Population pharmacokinetics and pharmacodynamics of escitalopram in overdose and the effect of activated charcoal.

AIMS: To describe the pharmacokinetics and pharmacodynamics (PKPD) of escitalopram in overdose and its effect on QT prolongation, including the effectiveness of single dose activated charcoal (SDAC). METHODS: The data set included 78 escitalopram overdose events (median dose, 140mg [10-560mg]). SDAC was administered 1.0 to 2.6 h after 12 overdoses (15%). A fully Bayesian analysis was undertaken in WinBUGS 1.4.3, first for a population pharmacokinetic (PK) analysis followed by a PKPD analysis. The developed PKPD model was used to predict the probability of having an abnormal QT as a surrogate for torsade de pointes. RESULTS: A one compartment model with first order input and first-order elimination described the PK data, including uncertainty in dose and a baseline concentration for patients taking escitalopram therapeutically. SDAC reduced the fraction absorbed by 31% and reduced the individual predicted area under the curve adjusted for dose (AUC(i) /dose). The absolute QT interval was related to the observed heart rate with an estimated individual heart rate correction factor (α= 0.35). The heart rate corrected QT interval (QT(c) ) was linearly dependent on predicted escitalopram concentration [slope = 87ms/(mgl(-1) )], using a hypothetical effect-compartment (half-life of effect-delay, 1.0h). Administration of SDAC significantly reduced QT prolongation and was shown to reduce the risk of having an abnormal QT by approximately 35% for escitalopram doses above 200mg. CONCLUSIONS: There was a dose-related lengthening of the QT interval that lagged the increase in drug concentration. SDAC resulted in a moderate reduction in fraction of escitalopram absorbed and reduced the risk of the QT interval being abnormal.

Buprenorphine exposure in infants of opioid-dependent mothers at birth.

BACKGROUND: Buprenorphine, a partial opioid agonist used in treating opioid dependence, is not approved in Australia for use in pregnancy. Nevertheless, many pregnant women choose to remain on the drug. AIM: To investigate cord/maternal transfer ratios for buprenorphine and norbuprenorphine in women at delivery. METHODS: Maternal and cord serum samples were collected from 10 maternal-infant pairs at delivery. Drug concentrations were measured by liquid chromatography-tandem mass spectrometry. Maternal and infant demographic information was collected. Linear regression was used to assess the relationship between maternal and cord measurements. RESULTS: Median (interquartile range) maternal age was 27 (23.8-32) years, with 90% of the women on buprenorphine before pregnancy. Median infant birthweight was 3148 (3088-3545) g and 60% of infants had neonatal abstinence requiring admission to a neonatal intensive care unit for a median of 8.5 (2.5-16.3) days. Median maternal buprenorphine daily dose was 8.5 mg (range 1-28 mg). Mean (95% confidence interval) cord serum concentrations of buprenorphine and norbuprenorphine were 0.4 (0.3-0.5) µg/L and 1.2 (0.9-1.4) µg/L, respectively. Mean maternal concentrations of buprenorphine and norbuprenorphine were 1.0 (0.6-1.4) µg/L and 1.2 (0.9-1.4) µg/L, respectively. Mean cord/maternal ratios were 0.43 (0.36-0.5) for buprenorphine and 0.53 (0.43-0.63) for norbuprenorphine. Maternal buprenorphine and norbuprenorphine concentrations and ratio of buprenorphine/norbuprenorphine explained 85.7, 69.6 and 94.4%, respectively, of variation in the corresponding cord concentrations. CONCLUSION: Usual therapeutic doses of buprenorphine administered to pregnant women resulted in low concentrations of buprenorphine and norbuprenorphine in maternal serum and a low transfer to the fetal circulation (cord plasma) at birth.

Duloxetine transfer across the placenta during pregnancy and into milk during lactation.

