Tertiary pediatric diabetes clinic. Participants: Ninety children (8 to 18 years of age), >50th percentile body mass index (BMI), with type 1 diabetes. Intervention: Metformin (up to 1 g twice a day) or placebo. Main Outcome Measure: Vascular function measured by brachial artery ultrasound [flow-mediated dilatation/glyceryl trinitrate-mediated dilatation (GTN)]. Results: Ninety participants were enrolled [41 boys, 13.6 (2.5) years of age, 45 per group], 10 discontinued intervention, and 1 was lost to follow-up. On metformin, GTN improved, independent of glycosylated hemoglobin (HbA1c), by 3.3 percentage units [95% confidence interval (CI) 0.3, 6.3, P = 0.03] and insulin dose reduced by 0.2 U/kg/d (95% CI 0.1, 0.3, P = 0.001) during 12 months, with effects from 3 months. Metformin had a beneficial effect on HbA1c at 3 months (P = 0.001) and difference in adjusted HbA1c between groups during 12 months was 1.0%; 95% CI 0.4, 1.5 (10.9 mmol/mol; 95% CI 4.4, 16.4), P = 0.001. There were no effects on carotid/aortic intima media thickness, BMI, lipids, blood pressure, or other cardiovascular risk factors. Median (95% CI) adherence, evaluated by electronic monitoring, was 75.5% (65.7, 81.5), without group differences. More gastrointestinal side effects were reported on metformin (incidence rate ratio 1.65, 95% CI 1.08, 2.52, P = 0.02), with no difference in hypoglycemia or diabetic ketoacidosis. Conclusions: Metformin improved vascular smooth muscle function and HbA1c, and lowered insulin dose in type 1 diabetes children. These benefits and good safety profile warrant further consideration of its use.

A new LC-MS/MS bioanalytical method for perindopril and perindoprilat in human plasma and milk.

A first of its kind, simple, rapid, and sensitive liquid chromatography mass spectrometry (LC-MS/MS) method was developed and validated for quantification of perindopril and perindoprilat in both human plasma and breast milk. The analytes and internal standards (phenazone and acetyl salicylic acid) were extracted from biological matrices by protein precipitation. A Phenomenex® C-18 column was used to provide an appropriate chromatographic separation of the analytes, followed by detection with tandem mass spectrometry. Gradient chromatographic and mass spectrometric detection conditions with mobile phases (A: 5% methanol + 0.1% formic acid in water v/v, and B: 95% methanol + 0.1% formic acid in water v/v) were developed to achieve a LOQ of 0.5 ng/mL in both human plasma and milk. The method was suitable of evaluating clinical samples. The mass transition was followed as m/z 369.10/172.00 for perindopril, m/z 339.00/168.10 for perindoprilat, m/z 188.90/55.95 for phenazone, and m/z 179.04/137.02 for acetyl salicylic acid. The developed method was optimized and validated with a linear range of 0.1-200 ng/mL (r 2 = better than 0.99 for both perindopril and perindoprilat). The precision and accuracy values were within 15% CV. The overall recovery of the analytes was 80-110%. The method has good specificity and repeatability. Stability studies were conducted in both human plasma and bovine milk for up to 3 months, at the storage conditions of 25, 4, and -80 °C.

A new LC-MS/MS bioanalytical method for atenolol in human plasma and milk.

AIM: A new sensitive LC-MS/MS method for the quantification of atenolol in human plasma and milk has been developed for clinical lactation studies. METHODS & RESULTS: Atenolol and the internal standard, phenazone, were extracted from biological matrices by protein precipitation. A Phenomenex® C-18 column and gradient chromatographic conditions were used for separation of the analyte, followed by detection with MS. Stability of samples was confirmed for atenolol in human plasma and milk for up to 3 months. Linearity range of 1-800 ng/ml (r2 = 0.9995), the precision within 15% CV and the recovery of the analyte (80-100% range) were achieved. CONCLUSION: A new validated analytical method for atenolol in plasma and milk was developed.

Treatment experiences of children and adolescents with attention-deficit/hyperactivity disorder.

AIM: To gain insight into the treatment experiences of children and adolescents diagnosed with attention-deficit/hyperactivity disorder (ADHD). METHODS: Convenience sampling was used to recruit eligible parents and carers at paediatric clinics of the Children's, Youth and Women's Health Service to participate in an interview to discuss experiences, using a semi-structured questionnaire. RESULTS: Thirty-five interviews were conducted. Twenty-five subjects had trialled an average of 1.5 interventions prior to receiving an ADHD diagnosis, namely, dietary modifications (46%), behavioural therapy (24%), learning assistance (8%) and natural remedies (8%). Following an ADHD diagnosis, 25 subjects tried an average of 2.8 interventions, most commonly behavioural therapies (48%), expressive therapies (48%) and fish oil (36%). All subjects started psychostimulant medication after receiving an ADHD diagnosis. Despite 52% of parents expressing initial reluctance towards psychostimulants, 97% reported positive experiences with use in terms of schooling, social interaction and family life. Of those being treated with psychostimulants, 22 (73%) were concurrently using other treatments at the time of interview. CONCLUSIONS: Few patients use psychostimulant medication in isolation, with the majority of parents using multiple approaches to manage their child's behaviour. Parents tried a variety of therapies before commencing psychostimulant medication, often because of fears regarding psychostimulant safety. Parents were generally happy with the results gained; however adolescents interviewed were less convinced of the benefits of psychostimulants.