OBJECTIVE: Duloxetine is an efficacious antidepressant; however, its safety during the perinatal period is uncertain. The objective of this study was to assess the transfer across the placenta and provide data on infant exposure to duloxetine via breast milk. METHODS: A multiparous 31-year-old woman with recurrent melancholic depression had responded poorly to previous antidepressants, but had a full remission on duloxetine. She elected to remain on duloxetine for her third pregnancy and while breastfeeding. She gave birth to a healthy term infant and there were no adverse events noted for the infant exposed to duloxetine. Duloxetine concentration was measured chromatographically in maternal and infant serum collected at birth, and in maternal milk and plasma and infant plasma 18 days later, (C/M) concentration ratio was calculated. Absolute and relative infant doses via milk were estimated and the percent drug in infant versus mother's plasma was calculated. RESULTS: Cord/maternal serum concentration ratio for duloxetine was 0.12. Absolute infant dose via milk was 7.6 µg/L and relative infant dose was 0.81%. The ratio of drug in the infant's plasma to that in maternal plasma during lactation also gave a 0.82% infant exposure estimate. CONCLUSIONS: The low C/M ratio suggests a limited transfer across the placenta. The relative infant dose via milk was low by comparison to most other antidepressants, and this estimate confirmed the amount of drug in infant plasma during lactation. Our data suggest that duloxetine may be used in pregnancy and lactation for selected patients in whom other antidepressants have not been successful.

Estimation of desvenlafaxine transfer into milk and infant exposure during its use in lactating women with postnatal depression.

This study characterises the extent of desvenlafaxine transfer into milk and provides data on infant exposure to desvenlafaxine via breast milk in ten women with postnatal depression and their breastfed infants. Desvenlafaxine concentration in milk and plasma was measured chromatographically in milk and in maternal and infant plasma collected at steady state. Theoretic and relative infant doses via milk were estimated and the per cent drug in infant versus mother's plasma was calculated. Theoretic infant dose via milk was 85 (53-117) µg kg(-1) day(-1) (mean and 95% confidence interval) and relative infant dose was 6.8% (5.5-8.1%). The ratio of drug in infant/maternal plasma also gave an infant exposure estimate of 4.8% (3.5-6.2%) for all ten infants and 5.3% (4.2-5.7%) in the eight infants who were exclusively breastfed. No adverse effects were seen in the infants. The relative infant dose was similar to that for previous studies using venlafaxine and was supported by a separate exposure measure using the ratio of drug in the infant's plasma relative to that in the mother's plasma. The theoretic infant dose of desvenlafaxine was 41-45% of that for venlafaxine and its metabolite desvenlafaxine in previous studies, reflecting the lower recommended maternal dose for desvenlafaxine. Although our data for desvenlafaxine use in lactation are encouraging and there are supporting data from venlafaxine studies, more patients and their infants need to be studied before the safety of desvenlafaxine as a single therapeutic agent can be fully assessed.

Assessment of infant dose through milk in a lactating woman taking amisulpride and desvenlafaxine for treatment-resistant depression.

This study presents the case of a 35-year-old breastfeeding mother who delivered her fourth child 5 months previously and was prescribed 100 mg amisulpride twice daily and 250 mg desvenlafaxine in the morning for treatment-resistant depression. Arriving at this regimen took approximately 2 months postbirth. Because she was keen to continue breastfeeding her infant, and published data on the use of amisulpride and desvenlafaxine were very limited, the clinical team sought assistance from the therapeutic drug monitoring laboratory to quantify infant dose-exposure to guide consideration of continuing breastfeeding. A sampling schedule for milk and plasma from mother and plasma from her infant was agreed and drug concentrations were measured by high-performance liquid chromatography. Absolute (theoretic) infant dose (µg/kg/d) was calculated as the product of the average concentration in milk and an assumed milk intake of 0.15 L/kg/day (294 mg/kg/day for desvenlafaxine and 183 mg/kg/day for amisulpride), and relative infant dose was estimated as absolute infant dose expressed as a percentage of the maternal dose in µg/kg/day (7.8% for desvenlafaxine and 6.1% for amisulpride). Consistent with the infant being partially breastfed, the ratio of drug in the infant's plasma to that in mother's plasma was lower at 1.7% for desvenlafaxine and 3.9% for amisulpride. A pediatric assessment of the infant found achievement of expected developmental progress for age and no detectable drug-related adverse effects. Assessing the safety of breastfeeding was difficult because it involved simultaneous use of two drugs for which there was limited previous experience. However, after discussion of the infant dose-exposure data and lack of adverse effects, the mother elected to continue partial breastfeeding for the next few months. The clinical team plans a reassessment of the infant's progress in 3 months.

Pharmacokinetics of metformin after enteral administration in insulin-resistant ponies.

OBJECTIVE: To determine pharmacokinetics and plasma steady-state kinetics of metformin after oral or nasogastric administration in insulin-resistant (IR) ponies. ANIMALS: 8 IR ponies. PROCEDURES: Metformin (30 mg/kg) was administered to 8 ponies via nasogastric tube Blood samples were collected at intervals for 24 hours. Plasma concentrations of metformin were measured via liquid chromatography-electrospray tandem mass spectroscopy Pharmacokinetic variables were determined via noncompartmental analysis. Metformin (15 mg/kg, PO, twice daily [8 am and 5 pm]) was administered to 4 ponies for an additional 20 days, and blood samples were obtained every 2 days. Plasma concentration at steady state (Css) was determined. RESULTS: Mean±SD elimination half-life (t1/2) of metformin was 11.7±5.2 hours, maxima plasma concentration was 748±269 ng/mL at 54±32 minutes, mean area under the curve was 355±92 microg.h/mL, and apparent clearance was 90.6±28.1 mL/min/kg. The Css was 122±22 ng/mL. CONCLUSIONS AND CLINICAL RELEVANCE: Metformin reportedly enhances insulin sensitivity of peripheral tissues without stimulating insulin secretion, but bioavailability in horses is low. The t1/2 of metformin in IR ponies was similar to that in humans. Actual clearance of metformin adjusted for bioavailability in IR ponies was similar to that in humans; however, during chronic oral administration at dosages reported in efficacy studies, the Css of metformin was less than values associated with therapeutic efficacy in humans The apparent lack of long-term efficacy of metformin in horses is likely attributable to low bioavailability, rather than to rapid clearance.

Use of duloxetine in pregnancy and lactation.

OBJECTIVE: To report a case of a woman who used duloxetine during pregnancy and breast-feeding. CASE SUMMARY: A 29-year-old woman was treated with duloxetine for depression during the second half of an uncomplicated gestation. She gave birth at term to a healthy female infant. A cord blood sample was obtained at birth. The mother continued the antidepressant while exclusively breast-feeding her infant. One month later, we collected blood and milk samples from the mother and a single blood sample from the infant. All samples were analyzed for the presence and concentrations of duloxetine. DISCUSSION: Duloxetine crosses the placenta at term and is excreted into breast milk. No evidence of developmental or other type of toxicity was observed in the infant at birth or during the first 32 days after birth. The published literature detailing human pregnancy experience with this antidepressant is limited to 11 cases in which women became pregnant while taking duloxetine. In 10 cases, the drug was discontinued when pregnancy was diagnosed and no outcome data were reported. In the eleventh case, an infant exposed to duloxetine 90 mg/day developed neonatal behavioral syndrome. One study examined the excretion of duloxetine into breast milk, but the mothers discontinued nursing for the study. In the present case, no adverse effects from exposure to the drug in milk were noted in the exclusively breast-fed infant. The possibility of functional/neurobehavioral deficits appearing later in life cannot be excluded because long-term follow-up has not been conducted in infants exposed to duloxetine in utero or during nursing. CONCLUSIONS: No developmental toxicity or other signs of toxicity were observed in an infant exposed to duloxetine during the second half of gestation and during breast-feeding in the first 32 days after birth. However, the possibility of functional/neurobehavioral deficits appearing later in life cannot be excluded.

Transfer of chloroquine and desethylchloroquine across the placenta and into milk in Melanesian mothers.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: The literature on placental and milk transfer of chloroquine and its major bioactive metabolite desethylchloroquine is sparse and incomplete. WHAT THIS STUDY ADDS: We have provided data on the transplacental transfer of chloroquine and desethylchloroquine in Melanesian women (n = 19), measured transfer of these drugs into breast milk (n = 16) and estimated absolute and relative infant doses for the breastfed infant. The data for desethylchloroquine are novel. In all three areas we have significantly increased both quantity and quality of the available database. AIMS: To investigate the transfer of chloroquine and its major bioactive metabolite desethylchloroquine across the placenta and into breast milk. METHODS: In Papua New Guinea, chloroquine (CQ; 25 mg base kg(-1)) is recommended for prophylaxis of malaria during pregnancy, and at the Alexishafen Health Centre women are routinely prescribed CQ at the time of delivery. Fetal-cord and maternal serum samples were collected at delivery (n = 19) and milk samples were collected from day 3 to day 17-21 after delivery (n = 16). CQ and its primary active metabolite desethylchloroquine (DECQ) were quantified by high-performance liquid chromatography. For both CQ and DECQ cord/maternal ratios (C/M) were calculated to characterize placental transfer, and infant exposure via milk was estimated by standard methods. RESULTS: The median (interquartile range) C/M was 1.1 (0.9, 1.6) for CQ and 1.2 (0.5, 1.8) for DECQ. The average concentration in milk over the time of sampling was 167 microg l(-1) (27, 340) for CQ and 54 microg l(-1) (22, 106) for DECQ. Estimated absolute and relative infant doses were 34 microg kg(-1) day(-1) (7, 50) and 15 microg kg(-1) day(-1) (4, 26), and 2.3% (0.5, 3.6) and 1.0% (0.4, 2.0) for CQ and DECQ (as CQ equivalents), respectively. CONCLUSION: Infant exposure to CQ and DECQ during pregnancy will be similar to that in the maternal circulation, and dependent on maternal dose and frequency. The median CQ + DECQ relative infant dose of 3.2% (as CQ equivalents) was low, confirming that use of CQ during lactation is compatible with breastfeeding.

Disposition and clinical outcome after intraperitoneal meperidine and ropivacaine administration during laparoscopic surgery.

BACKGROUND: Limited evidence supports the efficacy of intraperitoneal (IP) meperidine or local anesthetic for postoperative analgesia. Our study aims were to investigate analgesic efficacy and to quantify the plasma concentrations of meperidine and ropivacaine after IP administration. The null hypothesis was that there was no significant difference among groups for dynamic pain in the first 24 h after major abdominal laparoscopic surgery. METHODS: This double-blind, five parallel group, placebo-controlled, two-center trial randomized 250 women having laparoscopic surgery to receive IP meperidine 50 or 100 mg (groups M50 and M100), ropivacaine 150 mg (group R150), meperidine 50 mg and ropivacaine 150 mg (group M50R150), all with intramuscular saline, or IP saline, with intramuscular meperidine 50 mg (group C). The primary outcome was pain during recovery. A pharmacokinetic profile of the drugs was obtained. RESULTS: There were no significant differences among groups for mean (sd) dynamic pain scores in the postoperative care unit (2.2 [2.8], 2.5 [3.3], 1.6 [2.5], 2.6 [3.2], 2.7 [3.2] for groups C, M50, M100, R150, and M50R150, P = 0.50) or thereafter. There were no significant differences among groups for pain scores at rest, IV morphine use, recovery characteristics and patient satisfaction. After IP administration of meperidine 50 mg the plasma concentration (median average 55-60 microg/L) was approximately half that of an equivalent intramuscular dose (median average 113 mug/L). CONCLUSIONS: Compared with systemic opioid, IP meperidine and ropivacaine, alone or in combination, did not produce better pain relief or opioid dose-sparing after laparoscopic surgery.

Quetiapine and breast feeding.

OBJECTIVE: To quantify the relative infant dose of quetiapine during breast feeding, describe the milk:plasma (M:P) ratio, and determine the well-being of the exposed infant. CASE SUMMARY: A 26-year-old mother and her 3-month-old son were studied over a 24 hour quetiapine dose interval at steady-state. Quetiapine concentrations were quantified by high-performance liquid chromatography. Infant exposure was calculated as the concentration in milk multiplied by an estimated milk production of 0.15 L/kg/day and normalized to the weight-adjusted maternal dose. The average concentration in milk was 41 microg/L, the M:P ratio (measured using average concentrations in the elimination phase) was 0.29, and the relative infant dose was 0.09% of the maternal weight-adjusted dose (7273 microg/kg/day). The infant plasma concentration of 1.4 microg/L was some 6% of the corresponding maternal plasma concentration. No adverse effects were noted in the infant. DISCUSSION: Our findings of an infant exposure to quetiapine of less than 0.1% of the maternal dose and a lack of adverse effects confirm and extend the findings of 2 previous studies. CONCLUSIONS: Although limited, the data shown here support the prescription of quetiapine to a breast-feeding mother following a careful individual risk/benefit analysis. We suggest regular monitoring of infant progress and occasional measurement of quetiapine in the infant's plasma.

Olanzapine overdose: a series of analytically confirmed cases.

To describe the spectrum of clinical effects in olanzapine overdose and investigate the factors that predict severe outcomes. We analysed olanzapine-overdose events confirmed by drug analysis. Demographic, clinical and outcome data were recorded for each presentation. The relationship between dose and therapeutic olanzapine use, and outcomes (length of hospital stay, intensive care unit admission, mechanical ventilation, Glasgow coma score <9 and delirium) were investigated. Thirty-seven olanzapine overdose admissions were included. Median age was 30 years (interquartile range: 24-40 years), 24 women and 27 taking olanzapine therapeutically. Median ingested dose was 150 mg (range: 10-1600 mg). Olanzapine overdose was characterized by tachycardia (73%), central nervous system depression (43%), miosis (39%) and delirium (54%), which were either present on admission or developed within 6 h. There was no relationship between the dose and length of hospital stay, intensive care unit admission, Glasgow coma score <9 or delirium, but there was a trend towards more severe outcomes in patients not taking olanzapine therapeutically. Patients with delirium had an increased length of hospital stay and intensive care unit admission rate (50%) and 70% of them required physical or chemical restraint. Olanzapine overdose causes a high rate of delirium and central nervous system sedation that requires significant inpatient resources. Olanzapine overdoses should be initially observed for 6 h and patients not taking olanzapine regularly may have more severe effects.

Deliberate self-poisoning with tiagabine: an unusual toxidrome.

Tiagabine is an anticonvulsant acting by selective inhibition of neuronal and glial gamma-aminobutyric acid uptake, resulting in increased gamma-aminobutyric acid-mediated inhibition in the brain. Few reports in the literature describe the clinical course of severe tiagabine intoxication. A 44-year-old woman presented after deliberate self-poisoning with 100 tiagabine 15 mg tablets (1,500 mg; 25 mg/kg). Serum tiagabine level was 4,600 microg/L (1,725 mmol/L) at presentation, 20 times levels associated with therapeutic dosing. Intoxication was manifested by profuse vomiting, coma, myoclonus, generalized rigidity, bradycardia, hypertension, hypersalivation and generalized piloerection within 2 h of ingestion. The patient was intubated and management was supportive. Coma lasted until 10 h post-ingestion, but recovery was complicated by severe agitated delirium lasting 12 h. The patient recovered fully within 26 h of ingestion. Tiagabine deliberate self-poisoning was associated with the rapid onset of coma and an unusual toxidrome. Recovery, although complicated by agitated delirium, was complete within 26 h.

Gabapentin and breastfeeding: a case report.

The aim of this study was to describe the milk-plasma ratio and relative infant dose of gabapentin in a breastfeeding mother and to determine the well-being of her exposed infant. The mother-infant pair was studied over a 24-hour dose interval at steady state. Gabapentin concentrations were quantified by high-performance liquid chromatography. Infant exposure was calculated as concentration in milk multiplied by an estimated milk production of 0.15 L/kg/d and normalized to the weight-adjusted maternal dose. The milk-plasma ratio was 0.86; the relative infant dose was 2.34%. The absolute infant dose was approximately 3% of the children's dose for gabapentin, and the infant plasma level of 0.4 mg/L was approximately 6% of the maternal plasma drug concentration. No adverse effects attributable to gabapentin were noted in the infant. In combination with a previously published report, these limited data support the prescription of gabapentin to a breastfeeding mother after a careful individual risk-benefit analysis.

An inter-ethnic comparison study of clozapine dosage, clinical response and plasma levels.

The present study investigated clozapine dosage, plasma clozapine and metabolite levels, clinical and side-effect profiles in Asian versus Caucasian patients with chronic schizophrenia who were on stable maintenance treatment. Twenty Asian patients from Singapore and 20 Caucasian patients from Australia were systematically evaluated with the following rating scales: Positive and Negative Syndrome Scale for Schizophrenia, drug attitude scale (DAI-10), drug adverse reaction profile (Liverpool University Neuroleptic Side-effect Rating Scale), extrapyramidal side-effects scales (Abnormal Involuntary Movement Scale, Simpson and Angus Scale). Cigarette and caffeine consumption were recorded and steady-state plasma clozapine and metabolites levels were measured. Although Asian patients received a significantly lower mean clozapine dose (176 mg/day) than the Caucasian group (433 mg/day, P<0.001), plasma clozapine levels were similar between the groups. As a result, Asian patients had more than twice the effective clozapine concentration to dose ratio (P<0.001). The findings remained significant even after controlling for gender, body mass index, cigarette, alcohol and caffeine use. Conversely, the plasma metabolites (desmethylclozapine and clozapine N-oxide) to clozapine ratios were higher in the Caucasian patients (P<0.01). Compared to Caucasian patients, Asian patients appeared to have a lower dosage requirement for clinical efficacy. Hence, appropriate dose adjustment should be considered in Asian patients receiving maintenance clozapine therapy in clinical practice.

Death by oral ingestion of iodine.

We report the clinical and toxicological features of a case of fatal iodine ingestion, and summarize the physiology, clinical characteristics and management of iodine ingestion. Physicians are likely to have little experience in managing such patients, particularly with the advent of less toxic preparations, and therefore need ready access to management guidelines. This case also highlights the potential for substances to retain their toxicity over long periods of time.

Use of nicotine patches in breast-feeding mothers: transfer of nicotine and cotinine into human milk.

OBJECTIVE: Our objective was to assess the extent of exposure to nicotine and cotinine in breast-fed infants during maternal smoking and later during maternal use of the nicotine transdermal patch to achieve smoking cessation. METHODS: Fifteen lactating women (mean age, 32 years; mean weight, 72 kg) who were smokers (mean of 17 cigarettes per day) participated in a trial of the nicotine patch to assist in smoking cessation. Serial milk samples were collected from the women over sequential 24-hour periods when they were smoking and when they were stabilized on the 21-mg/d, 14-mg/d, and 7-mg/d nicotine patches. Nicotine and cotinine in milk were quantified by HPLC, and infant dose was calculated. Plasma concentrations of nicotine in the breast-fed infants were assessed, and the infants were also clinically assessed. RESULTS: Nicotine and cotinine concentrations in milk were not significantly different between smoking (mean of 17 cigarettes per day) and the 21-mg/d patch, but concentrations were significantly lower (P <.05) when patients were using the 14-mg/d and 7-mg/d patches than when smoking. There was also a downward trend in absolute infant dose (nicotine equivalents) from smoking or the 21-mg patch through to the 14-mg and 7-mg patches (P <.05 at both 14-mg and 7-mg doses, compared with smoking). Milk intake (shown as median and 25th to 75th percentile) by the breast-fed infants was similar while their mothers were smoking (585 mL/d [507-755 mL/d]) and subsequently when their mothers were using the 21-mg (717 mL/d [504-776 mL/d]), 14-mg (731 mL/d [535-864 mL/d]), and 7-mg (619 mL/d [520-706 mL/d]) patches (chi(2) = 3.19, P =.364). CONCLUSIONS: We conclude that the absolute infant dose of nicotine and its metabolite cotinine decreases by about 70% from when subjects were smoking or using the 21-mg patch to when they were using the 7-mg patch. In addition, use of the nicotine patch had no significant influence on the milk intake by the breast-fed infant. Undertaking maternal smoking cessation with the nicotine patch is, therefore, a safer option than continued smoking.

Transfer of olanzapine into breast milk, calculation of infant drug dose, and effect on breast-fed infants.

OBJECTIVE: This study characterized infant drug doses and breast-milk-to-plasma area-under-the-curve ratios for olanzapine and determined plasma concentrations and effects of this drug on breast-feeding infants. METHOD: Seven mother-infant nursing pairs were studied. Olanzapine was measured in plasma and milk with high-performance liquid chromatography over a dose interval (for six patients) or at a single time after dose ingestion (for one patient) at steady state. Infant drug exposure was estimated as the product of an assumed milk production rate and average drug concentration in milk, normalized to body weight, and expressed as a percentage of maternal drug dose, normalized to body weight. RESULTS: The median infant dose of olanzapine ingested through milk was 1.02% of the maternal dose; the median milk-to-plasma area-under-the-curve ratio was 0.38 for the six patients with data collected over the dose interval. Corresponding values in the patient with single-point data were 1.13% and 0.75. Olanzapine was not detected in the plasma of the six infants with an evaluable plasma sample. All of the infants were healthy and experienced no side effects. CONCLUSIONS: Breast-fed infants were exposed to a calculated olanzapine dose of approximately 1%-well below the 10% notional level of concern. In infant plasma, olanzapine was below the detection limit; there were no adverse effects on the infants. These data support the use of olanzapine during breast-feeding. However, the authors recommend that breast-fed infants be monitored closely and the decision to breast-feed be made after individual risk-benefit analysis.

Measurement of nicotine and cotinine in human milk by high-performance liquid chromatography with ultraviolet absorbance detection.

A high-performance liquid chromatographic (HPLC) assay for the determination of nicotine and cotinine in human milk was developed using an extraction by liquid-liquid partition combined with back extraction into acid, and followed by reverse-phase chromatography with UV detection of analytes. The assay was linear up to 500 microg/l for both nicotine and cotinine. Intra- and inter-day relative standard deviations (R.S.D.) were <10% (25-500 microg/l) for both nicotine and cotinine. Limits of quantitation (LOQ) were 10 and 12 microg/l for nicotine and cotinine, respectively, while the limits of detection (LOD) were 8 and 10 microg/l for nicotine and cotinine, respectively. The mean recoveries were 79-93% (range 25-500 microg/l) for nicotine and 78-89% (range 25-500 microg/l) for cotinine. The amount of fat in the milk did not affect the recovery. We found that this method was sensitive and reliable in measuring nicotine and cotinine concentrations in milk from a nursing mother who participated in a trial of the nicotine patch for smoking cessation.

The amount of fluvoxamine in milk is unlikely to be a cause of adverse effects in breastfed infants.

The aim of this study was to characterize milk/plasma (M/P) ratio, as well as relative infant dose and well-being, in 2 breastfeeding women taking fluvoxamine. The women (37 and 34 years old) and their infants (26 and 0.75 months old) were studied over a 24-hour dose interval at steady state. Fluvoxamine concentrations were measured by high-performance liquid chromatography. Infant exposure was measured as concentration in milk multiplied by an estimated milk production of 0.15 L/kg/d and normalized to the weight-adjusted maternal dose. M/P values of 1.34 and 1.21 were calculated for subjects 1 and 2, respectively, and relative infant doses were estimated to be 1.38% and 0.8%, respectively. No adverse effects in the infants were detected by the mother or on clinical examination, and fluvoxamine was not detected in the infants' plasma (limit of detection 2 micrograms/L). These limited data support the prescription of fluvoxamine to breastfeeding mothers after a careful, individual risk/benefit analysis is undertaken.